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Join the community, latest research, genome-ac-gan: enhancing synthetic genotype generation through auxiliary classification.

Shaked35/Genome-AC-GAN • None 2024

We conducted experiments to evaluate the performance of the Genome-AC-GAN and compare the AGs it generates with real genomic data as well as with AGs generated by previously published methods.

https://ieeexplore.ieee.org/document/10438484

stdcoutzrh/ConvLSR-Net • IEEE Transactions on Geoscience and Remote Sensing 2024

Convolutional Neural Networks (CNNs) can capture local context information well but cannot model the global dependencies.

recent research papers

Visually Dehallucinative Instruction Generation: Know What You Don't Know

ncsoft/idk • 15 Feb 2024

"When did the emperor Napoleon invented iPhone?"

recent research papers

ControlLM: Crafting Diverse Personalities for Language Models

recent research papers

This heightens the need to control model behaviors.

recent research papers

Criterion collapse and loss distribution control

In this work, we consider the notion of "criterion collapse," in which optimization of one metric implies optimality in another, with a particular focus on conditions for collapse into error probability minimizers under a wide variety of learning criteria, ranging from DRO and OCE risks (CVaR, tilted ERM) to non-monotonic criteria underlying recent ascent-descent algorithms explored in the literature (Flooding, SoftAD).

TIAViz: A Browser-based Visualization Tool for Computational Pathology Models

Throughout the development of a machine learning (ML) model in digital pathology, it is crucial to have flexible, openly available tools to visualize models, from their outputs and predictions to the underlying annotations and images used to train or test a model.

Unlocking Structure Measuring: Introducing PDD, an Automatic Metric for Positional Discourse Coherence

Recent large language models (LLMs) have shown remarkable performance in aligning generated text with user intentions across various tasks.

recent research papers

TEXTRON: Weakly Supervised Multilingual Text Detection through Data Programming

IITB-LEAP-OCR/TEXTRON • IEEE/CVF Winter Conference on Applications of Computer Vision (WACV) 2024

In order to solve this problem, we propose TEXTRON, a Data Programming-based approach, where users can plug various text detection methods into a weak supervision-based learning framework.

recent research papers

GeoEval: Benchmark for Evaluating LLMs and Multi-Modal Models on Geometry Problem-Solving

geoeval/geoeval • 15 Feb 2024

Yet, their proficiency in tackling geometry math problems, which necessitates an integrated understanding of both textual and visual information, has not been thoroughly evaluated.

Uncertainty Decomposition and Quantification for In-Context Learning of Large Language Models

Existing works have been devoted to quantifying the uncertainty in LLM's response, but they often overlook the complex nature of LLMs and the uniqueness of in-context learning.

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recent research papers

Poison Frogs Have a Strange Behavior That Scientists Seek to Explain

Three studies have recently explored toe-tapping, which seems to have something to do with frogs preying on insects.

By Elizabeth Landau

recent research papers

How Red Wine Lost Its Health Halo

For a glorious decade or two, the drink was lauded as good for the heart. What happened?

By Alice Callahan

recent research papers

Yale Apologizes for Its Connections to Slavery

The university also issued a historical study and announced steps to address this legacy, including new support for public education in New Haven, Conn.

By Jennifer Schuessler

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De dinosaurios a colibríes: un nuevo debate sobre la evolución de las aves

Por años los paleontólogos han sostenido que el asteroide que acabó con los dinosaurios impulsó la evolución de las aves. Un reciente estudio genético cuestiona esa teoría.

By Carl Zimmer

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Tipping Points for the Planet

Complex environmental systems are undergoing profound upheavals as a result of human activity.

By David Gelles and Manuela Andreoni

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A Columbia Surgeon’s Study Was Pulled. He Kept Publishing Flawed Data.

The quiet withdrawal of a 2021 cancer study by Dr. Sam Yoon highlights scientific publishers’ lack of transparency around data problems.

By Benjamin Mueller

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Abortions by Telemedicine and Mailed Pills Are Safe and Effective, Study Finds

Researchers analyzed the experiences of more than 6,000 women and found the method to be 98 percent effective and safe for 99 percent of patients.

By Pam Belluck

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Chinese Influence Campaign Pushes Disunity Before U.S. Election, Study Says

A long-running network of accounts, known as Spamouflage, is using A.I.-generated images to amplify negative narratives involving the presidential race.

By Tiffany Hsu

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Mysterious Pattern in a Cave Is Oldest Rock Art Found in Patagonia

About 8,200 years ago, in one of the last places settled by humans, prehistoric peoples began painting comblike designs as the climate shifted.

By Becky Ferreira

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¿Reproducirse sin sexo? Unas especies pueden hacerlo (pero ningún mamífero)

Algunas aves, ciertos reptiles y otros animales han logrado la partenogénesis, una alternativa para tener crías sin una pareja.

By Elizabeth Preston

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Recent advances in the treatment of osteoarthritis

Susanne grässel.

1 Department of Orthopedic Surgery, Exp. Orthopedics, ZMB/Biopark 1, Am Biopark 9, University of Regensburg, Regensburg, 93053, Germany

Dominique Muschter

Osteoarthritis (OA) is one of the most debilitating diseases and is associated with a high personal and socioeconomic burden. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Efforts to identify more tailored treatment options led to the development of strategies that enabled the classification of patient subgroups from the pool of heterogeneous phenotypes that display distinct common characteristics. To this end, the classification differentiates the structural endotypes into cartilage and bone subtypes, which are predominantly driven by structure-related degenerative events. In addition, further classifications have highlighted individuals with an increased inflammatory contribution (inflammatory phenotype) and pain-driven phenotypes as well as senescence and metabolic syndrome phenotypes. Most probably, it will not be possible to classify individuals by a single definite subtype, but it might help to identify groups of patients with a predominant pathology that would more likely benefit from a specific drug or cell-based therapy. Current clinical trials addressed mainly regeneration/repair of cartilage and bone defects or targeted pro-inflammatory mediators by intra-articular injections of drugs and antibodies. Pain was treated mostly by antagonizing nerve growth factor (NGF) activity and its receptor tropomyosin-related kinase A (TrkA). Therapies targeting metabolic disorders such as diabetes mellitus and senescence/aging-related pathologies are not specifically addressing OA. However, none of these therapies has been proven to modify disease progression significantly or successfully prevent final joint replacement in the advanced disease stage. Within this review, we discuss the recent advances in phenotype-specific treatment options and evaluate their applicability for use in personalized OA therapy.

Introduction

Osteoarthritis (OA) is a multi-factorial, mostly slowly progressing, and primarily non-inflammatory degenerative disorder of the synovial joints that is often age related and/or trauma induced. Degradative processes eventually lead to the irreversible destruction of the articular cartilage and other tissues of the joints. Although OA is the most common musculoskeletal condition worldwide that causes significant health, economic, and social problems, research efforts so far have not been able to define its exact etiology. Age-related wear of articular cartilage and subchondral bone, limb overuse, overloading and mal-alignment, genetic disorders, and metabolic syndromes (obesity, inflammatory responses, and diabetes) are important players in the onset and progression of OA 1 , 2 . For many years, strong and cost-intensive efforts have been undertaken to develop therapies to improve care, quality of life, and pain relief for OA patients. Therapeutic approaches predominantly addressed symptoms and tried to modify/improve structural features of affected joint tissues. Despite this, no therapies have been able to halt or delay OA progression satisfactorily or provided effective and long-lasting symptomatic relief. Currently, joint replacement with an artificial prosthesis is the most effective measure to improve pain sensation and quality of life in patients. The development of novel therapeutic approaches targeting the osteoarthritic degradative and inflammatory processes in cartilage, synovium, or bone requires a deep understanding of the disease status of these joint tissues at the time of the intervention. It is crucial to apply therapies at the early stages of the disease prior to major structural and functional alterations in the osteochondral unit; otherwise, these interventions will not be successful 3 . Structural and clinical features of OA are characterized by a high interpatient variability. This heterogeneity is considered to be a major factor associated with the complexity of OA and the ongoing difficulties to identify “one size fits all” therapies 4 , 5 .

It is accepted that defining OA subgroups based on risk factors is too simple, so it is of high clinical interest to identify specific OA phenotypes (subgroups of patients with similar clinically observable characteristics, i.e. genetic predispositions combined with environmental factors leading to tibiofemoral OA) and endotypes (disease subtypes defined functionally and pathologically by a molecular mechanism, i.e. different mechanisms leading to the same phenotype as tibiofemoral OA), which are the basis of accurate prognosis and development of personalized therapies 5 . Several attempts have been made to group and identify OA phenotypes according to pathobiological mechanisms. Felson defines criteria for characterizing OA phenotypes via an epidemiological approach 4 . He discriminates between generalized arthritis and joint-specific OA, secondary and primary OA, and incident and progressive OA. Another intriguing perspective is presented by Berenbaum et al ., who provide a novel definition of OA as a “mismatch disease” commonly referred to by evolutionary biologists 6 . This is defined as a condition that is more common today than in the past because the human body is not well adapted to certain features of modern environments. These features are high levels of physical inactivity, chronic low-grade inflammation, high body mass index, and obesogenic diets (processed foods which are high in sugar and saturated fat and low in fiber content). Other distinctions include the following phenotypes: chronic pain with central sensitization, inflammation, metabolic syndrome, bone and cartilage metabolism, and mechanical and minimal joint disease 7 . Deveza et al . divide according to mechanistic subgroups including senescence, inflammation, pain, and metabolic endotypes 5 .

However, one thing has to be kept in mind when trying to define subgroups of OA. Although OA can be initiated by multiple factors at multiple sites, mechanical overloading is still the key feature of its pathogenesis. Joint tissues are sensitive to physical stimuli, and OA may result from excessively aberrant or physiologically normal mechanical stresses on initially healthy or pathologically impaired articular cartilage, bone, and ligaments, respectively 8 . Brandt et al . pointed out in a commentary that they feel all OA is secondary due to the accumulation of intra-articular (i.a.) stress and all OA is primarily driven by mechanical stress on the joint 9 . They postulate a basic mechanical etiopathogenesis for common OA and would rather categorize it on the basis of the underlying mechanical abnormality like post-traumatic, failure to absorb repetitive impulsive loading, and congenital or developmental anatomic incongruities.

This review will select key OA pheno-endotypes according to relevant literature and current clinical trials/therapies that have been the most promising targets for recent clinical or pre-clinical studies.

Treatments targeting articular cartilage

OA is characterized by the degradation of articular cartilage and bone matrix components. Among the earliest are type II collagen and the proteoglycan aggrecan, leading to the loss of cartilage structure and function 10 , 11 . Cartilage matrix degeneration products are well investigated for drug target discovery. Several key anabolic and catabolic pathway enzymes are dysregulated in OA cartilage, providing the opportunity to identify and validate new drug targets 12 . To this end, novel combinations addressing existing known targets may be identified. This also includes combinations of therapeutics that are anti-catabolic and those that target anabolic signaling pathways. If investigated, this might lead to identifying novel efficacious add-ons from combining known drugs and targets. For better classification, there should be discrimination between disease-modifying OA drugs (DMOADs), which target pathways of cartilage catabolism and anabolism, and regenerative strategies based on stem cells and their components.

Anabolic drug: sprifermin

A promising anabolic DMOAD is sprifermin, which is a truncated version of human FGF18 that induces chondrocyte proliferation and cartilage matrix production. The results of a phase Ib study of i.a. injected sprifermin in patients with symptomatic knee OA found a statistically significant dose-dependent reduction in loss of total femorotibial cartilage thickness compared to placebo after 12 months of follow up 13 . Sprifermin is currently being studied in a phase II multicenter randomized dose-finding clinical study (clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01919164","term_id":"NCT01919164"}} NCT01919164 ). The i.a. administration of 100 μg of sprifermin to participants with symptomatic radiographic knee OA every 6 or 12 months vs. placebo resulted in an improvement in total femorotibial joint cartilage thickness after a follow up period of 2 years. This improvement was statistically significant, but clinical importance was not clear. Application of a lower dose, 30 μg of sprifermin, every 6 or 12 months vs. placebo did not result in a significant difference and it was uncertain whether the response was long lasting 14 ( Table 1A ).

BML, bone marrow lesion; IL, interleukin; IL-1R1, interleukin 1 receptor type 1; MMP, matrix metalloproteinase; NGF, nerve growth factor; OA, osteoarthritis; RA, rheumatoid arthritis; T2DM, type 2 diabetes mellitus; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Anabolic drug: BMP-7

Another approach was the application of BMP-7, where studies have shown a pro-anabolic effect, making BMP-7 a potential candidate to promote articular cartilage repair. Three clinical trials (two phase I and one phase II) investigated the administration of BMP-7 in patients with knee OA. Two trials were completed without results being posted ( {"type":"clinical-trial","attrs":{"text":"NCT01133613","term_id":"NCT01133613"}} NCT01133613 and {"type":"clinical-trial","attrs":{"text":"NCT01111045","term_id":"NCT01111045"}} NCT01111045 ), and one was completed with results published ( {"type":"clinical-trial","attrs":{"text":"NCT00456157","term_id":"NCT00456157"}} NCT00456157 ) 15 . There was no dose-limiting toxicity identified in the latter study. Most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. Notably, overall, the outcome of the BMP-7 group was similar to the placebo group, as both groups experienced a 20% improvement in pain ( Table 1A ).

Anti-catabolic drugs: MMP inhibitors

Inhibition of MMPs, i.e. MMP-13 and aggrecanases such as ADAMTS-4 and -5, which are key proteases responsible for cartilage matrix degradation in OA 45 , 46 , might be another way to delay cartilage destruction. A human clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT00041756","term_id":"NCT00041756"}} NCT00041756 ) involving knee OA patients receiving the MMP inhibitor PG-116800 (PG-530742), which has low affinity for both MMP-1 and MMP-7, was unfortunately terminated because of musculoskeletal toxicity 12 ( Table 1A ). The most frequent adverse effect was arthralgia (35% of patients), and 13% of patients reported hand adverse events (edema, palmar fibrosis, Dupuytren’s contracture, or persistent tendon thickness or nodules). As a result, MMP inhibitor PG-116800 has not been developed further as a treatment for knee OA 47 . Other more MMP-13 selective compounds, such as CP-544439, AZD-8955, and WAY-170523, are under investigation, but clinical data have not been released yet 13 . MMPs and aggrecanases are involved in cartilage matrix degradation, and a balanced activity of these proteases is critical for matrix homeostasis. An unbalanced protease activity favoring rapid cartilage matrix degradation in early OA pathogenesis might classify as an additional OA endotype, which then would qualify as a specific target for drug intervention.

These data demonstrate that compounds such as sprifermin (FGF18) and BMP-7 have promising pro-anabolic effects on cartilage tissue, whereas the inhibition of catabolic factors such as proteases has not shown beneficial effects in cartilage so far owing to adverse effects ( Table 1A ).

Regenerative therapies with stem cells

A total of 144 clinical trials investigating the therapeutic impact of stem cells on OA and on cartilage trauma have been reported to date at www.clinicaltrials.gov , suggesting regenerative medicine may be a promising therapy for future OA management. At first, case reports described the transplantation of mesenchymal stem cells (MSCs) through an invasive approach (surgery). Later, the introduction of autologous MSCs within the joint by i.a. injection, which represents a less-invasive strategy, was reported to be feasible and safe. Indeed, after i.a. injection into SCID mice, MSCs engrafted directly in the injured site, which has been suggested to avoid systemic distribution and toxicity as well as to promote longer survival of the cells 48 . Currently, mostly autologous MSCs and adipose-derived stem cells (ASCs) are applied for knee OA therapy, but very few approaches are targeting hip OA. Almost all of the trials are phase Ia/b safety and dose-finding studies with a low number of participants. About 45 of the listed studies are completed, but only six of them report results. A total of 55 of the trials that are recruiting or not yet recruiting indicate strongly increasing interest in stem cell therapy not only for traumatic cartilage injury but also for late-stage OA.

Extracellular vesicles derived from stem cells

Our literature search shows that stem cells, specifically autologous stem cells derived from bone marrow (BMSCs) and adipose tissue (ASCs), are preferred over other cell types for regenerative strategies. However, there is doubt among surgeons and researchers about whether or not stem cells are really the optimal tool for regenerative therapy.

After administration, stem cells tend to disappear quickly from the target tissue; however, their chondroprotective and immunomodulatory effects are long lasting. Presumably, the therapeutic effects are mainly mediated in a paracrine manner, as they appear to be independent of the engrafted cells 49 . When exposed to inflammatory signals, MSCs develop and show a rich secretory profile. After stimulation of these cells with tumor necrosis factor (TNF)-α, a proteomic approach identified 118 proteins, which were differentially expressed by human ASCs 50 . However, paracrine effects are not limited to soluble factors, as stem cells and other cell types produce extracellular vesicles (EVs), which are small phospholipid-bilayer-enclosed particles carrying many cytoplasmic components 51 , 52 . EVs play a role in a number of different cellular activities, such as communication between cells via horizontal transfer of mRNA and proteins, and they are distinguished according to size. EVs are attractive options for therapeutic use because of their unique physical and biological characteristics, which include high biocompatibility and intrinsic targeting activity 53 . Exosomes, the most-studied group of EV, can be as small as 30–150 nm in diameter, so it may be possible for them to passively diffuse through tissues 54 . Overall, the consensus is that stem cell secretomes and EVs applied for the treatment of cartilage pathology and knee OA had pleiotropic and overall positive effects 55 . In vitro , anti-catabolic, immunomodulatory, and regenerative properties were assigned to the secretome and EVs. Pre-clinical in vivo studies resulted in positive effects on the joint and confirmed the effectiveness of EV injections as a minimally invasive therapy 56 . Exosome injections partially improved the gait abnormality patterns in an OA mouse model 57 , and MSC secretome injections provided early (day seven) pain reduction in treated mice 58 . All together, these data support the translational potential of this regenerative approach. The promising in vitro and in vivo results support the potential of this new treatment strategy, opening up new perspectives for cell component-based therapies. EVs are proposed as next-generation biomarkers to predict the pathophysiological state of the joint 55 , assigning an important role for EVs in future therapies for the treatment of joint disorders. Remarkably, they constitute a simpler, and most of all safer, alternative to actual cell-based therapeutic strategies, as they are cell derived but not living cells and thus cannot proliferate or form tumors. As known for cells, EVs can also be combined with scaffolds, either bound on their surface or embedded within the biomaterial matrices. Specific activation signals such as ultrasound may enable the controlled release of specific subpopulations of EVs, i.e. exosomes.

Therapies addressing subchondral bone

Besides nutrient supply and metabolism, physiological and non-physiological shock absorption and support of overlying cartilage are the main functions of subchondral bone 59 , 60 . Therefore, any changes affecting bone cell metabolism, structural integrity, and architecture might render the bone more susceptible to aberrant loading or even induce abnormal reactions to normal physiological load. OA-related changes in subchondral bone structure were long regarded as an adaptation of bone to the biomechanical changes observed in articular cartilage. Recently, several pre-clinical and clinical studies demonstrated that alterations in bone structure might even precede and instead mediate cartilage pathology 61 , 62 and that OA progression is associated with temporal changes in bone structure 60 . In early OA, accelerated bone turnover leads to bone plate thinning and increased porosity, whereas the trabecular compartment shows increased trabecular spacing and decreased bone volume fraction. Progression of OA is accompanied by subchondral bone plate thickening, increased trabecular thickness, and increased bone volume fraction 60 . Bone marrow lesions (BMLs), a hallmark of OA, appear early on MRI and are associated with increased pain and cartilage degeneration 63 .

Therapies with bisphosphonates

Bisphosphonates (BPs) effectively slow down bone turnover by inhibiting osteoclast activity in osteoporosis, but their usability in OA remains uncertain 18 . There are indications that a specific patient subgroup might respond to BP use: intravenous zoledronic acid successfully reduced BML size and visual analogue scale (VAS) pain score after 6 months in a randomized controlled trial, though a second multicenter trial could not confirm the results 16 , 17 . Furthermore, a meta-analysis by Vaysbrot et al . identified similar effects in a trial using oral risedronate treatment in a patient subgroup with BMLs 18 . An active phase III trial ( {"type":"clinical-trial","attrs":{"text":"NCT02746068","term_id":"NCT02746068"}} NCT02746068 ) using AXS-02 (disodium zoledronate tetrahydrate) in knee OA with associated BMLs provided promising results in the reduction of pain supposedly by suppression of local acid and pro-inflammatory cytokine production 64 . The ongoing phenotype debate in OA raised the question of whether the effectiveness of BPs has been confounded owing to the heterogeneity of the patient group enrolled in clinical trials so far 64 . Indeed, BPs might be especially beneficial in patients with BML or high bone turnover in an early state of OA. Interestingly, pharmacologic agents like BPs that directly affect osteoclast activity effectively reduced pain. Recent research identified osteoclasts as the inducers of OA bone pain by induction of sensory innervation in a murine OA model 65 . Determination of more of these connections and more precise categorization of patient subgroups (like bone pain due to BML development or increased osteoclast activity/bone turnover) might lead to the repurposing of already existing drugs for new targets.

Drugs targeting bone cells

New therapeutic approaches include neutralization of cathepsin K, the major osteolytic protease released by osteoclasts. The “small molecule” cathepsin K inhibitor MIV-711 effectively attenuated joint pathology in a rabbit OA model 66 and slowed bone and cartilage degeneration in a phase IIa multicenter trial of primary knee OA 20 . With 26 weeks’ duration, the study was relatively short, and MIV-711 did not reduce pain during this time ( Table 1B ). Denosumab, a monoclonal antibody directed against RANKL and thereby inhibiting osteoclastogenesis, is currently tested in erosive OA of interphalangeal finger joints ( {"type":"clinical-trial","attrs":{"text":"NCT02771860","term_id":"NCT02771860"}} NCT02771860 ) and in knee OA (DISKO, ISRCTN96920058), but results have not been published to date. Potential new targets to address subchondral bone include TGFβ, which is elevated in OA synovial fluid 67 . Systemic blocking of TGF prevented bone and cartilage degeneration in a rodent OA model 68 , but targeting this specific molecule needs to take into consideration the physiological role of TGFβ as a differentiation stimulus for chondrocyte precursor cells 67 . Furthermore, OA bone is targeted by anabolic therapies. Teriparatide, a synthetic parathyroid hormone, effectively reduced chondrocyte apoptosis and attenuated OA progression after i.a. application in a surgical rat OA model 69 . Its effectivity is currently being evaluated in a phase II trial of knee OA ( {"type":"clinical-trial","attrs":{"text":"NCT03072147","term_id":"NCT03072147"}} NCT03072147 ).

Dietary supplementation of vitamin D 3

Additional dietary supplementation of vitamin D 3 (cholecalciferol) might be an option to target and strengthen bone in OA owing to its ability to increase calcium and phosphate uptake from the gut and its direct effect on bone cell metabolism 70 . Numerous trials for vitamin D 3 supplementation in OA patients can be found at clinicaltrials.gov, but there are contradictory reports about a relationship between vitamin D levels and a higher risk for OA incidence and progression 71 . A meta-analysis of randomized controlled trials revealed a reduction in WOMAC pain and improved joint function in OA patients after vitamin D 3 intake, but only at a concentration of 2,000 IU 72 . Cartilage degradation was not affected. Generally, vitamin D 3 intake might be beneficial for a large proportion of the population, as its deficiency is a worldwide problem and elderly people, who are also at an increased risk of OA, are often affected 73 .

Restoration of bone metabolism and structure might be a worthwhile goal because of the huge importance of this structure as a mechanic buffer for proper load perception and distribution. A detailed knowledge of timely changes in OA-related bone metabolism might enable a more precise use of bone anabolic and anti-catabolic therapies to restore or prevent bone degradation. Maintenance of bone structure and shock-absorbing abilities might prevent cartilage alterations and therefore put a hold on subsequent degradative events culminating in joint failure.

Treatments targeting inflammatory mediators and pathways

It is now commonly accepted that OA has an inflammatory component that might be more dominant in specific patient subgroups and joint tissues. The release of various pro-inflammatory mediators like prostaglandins, cytokines, and chemokines has been demonstrated in numerous pre-clinical OA animal models and in patients 74 . Synovitis is a common feature of inflammatory OA, and technical progress in imaging technologies like ultrasound and MRI revealed synovitis in a large number of patients at different disease stages 75 , 76 . A plethora of triggers including aberrant mechanical forces, metabolic syndrome, increased age, and fragments of cartilage extracellular matrix (ECM) or crystals might induce the release of these mediators from various responsive joint tissue cell types. A large number of recent review articles address cells and components of the innate immune system as the main drivers of OA inflammatory processes 77 , 78 . Non-steroidal anti-inflammatory drugs and glucocorticoids are commonly used to treat OA but are not optimal owing to moderate effectiveness and serious side-effects in long-term use 79 , 80 .

Anti-cytokine therapy

Most biologics used to treat OA-related inflammation were developed for rheumatoid arthritis (RA), a disease associated with more pronounced inflammation. So far, biologics targeting the inflammatory cytokines interleukin (IL)-1 and -6 as well as TNF-α have not been useful in the prevention of pain or structural progression of OA ( Table 1C ). Granulocyte/macrophage colony-stimulating factor (GM-CSF) was associated with inflammatory pain in a mouse OA model 81 and was associated with hip OA over knee OA in a study analyzing mononuclear cell contribution to synovial inflammation 82 . The anti-GM-CSF antibody otilimab (GSK3196165) was enrolled in a study for erosive hand OA and yielded promising results ( {"type":"clinical-trial","attrs":{"text":"NCT02683785","term_id":"NCT02683785"}} NCT02683785 ) 83 . Mavrilimumab, a GM-CSF receptor inhibitory antibody effective in RA 84 , might therefore also have potential as an OA drug. The predominantly low-grade and non-systemic inflammation observed in OA might explain the limited success of single cytokine blockade. Concentration on specific OA subsets like erosive hand OA associated with more pronounced inflammation potentially presents a responsive patient group for anti-cytokine biologics. Identification of a single potent driver of OA inflammation seems to be difficult, and broader approaches targeting general pro-inflammatory signaling pathway components might be more favorable ( Table 1C ).

Interference with pro-inflammatory signaling pathways

Targeting single cytokines has so far had little effect. Recent strategies aim to interfere with further upstream initiators of the pro-inflammatory signaling cascade. Hydroxychloroquine (HC), a chloroquine derivative used to treat malaria and inflammatory autoimmune disorders like RA, supposedly exerts its effects via Toll-like receptor (TLR) 7/9 85 . Several studies using HC in hand OA have failed to show effects so far 30 , 31 , and results from a study in knee OA are not obtainable yet ( {"type":"clinical-trial","attrs":{"text":"NCT01645176","term_id":"NCT01645176"}} NCT01645176 ). TLR downstream targets include molecules like MyD88, TRAF3/6, p38 MAPK, Janus kinases, and transcription factors like NF-κB 86 . Several attempts have been made to interfere with signaling molecules to inhibit inflammation in OA. The I-κB kinase inhibitor SAR113945 was tested in four trials of knee OA ( {"type":"clinical-trial","attrs":{"text":"NCT01113333","term_id":"NCT01113333"}} NCT01113333 , {"type":"clinical-trial","attrs":{"text":"NCT01598415","term_id":"NCT01598415"}} NCT01598415 , {"type":"clinical-trial","attrs":{"text":"NCT01511549","term_id":"NCT01511549"}} NCT01511549 , and {"type":"clinical-trial","attrs":{"text":"NCT01463488","term_id":"NCT01463488"}} NCT01463488 ), but, though the compound showed a good safety and tolerability profile, a larger proof-of-concept study failed to show superior efficacy 32 . A small subgroup of patients with effusion at baseline elicited a reduced WOMAC pain score after 56 days. Local delivery of a potent p38 MAPK inhibitor (PH-797804) reduced joint destruction and inflammation in a murine destabilization OA model 87 . The efficacy of PH-797804 compared to naproxen was evaluated in a clinical trial involving knee OA patients, but the results have not yet been disclosed ( {"type":"clinical-trial","attrs":{"text":"NCT01102660","term_id":"NCT01102660"}} NCT01102660 ). FX-005, another therapeutic p38 MAPK inhibitor with sustained-release kinetics, was evaluated in a phase I/II knee OA trial where it promoted pain relief superior to placebo after 4 weeks ( {"type":"clinical-trial","attrs":{"text":"NCT01291914","term_id":"NCT01291914"}} NCT01291914 ) ( Table 1C ). Direct targeting of the TLR would provide even higher upstream interference with OA immune activation, e.g. the application of a miR-21 inhibitor targeting TLR7 was able to induce long-lasting analgesia in an OA rat model 88 . As for anti-cytokine therapy, careful evaluation of individual patient inflammatory status will probably help to identify more responsive patient subgroups or joints.

Other immune system targets

The complement system might also be a potential source of therapeutic targets for OA therapy 89 , 90 . An increasing number of drugs targeting different factors of the complement cascade are available and were tested in the clinic for various diseases 91 , but, to the best of our knowledge, none of them has been tested in OA patients so far. Similarly, there is increasing awareness that adaptive immune mechanisms might be involved in OA pathophysiology 92 , 93 , but these insights have not been translated into therapeutic approaches so far. Identification of more immune system entities contributing to OA development and progression will provide even greater numbers of targets for potential OA therapeutics but requires meticulous analysis of timely and spatial involvement in disease-related processes.

Gene therapies

Novel genetic approaches are currently under evaluation for safety in clinical phase I studies. They include i.a. injection of recombinant adeno-associated virus type 2/5 (rAAV2.5) vector encoding IL-1 receptor antagonist (IL-1Ra) into one knee joint of patients with moderate OA of the knee ( {"type":"clinical-trial","attrs":{"text":"NCT02790723","term_id":"NCT02790723"}} NCT02790723 ) and FX201, a helper-dependent non-integrating adenovirus, containing the human IL-1Ra gene under the control of an inflammation-sensitive promoter ( {"type":"clinical-trial","attrs":{"text":"NCT04119687","term_id":"NCT04119687"}} NCT04119687 ). Moreover, new gene therapeutic targets include interferon (INF)-β (rAAV2.5 vector encoding human IFN-β under control of a NF-κB promoter, ART-I02) in subjects with RA or OA and active arthritis of the hand ( {"type":"clinical-trial","attrs":{"text":"NCT02727764","term_id":"NCT02727764"}} NCT02727764 ) as well as XT-150, a plasmid DNA carrying a variant of the human IL-10 transgene ( {"type":"clinical-trial","attrs":{"text":"NCT03477487","term_id":"NCT03477487"}} NCT03477487 ). Although results of these studies are not available yet, gene therapy offers great therapeutic potential as it is aimed at prolonged, site-specific, and controlled release of treatments in the target joints. Confining anti-cytokine or any anti-inflammatory treatment to specific joints could potentially prevent the side-effects observed with a more classic biologic treatment plan 94 . Virus-related delivery systems might provide superior performance over classical delivery systems but, clearly, safety aspects (e.g. immunogenicity of the vector, off-target and long-term effects) have to be taken seriously and analyzed carefully in relation to effectiveness before considering any kind of genetic therapy 95 . In general, data from an equine study using AAV2.5-delivered IL-1Ra showed promising results regarding pharmacodynamics and safety profile 96 . As mentioned above, first-in-human clinical trials will evaluate the safety profile of gene-related therapies and will give a general hint regarding the applicability of gene therapies for OA.

Treatments addressing pain

Apart from structural deterioration in OA joints, pain is a dominant and probably the most debilitating hallmark of OA pathology and the a priori reason why patients see a physician. Huge effort has been put into OA-related pain research to identify underlying mechanisms, but, because of its complexity, no general guidelines could be identified for its effective treatment 97 , 98 . The sensation of pain in OA does not show uniform appearance among patients and during progression. The source of OA pain includes nociceptive pain komma inflammatory pain and neuropathic pain as well as processes of peripheral and central sensitization. Structural features like BMLs, synovitis, and joint effusion show a strong association with pain intensity 63 , 99 , 100 .

Classical treatments include the use of acetaminophen (paracetamol), NSAIDs, and opioids, which induce a plethora of unwanted side effects. Here komma we will discuss the latest developments in therapies directly targeting neuronal structures to alleviate OA pain.

Anti-nerve growth factor antibody treatment

A huge effort has been made in the development of therapeutics targeting nerve growth factor (NGF). NGF might be released upon mechanical stimulation or inflammatory mediators from different cell types including osteoclasts, osteocytes, chondrocytes, synovial fibroblasts, and macrophages in pre-clinical OA studies and human OA 100 – 105 . After the first promising clinical tests using anti-NGF antibodies, the FDA stopped ongoing trials owing to reports of serious adverse side effects with fast progression of OA and increased demand for knee replacement surgery. After the identification of risk factors (NSAID use) and dose modifications, the hold was lifted in 2015 and clinical trials continued (extensively reviewed in 106 , 107 ). A new phase III trial of knee and hip OA using subcutaneous injections of tanezumab (monoclonal anti-NGF antibody) displayed modest improvements in pain and functional scores compared to control but again raised safety concerns after increased need for total joint replacement in the tanezumab group 33 . Active immunization against NGF might provide a new alternative to target chronic pain, as demonstrated in murine OA 108 . Although initial trials using anti-NGF antibodies looked promising, further studies are needed to warrant treatment safety.

Anti-nerve growth factor receptor strategy

New strategies to inhibit NGF-induced pain concentrate on the antagonization of its receptors tropomyosin-related kinase A (TrkA) and p75 NTR . TrkA inhibition effectively reduced pain behavior in several pre-clinical OA models 109 , 110 . Various molecules have been developed to target the TrkA receptor: pan Trk inhibitor {"type":"entrez-nucleotide","attrs":{"text":"GZ389988","term_id":"397051773","term_text":"GZ389988"}} GZ389988 ( {"type":"clinical-trial","attrs":{"text":"NCT02424942","term_id":"NCT02424942"}} NCT02424942 and {"type":"clinical-trial","attrs":{"text":"NCT02845271","term_id":"NCT02845271"}} NCT02845271 ), AR786 (allosteric selective TrkA inhibitor), ASP7962 (TrkA receptor antagonist, {"type":"clinical-trial","attrs":{"text":"NCT02611466","term_id":"NCT02611466"}} NCT02611466 111 ), ONO-4474 (pan Trk inhibitor), and VM902A (allosteric TrkA selective inhibitor). Only {"type":"entrez-nucleotide","attrs":{"text":"GZ389988","term_id":"397051773","term_text":"GZ389988"}} GZ389988 exhibited modest pain reduction compared to control after 4 weeks but no prolonged efficacy after 12 weeks 34 ( Table 1D ). NGF receptor p75 NTR concentration is increased in the blood, synovial fluid, and tissue macrophages of OA patients 112 and has been related to inflammatory pain in a rat model 113 . LEVI-04, a p75 neurotrophin receptor fusion protein (p75NTR-Fc), is currently being investigated in a phase I clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03227796","term_id":"NCT03227796"}} NCT03227796 ), but results are not available yet.

Ion channels

Furthermore, ion channels like transient receptor potential (Trp) and Nav1.7/Nav1.8 voltage-gated sodium channels gained attention as potential drug targets 114 , 115 . TRP vanilloid 1 (TRPV1) channels expressed by sensory neurons might be targeted using receptor agonists like capsaicin or resiniferatoxin. In various animal models, these molecules resulted in long-term desensitization or nerve degradation, thus reducing pain and neuropeptide release, but conflicting observations have been reported 114 . Currently, several active clinical trials are analyzing the use of topical and i.a. trans-capsaicin (CNTX-4975) in knee OA. Stevens et al . described a dose-dependent effect of i.a. CNTX-4975 that reduced pain compared to placebo over 24 weeks in patients with moderate-to-severe knee OA ( Table 1D ) 35 . The FDA assured Fast Track designation to CNTX-4975 for the treatment of OA knee pain in 2018. Several “small molecule” TRPV1 antagonists have been tested so far in healthy subjects but not in OA pain 116 , 117 , and some had to be stopped because of inefficiency or adverse effects, including NEO6860, which caused headache, nausea, fatigue, and increased blood pressure among other adverse effects 118 , 119 . A single dose of JNJ-39439335 (Mavatrep), a selective competitive TRPV1 receptor antagonist, was evaluated in phase I studies and successfully reduced pain and improved functional score in knee OA patients after 7 days, though future studies require dose adjustment owing to adverse events involving thermal perception 36 , 37 ( Table 1D ). Animal models indicate involvement of voltage-gated sodium channels Nav1.7 and Nav1.8 in pathological pain states 120 , and A-803467, a selective Nav1.8 channel-blocking agent, disrupted nociceptive signal transmission in monoiodoacetate (MIA)-induced OA 121 . Furthermore, Vertex’s sodium-channel blocker VX-150 showed efficacy in acute pain reduction and was granted a breakthrough therapeutic potential by the FDA, though results of a completed phase IIa clinical study have not been published yet ( {"type":"clinical-trial","attrs":{"text":"NCT02660424","term_id":"NCT02660424"}} NCT02660424 ) 122 .

Targeting peripheral opioid receptors

Opioids are effective analgesics but their use is limited due to serious adverse side effects like constipation, respiratory depression, tolerance, and dependence. Currently, new opioid receptor (OR) agonists with an improved safety profile targeting the µ, δ, and κ subtypes are in development. Selectively targeting the peripheral κ-OR might avoid side effects observed when drugs target the µ-OR. Cara Therapeutics developed the selective κ-OR agonist CR845 and evaluated its efficacy in knee and hip OA ( {"type":"clinical-trial","attrs":{"text":"NCT02524197","term_id":"NCT02524197"}} NCT02524197 and {"type":"clinical-trial","attrs":{"text":"NCT02944448","term_id":"NCT02944448"}} NCT02944448 ), reporting dose-dependent efficacy in the reduction of pain in hip OA over knee OA 38 ( Table 1D ).

Evolving new targets

Pain relief might also be achieved by targeting the nociceptin/orphanin FQ peptide receptor (NOP) 123 . Cebranopadol (GRT6005), a dual agonist for the NOP/µ-OR, proved to be safe and efficient in chronic back pain 124 and was recently tested in patients with painful knee OA ( {"type":"clinical-trial","attrs":{"text":"NCT01357837","term_id":"NCT01357837"}} NCT01357837 and {"type":"clinical-trial","attrs":{"text":"NCT01709214","term_id":"NCT01709214"}} NCT01709214 ). Other nerve-associated targets include the bradykinin B2 receptor (Fasitibant, {"type":"clinical-trial","attrs":{"text":"NCT02205814","term_id":"NCT02205814"}} NCT02205814 and {"type":"clinical-trial","attrs":{"text":"NCT01091116","term_id":"NCT01091116"}} NCT01091116 ) and the CB2 cannabinoid receptor ( {"type":"entrez-nucleotide","attrs":{"text":"GW842166","term_id":"295324833","term_text":"GW842166"}} GW842166 [ {"type":"clinical-trial","attrs":{"text":"NCT00479427","term_id":"NCT00479427"}} NCT00479427 and {"type":"clinical-trial","attrs":{"text":"NCT00447486","term_id":"NCT00447486"}} NCT00447486 ], LY2828360 [ {"type":"clinical-trial","attrs":{"text":"NCT01319929","term_id":"NCT01319929"}} NCT01319929 ]). Direct blockade of the sensory neuropeptide α-calcitonin gene-related peptide using LY2951742 (galcanezumab) failed to reduce pain in patients with mild-to-moderate OA 39 ( Table 1D ). CR4056, an imidazoline-2 ligand with powerful analgesic properties, inhibited inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons 125 and effectively reduced allodynia and hyperalgesia in two rat OA models 126 . A recent phase II trial in knee OA patients reported successful analgesia, especially in male patients and in overweight patients associated with the metabolic phenotype 40 ( Table 1D ).

Despite huge efforts invested in the development of new OA analgesics and although several candidates look promising and more and more potential drug targets are identified, pain reduction in OA is still relatively unsuccessful. The complex and diverse underlying mechanisms of OA pain, the timely and spatial alterations of pain types and sensitization, and the interaction of nerves and OA-related structural changes, immune reactions, and altered metabolic conditions still require more intense interdisciplinary research to achieve effective pain management.

Metabolic syndrome therapies related to OA

Metabolism can be altered in OA, and there are multiple metabolic components underlying metabolic dysregulation. The metabolic syndrome, characterized by excessive and long-term positive energy balance, is defined by several cardio-metabolic factors that commonly are found together with obesity, which are central adiposity, dyslipidemia, impaired fasting glucose levels, and hypertension. People with metabolic syndrome are prone to developing a variety of disorders, especially cardiovascular diseases, type 2 diabetes mellitus (T2DM), and some forms of tumor. The increase in prevalence of metabolic syndrome in industrialized nations, and an association with obesity, together with the fact that it was a rare disease in pre-industrial populations, leads to the hypothesis that the metabolic syndrome might be a major risk factor for OA nowadays 6 , 127 , 128 .

Besides hypertension, which seems to provide an elevated risk of knee OA 129 , T2DM and knee OA often coexist and are known for common risk factors such as obesity and aging. The mechanical impact of excess body weight on joints may explain lower limb OA. However, it is unclear whether T2DM is linked to OA independently of excess weight and whether T2DM is involved in OA pathology. A coexistence between the occurrence of T2DM and OA was shown, but a causal link is not yet established 130 . T2DM clearly has an unhealthy effect on OA via two pathways: (1) chronic hyperglycemia, which is connected to oxidative stress, abnormal production of pro-inflammatory cytokines and advanced glycation end products (AGEs) in joint tissues, and (2) insulin resistance, which may have local effects but may also maintain a systemic low-grade inflammatory state 131 .

Metabolic targets for osteoarthritis therapy

So, are there metabolic targets known that are suitable for OA therapy? Some experimental studies show that mTOR signaling pathways can activate autophagy, which might be an effective approach for treating OA 119 . OA chondrocytes where AMP kinase (AMPK) has been removed exhibit increased catabolic responses to pro-inflammatory cytokines and biochemical injury. These effects are attenuated by molecules that activate AMPK, indicating that decreased AMPK activity is associated with cartilage degradation 120 , 121 . Possibly, AMPK-activating drugs such as methotrexate, metformin, and sodium salicylate might be good candidates to combat OA progression. A Taiwanese study examined whether or not the use of a COX-2 inhibitor with metformin in OA patients with T2DM was related to fewer joint replacement surgeries than the use of a COX-2 inhibitor only 122 . At the end of a 10-year follow up period, fewer joint replacement surgeries seemed to be needed in the case group compared to the control group. This outcome may be attributed to the fact that a combination therapy decreases pro-inflammatory factors associated with OA progression much more than one without metformin therapy ( Table 1E ).

Statin usage and osteoarthritis

Some pre-clinical and clinical data are available regarding the effects of statin usage on OA progression. Farnahgi et al . aimed to define the effects of hypercholesterolemia on the progression of OA in a murine OA model 132 . Surgical destabilization of the medial meniscus in knees from mice which were fed a high-cholesterol diet compared to controls led to a severe increase in OA symptoms. Doses of free cholesterol as recommended clinically resulted in overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. Hypertrophic and degradative markers were upregulated in chondrocytes, resulting in increased breakdown of the cartilage matrix. The authors reported that the severity of these diet-induced OA symptoms was reduced by the application of atorvastatin and a mitochondrial-targeting antioxidant, thus implicating that hypercholesterolemia promotes OA progression by mitochondrial dysfunction in chondrocytes, which was in part a result of increasing ROS production and apoptosis.

In a post-hoc analysis of the SEKOIA trial, the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA was investigated. Results demonstrated that the use of statins was related to radiological deterioration over the course of 3 years irrespective of other potentially related factors, such as obesity or T2DM hypertension, disease duration, symptom intensity and radiological severity 42 . Another trial investigated the association between statin therapy initiation and incidence of hand OA, but no association was observed in this study 43 . A pooled analysis based on time-to-event analysis of four population-based large cohorts demonstrated that statin use is not associated with reduced risk of consultation or surgery for OA of the hip or knee 44 ( Table 1E ).

It appears that repurposing some drugs such as metformin might identify valuable candidates for the treatment of OA in the context of metabolic syndrome. However, clinical studies assessing the effect of other compounds, such as statins, on knee OA progression have shown conflicting results. In line with this, more data and a priori clinical studies are necessary to correlate unambiguously the increase of metabolic syndrome in modern times with OA.

Therapies targeting senescence and aging

Age is a key risk factor for the development of OA, and age-related changes within the joint might represent targets for therapy. Aging and OA are closely related but still occur independently of one another. Some hallmarks of aging can influence the development of OA, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteolytic homeostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication 137 , 138 . So far, no human clinical trials have been designed to specifically target aging-related processes, but pre-clinical studies targeting some of the age-related factors generated promising data which may lead to novel therapeutic strategies. In the meantime, there are several “senolytics” known, which have the potential to qualify as therapeutic agents to treat OA.

Cell cycle inhibitors

Cellular senescence leads to the senescence-associated secretory phenotype (SASP), which is characterized by cell-cycle arrest, enhanced production of pro-inflammatory cytokines and other factors 138 , and increased expression of the cell cycle inhibitor p16 Ink4a 139 . Baker et al . addressed the physiological relevance and effects of naturally occurring senescent cells. The authors injected a transgene, INK-ATTAC, which was previously established in their lab, into p16 Ink4a -expressing cells of wild-type mice to induce apoptosis 140 . Their study did not address OA specifically, but they convincingly demonstrated that p16 Ink4a -positive cells accumulate during adulthood and have a detrimental effect on lifespan and encourage age-dependent alterations in various organs. Removing these cells could offer an attractive approach to healthy lifespan extension in joint tissues, which overexpress this cell cycle inhibitor. A direct connection to OA was tested by using the p16-3MR transgenic mouse, which harbors a p16 INK4a (Cdkn2a) promoter 141 . Introducing OA in this mouse strain after anterior cruciate ligament transection (ACLT) allowed the selective following and removal of senescent cells. I.a. injection of a senolytic molecule, UBX0101, which selectively kills senescent cells, attenuated the development of post-traumatic OA, reduced pain and the production of SASP factors, and improved the development, phenotype, and function of human OA chondrocytes in 3D pellet culture. The half-life of UBX0101 was low, preventing systemic exposure, but was still effective in blocking cartilage degradation by eliminating senescent cells rather than blocking their SASP secretion.

Targeting cell cycle inhibitors appears to be an intriguing new strategy to halt OA progression by addressing a risk factor, aging, that is closely associated to OA.

Redox signal pathways and osteoarthritis

An important therapeutic target might be redox-signaling pathways and associated mitochondrial dysfunction in OA. It is accepted that increasing levels of ROS contribute to age-related diseases by promoting cellular dysfunction and abolishing physiological cell signaling pathways 142 . The prevention of mitochondrial peroxiredoxin (PRX) 3 hyperoxidation-induced expression of mitochondrial catalase abrogated p38-mediated cell death and restored homeostatic signaling to maintain the viability of aging chondrocytes 143 . Another promising target could be superoxide dismutase 2 (Sod2), as deletion of Sod2 enhanced the severity of OA in mice 144 . Another interesting target for counteracting oxidative stress-induced tissue damage might be nuclear receptor erythroid 2 related factor (Nrf2). Nrf2 is a key transcription factor that regulates the expression of phase II antioxidant enzymes. These enzymes protect against oxidative stress and tissue damage. Cai and colleagues explored the role of Nrf2 in OA pathogenesis and the effects of Nrf2 acetylation for histone deacetylase inhibitor (HDACi) protection. For this, they took advantage of two murine OA models: i.a. injection of MIA and destabilization of the medial meniscus (DMM) 145 . In order to analyze the efficacy of HDACi on protection from cartilage damage, a pan-HDACi, trichostatin A (TSA), was applied. TSA promoted the induction of Nrf2 downstream proteins in mouse joint tissues and reduced the expression of OA-associated proteins like several MMPs and pro-inflammatory cytokines. TSA markedly ameliorated the cartilage damage in both OA models but offered no significant protection in Nrf2-knockout mice, suggesting that the protective effect of HDACi on OA progression was Nrf2 dependent.

Addressing redox-signaling pathways and mitochondrial dysfunction will enable exciting novel strategies to combat cellular senescence in general and thereby eliminate a major risk factor for OA: age.

Antioxidants may also have bone-protective effects in OA pathology. Using a spontaneous OA model, the STR/Ort mice, Javaheri et al . treated these mice for 3 months with SFX-01®, a synthetic stable variant of sulforaphane, a naturally occurring antioxidant 146 . SFX-01® treatment both modifies bone architecture in the STR/Ort mice and likely reduces OA pain and improves gait without improving articular cartilage lesion severity and occurrence of osteophytes in the joints of these mice. These findings strengthen the possibility that bone-targeting therapies with antioxidants may have some merit and exert osteotrophic effects possibly not only in OA.

Conclusions and open questions

For a few years, a novel concept considered OA as a multi-faceted disease involving the whole joint and not only cartilage or synovium. This offers new options to identify and develop novel therapeutics and to re-profile candidate drugs. Recent advances in OA pathology have enlightened key roles of several new pathways, which can be targeted. However, as OA is a highly heterogeneous disease, a single therapeutic targeting a single joint tissue may not be effective and no “one size fits all” drug/therapy will ever be developed. Improved patient stratification in combination with advanced DMOADs and cell-based therapies might lead to the development of personalized OA therapeutics.

Attention to temporal changes in disease progression like the transition from high bone turnover in early OA to decreased bone turnover in the late stages or timely changes in the pain type requires precise knowledge of the underlying mechanistic alterations. Choosing appropriate medication for selective disease time-points might help tailor individual treatment regimens for each patient in the future. Additionally, OA might present itself with overlapping endotypes like, for instance, an inflammatory pain endotype that could benefit from a combination of pharmaceuticals addressing both pain and inflammation.

Many clinical studies have been conducted in OA that address mainly structural targets like cartilage and bone in combination with reduction of inflammation and pain. In general, success was marginal, and only very few drugs, i.e. sprifermin or some BPs, resulted in improvement of joint structure and function. In addition, targeting TrkA or TRPV1 led to pain relief; however, no pharmacological treatment was able to halt or reverse OA progression long term.

Data from the application of MSCs/ASCs generated some guarded optimism; however, so far, only cartilage lesions were addressed with cell-based therapies, whereas subchondral bone, tendons, and other joint tissues were not included. This is a crucial shortcoming, as OA is recognized as a whole-joint disease.

One central point to be considered for all future therapeutic approaches, either regenerative or pharmacological, is the mechanical status of the joint. With this in mind, it is strongly suggested that the altered joint mechanics that cause OA are addressed in a first-line therapy. If altered OA joint mechanics are not normalized and original biomechanical pathways are not restored, it will be most likely that pharmacological or biological treatments of articular cartilage or inflammatory processes will not be efficacious. Furthermore, modulation of derailed cellular mechanoreceptive pathways might provide new opportunities to halt structural tissue deterioration. OA is not a single disease with a common pathophysiological pathway, as many pathways and risk factors lead to mechanical failure of the joint ( Figure 1 ), so identifying early OA stages would certainly be advantageous for the development of more efficient, targeted therapies. Therefore, the identification of reliable biomarkers and even more advanced imaging methods as well as stronger inter-disciplinary treatment regimens is indispensable.

An external file that holds a picture, illustration, etc.
Object name is f1000research-9-24390-g0000.jpg

Intrinsic repair mechanisms are limited and therefore extrinsic repair support is required to restore or ameliorate joint function. DMOAD, disease-modifying osteoarthritis drug; SB, subchondral bone.

Considering these central points, personalized OA therapy is the ultimate goal, and recent advances in phenotype classification and targeted drug development might provide a pool of suitable therapeutic options in the future.

[version 1; peer review: 3 approved]

Funding Statement

This work was funded by the German Research Foundation (DFG) as part of subproject 4 (GR1301/19-1 and -2) of the Research Consortium ExCarBon/FOR 2407/1 and 2.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Frank Zaucke , Orthopaedic University Hospital Friedrichsheim gGmbh, Frankfurt, Germany No competing interests were disclosed.
  • Andrew Pitsillides , Skeletal Biology Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK No competing interests were disclosed.
  • Changhai Ding , Menzies Research Institute, University of Tasmania, Hobart, Tasmania, 7000, Australia No competing interests were disclosed.

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Recent Research

Scientists around the world make use of the observations collected from NASA's heliophysics missions to study space around Earth, around the sun and throughout the solar system.

Read on for a dive into recent papers published on a wide variety of topics: from the way material in the sun roils to create a constantly-dancing and exploding solar surface; the way magnetism from the sun, Earth and other planets create an interconnected system through our heliosphere; and how studying our own neighborhood can teach us about space around other stars far away.

List of recent heliophysics highlights:

  • First Observation of a Mass-Dependent Effect on the Fractionation of the Solar Wind
  • Energy Dissipation in Collisionless Shocks
  • Mapping Earth's Magnetotail
  • Catastrophes For Life From the Sun: Distant Past and Near Future

Science Questions

This atmospheric Picture of the Week, taken with the NASA/ESA Hubble Space Telescope, shows a dark, gloomy scene in the constellation of Gemini (The Twins). The subject of this image confused astronomers when it was first studied — rather than being classified as a single object, it was instead recorded as two objects, owing to its symmetrical lobed structure (known as NGC 2371 and NGC 2372, though sometimes referred to together as NGC 2371/2).  These two lobes are visible to the upper right and lower left of the frame, and together form something known as a planetary nebula. Despite the name, such nebulae have nothing to do with planets; NGC 2371/2 formed when a Sun-like star reached the end of its life and blasted off its outer layers, shedding the constituent material and pushing it out into space to leave just a superheated stellar remnant behind. This remnant is visible as the orange-tinted star at the centre of the frame, sitting neatly between the two lobes. The structure of this region is complex. It is filled with dense knots of gas, fast-moving jets that appear to be changing direction over time, and expanding clouds of material streaming outwards on diametrically opposite sides of the remnant star. Patches of this scene glow brightly as the remnant star emits energetic radiation that excites the gas within these regions, causing it to light up. This scene will continue to change over the next few thousand years; eventually the knotty lobes will dissipate completely, and the remnant star will cool and dim to form a white dwarf.  Links: Image of NGC 2371 published in 2008 Image of NGC 2371 published 1997

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Google’s new Gemini model can analyze an hour-long video — but few people can use it

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Last October, a research paper published by a Google data scientist, the CTO of Databricks Matei Zaharia and UC Berkeley professor Pieter Abbeel posited a way to allow GenAI models — i.e. models along the lines of OpenAI’s GPT-4 and ChatGPT — to ingest far more data than was previously possible. In the study, the co-authors demonstrated that, by removing a major memory bottleneck for AI models, they could enable models to process millions of words as opposed to hundreds of thousands — the maximum of the most capable models at the time.

AI research moves fast, it seems.

Today, Google announced the release of Gemini 1.5 Pro, the newest member of its Gemini family of GenAI models. Designed to be a drop-in replacement for Gemini 1.0 Pro (which formerly went by “Gemini Pro 1.0” for reasons known only to Google’s labyrinthine marketing arm), Gemini 1.5 Pro is improved in a number of areas compared with its predecessor, perhaps most significantly in the amount of data that it can process.

Gemini 1.5 Pro can take in ~700,000 words, or ~30,000 lines of code — 35x the amount Gemini 1.0 Pro can handle. And — the model being multimodal — it’s not limited to text. Gemini 1.5 Pro can ingest up to 11 hours of audio or an hour of video in a variety of different languages.

Google Gemini 1.5 Pro

Image Credits: Google

To be clear, that’s an upper bound.

The version of Gemini 1.5 Pro available to most developers and customers starting today (in a limited preview) can only process ~100,000 words at once. Google’s characterizing the large-data-input Gemini 1.5 Pro as “experimental,” allowing only developers approved as part of a private preview to pilot it via the company’s GenAI dev tool AI Studio . Several customers using Google’s Vertex AI  platform also have access to the large-data-input Gemini 1.5 Pro — but not all.

Still, VP of research at Google DeepMind Oriol Vinyals heralded it as an achievement.

“When you interact with [GenAI] models, the information you’re inputting and outputting becomes the context, and the longer and more complex your questions and interactions are, the longer the context the model needs to be able to deal with gets,” Vinyals said during a press briefing. “We’ve unlocked long context in a pretty massive way.”

Big context

A model’s context, or context window, refers to input data (e.g. text) that the model considers before generating output (e.g. additional text). A simple question — “Who won the 2020 U.S. presidential election?” — can serve as context, as can a movie script, email or e-book.

Models with small context windows tend to “forget” the content of even very recent conversations, leading them to veer off topic — often in problematic ways. This isn’t necessarily so with models with large contexts. As an added upside, large-context models can better grasp the narrative flow of data they take in and generate more contextually rich responses — hypothetically, at least.

There have been other attempts at — and experiments on — models with atypically large context windows.

AI startup Magic claimed last summer to have developed a large language model (LLM) with a 5 million-token context window. Two papers in the past year detail model architectures ostensibly capable of scaling to a million tokens — and beyond. (“Tokens” are subdivided bits of raw data, like the syllables “fan,” “tas” and “tic” in the word “fantastic.”) And recently, a group of scientists hailing from Meta, MIT and Carnegie Mellon developed a technique that they say removes the constraint on model context window size altogether.

But Google is the first to make a model with a context window of this size commercially available, beating the previous leader Anthropic’s 200,000-token context window — if a private preview counts as commercially available.

Google Gemini 1.5 Pro

Gemini 1.5 Pro’s maximum context window is 1 million tokens, and the version of the model more widely available has a 128,000-token context window, the same as OpenAI’s GPT-4 Turbo .

So what can one accomplish with a 1 million-token context window? Lots of things, Google promises — like analyzing a whole code library, “reasoning across” lengthy documents like contracts, holding long conversations with a chatbot and analyzing and comparing content in videos.

During the briefing, Google showed two prerecorded demos of Gemini 1.5 Pro with the 1 million-token context window enabled.

In the first, the demonstrator asked Gemini 1.5 Pro to search the transcript of the Apollo 11 moon landing telecast — which comes to around 402 pages — for quotes containing jokes, and then to find a scene in the telecast that looked similar to a pencil sketch. In the second, the demonstrator told the model to search for scenes in “Sherlock Jr.,” the Buster Keaton film, going by descriptions and another sketch.

Google Gemini 1.5 Pro

Gemini 1.5 Pro successfully completed all the tasks asked of it, but not particularly quickly. Each took between ~20 seconds and a minute to process — far longer than, say, the average ChatGPT query.

Google Gemini 1.5 Pro

Vinyals says that the latency will improve as the model’s optimized. Already, the company’s testing a version of Gemini 1.5 Pro with a 10 million-token context window.

“The latency aspect [is something] we’re … working to optimize — this is still in an experimental stage, in a research stage,” he said. “So these issues I would say are present like with any other model.”

Me, I’m not so sure latency that poor will be attractive to many folks — much less paying customers. Having to wait minutes at a time to search across a video doesn’t sound pleasant — or very scalable in the near term. And I’m concerned how the latency manifests in other applications, like chatbot conversations and analyzing codebases. Vinyals didn’t say — which doesn’t instill much confidence.

My more optimistic colleague Frederic Lardinois pointed out that the overall time savings might just make the thumb twiddling worth it. But I think it’ll depend very much on the use case. For picking out a show’s plot points? Perhaps not. But for finding the right screengrab from a movie scene you only hazily recall? Maybe.

Other improvements

Beyond the expanded context window, Gemini 1.5 Pro brings other, quality-of-life upgrades to the table.

Google’s claiming that — in terms of quality — Gemini 1.5 Pro is “comparable” to the current version of Gemini Ultra, Google’s flagship GenAI model, thanks to a new architecture comprised of smaller, specialized “expert” models. Gemini 1.5 Pro essentially breaks down tasks into multiple subtasks and then delegates them to the appropriate expert models, deciding which task to delegate based on its own predictions.

MoE isn’t novel — it’s been around in some form for years. But its efficiency and flexibility has made it an increasingly popular choice among model vendors (see: the model powering Microsoft’s language translation services).

Now, “comparable quality” is a bit of a nebulous descriptor. Quality where it concerns GenAI models, especially multimodal ones, is hard to quantify — doubly so when the models are gated behind private previews that exclude the press. For what it’s worth, Google claims that Gemini 1.5 Pro performs at a “broadly similar level” compared to Ultra on the benchmarks the company uses to develop LLMs while  outperforming Gemini 1.0 Pro on 87% of those benchmarks. ( I’ll note that outperforming Gemini 1.0 Pro is a low bar .)

Pricing is a big question mark.

During the private preview, Gemini 1.5 Pro with the 1 million-token context window will be free to use, Google says. But the company plans to introduce pricing tiers in the near future that start at the standard 128,000 context window and scale up to 1 million tokens.

I have to imagine the larger context window won’t come cheap — and Google didn’t allay fears by opting not to reveal pricing during the briefing. If pricing’s in line with Anthropic’s , it could cost $8 per million prompt tokens and $24 per million generated tokens. But perhaps it’ll be lower; stranger things have happened! We’ll have to wait and see.

I wonder, too, about the implications for the rest of the models in the Gemini family, chiefly Gemini Ultra. Can we expect Ultra model upgrades roughly aligned with Pro upgrades? Or will there always be — as there is now — an awkward period where the available Pro models are superior performance-wise to the Ultra models, which Google’s still marketing as the top of the line in its Gemini portfolio?

Chalk it up to teething issues if you’re feeling charitable. If you’re not, call it like it is: darn confusing.

A once-ignored community of science sleuths now has the research community on its heels

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A community of sleuths hunting for errors in scientific research have sent shockwaves through some of the most prestigious research institutions in the world — and the science community at large.

High-profile cases of alleged image manipulations in papers authored by the former president at Stanford University and leaders at the Dana-Farber Cancer Institute have made national media headlines, and some top science leaders think this could be just the start.

“At the rate things are going, we expect another one of these to come up every few weeks,” said Holden Thorp, the editor-in-chief of the Science family of scientific journals, whose namesake publication is one of the two most influential in the field. 

The sleuths argue their work is necessary to correct the scientific record and prevent generations of researchers from pursuing dead-end topics because of flawed papers. And some scientists say it’s time for universities and academic publishers to reform how they address flawed research. 

“I understand why the sleuths finding these things are so pissed off,” said Michael Eisen, a biologist, the former editor of the journal eLife and a prominent voice of reform in scientific publishing. “Everybody — the author, the journal, the institution, everybody — is incentivized to minimize the importance of these things.” 

For about a decade, science sleuths unearthed widespread problems in scientific images in published papers, publishing concerns online but receiving little attention. 

That began to change last summer after then-Stanford President Marc Tessier-Lavigne, who is a neuroscientist, stepped down from his post after scrutiny of alleged image manipulations in studies he helped author and a report criticizing his laboratory culture. Tessier-Lavigne was not found to have engaged in misconduct himself, but members of his lab appeared to manipulate images in dubious ways, a report from a scientific panel hired to examine the allegations said. 

In January, a scathing post from a blogger exposed questionable work from top leaders at the Dana-Farber Cancer Institute , which subsequently asked journals to retract six articles and issue corrections for dozens more. 

In a resignation statement , Tessier-Lavigne noted that the panel did not find that he knew of misconduct and that he never submitted papers he didn’t think were accurate. In a statement from its research integrity officer, Dana-Farber said it took decisive action to correct the scientific record and that image discrepancies were not necessarily evidence an author sought to deceive. 

“We’re certainly living through a moment — a public awareness — that really hit an inflection when the Marc Tessier-Lavigne matter happened and has continued steadily since then, with Dana-Farber being the latest,” Thorp said. 

Now, the long-standing problem is in the national spotlight, and new artificial intelligence tools are only making it easier to spot problems that range from decades-old errors and sloppy science to images enhanced unethically in photo-editing software.  

This heightened scrutiny is reshaping how some publishers are operating. And it’s pushing universities, journals and researchers to reckon with new technology, a potential backlog of undiscovered errors and how to be more transparent when problems are identified. 

This comes at a fraught time in academic halls. Bill Ackman, a venture capitalist, in a post on X last month discussed weaponizing artificial intelligence to identify plagiarism of leaders at top-flight universities where he has had ideological differences, raising questions about political motivations in plagiarism investigations. More broadly, public trust in scientists and science has declined steadily in recent years, according to the Pew Research Center .

Eisen said he didn’t think sleuths’ concerns over scientific images had veered into “McCarthyist” territory.

“I think they’ve been targeting a very specific type of problem in the literature, and they’re right — it’s bad,” Eisen said. 

Scientific publishing builds the base of what scientists understand about their disciplines, and it’s the primary way that researchers with new findings outline their work for colleagues. Before publication, scientific journals consider submissions and send them to outside researchers in the field for vetting and to spot errors or faulty reasoning, which is called peer review. Journal editors will review studies for plagiarism and for copy edits before they’re published. 

That system is not perfect and still relies on good-faith efforts by researchers to not manipulate their findings.

Over the past 15 years, scientists have grown increasingly concerned about problems that some researchers were digitally altering images in their papers to skew or emphasize results. Discovering irregularities in images — typically of experiments involving mice, gels or blots — has become a larger priority of scientific journals’ work.   

Jana Christopher, an expert on scientific images who works for the Federation of European Biochemical Societies and its journals, said the field of image integrity screening has grown rapidly since she began working in it about 15 years ago. 

At the time, “nobody was doing this and people were kind of in denial about research fraud,” Christopher said. “The common view was that it was very rare and every now and then you would find someone who fudged their results.” 

Today, scientific journals have entire teams dedicated to dealing with images and trying to ensure their accuracy. More papers are being retracted than ever — with a record 10,000-plus pulled last year, according to a Nature analysis . 

A loose group of scientific sleuths have added outside pressure. Sleuths often discover and flag errors or potential manipulations on the online forum PubPeer. Some sleuths receive little or no payment or public recognition for their work.

“To some extent, there is a vigilantism around it,” Eisen said. 

An analysis of comments on more than 24,000 articles posted on PubPeer found that more than 62% of comments on PubPeer were related to image manipulation. 

For years, sleuths relied on sharp eyes, keen pattern recognition and an understanding of photo manipulation tools. In the past few years, rapidly developing artificial intelligence tools, which can scan papers for irregularities, are supercharging their work. 

Now, scientific journals are adopting similar technology to try to prevent errors from reaching publication. In January, Science announced that it was using an artificial intelligence tool called Proofig to scan papers that were being edited and peer-reviewed for publication. 

Thorp, the Science editor-in-chief, said the family of six journals added the tool “quietly” into its workflow about six months before that January announcement. Before, the journal was reliant on eye-checks to catch these types of problems. 

Thorp said Proofig identified several papers late in the editorial process that were not published because of problematic images that were difficult to explain and other instances in which authors had “logical explanations” for issues they corrected before publication.

“The serious errors that cause us not to publish a paper are less than 1%,” Thorp said.

In a statement, Chris Graf, the research integrity director at the publishing company Springer Nature, said his company is developing and testing “in-house AI image integrity software” to check for image duplications. Graf’s research integrity unit currently uses Proofig to help assess articles if concerns are raised after publication. 

Graf said processes varied across its journals, but that some Springer Nature publications manually check images for manipulations with Adobe Photoshop tools and look for inconsistencies in raw data for experiments that visualize cell components or common scientific experiments.

“While the AI-based tools are helpful in speeding up and scaling up the investigations, we still consider the human element of all our investigations to be crucial,” Graf said, adding that image recognition software is not perfect and that human expertise is required to protect against false positives and negatives. 

No tool will catch every mistake or cheat. 

“There’s a lot of human beings in that process. We’re never going to catch everything,” Thorp said. “We need to get much better at managing this when it happens, as journals, institutions and authors.”

Many science sleuths had grown frustrated after their concerns seemed to be ignored or as investigations trickled along slowly and without a public resolution.  

Sholto David, who publicly exposed concerns about Dana-Farber research in a blog post, said he largely “gave up” on writing letters to journal editors about errors he discovered because their responses were so insufficient. 

Elisabeth Bik, a microbiologist and longtime image sleuth, said she has frequently flagged image problems and “nothing happens.” 

Leaving public comments questioning research figures on PubPeer can start a public conversation over questionable research, but authors and research institutions often don’t respond directly to the online critiques. 

While journals can issue corrections or retractions, it’s typically a research institution’s or a university’s responsibility to investigate cases. When cases involve biomedical research supported by federal funding, the federal Office of Research Integrity can investigate. 

Thorp said the institutions need to move more swiftly to take responsibility when errors are discovered and speak plainly and publicly about what happened to earn the public’s trust.  

“Universities are so slow at responding and so slow at running through their processes, and the longer that goes on, the more damage that goes on,” Thorp said. “We don’t know what happened if instead of launching this investigation Stanford said, ‘These papers are wrong. We’re going to retract them. It’s our responsibility. But for now, we’re taking the blame and owning up to this.’” 

Some scientists worry that image concerns are only scratching the surface of science’s integrity issues — problems in images are simply much easier to spot than data errors in spreadsheets. 

And while policing bad papers and seeking accountability is important, some scientists think those measures will be treating symptoms of the larger problem: a culture that rewards the careers of those who publish the most exciting results, rather than the ones that hold up over time. 

“The scientific culture itself does not say we care about being right; it says we care about getting splashy papers,” Eisen said. 

Evan Bush is a science reporter for NBC News. He can be reached at [email protected].

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Sample of DNA being pipetted into a petri dish over genetic results

‘The situation has become appalling’: fake scientific papers push research credibility to crisis point

Last year, 10,000 sham papers had to be retracted by academic journals, but experts think this is just the tip of the iceberg

Tens of thousands of bogus research papers are being published in journals in an international scandal that is worsening every year, scientists have warned. Medical research is being compromised, drug development hindered and promising academic research jeopardised thanks to a global wave of sham science that is sweeping laboratories and universities.

Last year the annual number of papers retracted by research journals topped 10,000 for the first time. Most analysts believe the figure is only the tip of an iceberg of scientific fraud .

“The situation has become appalling,” said Professor Dorothy Bishop of Oxford University. “The level of publishing of fraudulent papers is creating serious problems for science. In many fields it is becoming difficult to build up a cumulative approach to a subject, because we lack a solid foundation of trustworthy findings. And it’s getting worse and worse.”

The startling rise in the publication of sham science papers has its roots in China, where young doctors and scientists seeking promotion were required to have published scientific papers. Shadow organisations – known as “paper mills” – began to supply fabricated work for publication in journals there.

The practice has since spread to India, Iran, Russia, former Soviet Union states and eastern Europe, with paper mills supplying ­fabricated studies to more and more journals as increasing numbers of young ­scientists try to boost their careers by claiming false research experience. In some cases, journal editors have been bribed to accept articles, while paper mills have managed to establish their own agents as guest editors who then allow reams of ­falsified work to be published.

Dr Dorothy Bishop sitting in a garden

“Editors are not fulfilling their roles properly, and peer reviewers are not doing their jobs. And some are being paid large sums of money,” said Professor Alison Avenell of Aberdeen University. “It is deeply worrying.”

The products of paper mills often look like regular articles but are based on templates in which names of genes or diseases are slotted in at random among fictitious tables and figures. Worryingly, these articles can then get incorporated into large databases used by those working on drug discovery.

Others are more bizarre and include research unrelated to a journal’s field, making it clear that no peer review has taken place in relation to that article. An example is a paper on Marxist ideology that appeared in the journal Computational and Mathematical Methods in Medicine . Others are distinctive because of the strange language they use, including references to “bosom peril” rather than breast cancer and “Parkinson’s ailment” rather Parkinson’s disease.

Watchdog groups – such as Retraction Watch – have tracked the problem and have noted retractions by journals that were forced to act on occasions when fabrications were uncovered. One study, by Nature , revealed that in 2013 there were just over 1,000 retractions. In 2022, the figure topped 4,000 before jumping to more than 10,000 last year.

Of this last total, more than 8,000 retracted papers had been published in journals owned by Hindawi, a subsidiary of the publisher Wiley, figures that have now forced the company to act. “We will be sunsetting the Hindawi brand and have begun to fully integrate the 200-plus Hindawi journals into Wiley’s ­portfolio,” a Wiley spokesperson told the Observer .

The spokesperson added that Wiley had now identified hundreds of fraudsters present in its portfolio of journals, as well as those who had held guest editorial roles. “We have removed them from our systems and will continue to take a proactive … approach in our efforts to clean up the scholarly record, strengthen our integrity processes and contribute to cross-industry solutions.”

But Wiley insisted it could not tackle the crisis on its own, a message echoed by other publishers, which say they are under siege from paper mills. Academics remain cautious, however. The problem is that in many countries, academics are paid according to the number of papers they have published.

“If you have growing numbers of researchers who are being strongly incentivised to publish just for the sake of publishing, while we have a growing number of journals making money from publishing the resulting articles, you have a perfect storm,” said Professor Marcus Munafo of Bristol University. “That is exactly what we have now.”

The harm done by publishing poor or fabricated research is demonstrated by the anti-parasite drug ivermectin. Early laboratory studies indicated it could be used to treat Covid-19 and it was hailed as a miracle drug. However, it was later found these studies showed clear evidence of fraud, and medical authorities have refused to back it as a treatment for Covid.

“The trouble was, ivermectin was used by anti-vaxxers to say: ‘We don’t need vaccination because we have this wonder drug,’” said Jack Wilkinson at Manchester University. “But many of the trials that underpinned those claims were not authentic.”

Wilkinson added that he and his colleagues were trying to develop protocols that researchers could apply to reveal the authenticity of studies that they might include in their own work. “Some great science came out during the pandemic, but there was an ocean of rubbish research too. We need ways to pinpoint poor data right from the start.”

The danger posed by the rise of the paper mill and fraudulent research papers was also stressed by Professor Malcolm MacLeod of Edinburgh University. “If, as a scientist, I want to check all the papers about a particular drug that might target cancers or stroke cases, it is very hard for me to avoid those that are fabricated. Scientific knowledge is being polluted by made-up material. We are facing a crisis.”

This point was backed by Bishop: “People are building careers on the back of this tidal wave of fraudulent science and could end up running scientific institutes and eventually be used by mainstream journals as reviewers and editors. Corruption is creeping into the system.”

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Reproductive rights in America

Research at the heart of a federal case against the abortion pill has been retracted.

Selena Simmons-Duffin

Selena Simmons-Duffin

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The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy. Anna Moneymaker/Getty Images hide caption

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy.

A scientific paper that raised concerns about the safety of the abortion pill mifepristone was retracted by its publisher this week. The study was cited three times by a federal judge who ruled against mifepristone last spring. That case, which could limit access to mifepristone throughout the country, will soon be heard in the Supreme Court.

The now retracted study used Medicaid claims data to track E.R. visits by patients in the month after having an abortion. The study found a much higher rate of complications than similar studies that have examined abortion safety.

Sage, the publisher of the journal, retracted the study on Monday along with two other papers, explaining in a statement that "expert reviewers found that the studies demonstrate a lack of scientific rigor that invalidates or renders unreliable the authors' conclusions."

It also noted that most of the authors on the paper worked for the Charlotte Lozier Institute, the research arm of anti-abortion lobbying group Susan B. Anthony Pro-Life America, and that one of the original peer reviewers had also worked for the Lozier Institute.

The Sage journal, Health Services Research and Managerial Epidemiology , published all three research articles, which are still available online along with the retraction notice. In an email to NPR, a spokesperson for Sage wrote that the process leading to the retractions "was thorough, fair, and careful."

The lead author on the paper, James Studnicki, fiercely defends his work. "Sage is targeting us because we have been successful for a long period of time," he says on a video posted online this week . He asserts that the retraction has "nothing to do with real science and has everything to do with a political assassination of science."

He says that because the study's findings have been cited in legal cases like the one challenging the abortion pill, "we have become visible – people are quoting us. And for that reason, we are dangerous, and for that reason, they want to cancel our work," Studnicki says in the video.

In an email to NPR, a spokesperson for the Charlotte Lozier Institute said that they "will be taking appropriate legal action."

Role in abortion pill legal case

Anti-abortion rights groups, including a group of doctors, sued the federal Food and Drug Administration in 2022 over the approval of mifepristone, which is part of a two-drug regimen used in most medication abortions. The pill has been on the market for over 20 years, and is used in more than half abortions nationally. The FDA stands by its research that finds adverse events from mifepristone are extremely rare.

Judge Matthew Kacsmaryk, the district court judge who initially ruled on the case, pointed to the now-retracted study to support the idea that the anti-abortion rights physicians suing the FDA had the right to do so. "The associations' members have standing because they allege adverse events from chemical abortion drugs can overwhelm the medical system and place 'enormous pressure and stress' on doctors during emergencies and complications," he wrote in his decision, citing Studnicki. He ruled that mifepristone should be pulled from the market nationwide, although his decision never took effect.

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Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017. AP hide caption

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017.

Kacsmaryk is a Trump appointee who was a vocal abortion opponent before becoming a federal judge.

"I don't think he would view the retraction as delegitimizing the research," says Mary Ziegler , a law professor and expert on the legal history of abortion at U.C. Davis. "There's been so much polarization about what the reality of abortion is on the right that I'm not sure how much a retraction would affect his reasoning."

Ziegler also doubts the retractions will alter much in the Supreme Court case, given its conservative majority. "We've already seen, when it comes to abortion, that the court has a propensity to look at the views of experts that support the results it wants," she says. The decision that overturned Roe v. Wade is an example, she says. "The majority [opinion] relied pretty much exclusively on scholars with some ties to pro-life activism and didn't really cite anybody else even or really even acknowledge that there was a majority scholarly position or even that there was meaningful disagreement on the subject."

In the mifepristone case, "there's a lot of supposition and speculation" in the argument about who has standing to sue, she explains. "There's a probability that people will take mifepristone and then there's a probability that they'll get complications and then there's a probability that they'll get treatment in the E.R. and then there's a probability that they'll encounter physicians with certain objections to mifepristone. So the question is, if this [retraction] knocks out one leg of the stool, does that somehow affect how the court is going to view standing? I imagine not."

It's impossible to know who will win the Supreme Court case, but Ziegler thinks that this retraction probably won't sway the outcome either way. "If the court is skeptical of standing because of all these aforementioned weaknesses, this is just more fuel to that fire," she says. "It's not as if this were an airtight case for standing and this was a potentially game-changing development."

Oral arguments for the case, Alliance for Hippocratic Medicine v. FDA , are scheduled for March 26 at the Supreme Court. A decision is expected by summer. Mifepristone remains available while the legal process continues.

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AI gone wild —

Scientists aghast at bizarre ai rat with huge genitals in peer-reviewed article, it's unclear how such egregiously bad images made it through peer-review..

Beth Mole - Feb 15, 2024 11:16 pm UTC

An actual laboratory rat, who is intrigued.

Appall and scorn ripped through scientists' social media networks Thursday as several egregiously bad AI-generated figures circulated from a peer-reviewed article recently published in a reputable journal. Those figures—which the authors acknowledge in the article's text were made by Midjourney—are all uninterpretable. They contain gibberish text and, most strikingly, one includes an image of a rat with grotesquely large and bizarre genitals, as well as a text label of "dck."

AI-generated Figure 1 of the paper. This image is supposed to show spermatogonial stem cells isolated, purified, and cultured from rat testes.

The article in question is titled "Cellular functions of spermatogonial stem cells in relation to JAK/STAT signaling pathway," which was authored by three researchers in China, including the corresponding author Dingjun Hao of Xi’an Honghui Hospital. It was published online Tuesday in the journal Frontiers in Cell and Developmental Biology.

Frontiers did not immediately respond to Ars' request for comment, but we will update this post with any response.

Figure 2 is supposed to be a diagram of the JAK-STAT signaling pathway.

But the rat's package is far from the only problem. Figure 2 is less graphic but equally mangled. While it's intended to be a diagram of a complex signaling pathway, it instead is a jumbled mess. One scientific integrity expert questioned whether it provided an overly complicated explanation of "how to make a donut with colorful sprinkles." Like the first image, the diagram is rife with nonsense text and baffling images. Figure 3 is no better, offering a collage of small circular images that are densely annotated with gibberish. The image is supposed to provide visual representations of how the signaling pathway from Figure 2 regulates the biological properties of spermatogonial stem cells.

Some scientists online questioned whether the article's text was also AI-generated. One user noted that AI detection software determined that it was likely to be AI-generated; however, as Ars has reported previously, such software is unreliable .

Figure 3 is supposed to show the regulation of biological properties of spermatogonial stem cells by JAK/STAT signaling pathway.

The images, while egregious examples, highlight a growing problem in scientific publishing. A scientist's success relies heavily on their publication record, with a large volume of publications, frequent publishing, and articles appearing in top-tier journals, all of which earn scientists more prestige. The system incentivizes less-than-scrupulous researchers to push through low-quality articles, which, in the era of AI chatbots, could potentially be generated with the help of AI. Researchers worry that the growing use of AI will make published research less trustworthy. As such, research journals have recently set new authorship guidelines for AI-generated text to try to address the problem. But for now, as the Frontiers article shows, there are clearly some gaps.

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    Current Research in Biotechnology (CRBIOT) is a new primary research, gold open access journal from Elsevier.CRBIOT publishes original papers, reviews, and short communications (including viewpoints and perspectives) resulting from research in biotechnology and biotech-associated disciplines. Cur… View full aims & scope $2390

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    New advances in science, medicine, health, and technology.Stem cell research, drug research, and new treatments for disease.

  12. Research

    News about Research, including commentary and archival articles published in The New York Times.

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    Current Research in Food Science (CRFS) is a new primary research, gold open access journal from Elsevier. CRFS publishes original papers and short communications - including viewpoints and perspectives - resulting from research carried out on food systems and their components. Current Research …. View full aims & scope.

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  17. New global area estimates for coral reefs from high ...

    This paper acts as a scientific reference for the mapping framework and summary statistics for the Allen Coral Atlas. In summary, for shallow tropical reefs (−30° to 30° latitude) at 5-m-pixel resolution, we present: (1) their global extent and distribution, (2) the distribution of 11 geomorphic classes, and (3) the distribution of 6 benthic classes (Figure 1).

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    Recently published articles from subdisciplines of psychology covered by more than 90 APA Journals™ publications. For additional free resources (such as article summaries, podcasts, and more), please visit the Highlights in Psychological Research page. Browse and read free articles from APA Journals across the field of psychology, selected by ...

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  21. data analysis Latest Research Papers

    56204 (FIVE YEARS 23179) H-INDEX 229 (FIVE YEARS 27) Latest Documents Most Cited Documents Contributed Authors Related Sources Related Keywords Introduce a Survival Model with Spatial Skew Gaussian Random Effects and its Application in Covid-19 Data Analysis Journal of Statistical Sciences 10.52547/jss.15.2.567 2022 Vol 15 (2) pp. 567-590

  22. Google's new Gemini model can analyze an hour-long video

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  23. A once-ignored community of science sleuths now has the research

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    A research paper that raises questions about the safety of abortion has been retracted. The research is cited in a federal judge's ruling about the abortion pill mifepristone.

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