A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.

The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.

The tuatara genome reveals ancient features of amniote evolution.

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana1,2-is an iconic species that is endemic to New Zealand2,3. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes2,4. Here we analyse the genome of the tuatara, which-at approximately 5 Gb-is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.

Publisher Correction: The tuatara genome reveals ancient features of amniote evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Post-transcriptional control of the essential enzyme MurF by a small regulatory RNA in Brucella abortus.

Brucella abortus is a facultative, intracellular, zoonotic pathogen that resides inside macrophages during infection. This is a specialized niche where B. abortus encounters various stresses as it navigates through the macrophage. In order to survive this harsh environment, B. abortus utilizes post-transcriptional regulation of gene expression through the use of small regulatory RNAs (sRNAs). Here, we characterize a Brucella sRNAs called MavR (for MurF- and virulence-regulating sRNA), and we demonstrate that MavR is required for the full virulence of B. abortus in macrophages and in a mouse model of chronic infection. Transcriptomic and proteomic studies revealed that a major regulatory target of MavR is MurF. MurF is an essential protein that catalyzes the final cytoplasmic step in peptidoglycan (PG) synthesis; however, we did not detect any differences in the amount or chemical composition of PG in the ΔmavR mutant. A 6-nucleotide regulatory seed region within MavR was identified, and mutation of this seed region resulted in dysregulation of MurF production, as well as significant attenuation of infection in a mouse model. Overall, the present study underscores the importance of sRNA regulation in the physiology and virulence of Brucella.

Unconventional Superconducting Diode Effects via Antisymmetry and Antisymmetry Breaking.

Symmetry breaking plays a pivotal role in unlocking intriguing properties and functionalities in material systems. For example, the breaking of spatial and temporal symmetries leads to a fascinating phenomenon: the superconducting diode effect. However, generating and precisely controlling the superconducting diode effect pose significant challenges. Here, we take a novel route with the deliberate manipulation of magnetic charge potentials to realize unconventional superconducting flux-quantum diode effects. We achieve this through suitably tailored nanoengineered arrays of nanobar magnets on top of a superconducting thin film. We demonstrate the vital roles of inversion antisymmetry and its breaking in evoking unconventional superconducting effects, namely a magnetically symmetric diode effect and an odd-parity magnetotransport effect. These effects are nonvolatilely controllable through in situ magnetization switching of the nanobar magnets. Our findings promote the use of antisymmetry (breaking) for initiating unconventional superconducting properties, paving the way for exciting prospects and innovative functionalities in superconducting electronics.

Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities.

Obesity has been identified as an independent risk factor for severe outcomes in humans with coronavirus disease 2019 (COVID-19) and other infectious diseases. Here, we established a mouse model of COVID-19 using the murine betacoronavirus, mouse hepatitis virus 1 (MHV-1). C57BL/6 and C3H/HeJ mice exposed to MHV-1 developed mild and severe disease, respectively. Obese C57BL/6 mice developed clinical manifestations similar to those of lean controls. In contrast, all obese C3H/HeJ mice succumbed by 8 days postinfection, compared to a 50% mortality rate in lean controls. Notably, both lean and obese C3H/HeJ mice exposed to MHV-1 developed lung lesions consistent with severe human COVID-19, with marked evidence of diffuse alveolar damage (DAD). To identify early predictive biomarkers of worsened disease outcomes in obese C3H/HeJ mice, we sequenced RNA from whole blood 2 days postinfection and assessed changes in gene and pathway expression. Many pathways uniquely altered in obese C3H/HeJ mice postinfection aligned with those found in humans with severe COVID-19. Furthermore, we observed altered gene expression related to the unfolded protein response and lipid metabolism in infected obese mice compared to their lean counterparts, suggesting a role in the severity of disease outcomes. This study presents a novel model for studying COVID-19 and elucidating the mechanisms underlying severe disease outcomes in obese and other hosts.

KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7.

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and liver injury, has become a leading cause of end-stage liver diseases and liver transplantation. Krüppel-like factors 10 (KLF10) is a Cys2/His2 zinc finger transcription factor that regulates cell growth, apoptosis, and differentiation. However, whether it plays a role in the development and progression of NASH remains poorly understood. In the present study, we found that KLF10 expression was selectively upregulated in the mouse models and human patients with NASH, compared with simple steatosis (NAFL). Gain- and loss-of function studies demonstrated that hepatocyte-specific overexpression of KLF10 aggravated, whereas its depletion alleviated diet-induced NASH pathogenesis in mice. Mechanistically, transcriptomic analysis and subsequent functional experiments showed that KLF10 promotes hepatic lipid accumulation and inflammation through the palmitoylation and plasma membrane localization of fatty acid translocase CD36 via transcriptionally activation of zDHHC7. Indeed, both expression of zDHHC7 and palmitoylation of CD36 are required for the pathogenic roles of KLF10 in NASH development. Thus, our results identify an important role for KLF10 in NAFL-to-NASH progression through zDHHC7-mediated CD36 palmitoylation.

Implementation and impact of the World Health Organization integrated care for older people (ICOPE) program in China: a randomised controlled trial.

BACKGROUND: Fragmentation of services increases health and social care burden as people live longer with higher prevalence of diseases, frailty and dependency. Local evidence for implementing person-centred integrated care is urgently needed to advance practice and policies to achieve healthy ageing. OBJECTIVE: To test the feasibility and impact of World Health Organization's (WHO) Integrated Care for Older People (ICOPE) approach in China. DESIGN: A randomised controlled trial examining the feasibility of implementing ICOPE approach, evaluating its impact on health outcomes and health resource utilisation. SETTING: Primary care setting in urban and suburban communities of Chaoyang District, Beijing, China. SUBJECTS: Community-dwelling older adults screened as at-risk of functional declines and randomised into intervention (537) and control (1611) groups between September 2020 and February 2021. METHODS: A 6-month intervention program following WHO's ICOPE care pathways implemented by integrated care managers compared to standard available care. RESULTS: After 1 to 1 propensity score matching, participants in intervention and control groups (totally 938) had comparable baseline characteristics, demonstrated feasibility of implementing ICOPE with satisfaction by participants (97-99%) and providers (92-93%). All outcomes showed improvements after a 6-month intervention, while statistically significant least-squares mean differences (control-intervention) in vitality (Mini-Nutritional Assessment Short Form to measure vitality, -0.21, 95% CI, -0.40-0.02), mobility (Short Physical Performance Battery to measure mobility, -0.29, 95% CI, -0.44-0.14) and psychological health (Geriatric Depression Scale five items to measure psychological health, 0.09, 95% CI, 0.03-0.14) were observed (P < 0.05). CONCLUSIONS: It is feasible to localise and implement WHO's ICOPE approach in regions with fragmented resources such as China. Preliminary evidence supports its acceptance among key stakeholders and impact on health outcomes.

Dietary ω-3 polyunsaturated fatty acids are protective for myopia.

Myopia is a leading cause of visual impairment and blindness worldwide. However, a safe and accessible approach for myopia control and prevention is currently unavailable. Here, we investigated the therapeutic effect of dietary supplements of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on myopia progression in animal models and on decreases in choroidal blood perfusion (ChBP) caused by near work, a risk factor for myopia in young adults. We demonstrated that daily gavage of ω-3 PUFAs (300 mg docosahexaenoic acid [DHA] plus 60 mg eicosapentaenoic acid [EPA]) significantly attenuated the development of form deprivation myopia in guinea pigs and mice, as well as of lens-induced myopia in guinea pigs. Peribulbar injections of DHA also inhibited myopia progression in form-deprived guinea pigs. The suppression of myopia in guinea pigs was accompanied by inhibition of the "ChBP reduction-scleral hypoxia cascade." Additionally, treatment with DHA or EPA antagonized hypoxia-induced myofibroblast transdifferentiation in cultured human scleral fibroblasts. In human subjects, oral administration of ω-3 PUFAs partially alleviated the near-work-induced decreases in ChBP. Therefore, evidence from these animal and human studies suggests ω-3 PUFAs are potential and readily available candidates for myopia control.

van der Waals Self-Epitaxial Growth of Inch-Sized Superconducting Niobium Diselenide Films.

Ultrathin superconducting films are the basis of superconductor devices. van der Waals (vdW) NbSe2 with noncentrosymmetry exhibits exotic superconductivity and shows promise in superconductor electronic devices. However, the growth of inch-scale NbSe2 films with layer regulation remains a challenge because vdW structural material growth is strongly dependent on the epitaxial guidance of the substrate. Herein, a vdW self-epitaxy strategy is developed to eliminate the substrate driving force in film growth and realize inch-sized NbSe2 film growth with thicknesses from 2.1 to 12.1 nm on arbitrary substrates. The superconducting transition temperature of 5.1 K and superconducting transition width of 0.30 K prove the top homogeneity and quality of superconductivity among all of the synthetic NbSe2 films. Coupled with a large area and substrate compatibility, this work paves the way for developing NbSe2 superconductor electronics.

Serum proteome and metabolome uncover novel biomarkers for the assessment of disease activity and diagnosing of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting thousands of people. There are still no effective biomarkers for SLE diagnosis and disease activity assessment. We performed proteomics and metabolomics analyses of serum from 121 SLE patients and 106 healthy individuals, and identified 90 proteins and 76 metabolites significantly changed. Several apolipoproteins and the metabolite arachidonic acid were significantly associated with disease activity. Apolipoprotein A-IV (APOA4), LysoPC(16:0), punicic acid and stearidonic acid were correlated with renal function. Random forest model using the significantly changed molecules identified 3 proteins including ATRN, THBS1 and SERPINC1, and 5 metabolites including cholesterol, palmitoleoylethanolamide, octadecanamide, palmitamide and linoleoylethanolamide, as potential biomarkers for SLE diagnosis. Those biomarkers were further validated in an independent cohort with high accuracy (AUC = 0.862 and 0.898 for protein and metabolite biomarkers respectively). This unbiased screening has led to the discovery of novel molecules for SLE disease activity assessment and SLE classification.

Polarizer-free measurement of the full Stokes vector using a fiber-coupled superconducting nanowire single photon detector with a polarization extinction ratio of ∼2.

The characterization and manipulation of polarization state at single photon level are of great importance in research fields such as quantum information processing and quantum key distribution, where photons are normally delivered using single mode optical fibers. To date, the demonstrated polarimetry measurement techniques based on a superconducting nanowire single photon detector (SNSPD) require the SNSPD to be either highly sensitive or highly insensitive to the photon's polarization state, therefore placing an unavoidable challenge on the SNSPD's design and fabrication processes. In this article, we present the development of an alternative polarimetry measurement technique, of which the stringent requirement on the SNSPD's polarization sensitivity is removed. We validate the proposed technique by a rigorous theoretical analysis and comparisons of the experimental results obtained using a fiber-coupled SNSPD with a polarization extinction ratio of ∼2 to that obtained using other well-established known methods. Based on the full Stokes data measured by the proposed technique, we also demonstrate that at the single photon level (∼ -100 dBm), the polarization state of the photon delivered to the superconducting nanowire facet plane can be controlled at will using a further developed algorithm. Note that other than the fiber-coupled SNSPD, the only component involved is a quarter-wave plate (no external polarizer is necessary), which when aligned well has a paid insertion loss less than 0.5 dB.

Modeling of a multireflector terahertz imaging system using a geometrical optics model based on angular spectrum theory.

We propose a simulation method for a multireflector terahertz imaging system. The description and verification of the method are based on an existing active bifocal terahertz imaging system at 0.22 THz. Using the phase conversion factor and angular spectrum propagation, the computation of the incident and received fields requires only a simple matrix operation. The phase angle is used to calculate the ray tracking direction, and the total optical path is used to calculate the scattering field of defective foams. Compared with the measurements and simulations of aluminum disks and defective foams, the validity of the simulation method is confirmed in the field of view of 50 cm × 90 cm at 8 m. This work aims to develop better imaging systems by predicting their imaging behavior for different targets before manufacturing.

Image distortion by ambiguous multiple-photon detections in a superconducting nanowire single-photon imager and the correction method.

Scaling up superconducting nanowire single-photon detectors (SNSPDs) into a large array for imaging applications is the current pursuit. Although various readout architectures have been proposed, they cannot resolve multiple-photon detections (MPDs) currently, which limits the operation of the SNSPD arrays at high photon flux. In this study, we focused on the readout ambiguity of a superconducting nanowire single-photon imager applying time-of-flight multiplexing readout. The results showed that image distortion depended on both the incident photon flux and the imaging object. By extracting multiple-photon detections on idle pixels, which were virtual because of the incorrect mapping from the ambiguous readout, a correction method was proposed. An improvement factor of 1.3~9.3 at a photon flux of µ = 5 photon/pulse was obtained, which indicated that joint development of the pixel design and restoration algorithm could compensate for the readout ambiguity and increase the dynamic range.

Insulin reduces the transmission potential of chikungunya virus and activates the toll pathway in Aedes aegypti mosquitoes.

Chikungunya virus (CHIKV) is an alphavirus that has re-emerged globally over the last two decades and has the potential to become endemic in the United States due to the presence of competent mosquito vectors, Aedes aegypti and Aedes albopictus. CHIK disease is characterised by fever, rash, and joint pain, and causes chronic debilitating joint pain and swelling in >50% of infected individuals. Given the disease severity caused by CHIKV and the global presence of vectors to facilitate its spread, strategies to reduce viral transmission are desperately needed; however, the human biological factors driving CHIKV transmission are poorly understood. Towards that end, we have previously shown that mosquitoes fed on alphavirus-infected obese mice have reduced infection and transmission rates compared to those fed on infected lean mice despite similar viremia in lean and obese mice. One of the many host factors that increase in obese hosts is insulin, which was previously shown to impact the infection of mosquitoes by several flaviviruses. However, insulin's impact on alphavirus infection of live mosquitoes is unknown and whether insulin influences mosquito-borne virus transmission has not been tested. To test this, we exposed A. aegypti mosquitoes to bloodmeals with CHIKV in the presence or absence of physiologically relevant levels of insulin and found that insulin significantly lowered both infection and transmission rates. RNA sequencing analysis on mosquito midguts isolated at 1-day-post-infectious-bloodmeal (dpbm) showed enrichment in genes in the Toll immune pathway in the presence of insulin, which was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We then sought to determine if the Toll pathway plays a role in CHIKV infection of Ae. aegypti mosquitoes; therefore, we knocked down Myd88, a critical immune adaptor molecule for the Toll pathway, in live mosquitoes, and found increased CHIKV infection compared to the mock knockdown control group. Overall, these data demonstrate that insulin reduces CHIKV transmission by Ae. aegypti and activates the Toll pathway in mosquitoes, suggesting that conditions resulting in higher serum insulin concentrations may reduce alphavirus transmission. Finally, these studies suggest that strategies to activate insulin or Toll signalling in mosquitoes may be an effective control strategy against medically relevant alphaviruses.

Study on correlations of BDNF, PI3K, AKT and CREB levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia.

BACKGROUND: The pathogenesis of schizophrenia is still unknown. Nearly a half of schizophrenic patients have depressive symptoms and even some impulsive behaviors. The definite diagnosis of schizophrenia is an immense challenge. Molecular biology plays an essential role in the research on the pathogenesis of schizophrenia. OBJECTIVE: This study aims to analyze the correlations of serum protein factor levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia. METHODS: Seventy drug-naïve patients with first-episode schizophrenia and sixty-nine healthy volunteers from the health check center in the same period participated in this study. In both the patient group and control group, brain-derived neurotrophic factor (BDNF), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (AKT), and cAMP-response element binding protein (CREB) levels in the peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). The depressive emotion and impulsive behaviors were evaluated with Chinese versions of the Calgary Depression Scale for Schizophrenia (CDSS) and Short UPPS-P Impulsive Behavior Scale (S-UPPS-P), respectively. RESULTS: The serum levels of BDNF, PI3K, and CREB in the patient group were lower than those in the control group, while AKT level, total CDSS score and total S-UPPS-P score were all higher. In the patient group, total CDSS score, and total S-UPPS-P score were both correlated negatively with BDNF, PI3K, and CREB levels but positively with AKT level, and the lack-of-premeditation (PR) sub-scale score was not significantly correlated with BDNF, PI3K, AKT, and CREB levels. CONCLUSION: Our study results showed that the peripheral blood levels of BDNF, PI3K, AKT, and CREB in drug-naïve patients with first-episode schizophrenia were significantly different from those in the control group. The levels of these serum protein factors are promising biomarkers to predict schizophrenic depression and impulsive behaviors.

Systematic evaluation of membrane-camouflaged nanoparticles in neutralizing Clostridium perfringens ε-toxin.

Clostridium perfringens ε-toxin (ETX) is the main toxin leading to enterotoxemia of sheep and goats and is classified as a potential biological weapon. In addition, no effective treatment drug is currently available in clinical practice for this toxin. We developed membrane-camouflaged nanoparticles (MNPs) with different membrane origins to neutralize ETX and protect the host from fatal ETX intoxication. We evaluated the safety and therapeutic efficacy of these MNPs in vitro and in vivo. Compared with membranes from karyocytes, such as Madin-Darby canine kidney (MDCK) cells and mouse neuroblastoma N2a cells (N2a cells), membrane from erythrocytes, which do not induce any immune response, are superior in safety. The protective ability of MNPs was evaluated by intravenous injection and lung delivery. We demonstrate that nebulized inhalation is as safe as intravenous injection and that both modalities can effectively protect mice against ETX. In particular, pulmonary delivery of nanoparticles more effectively treated the challenge of inhaled toxins than intravenously injected nanoparticles. Moreover, MNPs can alter the biological distribution of ETX among different organs in the body, and ETX was captured, neutralized and slowly delivered to the liver and spleen, where nanoparticles with ETX could be phagocytized and metabolized. This demonstrates how MNPs treat toxin infections in vivo. Finally, we injected the MNPs into mice in advance to find out whether MNPs can provide preventive protection, and the results showed that the long-cycle MNPs could provide at least a 3-day protection in mice. These findings demonstrate that MNPs provide safe and effective protection against ETX intoxication, provide new insights into membrane choices and delivery routes of nanoparticles, and new evidence of the ability of nanoparticles to provide preventive protection against infections.

Probabilistic Energy-to-Amplitude Mapping in a Tapered Superconducting Nanowire Single-Photon Detector.

A spectrum-resolved photon detector is crucial for cutting-edge quantum optics, astronomical observation, and spectroscopic sensing. However, such an ability is rarely obtained because a direct linear conversion from weak single-photon energy to a readable electrical signal above the noise level without causing an avalanche is challenging. Here, we overcame these difficulties by building a probabilistic energy-to-amplitude mapping in a tapered superconducting nanowire single-photon detector and combining a computational reconstruction to obtain equivalent spectral resolving capacity. Distinguished dependence of pulse amplitude distributions on varied input spectra has been observed experimentally. As the energy-to-amplitude mapping is probabilistic, statistical measurements are required. By collecting around a few hundred photons, we have demonstrated wavelength perception over a wide spectral range from 600 to 1700 nm with a resolution of 100 nm. These findings represent a new approach to designing spectrum-sensitive SNSPDs for low-light spectroscopic applications.

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases.

Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin-Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and ß-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases.

Chondrocyte Thrombomodulin Protects against Osteoarthritis.

Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TMLeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1ß (IL-1ß)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TMLeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.