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There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.

Background: Testosterone replacement therapy (TRT) use is increasing in both men and women with demonstrated benefits for muscle strength, sexual function, and well-being. However, previous studies have linked exogenous testosterone to elevated rates of tendon injury in upper and lower extremities. TRT has also been associated with higher rates of surgical repair and markedly elevated reoperation rates. Limited institutional data are available on tendon rupture rates and treatment trends. Purpose: To investigate the association between prescription TRT and tendon rupture risk, with a specific focus on rotator cuff tear (RCT) incidence and repair/revision rates at a single academic institution. Study Design: Cohort study; Level of evidence, 3. Methods: We queried 1 institution's electronic health records using International Classification of Diseases (ICD-10) codes for patients ≥18 years with tendon rupture and prescription TRT use within 90 days of injury between 2015 and 2023. Individuals with risk factors predisposing them to tendon injury were excluded. A subanalysis of RCT was performed using a chart review of a subgroup of TRT patients and propensity-matched controls. Outcomes of interest included rupture location and rate, and, for the RCT, tear severity and rates of surgical repair/revision. Outcomes were compared between TRT users and nonusers. Results: We identified 410 TRT users and 14,474 nonusers with tendon rupture. Men on TRT had significantly higher rupture rates (3.6% vs 1.3%; odds ratio [OR], 2.88 [95% CI, 2.59-3.20]) across all ages and races. No significant increase in tendon rupture rate was observed in women on TRT. RCTs were the most common injury (77%). In the RCT subanalysis (78 TRT users, 355 matched controls), TRT users underwent nonoperative intervention more frequently than nonusers (74.4% vs 46.7%; OR, 3.3 [95% CI, 1.91-5.72]). Tear severity and revision rates did not differ significantly between groups. Conclusion: TRT is associated with increased tendon rupture risk in men but not women, potentially due to sex-specific differences in dosing. TRT users with RCT were less likely to undergo arthroscopic repair compared with matched controls, despite similar distributions of tear severity.

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.

We report a robust, versatile approach called CRISPR live-cell fluorescent in situ hybridization (LiveFISH) using fluorescent oligonucleotides for genome tracking in a broad range of cell types, including primary cells. An intrinsic stability switch of CRISPR guide RNAs enables LiveFISH to accurately detect chromosomal disorders such as Patau syndrome in prenatal amniotic fluid cells and track multiple loci in human T lymphocytes. In addition, LiveFISH tracks the real-time movement of DNA double-strand breaks induced by CRISPR-Cas9–mediated editing and consequent chromosome translocations. Finally, by combining Cas9 and Cas13 systems, LiveFISH allows for simultaneous visualization of genomic DNA and RNA transcripts in living cells.The LiveFISH approach enables real-time live imaging of DNA and RNA during genome editing, transcription, and rearrangements in single cells.

Trials of endovascular therapy for basilar artery occlusion, including vertebral occlusion extending into the basilar artery, have shown inconsistent results. We aimed to pool data to estimate safety and efficacy and to explore the benefit across pre-specified subgroups through individual patient data meta-analysis. VERITAS was a systematic review and meta-analysis that pooled patient-level data from trials that recruited patients with vertebrobasilar ischaemic stroke who were randomly assigned to treatment with either endovascular therapy or standard medical treatment alone. We included studies done between Jan 1, 2010, and Sept 1, 2023. The primary outcome was 90-day favourable functional status (modified Rankin Scale [mRS] score 0–3, with a score of 3 indicating moderate disability). Safety outcomes were symptomatic intracranial haemorrhage and 90-day mortality. We screened 934 titles and abstracts. Of these, seven (<1%) full texts were screened. We included four trials (ATTENTION, BAOCHE, BASICS, and BEST). The pooled data included 988 patients (556 [56%] in the intervention groups and 432 [44%] in the control groups; median age 67 years [IQR 58–74]; 686 (69%) were male and 302 (31%) were female). 904 (91%) patients were randomly assigned within 12 h of estimated stroke onset. Three RCTs were done in a Chinese population and one included European and Brazilian patients. The proportion of patients achieving favourable functional status was higher in the endovascular therapy than control group (90-day mRS score 0–3 in 251 [45%] participants vs 128 [30%]; adjusted common odds ratio 2·41 [95% CI 1·78–3·26]; p<0·0001). Endovascular therapy led to an increase in functional independence (mRS score 0–2 in 194 [35%] participants vs 89 [21%]; 2·52 [1·82–3·48]; p<0·0001) as well as a reduction in both the degree of overall disability (2·09 [1·61–2·71]; p<0·0001) and mortality (198 [36%] of 556 patients vs 196 [45%] of 432; 0·60 [0·45–0·80]; p<0·0001) at 90 days, despite higher rates of symptomatic intracranial haemorrhage (30 [5%] of 548 vs two [<1%] of 413; 11·98 [2·82–50·81]; p<0·0001). Heterogeneity of treatment effect was noted for baseline stroke severity (uncertain effect in baseline National Institutes of Health Stroke Scale <10) and occlusion site (greater benefit with more proximal occlusions) but not across subgroups defined by age, sex, baseline posterior circulation Alberta Stroke Program Early CT Score, presence of atrial fibrillation or intracranial atherosclerotic disease, and time from onset to imaging. VERITAS supports the robust benefit of endovascular therapy in patients with vertebrobasilar artery occlusion with moderate to severe symptoms, with approximately 2·5-times increased likelihood of achieving a favourable functional outcome. Despite a significant increase in symptomatic intracranial haemorrhage risk, endovascular therapy for vertebrobasilar artery occlusion was associated with a significant reduction in both overall disability and mortality. Although the benefit of endovascular therapy remains uncertain for patients vertebrobasilar artery occlusion presenting with mild stroke severity and extensive infarcts on neuroimaging, we found a significant clinical benefit across a range of patients with vertebrobasilar artery occlusion. None.

Structural variants are an underexplored source of genetic diversity. As part of the FarmGTEx Project, here we report a Holstein breed-specific pangenome graph (H20D) using Minigraph-Cactus and 40 phased haploid assemblies from 20 cows. H20D outperforms both assembly- and read-based long-read callers, and far exceeds short-read approaches, identifying over 10,000 additional structural variants per sample. It also significantly improves structural variant detection and genotyping relative to graphs built across breeds or from fewer/unphased assemblies, with particular advantages in complex regions. Using H20D, we genotype variants in 173 cattle and performed a GWAS, where a larger fraction of structural variants than SNPs reach genome-wide significance, implicating them as potential causal variants. Together, these results demonstrate the power of phased, within-breed pangenome graphs for accurate SV genotyping and trait mapping in dairy cattle. Structural variants are an underexplored source of genetic diversity. Here, the authors use phased pangenome graphs to improve detection of these variants in dairy cattle and link these variants to traits of economic importance.

Previous studies have observed evoked response latency as well as gamma band superior temporal gyrus (STG) auditory abnormalities in individuals with autism spectrum disorders (ASD). A limitation of these studies is that associations between these two abnormalities, as well as the full extent of oscillatory phenomena in ASD in terms of frequency and time, have not been examined. Subjects were presented pure tones at 200, 300, 500, and 1,000 Hz while magnetoencephalography assessed activity in STG auditory areas in a sample of 105 children with ASD and 36 typically developing controls (TD). Findings revealed a profile such that auditory STG processes in ASD were characterized by pre-stimulus abnormalities across multiple frequencies, then early high-frequency abnormalities followed by low-frequency abnormalities. Increased pre-stimulus activity was a ‘core’ abnormality, with pre-stimulus activity predicting post-stimulus neural abnormalities, group membership, and clinical symptoms (CELF-4 Core Language Index). Deficits in synaptic integration in the auditory cortex are associated with oscillatory abnormalities in ASD as well as patient symptoms. Increased pre-stimulus activity in ASD likely demonstrates a fundamental signal-to-noise deficit in individuals with ASD, with elevations in oscillatory activity suggesting an inability to maintain an appropriate ‘neural tone’ and an inability to rapidly return to a resting state prior to the next stimulus.

A core question in evolutionary biology is whether convergent phenotypic evolution is driven by convergent molecular changes in proteins or regulatory regions.We combined phylogenomic, developmental, and epigenomic analysis of 11 new genomes of paleognathous birds, including an extinct moa, to show that convergent evolution of regulatory regions, more so than protein-coding genes, is prevalent among developmental pathways associated with independent losses of flight. A Bayesian analysis of 284,001 conserved noncoding elements, 60,665 of which are corroborated as enhancers by open chromatin states during development, identified 2355 independent accelerations along lineages of flightless paleognaths, with functional consequences for driving gene expression in the developing forelimb. Our results suggest that the genomic landscape associated with morphological convergence in ratites has a substantial shared regulatory component.

Wildfires emit large amounts of black carbon and light-absorbing organic carbon, known as brown carbon, into the atmosphere. These particles perturb Earth’s radiation budget through absorption of incoming shortwave radiation. It is generally thought that brown carbon loses its absorptivity after emission in the atmosphere due to sunlight-driven photochemical bleaching. Consequently, the atmospheric warming effect exerted by brown carbon remains highly variable and poorly represented in climate models compared with that of the relatively nonreactive black carbon. Given that wildfires are predicted to increase globally in the coming decades, it is increasingly important to quantify these radiative impacts. Here we present measurements of ensemble-scale and particle-scale shortwave absorption in smoke plumes from wildfires in the western United States. We find that a type of dark brown carbon contributes three-quarters of the short visible light absorption and half of the long visible light absorption. This strongly absorbing organic aerosol species is water insoluble, resists daytime photobleaching and increases in absorptivity with night-time atmospheric processing. Our findings suggest that parameterizations of brown carbon in climate models need to be revised to improve the estimation of smoke aerosol radiative forcing and associated warming.Atmospheric short-wave absorption due to wildfire smoke is caused predominantly by dark brown carbon particles, according to observations from smoke plumes in the United States.

Inbred animals were historically chosen for genome analysis to circumvent assembly issues caused by haplotype variation but this resulted in a composite of the two genomes. Here we report a haplotype-aware scaffolding and polishing pipeline which was used to create haplotype-resolved, chromosome-level genome assemblies of Angus (taurine) and Brahman (indicine) cattle subspecies from contigs generated by the trio binning method. These assemblies reveal structural and copy number variants that differentiate the subspecies and that variant detection is sensitive to the specific reference genome chosen. Six genes with immune related functions have additional copies in the indicine compared with taurine lineage and an indicus-specific extra copy of fatty acid desaturase is under positive selection. The haplotyped genomes also enable transcripts to be phased to detect allele-specific expression. This work exemplifies the value of haplotype-resolved genomes to better explore evolutionary and functional variations. Taurine and indicine cattle have different desirable traits making them better adapted to different climates across the world. Here, Low et al. describe a pipeline to produce haplotype-resolved, chromosome-level genomes of Angus and Brahman cattle breeds from a crossbred individual and report on comparisons of the two genomes.