COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure1-4, but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63+ intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.

Controlling free electrons with optical whispering-gallery modes.

Free-electron beams are versatile probes of microscopic structure and composition1,2, and have revolutionized atomic-scale imaging in several fields, from solid-state physics to structural biology3. Over the past decade, the manipulation and interaction of electrons with optical fields have enabled considerable progress in imaging methods4, near-field electron acceleration5,6, and four-dimensional microscopy techniques with high temporal and spatial resolution7. However, electron beams typically couple only weakly to optical excitations, and emerging applications in electron control and sensing8-11 require large enhancements using tailored fields and interactions. Here we couple a free-electron beam to a travelling-wave resonant cavity mode. The enhanced interaction with the optical whispering-gallery modes of dielectric microresonators induces a strong phase modulation on co-propagating electrons, which leads to a spectral broadening of 700 electronvolts, corresponding to the absorption and emission of hundreds of photons. By mapping the near-field interaction with ultrashort electron pulses in space and time, we trace the lifetime of the the microresonator following a femtosecond excitation and observe the spectral response of the cavity. The natural matching of free electrons to these quintessential optical modes could enable the application of integrated photonics technology in electron microscopy, with broad implications for attosecond structuring, probing quantum emitters and possible electron-light entanglement.

Observation of fluctuation-mediated picosecond nucleation of a topological phase.

Topological states of matter exhibit fascinating physics combined with an intrinsic stability. A key challenge is the fast creation of topological phases, which requires massive reorientation of charge or spin degrees of freedom. Here we report the picosecond emergence of an extended topological phase that comprises many magnetic skyrmions. The nucleation of this phase, followed in real time via single-shot soft X-ray scattering after infrared laser excitation, is mediated by a transient topological fluctuation state. This state is enabled by the presence of a time-reversal symmetry-breaking perpendicular magnetic field and exists for less than 300 ps. Atomistic simulations indicate that the fluctuation state largely reduces the topological energy barrier and thereby enables the observed rapid and homogeneous nucleation of the skyrmion phase. These observations provide fundamental insights into the nature of topological phase transitions, and suggest a path towards ultrafast topological switching in a wide variety of materials through intermediate fluctuating states.

Cost savings of a primary care program for individuals recently released from prison: a propensity-matched study.

BACKGROUND: Criminal justice system costs in the United States have exponentially increased over the last decades, and providing health care to individuals released from incarceration is costly. To better understand how to manage costs to state budgets for those who have been incarcerated, we aimed to assess state-level costs of an enhanced primary care program, Transitions Clinic Network (TCN), for chronically-ill and older individuals recently released from prison. METHODS: We linked administrative data from Connecticut Department of Correction, Medicaid, and Department of Mental Health and Addiction Services to identify a propensity matched comparison group and estimate costs of a primary care program serving chronically-ill and older individuals released from incarceration between 2013 and 2016. We matched 94 people released from incarceration who received care at a TCN program to 94 people released from incarceration who did not receive care at TCN program on numerous characteristics. People eligible for TCN program participation were released from incarceration within the prior 6 months and had a chronic health condition or were over the age of 50. We estimated 1) costs associated with the TCN program and 2) costs accrued by Medicaid and the criminal justice system. We evaluated associations between program participation and Medicaid and criminal justice system costs over a 12-month period using bivariate analyses with nonparametric bootstrapping method. RESULTS: The 12-month TCN program operating cost was estimated at $54,394 ($146 per participant per month). Average monthly Medicaid costs per participant were not statistically different between the TCN ($1737 ± $3449) and comparison ($1356 ± $2530) groups. Average monthly criminal justice system costs per participant were significantly lower among TCN group ($733 ± $1130) compared with the matched group ($1276 ± $1738, p < 0.05). We estimate every dollar invested in the TCN program yielded a 12-month return of $2.55 to the state. CONCLUSIONS: Medicaid investments in an enhanced primary care program for individuals returning from incarceration are cost neutral and positively impact state budgets by reducing criminal justice system costs.

Probing Chirality with Inelastic Electron-Light Scattering.

Circular dichroism spectroscopy is an essential technique for understanding molecular structure and magnetic materials; however, spatial resolution is limited by the wavelength of light, and sensitivity sufficient for single-molecule spectroscopy is challenging. We demonstrate that electrons can efficiently measure the interaction between circularly polarized light and chiral materials with deeply subwavelength resolution. By scanning a nanometer-sized focused electron beam across an optically excited chiral nanostructure and measuring the electron energy spectrum at each probe position, we produce a high-spatial-resolution map of near-field dichroism. This technique offers a nanoscale view of a fundamental symmetry and could be employed as "photon staining" to increase biomolecular material contrast in electron microscopy.

Probing Light Atoms at Subnanometer Resolution: Realization of Scanning Transmission Electron Microscope Holography.

Atomic resolution imaging of light elements in electron-transparent materials has long been a challenge. Biomolecular materials, for example, are rapidly altered by incident electrons. We demonstrate a scanning transmission electron microscopy (STEM) technique, called STEM holography, capable of efficient structural analysis of beam-sensitive nanomaterials. STEM holography measures the absolute phase and amplitude of electrons passed through a specimen via interference with a vacuum reference wave. We use an amplitude-dividing nanofabricated grating to prepare multiple beams focused at the sample. We configure the postspecimen microscope imaging system to overlap the beams, forming an interference pattern. We record and analyze the pattern at each 2D-raster-scan-position, reconstructing the complex object wave. As a demonstration, we image gold nanoparticles on an amorphous carbon substrate at 2.4 Å resolution. STEM holography offers higher contrast of the carbon while maintaining gold atomic lattice resolution compared to high angle annular dark field STEM.

A series of Cre-ER(T2) drivers for manipulation of the skeletal muscle lineage.

We report the generation of five mouse strains with the tamoxifen-inducible Cre (Cre-ER(T) (2) ; CE) gene cassette knocked into the endogenous loci of Pax3, Myod1, Myog, Myf6, and Myl1, collectively as a resource for the skeletal muscle research community. We characterized these CE strains using the Cre reporter mice, R26R(L) (acZ) , during embryogenesis and show that they direct tightly controlled tamoxifen-inducible reporter expression within the expected cell lineage determined by each myogenic gene. We also examined a few selected adult skeletal muscle groups for tamoxifen-inducible reporter expression. None of these new CE alleles direct reporter expression in the cardiac muscle. All these alleles follow the same knock-in strategy by replacing the first exon of each gene with the CE cassette, rendering them null alleles of the endogenous gene. Advantages and disadvantages of this design are discussed. Although we describe potential immediate use of these strains, their utility likely extends beyond foreseeable questions in skeletal muscle biology.

Arrest History and Health Among U.S. Sexual and Gender Minority Youth, 2022.

INTRODUCTION: Sexual and gender minority youth, who experience high mental and behavioral health needs, are overrepresented in the criminal legal system, which may exacerbate these needs. This study examined the associations between arrest history and mental and behavioral health among sexual and gender minority youth. METHODS: Using cross-sectional survey data from the 2022 LGBTQ+ National Teen Survey, this study created a case-control sample of 287 sexual and gender minority youth with an arrest history and 1,148 propensity-matched sexual and gender minority youth without an arrest history. Associations between arrest history and sexual and gender minority developmental milestones, minority stressors, and mental and behavioral health outcomes were examined. Statistical analyses were conducted between 2022 and 2024. RESULTS: Arrest history was significantly associated with several sexual and gender minority developmental milestones (e.g., earlier age of identity realization and disclosure) and minority stressors (e.g., greater bullying and parental rejection). Sexual and gender minority youth with an arrest history had poorer mental and behavioral health, including greater sleep disturbance (AOR=1.46; 95% CI=1.08, 2.00) and positive screenings for depression (AOR=1.60; 95% CI=1.20, 2.14), anxiety (AOR=1.35; 95% CI=1.01, 1.82), and risk for substance use disorder development (AOR=5.81; 95% CI=4.26, 7.94). CONCLUSIONS: Arrest history is associated with the mental and behavioral health of sexual and gender minority youth, highlighting systemic inequities. Tailored public health interventions are needed to reduce criminal-legal contact in this population.

Predicting COVID-19 Outbreaks in Correctional Facilities Using Machine Learning.

Introduction. The risk of infectious disease transmission, including COVID-19, is disproportionately high in correctional facilities due to close living conditions, relatively low levels of vaccination, and reduced access to testing and treatment. While much progress has been made on describing and mitigating COVID-19 and other infectious disease risk in jails and prisons, there are open questions about which data can best predict future outbreaks. Methods. We used facility data and demographic and health data collected from 24 prison facilities in the Pennsylvania Department of Corrections from March 2020 to May 2021 to determine which sources of data best predict a coming COVID-19 outbreak in a prison facility. We used machine learning methods to cluster the prisons into groups based on similar facility-level characteristics, including size, rurality, and demographics of incarcerated people. We developed logistic regression classification models to predict for each cluster, before and after vaccine availability, whether there would be no cases, an outbreak defined as 2 or more cases, or a large outbreak, defined as 10 or more cases in the next 1, 2, and 3 d. We compared these predictions to data on outbreaks that occurred. Results. Facilities were divided into 8 clusters of sizes varying from 1 to 7 facilities per cluster. We trained 60 logistic regressions; 20 had test sets with between 35% and 65% of days with outbreaks detected. Of these, 8 logistic regressions correctly predicted the occurrence of an outbreak more than 55% of the time. The most common predictive feature was incident cases among the incarcerated population from 2 to 32 d prior. Other predictive features included the number of tests administered from 1 to 33 d prior, total population, test positivity rate, and county deaths, hospitalizations, and incident cases. Cumulative cases, vaccination rates, and race, ethnicity, or age statistics for incarcerated populations were generally not predictive. Conclusions. County-level measures of COVID-19, facility population, and test positivity rate appear as potential promising predictors of COVID-19 outbreaks in correctional facilities, suggesting that correctional facilities should monitor community transmission in addition to facility transmission to inform future outbreak response decisions. These efforts should not be limited to COVID-19 but should include any large-scale infectious disease outbreak that may involve institution-community transmission. Highlights: The risk of infectious disease transmission, including COVID-19, is disproportionately high in correctional facilities.We used machine learning methods with data collected from 24 prison facilities in the Pennsylvania Department of Corrections to determine which sources of data best predict a coming COVID-19 outbreak in a prison facility.Key predictors included county-level measures of COVID-19, facility population, and the test positivity rate in a facility.Fortifying correctional facilities with the ability to monitor local community rates of infection (e.g., though improved interagency collaboration and data sharing) along with continued testing of incarcerated people and staff can help correctional facilities better predict-and respond to-future infectious disease outbreaks.

The Mohawk homeobox gene represents a marker and osteo-inhibitory factor in calvarial suture osteoprogenitor cells.

The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (MkxCG; R26RtdT) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx+ suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx+ cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.

Skeletal Muscle Satellite Cells Co-Opt the Tenogenic Gene Scleraxis to Instruct Regeneration.

Skeletal muscles connect bones and tendons for locomotion and posture. Understanding the regenerative processes of muscle, bone and tendon is of importance to basic research and clinical applications. Despite their interconnections, distinct transcription factors have been reported to orchestrate each tissue's developmental and regenerative processes. Here we show that Scx expression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence. Scx expression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specific Scx gene inactivation (ScxcKO), we show that Scx function is required for SC expansion/renewal and robust new myofiber formation after injury. We combined single-cell RNA-sequencing and CUT&RUN to identify direct Scx target genes during muscle regeneration. These target genes help explain the muscle regeneration defects of ScxcKO, and are not overlapping with Scx -target genes identified in tendon development. Together with a recent finding of a subpopulation of Scx -expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt the Scx gene via different mechanisms.

Multilevel stigma and depression among a national sample of Black and Latinx LGBTQ+ adolescents in the United States.

Limited research has examined how multiple forms of oppression (e.g., racism, heterosexism, transphobia)-manifesting across multiple levels (e.g., interpersonal, structural)-can place Black and Latinx lesbian, gay, bisexual, transgender, queer, and other sexual/gender minority (LGBTQ+) adolescents at increased risk for internalizing psychopathology, including depression. Utilizing a national sample of 2,561 Black and Latinx LGBTQ+ adolescents (aged 13-17), we examined associations among depressive symptoms and several adolescent-focused manifestations of stigma, including: (a) interpersonal racial/ethnic bullying, (b) interpersonal sexual orientation bullying, (c) nine state-level forms of structural stigma or protection for LGBTQ+ adolescents, and (d) a new adolescent-focused composite index of state-level anti-LGBTQ+ structural stigma. Racial/ethnic bullying and sexual orientation bullying were found to be prevalent among the sample and were associated-both independently and jointly-with increased depressive symptoms. One harmful state-level anti-LGBTQ+ structural stigma indicator (i.e., anti-LGBTQ+ community attitudes) and seven protective state-level anti-LGBTQ+ structural stigma indicators (e.g., conversion therapy bans) were associated with odds of depressive symptoms, in the expected directions. Black and Latinx LGBTQ+ adolescents residing in states with greater overall anti-LGBTQ+ structural stigma reported increased depressive symptoms, even when adjusting for racial/ethnic and sexual orientation bullying. Additionally, Black and Latinx LGBTQ+ adolescents living in the most stigmatizing states demonstrated 32% increased odds of depressive symptoms, as compared to those living in the most LGBTQ+ affirming states. Multilevel, intersectional interventions could have optimal effects on the mental health and resilience of Black and Latinx LGBTQ+ adolescents. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Efficacy and selectivity of tumor-treating field therapy for triple-negative breast cancer cells via in-house delivery device.

PURPOSE: Triple-negative breast cancer continues to be one of the leading causes of death in women, making up 7% of all cancer deaths. Tumor-treating electric fields are low-energy, low-frequency oscillating electric fields that induce an anti-proliferative effect on mitotic cells in glioblastoma multiforme, non-small cell lung cancer, and ovarian cancer. Little is known about effects of tumor-treating fields on triple-negative breast cancer and known research for tumor-treating fields only utilizes low (< 3 V/cm) electric field intensities. METHODS: We have developed an in-house field delivery device capable of high levels of customization to explore a much wider variety of electric field and treatment parameters. Furthermore, we investigated the selectivity of tumor-treating field treatment between triple-negative breast cancer and human breast epithelial cells. RESULTS: Tumor-treating fields show greatest efficacy against triple-negative breast cancer cell lines between 1 and 3 V/cm electric field intensities while having little effect on epithelial cells. CONCLUSION: These results provide a clear therapeutic window for tumor-treating field delivery to triple-negative breast cancer.

"We know what's going on in our community": A qualitative analysis identifying community assets that deter gun violence.

Communities of color are disproportionately impacted by gun violence. Unlocking potential community-led solutions could be the key to quelling the gun violence epidemic and its impact on these communities. In this qualitative study, we explored community perspectives on local assets that may prevent and mitigate gun violence. We conducted semi-structured, in-depth interviews (n = 45) among individuals not directly involved in gun violence (i.e., shooting victim or perpetrator) despite having a high probability of being involved in gun violence in New Haven, CT. Participants were asked to describe social structures that may deter local gun violence. Here, we report emergent themes to preventing gun violence across multiple levels, including role models (interpersonal), social cohesion and home ownership (neighborhood), and community-based organizations (organizational). Our findings suggest that investments in stable housing, efforts to build social cohesion, access to community-based mental health services, and youth activities are needed to curb the drivers of community gun violence.

Role of the Intersections of Gender, Race and Sexual Orientation in the Association between Substance Use Behaviors and Sexually Transmitted Infections in a National Sample of Adults with Recent Criminal Legal Involvement.

Limited research has focused on how substance use and sexual risk behaviors differ among individuals impacted by the criminal legal system based on social identities. Using the National Survey on Drug Use and Health, we estimated relative risk for reporting a sexually transmitted infection (STI) among intersectional social groups with criminal legal involvement using a modified Poisson regression. We then utilized multivariate logistic regression and marginal effects to measure associations between substance use behaviors and STIs and to estimate whether these varied among the intersectional social groups with elevated STI rates. Three groups had elevated risk of reporting an STI compared to white, heterosexual men: white, heterosexual women (1.53, 95% CI: 1.05-2.20); Black, heterosexual women (2.03, 95% CI: 1.18-3.49); and white, gay or bisexual men (5.65, 95% CI: 2.61-12.20). Considering the intersections of gender, race, and sexual orientation, elevated risks for STIs among white and Black heterosexual women were mitigated after adjusting for substance use alongside other confounders. Only those who identified as white, gay or bisexual, and male had increased STI risk after controlling for substance use. Interventions targeting Black and white heterosexual women's sexual health following incarceration should focus on substance use and interventions targeting white, gay or bisexual men should focus on healthy sexual behaviors, HIV/STI screening, and care continuum efforts.

Availability of Accessible Representative Health Data to Examine Sexual and Gender Minority Disparities in Incarceration and Its Health Implications in the United States, 2010-2020.

Purpose: To facilitate identification of the impact of incarceration on the health of sexual and gender minority (SGM) populations, we sought to identify publicly accessible, representative health datasets that assessed SGM status and incarceration history from 2010 to 2020 and to examine SGM disparities in lifetime incarceration experiences. Methods: Datasets were identified and analyzed through a multistep process: (1) content search of 76 health datasets; (2) consultation with 14 subject matter experts; (3) a systematic review; and (4) a data analysis stage. Utilizing the identified health datasets, we produced representative estimates of sexual minority (SM) incarceration disparities. Results: Five publicly accessible databases were identified that assessed SM status and incarceration history; none assessed gender minority status and incarceration history. Across datasets, the weighted prevalence of lifetime incarceration among SM populations was substantially higher (range = 17.5%-26.3%) than among non-SM populations (range = 4.6%-21.2%). Conclusion: Few publicly accessible, representative health datasets collect standardized information regarding SM status and incarceration history, and none assess diverse gender identities and incarceration history. These data suggest that a disproportionate proportion of SM individuals may experience incarceration compared with non-SM individuals. Research assessing the health effects of incarceration on SGM populations remains limited; publicly accessible, representative health data are needed to address this gap.

A pilot test of a treatment to address intersectional stigma, mental health, and HIV risk among gay and bisexual men of color.

We tested the feasibility and acceptability of a group therapy treatment that addresses the intersecting stigma-related stressors theorized to drive elevated mental health risk, sexual health risk, and their co-occurrence among Black and Latino gay, bisexual, and other men who have sex with men (GBM). First, we modified an existing 10-week, one-on-one, cognitive-behavioral treatment addressing co-occurring health risks among GBM to develop a group-based, intersectionally informed treatment for GBM of color. Then, an open pilot was conducted (n = 21, across two cohorts) with young Black and Latino GBM. An evaluation of feasibility metrics (e.g., eligibility-enrollment ratio, session attendance, rate of retention) supported overall treatment feasibility. Qualitative data suggest high acceptability of the treatment length, format, and content-and revealed a powerful theme: The treatment and group composition led participants to feel less alone as GBM of color. To further evaluate acceptability, baseline and 3-month posttreatment assessments and exit interviews were used to examine the treatment's impact on stigma coping, mental health, and sexual health. Expected changes were found for: (a) stigma coping, as demonstrated by decreases in perceived sexual minority stress, racial minority stress, and intersectional stress; (b) mental health, including depression, anxiety, stress, and suicidality, but not alcohol use; and (c) sexual health, including condom use efficacy, sexual compulsivity, and preexposure prophylaxis uptake; with partial support for decreased in human immunodeficiency virus; HIV-transmission risk acts. This study lays the groundwork for a group treatment to address intersectional stigma, mental health, and HIV risk among young Black and Latino GBM in the U.S. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mental Health Among Sexual and Gender Minority Youth Incarcerated in Juvenile Corrections.

OBJECTIVES: This study examined differences by sexual and gender minority (SGM) and incarceration statuses in mental health indicators among youth. METHODS: Population-based, cross-sectional data are from the 2019 Minnesota Student Survey (N = 72 324) and includes public school students (Mage = 15.49) and youth incarcerated in juvenile correctional facilities (Mage = 15.48). We categorized youth into 4 groups: (1) non-SGM youth in public schools, (2) non-SGM youth in correctional facilities, (3) SGM youth in public schools, and (4) SGM youth in correctional facilities. Multivariable regression models assessed associations among SGM and incarceration statuses and mental health indicators after controlling for sociodemographic characteristics and exposure to adverse childhood experiences. RESULTS: More youth in juvenile correctional facilities identified as SGM (28.8%) compared with youth in public schools (20.4%, P = .002). SGM youth in correctional facilities reported a higher prevalence of suicidal ideation (42.2%), suicide attempt (37.5%), and self-harm (57.8%) compared with all other groups. Depressive symptom severity was similarly elevated among SGM youth in correctional facilities and SGM youth in public schools. SGM youth in correctional facilities, compared with non-SGM youth in public schools, demonstrated elevated odds of suicide ideation (adjusted odds ratio [aOR] = 2.2, 95% confidence interval [95% CI] = 1.3-3.9), suicide attempt (aOR = 6.3, 95% CI = 3.6-10.9), and self-harm (aOR = 3.6, 95% CI = 2.1-6.3). CONCLUSIONS: Incarcerated SGM youth disproportionately experience negative mental health indicators. Findings suggest that tailored, intersectional, and responsive mental health interventions are needed to support incarcerated SGM youth.

Coordinate roles for collagen VI and biglycan in regulating tendon collagen fibril structure and function.

Tendon is a vital musculoskeletal tissue that is prone to degeneration. Proper tendon maintenance requires complex interactions between extracellular matrix components that remain poorly understood. Collagen VI and biglycan are two matrix molecules that localize pericellularly within tendon and are critical regulators of tissue properties. While evidence suggests that collagen VI and biglycan interact within the tendon matrix, the relationship between the two molecules and its impact on tendon function remains unknown. We sought to elucidate potential coordinate roles of collagen VI and biglycan within tendon by defining tendon properties in knockout models of collagen VI, biglycan, or both molecules. We first demonstrated co-expression and co-localization of collagen VI and biglycan within the healing tendon, providing further evidence of cooperation between the two molecules during nascent tendon matrix formation. Deficiency in collagen VI and/or biglycan led to significant reductions in collagen fibril size and tendon mechanical properties. However, collagen VI-null tendons displayed larger reductions in fibril size and mechanics than seen in biglycan-null tendons. Interestingly, knockout of both molecules resulted in similar properties to collagen VI knockout alone. These results indicate distinct and non-additive roles for collagen VI and biglycan within tendon. This work provides better understanding of regulatory interactions between two critical tendon matrix molecules.