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Rapid disassembly and Piwi-independent reassembly of Drosophila piRNA cluster heterochromatin following acute heat shock
Full text linkEnvironmental stress activates transposons and is proposed to generate genetic diversity that facilitates adaptive evolution. piRNAs guide germline transposon silencing, but the impact of stress on the piRNA pathway is not well understood. In Drosophila, the Rhino-Deadlock-Cuff complex (RDC) drives transcription of clusters composed of nested transposon fragments, generating precursors that are processed into mature piRNAs in the cytoplasm. We show that acute heat shock triggers rapid, reversable loss of RDC localization and cluster transcript expression with coordinate changes in the cytoplasmic processing machinery. Maternal piRNAs bound to Piwi are proposed to guide Rhino localization to clusters during early embryogenesis. However, RDC re-localization after heat shock is accelerated in piwi mutants and delayed in thoc7 mutants, which disrupt piRNA precursor binding to THO complex, and we show that maternally deposited piRNAs are dispensable for RDC localization to the major 42AB cluster. Cluster specification is reconsidered in light of these findings.1 year2026/12/1
Employment Outcomes among People with Disabilities: Macro-Level Determinants
Full text linkA systematic scoping review of research published between 2000 and 2020 on employment of people with disabilities, that was funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), was conducted by CeKTER researchers. All papers comparing people with disabilities to those without were excluded from the systematic scoping review. Among over 100 publications reviewed there was a wide and very disparate array of findings with numerous variables used and varying research questions. This result belies summative findings. There are numerous ways of organizing the disparate findings. This brief is part of a series of findings from CeKTER’s systematic scoping review. In this brief we report on findings about a range of macro-level determinants impacting the employment of people with disabilities, including community-related and system-level determinants. Please note that all comparisons are always about corresponding peers with disabilities.The contents of this product were funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), Grant #90DPEM0004. NIDILRR is a Center within the Administration for Community Living (ACL). ACL is an agency in the Department of Health and Human Services (HHS). The contents of this product do not necessarily represent the policy of NIDILRR, ACL, or HHS and you should not assume endorsement by the Federal Government.No embarg
SUMMIT MAX: A randomized trial of the super large bore HiPoint Reperfusion System versus Vecta System for aspiration thrombectomy
Full text linkRapid and complete recanalization is a primary goal in the endovascular treatment of large vessel occlusion stroke. The effectiveness and safety of super large bore aspiration catheters (.088" inner diameter) for the treatment of large vessel occlusion stroke have not been demonstrated in a randomized trial. SUMMIT MAX was a prospective, randomized, controlled, open label clinical trial of patients with ICA and MCA M1 occlusions, comparing the super large bore HiPoint Reperfusion system (Route 92 Medical) to the Vecta Aspiration system (Stryker Neurovascular) (NCT05018650). We hypothesized that the effectiveness and safety of the HiPoint reperfusion system was non-inferior (12.5% non-inferiority margin) to the Vecta Aspiration system. The primary effectiveness endpoint was successful reperfusion, defined as mTICI ≥ 2b as adjudicated by an independent core lab, using only the assigned study device, with any use of a non-study device prior to or following use of study device defined as failure. The primary safety endpoint was symptomatic intracranial hemorrhage (sICH) within 24h (-8/+24) post-procedure. There were 250 patients enrolled of whom 166 met criteria for the modified intent-to-treat population: 89 in HiPoint and 77 in Vecta. The median age was 69; 54.2% were female. Successful reperfusion with any adjunctive therapy counted as a failure was 77.5% (69/89) in the HiPoint group versus 50.6% (39/77) in the Vecta group (p<0.0001 for non-inferiority). SICH within 24h (-8/+24h) post procedure was similar between groups (3.6% vs. 2.7%, respectively). At 90 days, good clinical outcome (mRS<2) was achieved in 50.6% in the HiPoint group and 53.3% in the Vecta group (absolute difference -2.8%, 95% CI -18.2%, 12.7%, p=0.75). In this randomized trial of patients with anterior large vessel occlusion, the super large bore HiPoint system was non-inferior to the Vecta system in achieving successful reperfusion, with a similar safety profile. This study supports the super large bore HiPoint system for mechanical thrombectomy. NCT05018650.No embarg
Meniscal degeneration among knees without radiographic osteoarthritis correlates with changes in disease activity and subsequent cumulative damage: Data from the Osteoarthritis Initiative
Full text linkObjective: To explore the relationship between meniscal degeneration (intrameniscal signal alteration without a tear) and future osteoarthritis pathology measured by composite scores based on magnetic resonance imaging (MRI): disease activity (bone marrow lesion and effusion-synovitis volumes) and cumulative damage (articular cartilage damage).
Design: This analysis involved 225 participants from the Osteoarthritis Initiative with intact menisci (defined as normal or meniscal degeneration without tear) on MRI and no radiographic knee osteoarthritis at baseline. We used longitudinal MRIs from an existing study to calculate disease activity and cumulative damage. We used robust regression models to assess the association between baseline meniscal degeneration (exposure) and disease activity or cumulative damage at baseline and four annual follow-up visits (outcomes), adjusting for gender, race, age, static alignment, and body mass index.
Results: Our sample included 110 participants with normal menisci (77% Female, 55 [SD 7] average years of age) and 115 with meniscal degeneration (60% Female, 61 [SD 9] average years of age). Knees with meniscal degeneration were more likely to have, on average, 0.21 greater disease activity at 12 months than knees with normal menisci (parameter estimate=0.21, 95% CI=0.09, 0.33); this association persisted over time. In contrast, the association between meniscal degeneration and cumulative damage only became statistically significant at the 48-month visit (parameter estimate=0.74, 95% CI=0.18, 1.31).
Conclusions: Meniscal degeneration related to worsening disease activity earlier than articular cartilage damage among knees without radiographic osteoarthritis. Meniscal degeneration and disease activity are promising biomarkers for early detection, monitoring osteoarthritis, and informing potential early intervention strategies.No embarg
miR-124 acts During Drosophila Development to Determine the Phase of Adult Circadian Behavior
No full textThe circadian clock enables organisms to optimize their metabolism, physiology, and behavior with the time-of-day. However, circadian rhythms benefit organisms only if they are properly synchronized with the day/night cycle; circadian misalignment can have detrimental effects on animals' wellbeing and survival. We previously showed that in , loss of the microRNA advances the phase of circadian evening locomotor activity by several hours under constant darkness conditions. Interestingly, we now report that loss of also delays morning activity under a light/dark cycle with a short photoperiod. We recapitulated these opposite phase phenotypes by eliminating during larval development, but not when this microRNA is lost during pupation to adulthood. The loss of results in significant miswiring within the circadian neural network and severely alters neural activity rhythms in the ventral Lateral Neurons (s-LNvs) and the posterior Dorsal Neurons 1 (DN1ps), which control the timing of morning and evening activity. Silencing the s-LNvs in mutant flies restores the phase of evening activity, while activating the DN1ps rescues the phases of both morning and evening activities. Our findings thus reveal the pivotal role of in sculpting the circadian neural network during development and its long-lasting impact on circuit activity and adult circadian behavior.No embarg
Publisher preferences for a journal transparency tool: A modified three-round Delphi study
No full textBACKGROUND: We propose the creation of a journal transparency tool (JTT), which will allow users to obtain information about a given scholarly journal's operations and policies. We are obtaining preferences from different stakeholders to inform the development of this tool. This study aimed to identify the publishing community's preferences for the JTT.
METHODS: We conducted a modified three-round Delphi survey. Representatives from publishing houses and journal publishers were recruited through purposeful and snowball sampling. The first two Delphi rounds involved an online survey with items about JTT metrics and user features. During the third round, participants discussed and voted on JTT metric items that did not reach consensus after round 2 within a virtual consensus meeting. We defined consensus as 80% agreement to include or exclude an item in the JTT.
RESULTS: Eighty-six participants completed the round 1 survey, and 43 participants (50% of round 1) completed the round 2 survey. In both rounds, respondents voted on JTT user feature and JTT metric item preferences and answered open-ended survey questions regarding the JTT. In round 3, a total of 21 participants discussed and voted on JTT metric items that did not reach consensus after round 2 during an online consensus group meeting. Fifteen out of 30 JTT metric items and none of the four JTT user feature items reached the 80% consensus threshold after all rounds of voting. Analysis of the round 3 online consensus group transcript resulted in two themes: 'factors impacting support for JTT metrics' and 'suggestions for user clarity.'
CONCLUSIONS: Participants suggested that the publishing community's primary concerns for a JTT are to ensure that the tool is relevant, user-friendly, accessible, and equitable. The outcomes of this research will contribute to developing and refining the tool in accordance with publishing preferences.No embarg
COVID-19 test positivity, vaccine uptake, and mortality among Veterans with SCI/D
No full textBACKGROUND: Between January 2020 and December 2023, the United States reported over 103 million COVID-19 cases and 1.1 million related deaths. Veterans with spinal cord injuries and disorders (VSCI/D) are particularly vulnerable due to chronic health conditions and comorbidities, which increases COVID-19 infection and mortality risk from exposure to others who they depend on for care. This manuscript highlights factors associated with COVID-19 vaccine uptake in VSCI/D.
OBJECTIVE: This study aimed to explore Veteran demographic and clinical factors associated with COVID-19 test positivity, vaccine uptake, and COVID-19-related mortality among VSCI/D in the 2-year period following the start of the pandemic.
METHODS: This observational cohort study used the Veterans Health Administration's (VHA) Spinal Cord Injuries and Disorders Registry to identify VSCI/D alive on March 20, 2020. Outcome measures included COVID-19 test positivity, vaccine uptake, and mortality within 30 days of a positive test over a 2-year period.
RESULTS: Among 17,522 VSCI/D, 12% had a positive COVID-19 test at least once in the two-year period following March 20, 2020, 73% received at least one COVID-19 vaccine dose in the 2-year period, and 47% received at least three doses. COVID-related mortality occurred in 67 (0.4%; 67/17,522) VSCI/D in the first year of the pandemic and 46 in the second year (0.6% two-year mortality; 113/17,522).
CONCLUSION: Less than half of VSCI/D received three COVID-19 vaccine doses, suggesting opportunities for quality improvement efforts. Peer support services may help improve vaccine uptake among VSCI/D in the future.No embarg
Brain dynamics reflecting an intra-network brain state is associated with increased posttraumatic stress symptoms in the early aftermath of trauma
No full textPost-traumatic stress (PTS) encompasses a range of psychological responses following trauma, which may lead to more severe outcomes such as post-traumatic stress disorder (PTSD). Identifying early neuroimaging biomarkers that link brain function to PTS outcomes is critical for understanding PTSD risk. This longitudinal study examines the association between brain dynamic functional network connectivity (dFNC) and current/future PTS symptom severity, and the impact of sex on this relationship. By analyzing 275 participants' dFNC data obtained ~2 weeks after trauma exposure, we noted that brain dynamics of an inter-network brain state link negatively with current (=-0.197, = 0.0079) and future (=-0.176, = 0.0176) PTS symptom severity. Also, dynamics of an intra-network brain state correlated with future symptom intensity ( = 0.205, = 0.0079). We additionally observed that the association between the network dynamics of the inter-network and intra-network brain state with symptom severity is more pronounced in female group. Our findings highlight a potential link between brain network dynamics in the aftermath of trauma with current and future PTSD outcomes, with a stronger effect in female group, underscoring the importance of sex differences.No embarg
VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in 's orthologue in . Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPR ). The cellular and behavioral changes caused by mutations in advance the development of animal models that are needed to study SCAR4 pathogenesis
Intervention Stage Completion and Behavioral Health Outcomes: An Integrated Behavioral Health and Primary Care Randomized Pragmatic Trial
No full textPurpose: We performed a pragmatic, cluster randomized controlled trial of a comprehensive practice-level, multistage practice transformation intervention aiming to increase behavioral health integration in primary care practices and improve patient outcomes. We examined associations between completion of intervention stages and patient outcomes across a heterogeneous national sample of primary care practices.
Methods: Forty-two primary care practices across the United States with colocated behavioral health and 2,945 patients with multiple chronic medical and behavioral health conditions completed surveys at baseline, midpoint, and 2-year follow-up. We examined effects of intervention on patient health and primary care integration outcomes using multilevel mixed-effects models, controlling for baseline outcome measurements.
Results: No differences were found associated with the number of intervention stages completed and patient health outcomes including depression, anxiety, fatigue, sleep disturbance, pain, pain interference, social participation, and physical function. However, the completion of each intervention stage was associated with increases in Practice Integration Profile domain scores and confirmed with modeling using multiple imputation for the following: workflow 3.5 (95% CI, 0.9 to 6.1), integration methods 4.6 (95% CI, 1.5 to 7.6), patient identification 2.9 (95% CI, 0.9 to 5.0), and total integration 2.7 (95% CI, 0.7 to 4.7).
Conclusion: A practice-centric flexible practice transformation intervention improved integration of behavioral health in primary care across heterogeneous primary care practices treating patients with multiple chronic conditions when accounting for completion of intervention stages. Interventions that allow practices to flexibly improve care have the potential to help complex patient populations. Future research is needed to determine how to best target patient health outcomes at the population level.No embarg