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The endoplasmic reticulum–mitochondria encounter structure (ERMES) connects the mitochondrial outer membrane with the ER. Multiple functions have been linked to ERMES, including maintenance of mitochondrial morphology, protein assembly and phospholipid homeostasis. Since the mitochondrial distribution and morphology protein Mdm10 is present in both ERMES and the mitochondrial sorting and assembly machinery (SAM), it is unknown how the ERMES functions are connected on a molecular level. Here we report that conserved surface areas on opposite sides of the Mdm10 β-barrel interact with SAM and ERMES, respectively. We generated point mutants to separate protein assembly (SAM) from morphology and phospholipid homeostasis (ERMES). Our study reveals that the β-barrel channel of Mdm10 serves different functions. Mdm10 promotes the biogenesis of α-helical and β-barrel proteins at SAM and functions as integral membrane anchor of ERMES, demonstrating that SAM-mediated protein assembly is distinct from ER-mitochondria contact sites. The protein Mdm10 is known to be present in the endoplasmic reticulum-mitochondria encounter structure (ERMES) and in mitochondrial sorting and assembly machinery (SAM). Here, the authors examine how this protein interacts with SAM and EMRES, showing that the SAM-mediated protein machinery is independent of ERMES.

Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases hair cell regeneration, however, these cells fail to fully mature. Here, we profiled mouse utricles at 14 time points, and defined transcriptomes of developing and mature vestibular hair cells. To mimic native hair cells which downregulate endogenous ATOH1 as they mature, we engineered viral vectors carrying the supporting cell promoters GFAP and RLBP1. In utricles damaged ex vivo, both CMV-ATOH1 and GFAP-ATOH1 increased regeneration more effectively than RLBP1-ATOH1, while GFAP-ATOH1 and RLBP1-ATOH1 induced hair cells with more mature transcriptomes. In utricles damaged in vivo, GFAP-ATOH1 induced regeneration of hair cells expressing genes indicative of maturing type II hair cells, and more hair cells with bundles and synapses than untreated organs. Together our results demonstrate the efficacy of spatiotemporal control of ATOH1 overexpression in inner ear hair cell regeneration. By using a supporting cell promoter, the authors show that transient expression of Atoh1 drives regeneration and maturation of hair cells in the mature mouse vestibular organs, with transcriptomes similar to maturing type II hair cells.

With increasing survival rates, the functional outcome and quality of life of trauma patients are gaining more importance. Survivors suffer from chronic pain, psychosomatic disorders, and unemployment as well as increased post-traumatic morbidity, which can lead to an impaired quality of life. So far, the TraumaRegister DGU ® records patient data during in-hospital treatment. In this study severely injured patients after major trauma are assessed when discharged from hospital, as well as 6, 12 and 18 months after trauma. The aim is to document cross-sector patient pathways and to identify and quantify the factors influencing the health-related quality of life (hrQoL) and the return to work (RTW), using patient-reported experience measures (PREM) and patient reported outcome measures (PROM). Patients are recruited in certified trauma centers of the German Society for Trauma Surgery (DGU). This study protocol describes the methodology of the prospective multicentre study of LeAf Trauma. Translation of the results will be implemented by using the network structures of the German Society for Trauma Surgery (DGU) for the treatment of patients with major trauma.

The ribbon is the structural hallmark of cochlear inner hair cell (IHC) afferent synapses, yet its role in information transfer to spiral ganglion neurons (SGNs) remains unclear. We investigated the ribbon’s contribution to IHC synapse formation and function using KO mice lacking RIBEYE. Despite loss of the entire ribbon structure, synapses retained their spatiotemporal development and KO mice had a mild hearing deficit. IHCs of KO had fewer synaptic vesicles and reduced exocytosis in response to brief depolarization; a high stimulus level rescued exocytosis in KO. SGNs exhibited a lack of sustained excitatory postsynaptic currents (EPSCs). We observed larger postsynaptic glutamate receptor plaques, potentially compensating for the reduced EPSC rate in KO. Surprisingly, large-amplitude EPSCs were maintained in KO, while a small population of low-amplitude slower EPSCs was increased in number. The ribbon facilitates signal transduction at physiological stimulus levels by retaining a larger residency pool of synaptic vesicles.

A well-known conjecture states that constant functions are extremizers of the L^2 L^6 Tomas–Stein extension inequality for the circle. We prove that functions supported in a 6/80 -neighborhood of a pair of antipodal points on S^1 satisfy the conjectured sharp inequality. In the process, we make progress on a program formulated by Carneiro, Foschi, Oliveira e Silva and Thiele to prove the sharp inequality for all functions.

Background/Objectives Over the past 50 years, the concept of the golden hour of shock was established as one of the central tenets of emergency trauma medicine. A shorter duration of prehospital care correlates with a positive change in outcome in numerous studies. Dispatching by the public safety answering points has hardly been discussed to date. Thanks to improved vehicle safety, additional accident data is now available to the emergency call centers. Methods We investigated the effects of third-party system emergency calls (TPS-eCalls), which have become mandatory in new passenger cars in the EU in 2018, on dispatching in the emergency medical services (EMS). For this purpose, we linked the data of a public-safety answering point (PSAP) and an EMS. All emergency service deployments from 01/01/2023 to 31/12/2023 were evaluated. N  = 1546 rescue missions were dispatched after motor vehicle accidents (MVA), 111 after TPS-eCall-alerts, 1435 after conventional alerts. Results Dispatching in the PSAP currently took longer after TPS-eCall alerts than conventional alerts (01:39 ± 01:40 min vs. 02:41 ± 02:01 min, p  ≤ 0.001). The differences were only significant in the case of accidents involving ≤ 2 passengers. Conclusions TPS-eCall data will be available increasingly. The future expansion data availability offers the opportunity to include objective accident data (airbag deployment, number of occupants, change of velocity) in the dispatching process. Adequate technical connection can improve dispatching and shorten preclinical treatment, especially for complex events with more than 2 passengers.

Background With the aging population, the number of geriatric trauma patients continues to rise, posing significant challenges for emergency care and trauma management. Structured trauma team activation (TTA) protocols aim to provide timely and adequate treatment for severely injured patients. However, evidence suggests that current triage criteria may inadequately address the specific needs of geriatric patients, potentially leading to undertriage and worse outcomes. Methods The prospective, multicentre observational cohort study analysed trauma team activation and triage practices for patients aged ≥ 70 years across 12 Level 1 trauma centres across rural and urban regions in Germany and Switzerland. Data were prospectively collected from December 2020 to February 2021, following the STROBE guidelines. Triage decisions were compared with the TAcTIC (Trauma Team Activation and Trauma/Injury Care) consensus criteria to assess undertriage and overtriage rates. Key outcomes included trauma team activation rates, injury severity, transport characteristics, and early mortality. Results Among 3,753 trauma patients, 1,371 (36.5%) were geriatric (≥ 70 years). Trauma team activation was significantly lower in the geriatric group (15.8%) compared to younger patients (31.8%), despite similar injury severity. Post-hoc analysis revealed that 53.8% of geriatric patients requiring trauma care were undertriaged. Head injuries (47.7%) and pelvic fractures (5.7%) were more common in geriatric patients in comparison to the younger cohort. Mortality within 48 h was more than three times as high in geriatric patients (1.8% vs. 0.5%). Conclusion A significant undertriage rate (53.8%) was identified among geriatric trauma patients, contributing to delayed care and increased mortality. Undertriage of geriatric trauma patients remains a critical issue, reflecting the insufficiency of current trauma activation protocols. Tailored triage criteria that even more consider age-related physiological differences, comorbidities, and frailty are urgently needed. Future updates to trauma guidelines should aim to reduce undertriage and improve outcomes for this vulnerable population. Clinical trial number Not applicable

Deafness-causing deficiencies in otoferlin ( OTOF ) have been addressed preclinically using dual adeno-associated virus (AAV)-based approaches. However, timing of transduction, recombination of mRNA, and protein expression with dual hybrid AAV methods methods have not previously been characterized. Here, we have established an ex vivo assay to determine the kinetics of dual-AAV mediated expression of OTOF in hair cells of the mouse utricle. We utilized two different recombinant vectors that comprise DB-OTO, one containing the 5′ portion of OTOF under the control of the hair cell-specific Myo15 promoter, and the other the 3′ portion of OTOF . We explored specificity of the Myo15 promoter in hair cells of the mouse utricle, established dose response characteristics of DB-OTO ex vivo in an OTOF-deficient mouse model, and demonstrated tolerability of AAV1 in utricular hair cells. Furthermore, we established deviations from a one-to-one ratio of 5′ to 3′ vectors with little impact on recombined OTOF . Finally, we established a plateau in quantity of recombined OTOF mRNA and protein expression by 14 to 21 days ex vivo with comparable recovery timing to that in vivo model. These findings demonstrate the utility of an ex vivo model system for exploring expression kinetics and establish in vivo and ex vivo recovery timing of dual AAV-mediated OTOF expression.

Background Actinic keratoses (AK) are common precancerous lesions of the skin due to cumulative sun exposure. A variety of interventions are available for the treatment; however, the majority of randomised controlled trials (RCTs) and meta-analyses focus on short-term efficacy outcomes. This network meta-analysis aims to investigate the long-term (> 12 months) efficacy of interventions for AK. Methods To identify relevant studies, we will perform a systematic literature research in MEDLINE, Embase, and CENTRAL and hand-search pertinent trial registers. Two authors will independently screen titles and abstracts for eligibility. We will include RCTs with an inter-individual (parallel arm) design. The study population includes patients with a clinical or histopathologic diagnosis of AK. Eligibility will be restricted to the following interventions: surgical approaches, cryosurgery, ablative laser treatment, topical drug treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, or photodynamic therapy. As outcomes, we will consider the following endpoints: (1) the participant complete clearance rate, (2) the participant partial clearance rate, (3) the lesion-specific clearance, (4) the mean lesion reduction per patient, and (5) the number of withdrawals due to adverse events after at least 12 months after the end of treatment. Monotherapy or placebo will serve as a comparison. Estimates of effects from individual studies will be pooled using a random-effects model. Heterogeneity will be evaluated based on I 2 and chi-square test. The risk of bias will be estimated with the Cochrane Risk of Bias Tool by two review authors independently. The quality of evidence of the outcomes will be assessed with the GRADE approach. A network meta-analysis will be performed to combine direct and indirect evidence from the included RCTs. Discussion The potential of interventions to achieve a sustained clearance of AK has not been assessed to date. To investigate the long-term efficacy of interventions is important as the natural disease course is highly variable and relapses occur frequently even after initial lesion clearance. This review will help to set a framework for clinical decision making in patients with AK. Systematic review registration CRD42018095903 (PROSPERO)

Functional magnetic resonance imaging (fMRI) hypothesis testing based on the blood oxygenation level dependent (BOLD) contrast mechanism typically involves a search for a positive effect during a specific task relative to a control state. However, aside from positive BOLD signal changes there is converging evidence that neuronal responses within various cortical areas also induce negative BOLD signals. Although it is commonly believed that these negative BOLD signal changes reflect suppression of neuronal activity direct evidence for this assumption is sparse. Since the somatosensory system offers the opportunity to quantitatively test sensory function during concomitant activation and has been well-characterized with fMRI in the past, the aim of this study was to determine the functional significance of ipsilateral negative BOLD signal changes during unilateral sensory stimulation. For this, we measured BOLD responses in the somatosensory system during unilateral electric stimulation of the right median nerve and additionally determined the current perception threshold of the left index finger during right-sided electrical median nerve stimulation as a quantitative measure of sensory function. As expected, positive BOLD signal changes were observed in the contralateral primary and bilateral secondary somatosensory areas, whereas a decreased BOLD signal was observed in the ipsilateral primary somatosensory cortex (SI). The negative BOLD signal changes were much more spatially extensive than the representation of the hand area within the ipsilateral SI. The negative BOLD signal changes in the area of the index finger highly correlated with an increase in current perception thresholds of the contralateral, unstimulated finger, thus supporting the notion that the ipsilateral negative BOLD response reflects a functionally effective inhibition in the somatosensory system.