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Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

Objective: Present study aims to: 1) examine demographic correlates of LGB, asexual, or not sure participants; 2) describe the prevalence of diverse sexual behaviors; 3) assess the prevalence of event-level sexual behaviors; and 4) examine predictors of sexual pleasure. Participants: 761 non-heterosexual undergraduates at a large, public U.S. university. Methods: Randomly sampled undergraduate students completed a confidential, cross-sectional online survey. Results: Of 761 non-heterosexual respondents; 567 identified as LGB, 47 asexual, and 147 not sure. Asexual students, those not sure were less likely to report having engaged in solo and partnered sexual activities and report sexual activities being less pleasurable at most recent sexual event, compared with LGB students. This difference (relative to LGB) became nonsignificant when accounting for reported sexual activities. Conclusions: Our findings inform how college students define and experience their sexual identities and assist college health professionals in training on sexuality and prevention of risk factors.

The Fourth Cell Stress Society International workshop on small heat shock proteins (sHSPs), a follow-up to successful workshops held in 2014, 2016 and 2018, took place as a virtual meeting on the 17-18 November 2022. The meeting was designed to provide an opportunity for those working on sHSPs to reconnect and discuss their latest work. The diversity of research in the sHSP field is reflected in the breadth of topics covered in the talks presented at this meeting. Here we summarise the presentations at this meeting and provide some perspectives on exciting future topics to be addressed in the field.

Abstract On 25 April 2015, the Gorkha earthquake triggered a large rock-ice avalanche and an air blast disaster in the Langtang Valley, Nepal. More than 350 people were killed or left missing. Here we reconstruct the evolution of the Langtang avalanche-air blast using field investigations and numerical modeling and examine the influence of two primary climate-related phenomena: snowfall anomalies and warm temperatures. Our findings suggest a deep snow cover fosters the formation of a dispersed avalanche, which increases the mobility and destructive power of the powder cloud air blast. Elevated air temperatures intensify meltwater production and lubricate the flowing mass. Both mechanisms contributed to the Langtang disaster. Our study underscores the essential impact of snow cover and air temperature on the risk assessment of high-altitude rock-ice avalanches, highlighting how seasonal and climatic variations affect avalanche runout and air blast dynamics.

Abstract Sulfur mustard (SM) is a highly toxic chemical warfare agent. Exposure to SM results in various pathologies including skin lesions with subsequent impaired wound healing. To date, there are no effective treatments available. Here we discover a SM-triggered pathomechanism involving miR-497-5p and its target survivin which contributes to keratinocyte dysfunction. Transcriptome analysis using RNA-seq in normal human epidermal keratinocytes (NHEK) revealed that SM evoked differential expression of 1896 mRNAs and 25 miRNAs with many of these RNAs known to be involved in keratinocyte function and wound healing. We demonstrated that keratinocyte differentiation and proliferation were efficiently regulated by miRNAs induced in skin cells after exposure to SM. The inhibition of miR-497-5p counteracted SM-induced premature differentiation and stimulated proliferation of NHEK. In addition, we showed that microneedle-mediated transdermal application of lipid-nanoparticles containing miR-497-5p inhibitor restored survivin biosynthesis and cellular functionality upon exposure to SM using human skin biopsies. Our findings expand the current understanding of SM-associated molecular toxicology in keratinocytes and highlight miR-497-5p as feasible clinical target for specific skin therapy in SM-exposed patients and beyond.

Abstract Background Seasonal influenza epidemics have a substantial public health and economic burden, which can be alleviated through vaccination. The World Health Organization (WHO) recommends a 75% vaccination coverage rate (VCR) in: older adults (aged ≥ 65 years), individuals with chronic conditions, pregnant women, children aged 6–24 months and healthcare workers. However, no European country achieves this target in all risk groups. In this study, potential public health and economic benefits achieved by reaching 75% influenza VCR was estimated in risk groups across four European countries: France, Italy, Spain, and the UK. Methods A static epidemiological model was used to estimate the averted public health and economic burden of increasing the 2021/2022 season VCR to 75%, using the efficacy data of standard-dose quadrivalent influenza vaccine. For each country and risk group, the most recent data on population size, VCR, pre-pandemic influenza epidemiology, direct medical costs and absenteeism were identified through a systematic literature review, supplemented by manual searching. Outcomes were: averted influenza cases, general practitioner (GP) visits, hospitalisations, case fatalities, number of days of work lost, direct medical costs and absenteeism-related costs. Results As of the 2021/2022 season, the UK achieved the highest weighted VCR across risk groups (65%), followed by Spain (47%), France (44%) and Italy (44%). Based on modelling, the 2021/2022 VCR prevented an estimated 1.9 million influenza cases, avoiding 375,200 GP visits, 73,200 hospitalisations and 38,400 deaths. To achieve the WHO 75% VCR target, an additional 24 million at-risk individuals would need to be vaccinated, most of which being older adults and patients with chronic conditions. It was estimated that this could avoid a further 918,200 influenza cases, 332,000 GP visits, 16,300 hospitalisations and 6,300 deaths across the four countries, with older adults accounting for 52% of hospitalisations and 80% of deaths. An additional €84 million in direct medical costs and €79 million in absenteeism costs would be saved in total, with most economic benefits delivered in France. Conclusions Older adults represent most vaccine-preventable influenza cases and deaths, followed by individuals with chronic conditions. Health authorities should prioritise vaccinating these populations for maximum public health and economic benefits.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

Summary: We developed a method that utilizes fluorescent labeling of nuclear envelopes alongside cytometry sorting for the selective isolation of Purkinje cell (PC) nuclei. Beginning with SUN1 reporter mice, we GFP-tagged envelopes to confirm that PC nuclei could be accurately separated from other cell types. We then developed an antibody-based protocol to make PC nuclear isolation more robust and adaptable to cerebellar tissues of any genotypic background. Immunofluorescent labeling of the nuclear membrane protein RanBP2 enabled the isolation of PC nuclei from C57BL/6 cerebellum. By analyzing the expression of PC markers, nuclear size, and nucleoli number, we confirmed that our method delivers a pure fraction of PC nuclei. To demonstrate its applicability, we isolated PC nuclei from spinocerebellar ataxia type 7 (SCA7) mice and identified transcriptional changes in known and new disease-associated genes. Access to pure PC nuclei offers insights into PC biology and pathology, including the nature of selective neuronal vulnerability. Motivation: Cerebellar Purkinje cells (PCs) play a central role in controlling voluntary movements, coordination, and motor learning. PC degeneration and death are hallmarks of many human neurological disorders, including multiple forms of spinocerebellar ataxia. Unfortunately, PCs comprise a relatively small population of cells in the cerebellum, constituting less than 1% of the total cell count. This makes studying PC-related pathology using omics approaches exceptionally challenging. Here, we introduce a protocol that addresses the need for obtaining pure fractions of PC nuclei for subsequent cell-specific analysis.

Acute heart failure (HF) is associated with poor prognosis. After the acute event, there is a vulnerable period during which the patient has a marked risk of readmission or death. Therefore, early optimization of treatment is mandatory during the vulnerable period. The objective of this article is to provide recommendations to address the management of patients with HF during the vulnerable period from a practical point of view. A group of Mexican experts met to prepare a consensus document. The vulnerable period, with a duration of up to 6 months after the acute event – either hospitalization, visit to the emergency department or the outpatient clinic/day hospital – represents a real window of opportunity to improve outcomes for these patients. To best individualize the recommendations, the management strategies were divided into three periods (early, intermediate and late vulnerable period), including not only therapeutic options but also evaluation and education. Importantly, the recommendations are addressed to the entire cardiology team, including physicians and nurses, but also other specialists implicated in the management of these patients. In conclusion, this document represents an opportunity to improve the management of this population at high risk, with the aim of reducing the burden of HF.

BackgroundGlobal efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.MethodsIn the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).ResultsSeveral studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.ConclusionsIn this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Background and purposeMobile stroke units (MSU) have been demonstrated to improve prehospital stroke care in metropolitan and rural regions. Due to geographical, social and structural idiosyncrasies of the German city of Mannheim, concepts of established MSU services are not directly applicable to the Mannheim initiative. The aim of the present analysis was to identify major determinants that need to be considered when initially setting up a local MSU service.MethodsLocal stroke statistics from 2015 to 2021 were analyzed and circadian distribution of strokes and local incidence rates were calculated. MSU patient numbers and total program costs were estimated for varying operating modes, daytime coverage models, staffing configurations which included several resource sharing models with the hospital. Additional case-number simulations for expanded catchment areas were performed.ResultsMedian time of symptom onset of ischemic stroke patients was 1:00 p.m. 54.3% of all stroke patients were admitted during a 10-h time window on weekdays. Assuming that MSU is able to reach 53% of stroke patients, the average expected number of ischemic stroke patients admitted to MSU would be 0.64 in a 10-h shift each day, which could potentially be increased by expanding the MSU catchment area. Total estimated MSU costs amounted to € 815,087 per annum. Teleneurological assessment reduced overall costs by 11.7%.ConclusionThis analysis provides a framework of determinants and considerations to be addressed during the design process of a novel MSU program in order to balance stroke care improvements with the sustainable use of scarce resources.

Abstract Background Appropriate use of available inpatient beds is an ongoing challenge for US hospitals. Historical capacity goals of 80% to 85% may no longer serve the intended purpose of maximizing the resources of space, staff, and equipment. Numerous variables affect the input, throughput, and output of a hospital. Some of these variables include patient demand, regulatory requirements, coordination of patient flow between various systems, coordination of processes such as bed management and patient transfers, and the diversity of departments (both inpatient and outpatient) in an organization. Methods Mayo Clinic Health System in the Southwest Minnesota region of the US, a community-based hospital system primarily serving patients in rural southwestern Minnesota and part of Iowa, consists of 2 postacute care and 3 critical access hospitals. Our inpatient bed usage rates had exceeded 85%, and patient transfers from the region to other hospitals in the state (including Mayo Clinic in Rochester, Minnesota) had increased. To address these quality gaps, we used a blend of Agile project management methodology, rapid Plan-Do-Study-Act cycles, and a proactive approach to patient placement in the medical-surgical units as a quality improvement initiative. Results During 2 trial periods of the initiative, the main hub hospital (Mayo Clinic Health System hospital in Mankato) and other hospitals in the region increased inpatient bed usage while reducing total out-of-region transfers. Conclusion Our novel approach to proactively managing bed capacity in the hospital allowed the region’s only tertiary medical center to increase capacity for more complex and acute cases by optimizing the use of historically underused partner hospital beds.

Mountain forests have a substantial protective function in preventing natural hazards, in part due to the presence of dead wood on the forest floor. Rates of deadwood accumulation have increased within the Alps and are predicted to rise further, due to natural disturbances. In particular, higher windthrow event frequencies are expected, primarily due to large-scale even-aged forest stands in many alpine regions combined with climate change. We quantified the rockfall protection effect of mountain forests with and without deadwood, in unprecedented detail, in experiments using two rock shapes with important hazard potential and masses of 200–3200 kg. Based on a multi-camera setup, pre- and post-experimentally retrieved high-resolution lidar data, and rock data measured in situ, we precisely reconstructed 63 trajectories. The principal parameters of interest describing the rockfall kinematics were retrieved for each trajectory. A total of 164 tree impacts and 55 deadwood impacts were observed, and the currently applied energy absorption curves – partially only derived theoretically – could consequently be corroborated or even expanded to a greater absorption performance of certain species than hitherto assumed. Standing trees, in general, and deadwood, in particular, were found to strongly impede the notorious lateral spreading of platy rocks. Platy rocks featured a shorter mean runout distance than their compact counterparts of similar weight, even in the absence of deadwood. These results indicate that the higher hazard potential of platy rocks compared with more compact rocks, previously postulated for open-field terrain, applies less to forested areas. Last, reproducing the experimental setting showcases how complex forest states can be treated within rockfall simulations. Overall, the results of this study highlight the importance of incorporating horizontal forest structures accurately in simulations in order to obtain realistic deposition patterns.

A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.