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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.

BACKGROUND: FXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

This study evaluated the feasibility of recruiting hospitalized older adults into a randomized controlled trial (RCT) comparing an animal-assisted intervention (AAI) involving visits from therapy dogs with an active control (conversation with a volunteer) and treatment as usual (TU) for addressing health and mental health outcomes. Recruitment occurred on acute care hospital units and a long-term physical rehabilitation facility. Feasibility data included the number of recruitment contacts, recruitment rate, and reasons for non-enrollment. The recruitment pool included 1124 patients; the recruitment rate was 4.8% (n = 54). This study explored the difficulties inherent in recruiting medically ill, hospitalized older adults for an RCT of hospital-based therapy dog visits. We believe this is the first RCT of its kind to evaluate the feasibility of recruiting this population for an animal-assisted intervention. Although the intervention was well received, older adults’ illnesses presented significant barriers to study enrollment. Strategies for improving the recruitment of hospitalized older adults for RCTs are discussed.

Abstract Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. Study Design The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow‐up. Three hundred patients, aged 18–75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I–III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high‐density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. Discussion The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.

This paper continues the study of two numbers that are associated with Lie groups. The first number is \(N(G,m)\), the number of conjugacy classes of elements in \(G\) whose order divides \(m\). The second number is \(N(G,m,s)\), the number of conjugacy classes of elements in \(G\) whose order divides \(m\) and which have \(s\) distinct eigenvalues, where we view \(G\) as a matrix group in its smallest-degree faithful representation. We describe systematic algorithms for computing both numbers for \(G\) a connected and simply-connected exceptional Lie group. We also provide explicit results for all of \(N(G,m)\), \(N(G_2,m,s)\), and \(N(F_4,m,s)\). The numbers \(N(G,m,s)\) were previously known only for the classical Lie groups; our results for \(N(G,m)\) agree with those already in the literature but are obtained differently.Mathematics Subject Classifications: 05A15, 05E16, 22E40, 22E10, 22E15Keywords: Lie groups, conjugacy classes, element of finite order, Burnside's lemma

Linguists propose the existence of linguistic trees and define the merge operation to construct complex sentences from simpler elements. Previous neuroimaging studies, primarily utilizing 3T scanners, have identified an extensive fronto-temporal network involved in forming linguistic structures and executing merge operations. Intracranial recordings in these areas reveal a more distributed picture, with adjacent regions undertaking diverse linguistic tasks.We designed a 7T fMRI visual task to investigate the neural coding of syntactic operations. In healthy French-speaking participants, we initially identified the language network using a localizer. Subsequently, we employed short 3-word stimuli, presented briefly (200ms), to explore the response profiles within the language network. These stimuli included control conditions, affirmative statements, and interrogative sentences, all matched for letter and character count.Preliminary results indicate that 200ms is sufficient to differentiate between sentences and non-sentences, and suggest a finely-tuned specialization for syntactic operations within language network subregions.

COVID-19 adversely impacted parents with substance use disorders (SUDs) as evidenced by increased overdoses. This study used a qualitative approach to examine COVID’s impact on experiences and perceptions of a parenting program designed for mothers in recovery from SUDs, “Mothering from the Inside Out” (MIO), implemented through Early Intervention (EI) home-visiting services. Four EI programs participated in training and implementation of MIO. Subjects included 10 eligible EI providers trained in August 2019 or August 2021 and 11 mothers in recovery from SUDs. More mothers completed MIO during the pandemic compared to before. We conducted inductive thematic analysis of exit interviews and field notes, along with interpretation of process measures of intervention implementation. Initially, the switch to telehealth negatively impacted the provider-parent relationship but made engagement logistically easier for some mothers. Parent and provider participants reported the need for additional psychosocial support due to increased stressors, as well as ways that MIO helped them cope during the pandemic. COVID made EI enrollment of families more difficult in general; however once enrolled, telehealth improved retention in MIO, meeting a critical need during the pandemic.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring painful nodules, abscesses, and sinus tracts in apocrine gland-rich areas. The demographics of HS are not well-established in the United States. Purpose: The purpose of this study was to investigate the HS rate by demographics using the All of Us open-access database initiative from the National Institutes of Health in the United States. Methods: A cross-sectional statistical analysis of patients diagnosed with HS (ICD-10-CM code L73.2) in the All of Us open-access database was performed. Prevalence rates were calculated using Wald’s method with 95% confidence intervals (CIs). Results: Among 407,333 participants, 1616 cases of HS were identified, representing an overall prevalence of 0.40% (95% CI, 0.38–0.42) with a 4:1 female-to-male ratio. The prevalence varied among racial groups: 0.28% in Whites, 0.76% in Blacks, 0.37% in Hispanics, and 0.10% in Asians. The 18–25 age group showed the highest prevalence at 1.70% (95% CI, 1.46–2.00), with a steady decrease in older age groups. Conclusion: Women, Blacks, and younger people (18–25) have a higher prevalence of HS.

Abstract Ferroptosis is a regulated and non-apoptotic form of cell death mediated by iron-dependent peroxidation of polyunsaturated fatty acyl tails in phospholipids. Research of the past years has shed light on the occurrence of ferroptosis in organ injury and degenerative diseases of the brain, kidney, heart, and other tissues. Hence, ferroptosis inhibition may prove therapeutically beneficial to treat distinct diseases. In this study, we explored the ferroptosis-modulating activity of seratrodast, an inhibitor of thromboxane A2 (TXA2) receptor, which is approved in some countries for the treatment of asthma. Interestingly, seratrodast suppressed ferroptosis, but not apoptosis and necroptosis; thus, demonstrating selective anti-ferroptotic activity. While seratrodast itself does not inhibit lipid peroxidation, it exhibits potent radical-trapping antioxidant activity upon reduction to its corresponding hydroquinone form—analogously to ubiquinone and vitamin K. Importantly, seratrodast ameliorated the severity of renal ischemia-reperfusion injury in mice. Together, this study provides a drug repurposing case, where seratrodast—a marketed drug—can undergo fast-forward preclinical/clinical development for the inhibition of ferroptosis in distinct degenerative diseases.

Abstract Background Incarceration provides an opportunity for health interventions, including opioid use disorder (OUD) treatment and prevention of opioid-related overdoses post-release. All FDA-approved forms of medication for OUD (MOUD) treatment were mandated in several Massachusetts jails in 2019, with some jails offering extended-release buprenorphine (XR-Bup). Little is known about patient perspectives on and experiences with XR-Bup in carceral settings. Methods We conducted semi-structured interviews in 2022 with community-dwelling people who received MOUD during a recent incarceration in a Massachusetts jail. We asked participants about their experiences with and perspectives on XR-Bup while in jail. Qualitative data were double-coded deductively and reviewed inductively to identify emergent themes, which were structured using the Theoretical Framework of Acceptability (TFA). Results Participants (n = 38) had a mean age of 41.5 years, were 86% male, 84% White, 24% Hispanic, and 95% continued to receive MOUD at the time of their interview, including 11% receiving XR-Bup. Participants who viewed XR-Bup favorably appreciated avoiding the taste of sublingual buprenorphine; avoiding procedural difficulties and indignities associated with daily dosing in carceral settings (e.g., mouth checks, stigmatizing treatment from correctional staff); avoiding daily reminders of their addiction; experiencing less withdrawal; having extra time for other activities, such as work; and reduction of diversion of MOUD within the jail setting. Participants who viewed XR-Bup less favorably preferred to maintain their daily dosing routine; liked daily time out of their housing unit; wanted to know what was “going into my body everyday”; and feared needles and adverse events. Participants also reported that jail clinicians used XR-Bup for patients who were previously caught diverting sublingual buprenorphine, suggesting limited patient participation in decision-making around XR-Bup initiation in some jails. Conclusion People who received MOUD in Massachusetts jails had both favorable and unfavorable views and experiences with XR-Bup. Understanding these preferences can inform protocols in jails that are considering implementation of XR-Bup treatment.

Participation is one key element of inclusive education. While the inclusion rate in German schools is rising, little is known with regard to children's participation in this context. This study examines the participation of children with and without impairments at three inclusive primary schools in Bavaria. Cross-sectional data was collected in parents and teachers of 124 3rd grade pupils (girls: n = 62, age: M = 9.5 years; boys: n = 62, age: M = 9.6). 27% of the parents stated their children had impairments (4.9% physical, 13.1% mental/ intellectual and 9.0% other/multiple). Participation in school and other life areas ('neighborhood & community', 'home' and 'living activities') was assessed by the 'Child and Adolescent Scale of Participation (CASP)'. Parents and teachers of children with impairments reported significantly lower scores in all CASP subsections and total score. In school, according to teacher rating, all pupils showed the lowest participation scores in educational activities with other children in the classroom and in communicating with children/adults. The results highlight the continuing challenges to reach meaningful participation of all children as a condition for effective inclusive education. This seems to be true not only for school but also for other social contexts.

Many neurons in the central nervous system produce a single primary cilium that serves as a specialized signaling organelle. Several neuromodulatory G-protein-coupled receptors (GPCRs) localize to primary cilia in neurons, although it is not understood how GPCR signaling from the cilium impacts circuit function and behavior. We find that the vertebrate ancient long opsin A (VALopA), a Gi-coupled GPCR extraretinal opsin, targets to cilia of zebrafish spinal neurons. In the developing 1-d-old zebrafish, brief light activation of VALopA in neurons of the central pattern generator circuit for locomotion leads to sustained inhibition of coiling, the earliest form of locomotion. We find that a related extraretinal opsin, VALopB, is also Gi-coupled, but is not targeted to cilia. Light-induced activation of VALopB also suppresses coiling, but with faster kinetics. We identify the ciliary targeting domains of VALopA. Retargeting of both opsins shows that the locomotory response is prolonged and amplified when signaling occurs in the cilium. We propose that ciliary localization provides a mechanism for enhancing GPCR signaling in central neurons.

Public breeding programs are pushing to implement demand-led breeding to increase variety adoption, while tackling multiple challenges for increased production under climate change. This has included the improvement of variety target product profiles involving multiple stakeholders. A special case involves the unexpected and rapid spread of the Shangi potato variety in Kenya. This variety was not an especially outstanding variety and the levels of its traits did not exceed the expected thresholds defined in the target product profile for table potato in East Africa. By examining the customer segments looking at gender but also social contexts of smallholder and disadvantaged farmers such as access to markets, inputs, and labor, it became apparent that ready availability of potatoes for consumption, processing, or planting was of prime importance. Given the storage and market constraints, Shangi's very short dormancy, which had been assumed to be a negative trait for farmers, women cottage processors and consumers, was actually meeting the needs for available product and planting material. Consequently, this provided these groups increased control over their productive activities. The case study presented here analyzes different components of potato variety change in Kenya. It explores the challenges and tradeoffs faced by public sector breeding programs and how gender analysis from a broader inclusion perspective can uncover the underlying causes of varietal adoption. Focusing on the Shangi potato variety, the case study reveals a series of lessons learned that have re-shaped the definition of breeding priorities.

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.SignificanceMutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.