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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.

BACKGROUNDFXLEARN, 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 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.

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.

The COVID-19 pandemic forced the education sector to transform significantly in order to support students across the world. Technology played a crucial role in enhancing and adapting traditional learning to digital resources and networks, which are now an essential component of education. However, there is concern about the quality of teaching and its effectiveness in remote teaching due to the lack of real-life feel of more traditional face-to-face education. Our study analysed two separate groups of students enrolled in the same course but provided with either face-to-face or remote teaching. The results show that there is no statistically significant difference in students' performance or gain, even for laboratory work and resulting reports. However, there was a statistically significant difference in Turnitin scores between these groups, with the remote students having higher levels of plagiarism compared to the traditional face-to-face students. These results support the theory that remote teaching can be a valid alternative, if not a substitute, to face-to-face teaching in the future. The study's findings are expected to help instructors who are thinking about providing programs through blended learning in the post-pandemic era.

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.

Abstract Background Opioid-related overdose is the leading cause of death for people recently released from incarceration, however treatment with medications for opioid use disorder (MOUD) during incarceration can reduce the mortality risk. This study seeks to qualitatively analyze perceptions of post-release overdose risk from the perspectives of people who received MOUD while incarcerated in one of eight Massachusetts jails during 2021–2022 using the Risk Environment Framework to guide analyses. Methods N = 38 participants with lived experience of MOUD treatment during incarceration who are now living in the community were interviewed on factors that may contribute to or protect against post-release overdose risk. Themes were identified inductively and deductively using the Risk Environment Framework and its domains, which organizes themes along physical, social, economic, and policy environments on both the micro- and macro- scales. Results The physical risk environment included loss of opioid tolerance during incarceration, polysubstance use, and the toxicity of the regional drug supply as key producers of increased risk for post-release overdose. Social drivers of risk included peer group risk norms—including peer-driven harm reduction practices and interpersonal relationships between drug sellers and buyers—as well as macro-level social determinants of health such as housing insecurity and availability of mental health services. Economic drivers of post-release overdose risk included lack of income generation during incarceration and employment challenges. Participants discussed several aspects of policy that contribute to post-release overdose risk, including availability of harm reduction supplies, public health services, and broader policy around MOUD. Conclusions The perspectives of people with lived experience are vital to understanding the disproportionate risks of overdose for those recently released from incarceration. Our results highlight the intersectional factors that produce and reproduce the post-release overdose risk environment, providing support for interventions across each domain of the Risk Environment Framework. By capturing perspectives from people with lived experience of OUD and incarceration during this critical period of risk, we can better identify interventions that target and mitigate overdose-related harm in this population.

Abstract Background Supervised injectable opioid treatment (SIOT) is a promising alternative for people living with opioid use disorder (OUD) who have not sufficiently benefitted from oral opioid substitution treatment. Yet, SIOT utilization remains limited in Germany. We propose that this is due to beliefs, or schemas, on SIOT among people living with OUD. Drawing from medical sociology and social psychology, this study explores the emergence and evolution of such schemas on SIOT. Methods We conducted semi-structured interviews with 34 individuals currently in or eligible for SIOT in two German outpatient treatment facilities and paralleled an inductive qualitative content analysis with the exploration of individual cases. Results The analysis revealed that peer-to-peer interaction and individuals’ practical experiences in therapy are crucial in constructing and changing idiosyncratic and shared schemas of SIOT. When facing ambiguous information, cognitive strategies like subtyping served to mitigate uncertainty. Conclusion This research has important practical implications for integrating experiential knowledge into clinical care and improve information sharing among people living with OUD. A nuanced understanding of the complex network of informal advice-seeking and -giving among people living with OUD is indispensable to adequately expand treatment modalities of proven effectiveness.

Abstract The COVID-19 pandemic forced the education sector to transform significantly in order to support students across the world. Technology played a crucial role in enhancing and adapting traditional learning to digital resources and networks, which are now an essential component of education. However, there is concern about the quality of teaching and its effectiveness in remote teaching due to the lack of real-life feel of more traditional face-to-face education. Our study analysed two separate groups of students enrolled in the same course but provided with either face-to-face or remote teaching. The results show that there is no statistically significant difference in students’ performance or gain, even for laboratory work and resulting reports. However, there was a statistically significant difference in Turnitin scores between these groups, with the remote students having higher levels of plagiarism compared to the traditional face-to-face students. These results support the theory that remote teaching can be a valid alternative, if not a substitute, to face-to-face teaching in the future. The study’s findings are expected to help instructors who are thinking about providing programs through blended learning in the post-pandemic era.

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 Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).Patients and methods Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.Results In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.Conclusions Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.Trial registration number NCT03668119.

The subtitle of the book under review suggests that it deals with modern relationships between Hindus and Muslims in India, but the scope of the book is actually much wider. It deals with the general question of the various Muslim views of the relationship between Muslims and adherents of other civilizations and religions, ranging from the 9th century al-ʿĀmirī and the 11th century al-Bīrūnī, to the 18th century Mirzā Maẓhar Jān-i Jānān and thinkers of the 19th and 20th centuries, including such luminaries as Abū al-Kalām Āzād, Aḥmad Riźā Khān, Sayyid Aḥmad Khān and several Deobandī scholars. One of the great virtues of the book is the author’s use of the sources, some of them rarely mentioned in scholarly literature and certainly not to this extent and in such detail. In an academic culture in which various “narratives” have taken the pride of place, it is most welcome to have a work which is replete with theory, but also surveys and analyzes a substantial amount of hitherto unknown source material. The book is also another proof of the great variety of Muslim tradition which enables Muslim scholars to find Islamic justification for their modern world views and policies, even if these are contradictory to each other. Because of its rich content – much of it unknown – the book deserves a detailed review.

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.

Abstract Background Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. Methods RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. Results Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. Conclusions RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.