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A central factor in the maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1), although dispensable for polarity and cellular turnover during intestinal homeostasis, is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNA-seq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt ligands. This occurs via the transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to increased niche Wnt signaling.

Niche-derived factors regulate tissue stem cells, but apart from the mechanosensory pathways, the effect of niche geometry is not well understood. We used organoids and bioengineered tissue culture platforms to demonstrate that the conical shape of Lgr5+ small intestinal stem cells (ISCs) facilitate their self-renewal and function. Inhibition of non-muscle myosin II (NM II)-driven apical constriction altered ISC shape and reduced niche curvature and stem cell capacity. Niche curvature is decreased in aged mice, suggesting that suboptimal interactions between old ISCs and their niche develop with age. We show that activation of NM IIC or physical restriction to young topology improves in vitro regeneration by old epithelium. We propose that the increase in lateral surface area of ISCs induced by apical constriction promotes interactions between neighboring cells, and the curved topology of the intestinal niche has evolved to maximize signaling between ISCs and neighboring cells.

Studies investigating autistic community research priorities indicate a mismatch between what autism research focuses on and what autistic people want to see researched. Furthermore, there has not been a research priority-setting exercise specifically with autistic people in Scotland, where there are unique cultural, political and social contexts. Using a community-based participatory design, we aimed to identify the research priorities of autistic adults living in Scotland. Autistic and non-autistic researchers designed and conducted a survey where 225 autistic adults rated and ranked research topics in order of importance and provided qualitative feedback on issues and questions important to them. The top five research priorities were mental health/well-being, identification and diagnosis of autistic people, support services, knowledge and attitudes towards autistic people and issues impacting autistic women. There were differences in priorities according to different intersections of identity, and qualitative responses indicated a desire for research to focus on support and understanding. The bottom three priorities concerned genetics, treatments and interventions and causes. These findings emphasise the need to address the gap between what autism research focuses on and the everyday lives of autistic people. Although research has the potential to improve autistic people's lives, lots of funding goes towards research looking at topics which autistic people say has little impact in their everyday lives. Autistic people's lives can be different depending on where they live, and Scotland is a unique country in many ways. We wanted to find out which topics autistic people in Scotland want to see research on. Our team of autistic and non-autistic researchers (including university-based and community researchers) created a survey where 225 autistic adults rated and ranked the importance of possible research topics and shared their thoughts on what topics mattered to them. The five most important topics were mental health and well-being, identifying and diagnosing autistic people, support services (including healthcare and social care), non-autistic people's knowledge and attitudes and issues impacting autistic women. The three least important topics were genetics or biological aspects of autism, autism treatments/interventions and causes of autism. Our findings indicate that autistic people in Scotland want research to focus on things that matter to their day-to-day lives. Also, the Scottish government says they will be listening to autistic people in their latest policy plans, and we believe that considering autistic people's research priorities is an important part of this. Our findings also add to growing calls for change to happen in how and what autism researchers do research on. [ABSTRACT FROM AUTHOR]

This article provides empirical evidence of 'defensive mediatization strategies' in the field of sport. These are strategies used by actors individually and collectively to control and sometimes avoid media publicity—for example, by refusing requests for media interviews, or in the case of an organization, by making media literacy training available to its staff. In this article, we use the concept of defensive mediatization strategies to identify and illuminate some of the challenges facing professional sports journalists in the postbroadcast era. The article draws on findings from an ongoing study of the relationships between professional sports organizations, athletes, and journalists, but reports only on interviews conducted with experienced sports journalists in Ireland and Britain (n = 16). Our analysis identifies a number of defensive mediatization strategies used by sports organizations, including increased levels of in-house media, differential treatment of journalists, and an increasingly competitive stance towards journalism generally. We also consider a potentially more pernicious strategy: the hiring of professional sports journalists as internal communications advisers—a switching of role positions that might be termed 'poacher turned gamekeeper'. The article organizes findings according to the three categories of defensive mediatization strategies identified in the extant literature (persistence, shielding, and immunization) and proposes a fourth category, which we label steering. [ABSTRACT FROM AUTHOR]

Abstract Background Although taxonomy is often used informally to evaluate the results of phylogenetic inference and the root of phylogenetic trees, algorithmic methods to do so are lacking. Results In this paper we formalize these procedures and develop algorithms to solve the relevant problems. In particular, we introduce a new algorithm that solves a "subcoloring" problem to express the difference between a taxonomy and a phylogeny at a given rank. This algorithm improves upon the current best algorithm in terms of asymptotic complexity for the parameter regime of interest; we also describe a branch-and-bound algorithm that saves orders of magnitude in computation on real data sets. We also develop a formalism and an algorithm for rooting phylogenetic trees according to a taxonomy. Conclusions The algorithms in this paper, and the associated freely-available software, will help biologists better use and understand taxonomically labeled phylogenetic trees.

Background: Middle meningeal artery embolization (MMAE) is a safe and effective treatment for chronic subdural hematoma (cSDH); however, the appropriate level of postoperative care is unknown., Objective: To evaluate whether elective MMAE for cSDH could be safely performed in an outpatient setting., Methods: This was a multicenter, retrospective study of patients with cSDH who underwent elective MMAE. Patients were categorized as either inpatient (admitted for ≥1 night of hospitalization after MMAE) or outpatient (discharged on the same day of MMAE). Patient demographics, radiological data, procedural details, and follow-up data were collected. The primary endpoint was periprocedural complications, and secondary outcomes included emergency department (ED) visits or unplanned readmission within 24 hours, 1-7 days, and 8-30 days after MMAE., Results: Elective MMAE procedures were carried out in 190 patients, of which 45.3% (n=86) were outpatient procedures and 54.7% (n=104) inpatient. There were 7 (3.7%) periprocedural complications (one outpatient, six inpatient; P=0.12). Five patients presented to the ED and were readmitted within 24 hours of MMAE (three outpatient, two inpatient). Six patients presented to the ED 1-7 days after MMAE (three outpatient, three inpatient); three were subsequently admitted (one outpatient and two inpatient). Nine patients presented to the ED 8-30 days after MMAE (two outpatient and seven inpatient); three were subsequently readmitted (all inpatient). No elective outpatient MMAE resulted in a readmission attributable to the procedure within the examined time frame., Conclusion: Elective MMAE can be safely performed as an outpatient procedure without increased risk of postprocedural adverse events in most eligible patients with cSDH., Competing Interests: Competing interests: CPK: Research grant support from Integra, Penumbra, Viz.AI, Siemens, Medtronic, Minnetronix, Longeviti, Irras, ICE Neurosystems, CVAID, Endostream, and Microtransponder; equity interest in Precision Recovery, Borealis, E8, Borvo, and Metis Innovative. Metis Innovative is an investment group that has coordinated investments in Synchron, Proprio, Fluid Biomed, Von Vascular, and Precision Recovery. JKB: Consulting for Stryker, Microvention, Cerenovus, Q’Apel, Balt and Siemens. RG: Consulting for Cerenovus, Stryker, Balt, Rapid Medical and Medtronic. MRL: Unrestricted educational grants from Medtronic and Stryker; equity interest in Proprio, Synchron, Hyperion Surgical, Stroke Diagnostics, Fluid Biomed, Apertur; consulting for Aeaean Advisers, Metis Innovative, Stereotaxis, Genomadix, AIDoc; data safety monitoring board of Arsenal Medical; editorial board of Journal of NeuroInterventional Surgery., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objective: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors., Methods: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures., Results: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively., Conclusions: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Introduction This research, through the analysis of the case-law of the Inter-American Court of Human Rights (IACtHR), seeks to shed light on the nexus between families of the missing' claims, their agency and State compliance with reparations. The IACtHR has a unique follow-up system in the area of reparations, where victims can directly address the judges during hearings. This paper suggests that victims' participation - before and after the judgment- pervades the legal rigidity of international jurisdictions and contributes to a better understanding of reparations., Introduction: The number of forcibly displaced immigrants seeking asylum in the United States continues to rapidly increase. Movement from Latin America to the United States was the third-largest migration worldwide in 2017 (Leyva-Flores et al., 2019). As migration patterns change, understanding the background and trauma profile of newly displaced populations is essential to meet their health needs and aid successful resettlement. University-affiliated student-run asylum clinics conduct a growing number of forensic medical evaluations of asylum seekers and provide a vital lens to study changes in this population's profile over time., Methods: A retrospective review was conducted of the first 102 asylum seekers receiving forensic medical evaluations between 2019 and 2021 at a university-affiliated student- run clinic, reporting demographics; trauma, medical, and mental health histories; referral patterns; and legal outcomes. Bivariate statistics were used to investigate the relationship between past trauma and mental health outcomes., Results: Clients reported an average of 4.4 different types of physical, psychological, and sexual ill-treatment per person. The current mental health burden was extensive with 86.9 percent of clients reporting symptoms of PTSD and/or depression. Clinician-student teams evaluated clients within a clinic structure deploying a continuous improvement model to reduce common barriers to forensic evaluations and promote longitudinal follow- up and referrals., Discussion: This study demonstrates the complexity of trauma exposure reported by asylum seekers, contributes to the evidence on how trauma results in mental health outcomes, and describes trauma-centred clinic adaptations that reduce barriers to forensic evaluations known to improve the rates of legal protection.