Three modes of evolution?Remarks on rates of evolution and time scaling.

Rates of evolution get smaller when they are measured over longer time intervals. As first shown by Gingerich, rates of morphological change measured from fossil time series show a robust minus-one scaling with time span, implying that evolutionary changes are just as large when measured over a hundred years as when measured over a hundred-thousand years. On even longer time scales, however, the scaling shifts toward a minus-half exponent consistent with evolution behaving as Brownian motion, as commonly observed in phylogenetic comparative studies. Here, I discuss how such scaling patterns arise, and I derive the patterns expected from standard stochastic models of evolution. I argue that observed shifts cannot be easily explained by simple univariate models, but require shifts in mode of evolution as time scale is changing. To illustrate this idea, I present a hypothesis about three distinct, but connected, modes of evolution. I analyze the scaling patterns predicted from this, and use the results to discuss how rates of evolution should be measured and interpreted. I argue that distinct modes of evolution at different time scales act to decouple micro- and macroevolution, and criticize various attempts at extrapolating from one to the other.

Stable measurement of chemistry, immunochemistry, and hematology analytes in a heparin-based anticoagulant with iloprost additive: A promising candidate for the polyvalent blood collection tube.

INTRODUCTION: A polyvalent blood collection tube could potentially reduce the number and volume of blood samples drawn from patients and reduce the risk of tube mix-ups in a point-of-care setting in the emergency department and the intensive care unit. METHODS: Four different concentrations of our experimental heparin anticoagulant with iloprost additive (HEP-ILOP 50 nM, 150 nM, 1000 nM, and 10 µM, respectively) were tested for significant differences and bias performance specifications against EDTA for 29 hematology analytes, and the highest concentration (HEP-ILOP 10 µM) against lithium heparin for 14 chemistry and immunochemistry analytes. Samples were drawn from 79 consenting subjects from the Oncology Department (n = 38) and the Intensive and Intermediary Care Unit (n = 41). RESULTS: For hematology analytes, the HEP-ILOP formulation generally provided stable measurement within optimal requirements within 5 h after sampling (mean 104 ± 56 min), with very little difference between the four HEP-ILOP concentrations. Because of differences in platelet and red blood cell swelling between EDTA and HEP-ILOP, all size-dependent analytes required proportional factorization to produce similar results. Platelet count by impedance similarly required factorization, whereas the fluorescent method provided results identical with EDTA. Chemistry and immunochemistry analytes were within optimal requirements except for potassium, lactate dehydrogenase, and glucose, indicating a cytoprotective effect of iloprost reducing cell metabolism and rupture, thereby producing results closer to in vivo conditions. CONCLUSIONS: Our novel dry-sprayed anticoagulant formulation, HEP-ILOP, is a promising candidate for a polyvalent blood collection tube, enabling the analysis of hematology, chemistry, and immunochemistry analytes in the same tube.

Systematic large-scale application of ClinGen InSiGHT APC -specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases.

Background: Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUS), APC-specific ACMG/AMP variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP). Methods: A streamlined algorithm using the APC -specific criteria was developed and applied to assess all APC variants in ClinVar and the InSiGHT international reference APC LOVD variant database. Results: A total of 10,228 unique APC variants were analysed. Among the ClinVar and LOVD variants with an initial classification of (Likely) Benign or (Likely) Pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUS were reclassified into clinically actionable classes, the vast majority as (Likely) Benign. The total number of VUS was reduced by 37%. In 21 out of 36 (58%) promising APC variants that remained VUS despite evidence for pathogenicity, a data mining-driven work-up allowed their reclassification as (Likely) Pathogenic. Conclusions: The application of APC -specific criteria substantially reduced the number of VUS in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalisable model for other gene-/disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUS that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

Personalized Intervention Based on Early Detection of Atherosclerosis: JACC State-of-the-Art Review.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required-moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

Interpretability of high-resolution transmission electron microscopy images.

High-resolution electron microscopy is a well-suited tool for characterizing the nanoscale structure of materials. However, the interaction of the sample and the high-energy electrons of the beam can often have a detrimental impact on the sample structure. This effect can only be alleviated by decreasing the number of electrons to which the sample is exposed but will come at the cost of a decreased signal-to-noise ratio in the resulting image. Images with low signal to noise ratios are often challenging to interpret as parts of the sample with a low interaction with the electron beam are reproduced with very low contrast. Here we suggest simple measures as alternatives to the conventional signal-to-noise ratio and investigate how these can be used to predict the interpretability of the electron microscopy images. We test the models on a sample consisting of gold nanoparticles supported on a cerium dioxide substrate. The models are evaluated based on series of images acquired at varying electron dose.

A Population-Based Long-Term Follow-Up of Soft Tissue Angiosarcomas: Characteristics, Treatment Outcomes, and Prognostic Factors.

Angiosarcoma is a rare aggressive and understudied soft tissue sarcoma with pending evidence-based treatment guidelines due to varying study cohorts and inconsistent outcome measures. Surgery with wide resection is currently considered to be the cornerstone in management. In a population-based cohort identified from Danish National Health Registers between 2000 and 2017, this study aimed to define prognostic factors in patients with newly diagnosed soft tissue angiosarcoma. Kaplan-Meier survival analysis demonstrated 5-year overall survival of 28%. Competing risk analysis demonstrated cumulative incidence of local recurrence of 30% and metastasis of 43%. Multivariable Cox models among 154 included patients demonstrated age above 60 years and metastasis to be independently associated with worse overall survival. Cutaneous tumors, surgery, and negative resection margin were independently associated with improved overall survival. Adjuvant oncological treatment did not improve overall survival, risk of metastasis, or recurrence. Negative margin was not associated with lower risk of recurrence and metastasis. We conclude that, despite demonstrated improved survival after surgery with wide resection, overall survival remains poor.

Epigenetic Modifications of White Blood Cell DNA Caused by Transient Fetal Infection with Bovine Viral Diarrhea Virus.

Bovine viral diarrhea virus (BVDV) infections cause USD 1.5-2 billion in losses annually. Maternal BVDV after 150 days of gestation causes transient fetal infection (TI) in which the fetal immune response clears the virus. The impact of fetal TI BVDV infections on postnatal growth and white blood cell (WBC) methylome as an index of epigenetic modifications was examined by inoculating pregnant heifers with noncytopathic type 2 BVDV or media (sham-inoculated controls) on Day 175 of gestation to generate TI (n = 11) and control heifer calves (n = 12). Fetal infection in TI calves was confirmed by virus-neutralizing antibody titers at birth and control calves were seronegative. Both control and TI calves were negative for BVDV RNA in WBCs by RT-PCR. The mean weight of the TI calves was less than that of the controls (p < 0.05). DNA methyl seq analysis of WBC DNA demonstrated 2349 differentially methylated cytosines (p ≤ 0.05) including 1277 hypomethylated cytosines, 1072 hypermethylated cytosines, 84 differentially methylated regions based on CpGs in promoters, and 89 DMRs in islands of TI WBC DNA compared to controls. Fetal BVDV infection during late gestation resulted in epigenomic modifications predicted to affect fetal development and immune pathways, suggesting potential consequences for postnatal growth and health of TI cattle.

Actionability and familial uptake following opportunistic genomic screening in a pediatric cancer cohort.

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified. A secondary finding was reported to 19/595 (3.2%) probands primarily in genes related to cardiovascular and lipid disorders. After a mean follow up time of 1.6 years (Interquartile range (IQR): 0.57-1.92 yrs.) only 12 (63%) of these variants were found to be medically actionable. Clinical follow up or treatment was planned in 16 relatives, and as in the probands, the prescribed treatment was primarily betablockers or cholesterol lowering therapy. No invasive procedures or implantation of medical devices were performed in probands or relatives, and no reproductive counseling was requested. After an average of 1.6 years of follow-up 2.25 relatives per family with an actionable finding had been tested. This real-world experience of OGS grants new insight into the practical implementation effects and derived health care demands of genotype-first screening. The resulting health care effect and impact on demand for genetic counseling and workup in relatives extends beyond the effect in the probands.

Evolvability predicts macroevolution under fluctuating selection.

Heritable variation is a prerequisite for evolutionary change, but the relevance of genetic constraints on macroevolutionary timescales is debated. By using two datasets on fossil and contemporary taxa, we show that evolutionary divergence among populations, and to a lesser extent among species, increases with microevolutionary evolvability. We evaluate and reject several hypotheses to explain this relationship and propose that an effect of evolvability on population and species divergence can be explained by the influence of genetic constraints on the ability of populations to track rapid, stationary environmental fluctuations.

Controversies in orthopaedic oncology.

Chondrosarcoma is the second most common surgically treated primary bone sarcoma. Despite a large number of scientific papers in the literature, there is still significant controversy about diagnostics, treatment of the primary tumour, subtypes, and complications. Therefore, consensus on its day-to-day treatment decisions is needed. In January 2024, the Birmingham Orthopaedic Oncology Meeting (BOOM) attempted to gain global consensus from 300 delegates from over 50 countries. The meeting focused on these critical areas and aimed to generate consensus statements based on evidence amalgamation and expert opinion from diverse geographical regions. In parallel, periprosthetic joint infection (PJI) in oncological reconstructions poses unique challenges due to factors such as adjuvant treatments, large exposures, and the complexity of surgery. The meeting debated two-stage revisions, antibiotic prophylaxis, managing acute PJI in patients undergoing chemotherapy, and defining the best strategies for wound management and allograft reconstruction. The objectives of the meeting extended beyond resolving immediate controversies. It sought to foster global collaboration among specialists attending the meeting, and to encourage future research projects to address unsolved dilemmas. By highlighting areas of disagreement and promoting collaborative research endeavours, this initiative aims to enhance treatment standards and potentially improve outcomes for patients globally. This paper sets out some of the controversies and questions that were debated in the meeting.

Genome-wide association study reveals a locus in ADARB2 for complete freedom from headache in Danish Blood Donors.

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders.

Large-cage occupation and quantum dynamics of hydrogen molecules in sII clathrate hydrates.

Hydrogen clathrate hydrates are ice-like crystalline substances in which hydrogen molecules are trapped inside polyhedral cages formed by the water molecules. Small cages can host only a single H2 molecule, while each large cage can be occupied by up to four H2 molecules. Here, we present a neutron scattering study on the structure of the sII hydrogen clathrate hydrate and on the low-temperature dynamics of the hydrogen molecules trapped in its large cages, as a function of the gas content in the samples. We observe spectral features at low energy transfer (between 1 and 3 meV), and we show that they can be successfully assigned to the rattling motion of a single hydrogen molecule occupying a large water cage. These inelastic bands remarkably lose their intensity with increasing the hydrogen filling, consistently with the fact that the probability of single occupation (as opposed to multiple occupation) increases as the hydrogen content in the sample gets lower. The spectral intensity of the H2 rattling bands is studied as a function of the momentum transfer for partially emptied samples and compared with three distinct quantum models for a single H2 molecule in a large cage: (i) the exact solution of the Schrödinger equation for a well-assessed semiempirical force field, (ii) a particle trapped in a rigid sphere, and (iii) an isotropic three-dimensional harmonic oscillator. The first model provides good agreement between calculations and experimental data, while the last two only reproduce their qualitative trend. Finally, the radial wavefunctions of the three aforementioned models, as well as their potential surfaces, are presented and discussed.

Adhesin domains responsible for binding bacteria to surfaces they colonize project outwards from companion split domains.

Bacterial adhesins attach their hosts to surfaces that the bacteria will colonize. This surface adhesion occurs through specific ligand-binding domains located towards the distal end of the long adhesin molecules. However, recognizing which of the many adhesin domains are structural and which are ligand binding has been difficult up to now. Here we have used the protein structure modeling program AlphaFold2 to predict structures for these giant 0.2- to 1.5-megadalton proteins. Crystal structures previously solved for several adhesin regions are in good agreement with the models. Whereas most adhesin domains are linked in a linear fashion through their N- and C-terminal ends, ligand-binding domains can be recognized by budding out from a companion core domain so that their ligand-binding sites are projected away from the axis of the adhesin for maximal exposure to their targets. These companion domains are "split" in their continuity by projecting the ligand-binding domain outwards. The "split domains" are mostly ß-sandwich extender modules, but other domains like a ß-solenoid can serve the same function. Bioinformatic analyses of Gram-negative bacterial sequences revealed wide variety ligand-binding domains are used in their Repeats-in-Toxin adhesins. The ligands for many of these domains have yet to be identified but known ligands include various cell-surface glycans, proteins, and even ice. Recognizing the ligands to which the adhesins bind could lead to ways of blocking colonization by bacterial pathogens. Engineering different ligand-binding domains into an adhesin has the potential to change the surfaces to which bacteria bind.

Elevated cobalt levels in metal-on-polyethylene knee megaprostheses: a prospective 1-year cohort study of 56 patients with hip and knee megaprostheses.

BACKGROUND AND PURPOSE: Concerns have emerged regarding elevated levels of cobalt and chromium in patients with metal-on-metal megaprostheses. This prospective study aims to identify systemic cobalt and chromium levels in metal-on-polyethylene knee and hip megaprostheses and their associations with other factors. METHODS: 56 patients underwent knee or hip megaprosthesis surgery at 2 sarcoma centers. Serum cobalt and chromium levels were measured preoperatively and thrice within the first year using inductively coupled plasma mass spectrometry. RESULTS: A statistically significant difference in serum cobalt levels (1.4 ppb; 95% confidence interval [CI] 0.0-3.3) was observed 1 year after knee megaprosthesis surgery compared with preoperative levels. In contrast no difference in chromium levels was observed after 1 year compared with preoperative levels (0.05 ppb; CI 0.0-0.8). An association between younger age, higher eGFR, and increased cobalt levels was observed. No significant correlations were found between ion levels and resection length or the number of modular connections. CONCLUSION: We found elevated serum ion levels in metal-on-polyethylene knee megaprostheses in contrast to metal-on-polyethylene hip megaprostheses. Furthermore, a positive correlation between cobalt and chromium levels, and between cobalt and eGFR was identified, along with a negative correlation between cobalt and age. This study highlights the importance of monitoring systemic cobalt and chromium levels in patients with megaprostheses.

Bringing Real Inquiry-Based Science to Diverse Secondary Educational Environments: A Virtual Zebrafish Laboratory to Investigate Environmental Health.

The goal of the University of Wisconsin-Milwaukee WInSTEP SEPA program is to provide valuable and relevant research experiences to students and instructors in diverse secondary educational settings. Introducing an online experience allows the expansion of a proven instructional research program to a national scale and removes many common barriers. These can include lack of access to zebrafish embryos, laboratory equipment, and modern classroom facilities, which often deny disadvantaged and underrepresented students from urban and rural school districts valuable inquiry-based learning opportunities. An online repository of zebrafish embryo imagery was developed in the Carvan laboratory to assess the effects of environmental chemicals. The WInSTEP SEPA program expanded its use as an accessible online tool, complementing the existing classroom experience of our zebrafish module. This virtual laboratory environment contains images of zebrafish embryos grown in the presence of environmental toxicants (ethanol, caffeine, and nicotine), allowing students to collect data on 19 anatomical endpoints and generate significant amounts of data related to developmental toxicology and environmental health. This virtual laboratory offers students and instructors the choice of data sets that differ in the independent variables of chemical concentration and duration of postfertilization exposure. This enables students considerable flexibility in establishing their own experimental design to match the curriculum needs of each instructor.

Novel Alu insertion in the ZEB2 gene causing Mowat-Wilson syndrome.

Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat-Wilson syndrome, a rare neurodevelopmental disorder, in an 8-year-old boy displaying the typical clinical features for Mowat-Wilson syndrome. The variant was not initially detected in genome sequencing data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene. Nanopore long-read sequencing confirmed the Alu insertion, leading to the formation of a premature stop codon and likely haploinsufficiency of ZEB2. This underscores the importance of deep phenotyping and mobile element insertion analysis in uncovering genetic causes of monogenic disorders as these elements might be overlooked in standard next-generation sequencing protocols.

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

ciRS-7 and miR-7 regulate ischemia-induced neuronal death via glutamatergic signaling.

Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.