Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform.

Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype-driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina-enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell-type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non-consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non-coding regions or structural variants that remained undetected, warranting future WGS studies.

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Aberrant methylation in neurofunctional gene serves as a hallmark of tumorigenesis and progression in colorectal cancer.

BACKGROUND: DNA methylation is one of the most promising biomarkers in predicting the prognosis of colorectal cancer (CRC). We aimed to develop a DNA methylation biomarker that could evaluate the prognosis of CRC. METHODS: A promising DNA methylation biomarker was developed by hypermethylated genes in cancer tissue that were identified from Illumina EPIC methylation arrays. A cohort comprising 30 pairs of snap-frozen tumor tissue and adjacent normal tissue was used for correlation analysis between the methylation and expression status of the marker. The other cohort comprising 254 formalin-fixed paraffin-embedded (FFPE) tumor tissue from 254 CRC patients was used for prognosis analysis. RESULTS: Regulating synaptic membrane exocytosis 2 (RIMS2) was hypermethylated and lowly expressed in CRC comparing to adjacent normal tissue. Hypermethylation of RIMS2 in CRC was correlated with less frequent KRAS mutant and high differentiation. RIMS2 promoter methylation showed independent predictive value for survival outcome (P = 0.015, HR 1.992, 95% CI [(1.140-3.48)]), and a combination of RIMS2 methylation with KRAS status could predict prognosis better. CONCLUSIONS: RIMS2 is frequently hypermethylated in CRC, which can silence the expression of RIMS2. RIMS2 methylation is a novel biomarker for predicting the prognosis of CRC.

CircRIMS promotes cerebral ischemia-reperfusion injury through increasing apoptosis and targeting the miR-96-5p/JAK/STAT1 axis.

OBJECTIVE: This study aims to explore the function of circRIMS in cerebral ischemia/reperfusion (CIR) and its regulatory mechanism. METHOD: The expression of the circRIMS was examined in GEO chip data and validated by qRT-PCR analysis. A middle cerebral artery occlusion/repression (MCAO/R) model was developed using C57BL/6J mice. Starbase and circinteractome were employed to identify the target miRNA and mRNA. The result was confirmed by dual-luciferase reporter assay, and biotinylated RNA-pulldown assay. The cell viability and apoptosis were confirmed through CCK-8 and flow cytometry assay. RESULTS: This study revealed that circRIMS expression was upregulated in MCAO mice model and OGD/RX-simulated cell model. Knockdown circRIMS demonstrated the functional of circRIMS in increasing cell viability, reducing apoptosis, LDH activity and inflammatory factors secretion in OGD/RX-simulated CIR injury in vitro. Additionally, miR-96-5p was identified as a target of circRIMS, while the STAT1 gene is a downstream gene of miR-96-5p, and JAK was also considered to be a downstream gene of the JAK-STAT pathway. Furthermore, inhibition of miR-96-5p or overexpression of STAT1 promoted the progression of CIR injury by elevating apoptosis, reducing cell viability, and increasing the secretion of inflammatory cytokines. CONCLUSION: CircRIMS contributes to the progression of CIR injury via regulating miR-96-5p/JAK/STAT1 axis.

CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event.

BACKGROUND: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis. OBJECTIVE: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event. METHODS: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (ß = 1.41; 95% confidence interval (CI) = 1.10-1.79; p < 0.01) and serum NfL levels (ß = 2.30; 95% CI = 1.47-3.60; p < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (ß = 1.45; 95% CI = 1.11-1.90; p < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses. CONCLUSION: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.

Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

A clinical and electrophysiological case study of a child with a novel frame shift mutation in the CACNA1F and missense variation of RIMS1 genes.

PURPOSE: The purpose of this paper is to present a case study illustrating the importance of electrophysiological investigation in the diagnosis and serial monitoring of isolated congenital nystagmus. RESULTS: Serial electophysiological monitoring was undertaken in the male proband over a 9-year period commencing with initial assessment at 12 weeks of age: Skin electroretinograms (sERGs) were initially absent but subsequently revealed low-amplitude responses, electronegative morphologies and notched flicker responses suggestive of incomplete congenital stationary night blindness (CSNB2), but with an absent dark-adapted rod-specific response, while flash visual evoked potentials (fVEPs) demonstrated persistent crossed asymmetry, typical of albinoid misrouting of the optic nerves. Molecular investigation confirmed a novel hemizygous frame shift mutation in the CACNA1F gene, considered to be pathogenic and causative of X-linked CSNB2; additionally, a novel heterozygous missense variation in one copy of the RIMS1 gene was identified, pathogenic mutations of which underpin late-onset autosomal dominant cone-rod dystrophy (type 7). Segregation studies confirmed maternal inheritance of both mutations in the clinically asymptomatic mother in whom depressed rod-specific responses were confirmed on sERG. The child's visual acuity has remained stable as have the sERGs which have been verified by recordings using scleral electrodes. CONCLUSIONS: The importance of recording ERGs as part of evaluating infants who present with nystagmus, even with a normal fundus appearance, is supported. Further, sERGs were able to distinguish an apparent variant of CSNB2 and could give consistent results over many years. FVEP results add to the evidence that albinoid misrouting of the optic nerves may occur in cases of CSNB2. ERGs and fVEPs can provide valuable information in discriminating the relative diagnostic importance of multiple genetic abnormalities.

Characterisation of corneas following different time and storage methods for their use as a source of stem-like limbal epithelial cells.

The transplantation of expansions of limbal epithelial stem cells (LESC) remains one of the most efficient therapies for the treatment of limbal stem cell deficiency (LSCD) to date. However, the available donor corneas are scarce, and the corneas conserved for long time, under hypothermic conditions (after 7 days) or in culture (more than 28 days), are usually discarded due to poor viability of the endothelial cells. To establish an objective criterion for the utilisation or discarding of corneas as a source of LESC, we characterized, by immunohistochemistry analysis, donor corneas conserved in different conditions and for different periods of time. We also studied the potency of LESCs isolated from these corneas and maintained in culture up to 3 cell passages. We hoped that the study of markers of LESCs present in both the corneoscleral histological sections and the cell cultures would show the adequacy of the methods used for cell isolation and how fit the LESC enrichment of the obtained cell populations to be expanded was. Thus, the expressions of markers of the cells residing in the human limbal and corneal epithelium (cytokeratin CK15 and CK12, vimentin, Collagen VII, p63α, ABCG2, Ki67, Integrin ß4, ZO1, and melan A) were analysed in sections of corneoscleral tissues conserved in hypothermic conditions for 2-9 days with post-mortem time (pmt) < 8 h or for 1 day with pmt > 16 h, and in sclerocorneal rims maintained in an organ culture medium for 29 days. Cell populations isolated from donor corneoscleral tissues were also assessed based on these markers to verify the adequacy of isolation methods and the potential of expanding LESCs from these tissues. Positivity for several putative stem cell markers such as CK15 and p63α was detected in all corneoscleral tissues, although a decrease was recorded in the ones conserved for longer times. The barrier function and the ability to adhere to the extracellular matrix were maintained in all the analysed tissues. In limbal epithelial cell cultures, a simultaneous decrease in the melan A melanocyte marker and the putative stem cell markers was detected, suggesting a close relationship between the melanocytes and the limbal stem cells of the niche. Holoclones stained with putative stem cell markers were obtained from long-term, hypothermic, stored sclerocorneal rims. The results showed that the remaining sclerocorneal rims after corneal transplantation, which were conserved under hypothermic conditions for up to 7 days and would have been discarded at a first glance, still maintained their potential as a source of LESC cultures.

Implementation of a Research Information Management System in a Pediatric Hospital.

Faculty publications have been collected in universities, health, and medical institutions for many years, and Cincinnati Children's is no exception. Since 1949, a yearly list of faculty publications was manually compiled using multiple data sources and disseminated by the Edward L. Pratt Research Library. Products to centralize faculty publication collection and analysis with bibliometric tools are growing in popularity. This article will review the collaborative decision to choose a Research Information Management System and the implementation process including successes, challenges, and future opportunities.

Promoting and Tracking Institutional Scholarship with Implementation of a Librarian-Curated Digital Repository and Research Information Management System.

Library staff at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell implemented a digital repository to collect and showcase the scholarly output of the medical school and the Northwell Health system. This repository, entitled Zucker School of Medicine Academic Works, promotes scholarship by faculty, trainees, and staff via a centralized public website. With links to the full text and faculty profiles, the repository facilitates access and discoverability in alignment with the value of scholarship at the institution. Subsequent implementation of a research information management system to harvest publications further enhances the goals of tracking, promoting, and reporting impact of the scholarly activities. This article reviews successes and challenges, and collaboration with other stakeholder departments.

Design of Complete Dentures by Adopting CAD Developed for Fixed Prostheses.

The demand for complete dentures is expected to increase worldwide, but complete dentures are mainly designed and fabricated manually involving a broad series of clinical and laboratory procedures. Therefore, the quality of complete dentures largely depends on the skills of the dentist and technician, leading to difficulty in quality control. Computer-aided design and manufacturing (CAD/CAM) has been used to design and fabricate various dental restorations including dental inlays, veneers, crowns, partial crowns, and fixed partial dentures (FPDs). It has been envisioned that the application of CAD/CAM technology could reduce intensive clinical/laboratory work for the fabrication of complete dentures; however, CAD/CAM is seldom used to fabricate complete dentures due to the lack of suitable CAD software to design virtual complete dentures although the CAM techniques are in a much advanced stage. Here we report the successful design of virtual complete dentures using CAD software of 3Shape Dental System 2012, which was developed for designing fixed prostheses instead of complete dentures. Our results demonstrated that complete dentures could be successfully designed by the combination of two modeling processes, single coping and full anatomical FPD, available in the 3Shape Dental System 2012.

Differential synaptic distribution of the scaffold proteins Cask and Caskin1 in the bovine retina.

Scaffold proteins organize pre- and postsynaptic compartments and align pre- and postsynaptic events. Cask is a multi-domain scaffold protein essential for brain synaptic functions. Caskin1 is a recently discovered, brain-specific Cask-interacting multi-domain protein of unknown function. In the present study, we determined the localization of these scaffold proteins in the bovine retina. The retina contains tonically active ribbon synapses and conventional synapses. We found Cask highly enriched in virtually all retinal synapses. Cask was localized in close vicinity to the active zone protein RIM1/2 in ribbon and conventional synapses. Caskin1 is also enriched in retinal synapses but is present only in a subset of Cask-positive synapses. These findings suggest that Cask plays an important role in all retinal synapses. In contrast, Caskin1 appears to execute more specialized functions in distinct sets of retinal synapses, possibly for neuronal pathway formation and stabilization of distinct synaptic contacts.

Gene knockout of RNA binding motif 5 in the brain alters RIMS2 protein homeostasis in the cerebellum and Hippocampus and exacerbates behavioral deficits after a TBI in mice.

RNA binding motif 5 (RBM5) is a tumor suppressor in cancer but its role in the brain is unclear. We used conditional gene knockout (KO) mice to test if RBM5 inhibition in the brain affects chronic cortical brain tissue survival or function after a controlled cortical impact (CCI) traumatic brain injury (TBI). RBM5 KO decreased baseline contralateral hemispheric volume (p < 0.0001) and exacerbated ipsilateral tissue loss at 21 d after CCI in male mice vs. wild type (WT) (p = 0.0019). CCI injury, but not RBM5 KO, impaired beam balance performance (0-5d post-injury) and swim speed on the Morris Water Maze (MWM) (19-20d) (p < 0.0001). RBM5 KO was associated with mild learning impairment in female mice (p = 0.0426), reflected as a modest increase in escape latency early in training (14-18d post-injury). However, KO did not affect spatial memory at 19d post-injury in male or in female mice but it was impaired by CCI in females (p = 0.0061). RBM5 KO was associated with impaired visual function in male mice on the visible platform test at 20d post-injury (p = 0.0256). To explore signaling disturbances in KOs related to behavior, we first cross-referenced known brain-specific RBM5-regulated gene targets with genes in the curated RetNet database that impact vision. We then performed a secondary literature search on RBM5-regulated genes with a putative role in hippocampal function. Regulating synaptic membrane exocytosis 2 (RIMS) 2 was identified as a gene of interest because it regulates both vision and hippocampal function. Immunoprecipitation and western blot confirmed protein expression of a novel ~170 kDa RIMS2 variant in the cerebellum, and in the hippocampus, it was significantly increased in KO vs WT (p < 0.0001), and in a sex-dependent manner (p = 0.0390). Furthermore, male KOs had decreased total canonical RIMS2 levels in the cerebellum (p = 0.0027) and hippocampus (p < 0.0001), whereas female KOs had increased total RIMS1 levels in the cerebellum (p = 0.0389). In summary, RBM5 modulates brain function in mammals. Future work is needed to test if RBM5 dependent regulation of RIMS2 splicing effects vision and cognition, and to verify potential sex differences on behavior in a larger cohort of mice.

Research and experimental verification of lightweight loader rims.

The safety performance and structural stiffness of a rim, which is the main load-bearing structure of the loader during operation, influence the overall performance, stability, and braking capabilities of the machine. In the industry, researchers are currently pursuing lightweight and high-strength rims as a primary objective. A low weight not only enhances machinery fuel efficiency but also aligns with societal demands for sustainable development, energy conservation, and emission reduction. In this article, multiobjective optimization analysis on rims composed of three different materials is performed, and the relationships between various optimization parameters and target parameters are established using the results of response surface construction. Multiobjective genetic algorithms are utilized to derive various optimization plans, which are subsequently evaluated through static analysis, fatigue analysis, and weight loss analysis. The final optimization plan is determined based on the calculation results while considering production costs. Field tests are conducted on the optimized rims under various working conditions to verify the test results, evaluate the reliability of the finite element analysis results, and confirm the safety of the optimized rim.

Validation of the Revised Impact of Miscarriage Scale in the Republic of Burundi: A cross-sectional multicenter study.

OBJECTIVE: The objective of this study was to translate and validate the Revised Impact of Miscarriage Scale (RIMS) into Kirundi for use among women and men in Burundi. Additionally, the study aimed to compare the experience and personal meaning of miscarriage between women and men. METHODS: This is a cross-sectional multicentered study. The RIMS was translated into Kirundi. Cronbach coefficient alpha and its internal consistency were measured for both genders. An exploratory factor analysis (EFA) was used to determine the underlying factors and the shared variance. Both women and men completed the RIMS questionnaire, while women completed sociodemographic, reproductive and mental health questions. RESULTS: In all, 79 couples completed the RIMS. The original factor structure was retained after the EFA, with 68% of the shared variance explained in the three-factor solution with 16 questions. Isolation/guilt, Loss of baby, and Devastating event. The internal consistency for women and men combined was α = 0.928. Although women scored higher on the factors of Isolation/guilt and Loss of baby, there were no significant differences in the Devastating event factor between women and men. Couples scores were positively correlated. Women who had experienced a previous miscarriage were more significantly impacted by all three factors compared to women experiencing their first miscarriage. CONCLUSIONS: The Kirundi translation of the RIMS retained the original factor structure and demonstrated excellent internal consistency α = 0.928 in women and men combined. The RIMS could be a tool for caregivers to identify individuals who require additional support after a miscarriage.

Multi-element isotopic analysis of hot particles from Chornobyl.

Microscopic fuel fragments, so-called "hot particles", were released during the 1986 accident at the Chornobyl nuclear powerplant and continue to contaminate the exclusion zone in northern Ukraine. Isotopic analysis can provide vital information about sample origin, history and contamination of the environment, though it has been underutilized due to the destructive nature of most mass spectrometric techniques, and inability to remove isobaric interference. Recent developments have diversified the range of elements that can be investigated through resonance ionization mass spectrometry (RIMS), notably in the fission products. The purpose of this study is to demonstrate the application of multi-element analysis on hot particles as relates to their burnup, particle formation in the accident, and weathering. The particles were analysed with two RIMS instruments: resonant-laser secondary neutral mass spectrometry (rL-SNMS) at the Institute for Radiation Protection and Radioecology (IRS) in Hannover, Germany, and laser ionization of neutrals (LION) at Lawrence Livermore National Laboratory (LLNL) in Livermore, USA. Comparable results across instruments show a range of burnup dependent isotope ratios for U and Pu and Cs, characteristic of RBMK-type reactors. Results for Rb, Ba and Sr show the influence of the environment, retention of Cs in the particles and time passed since fuel discharge.

Single tertiary center experience using Gore Cardioform Atrial Septal Defect Occluder for secundum atrial septal defect closure with a focus on deficient rims.

BACKGROUND: The data on the use of Gore Cardioform Septal Occluder (GCA; W. L. Gore and Associates, Inc.) for atrial septal defect (ASD) with deficient rims is limited. METHODS: All patients evaluated by transesophageal echocardiogram (TEE) for ASD occlusion were included. TEE planes at 35°, 0°, and 90° were assessed for anterior-superior (AS) and posterior (P), anterior-inferior (AI) and posterior-superior (PS), as well as superior (S) and inferior (I) rims. ASD size >20 mm, and rims less than 5 mm were defined as large and deficient, respectively. We included patients who had a procedural failure along with the patients in whom the procedure was not attempted after echocardiogram in the unsuccessful group. RESULTS: In 148 patients, the median weight, age, and ASD size were 36 kg (range, 8-60 kg), 11.8 years (range, 1-60 years), and 14.2 ± 8.28 mm, respectively. One or more deficient rims were noted in 112 of 148 (75.7%): 99 (67%) AS, 36 (24%) P, 17 (11%) AI, 30 (20%) PS, 26 (18%) S, and 33 (22%) I. ASD closure was performed in 115 (78%) patients. The procedure was successful in 111 (96.5%) patients with procedural failure in 4 (3.4%) patients. Multiple deficient rims were associated with reduced procedural success (OR 0.36, 95% CI, 0.25-0.56). On multivariate analysis deficient P, PS, and I rims were associated with an unsuccessful group (P = .001, .046, and .005, respectively). Complications included 1 device embolization, 1 vascular injury, and 5 arrhythmias. CONCLUSIONS: Transcatheter closure of ASDs with deficient rims is feasible using GCA. Large ASDs with deficient P, PS, and I rims were associated with unsuccessful closure. Risk stratification and comprehensive evaluation of ASD rims is vital for the use of GCA.

Diverse glasses revealed from Chang'E-5 lunar regolith.

Lunar glasses with different origins act as snapshots of their formation processes, providing a rich archive of the Moon's formation and evolution. Here, we reveal diverse glasses from Chang'E-5 (CE-5) lunar regolith, and clarify their physical origins of liquid quenching, vapor deposition and irradiation damage respectively. The series of quenched glasses, including rotation-featured particles, vesicular agglutinates and adhered melts, record multiple-scale impact events. Abundant micro-impact products, like micron- to nano-scale glass droplets or craters, highlight that the regolith is heavily reworked by frequent micrometeorite bombardment. Distinct from Apollo samples, the indigenous ultra-elongated glass fibers drawn from viscous melts and the widespread ultra-thin deposited amorphous rims without nanophase iron particles both indicate a relatively gentle impact environment at the CE-5 landing site. The clarification of multitype CE-5 glasses also provides a catalogue of diverse lunar glasses, meaning that more of the Moon's mysteries, recorded in glasses, could be deciphered in future.

B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

BACKGROUND: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. METHODS: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). INTERPRETATION: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. FUNDING: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

The impact of the COVID-19 pandemic on physical therapy practice for people with multiple sclerosis: A multicenter survey study of the RIMS network.

BACKGROUND: The impact of the COVID-19 pandemic on physical therapy services for people with multiple sclerosis (pwMS) is unknown. Therefore, the Special Interest Group for Mobility (SIG Mobility) of the European Network for Best Practice and Research in Multiple Sclerosis Rehabilitation (RIMS) has undertaken the initiative to examine the impact of the COVID-19 outbreak on physical therapy services and physical activity participation in pwMS across Europe, Israel and Australia. OBJECTIVE: To describe the impact of the COVID-19 outbreak on physical therapy practice from the perspective of the therapist. METHODS: An online survey was developed and conducted from December 2020 to July 2021. The survey (50 questions), included multiple-choice questions and open-ended responses. RESULTS: In total, 215 physical therapists (PT's) from 9 countries (Australia, Belgium, the Czech Republic, Ireland, Israel, Italy, Norway, Spain, and Turkey) participated in the study. The therapy most affected during the pandemic was aerobic training/conditioning exercises; 33.5% reported that these activities were either reduced or unavailable. In contrast, 15% of the PTs reported increased use of relaxation/mind body techniques and/or fatigue management programs during the pandemic. PTs reported a mixture of positive and negative feelings about the therapeutic sessions offered during the pandemic. Most reported positive feelings included "positive" (26.5%), and "optimistic" (24.7%). Negative feelings most frequently reported included "worried" (30.7%), and "hesitant" (20.9%). The PTs reported a 10% decrease in the use of hands-on techniques and a 10% increase in the use of oral instructions when treating moderately and severely pwMS during as compared to before the pandemic. CONCLUSION: The COVID-19 pandemic has affected physical therapy services in pwMS internationally in terms of content, frequency of use and format.