bluuebunny/crossref_metadata_2025_split huggingface dataset:
HTLV-1 infected T cells cause bone loss via small extracellular vesicles
Authors: Pokhrel Nitin Kumar , Panfil Amanda , Habib Haniya , Seeniraj Sham , Joseph Ancy , Rauch Daniel , Cox Linda , Sprung Robert , Gilmore Petra Erdmann , Zhang Qiang , Townsend R Reid , Yu Lianbo , Yilmaz Ayse Selen , Aurora Rajeev , Park William , Ratner Lee , Weilbaecher Katherine N , Veis Deborah J 
Published: March 2024

AbstractAdult T cell leukemia (ATL), caused by infection with human T cell leukemia virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T lead to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted formation of mature osteoclasts, while those from HTLV/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine RANKL, suggesting an alternative mechanism. HTLV/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV injected over mouse calvaria in the presence of low dose RANKL caused more osteolysis than RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukemia.
miR-155 expression and function in leukemic stem cells
Authors: Garzon Ramiro , Croce Carlo M 
Published: March 2024

ABSTRACTIt has been reported that elevated levels of miR-155 have been reported in patients with Acute Myeloid Leukemia (AML) bearingFLT3-ITD mutations and is independent ofFLT3-ITD signaling. However, it is unclear how miR-155 is expressed in leukemic stem cells (LCS) and whether miR-155 has any role regulating LSC functions. In this manuscript, we defined the expression of miR-155 in clearly defined LCSs population and showed that miR-155 is regulating self-renewal and quiescence of LSCs.
Clinical Performance of Cas13a-based Point-of-Care Lateral Flow Assay for DetectingNeisseria gonorrhoeae
Authors: Allan-Blitz Lao-Tzu , Sanders Gabriela , Shah Palak , Adams Gordon , Jarolimova Jana , Ard Kevin , Branda John A. , Klausner Jeffrey D. , Sabeti Pardis C. , Lemieux Jacob E. 
Published: March 2024

AbstractBackgroundDiagnosis ofNeisseria (N.) gonorrhoeaeis dependent on nucleic acid amplification testing (NAAT), which is not available in resource-limited settings where the prevalence of infection is highest. Recent advances in molecular diagnostics leveraging the high specificity of CRISPR enzymes can permit field-deployable, point-of-care lateral flow assays. We previously reported on the development andin vitroperformance of a lateral flow assay for detectingN. gonorrhoeae. Here we aimed to pair that assay with point-of-care DNA extraction techniques and assess the performance on clinical urine specimens.MethodsWe collected an additional urine specimen among individuals enrolling in an ongoing clinical trial at the Massachusetts General Hospital Sexual Health Clinic who presented with symptoms of urethritis or cervicitis (urethral or vaginal discharge, dysuria, or dyspareunia). We then assessed thermal, detergent, and combination DNA extraction conditions, varying the duration of heat at 95°C and concentration of Triton X. We assessed the efficacy of the various DNA extraction methods by quantitative polymerase chain reaction (qPCR). Once an extraction method was selected, we incubated samples for 90 minutes to permit isothermal recombinase polymerase amplification. We then assessed the performance of lateral flow Cas13a-based detection using our previously designedporA probe and primer system forN. gonorrhoeaedetection, comparing lateral flow results with NAAT results from clinical care.ResultsWe assessed DNA extraction conditions on 3 clinical urine specimens. There was no consistent significant difference in copies per microliter of DNA obtained using more or less heat. On average, we noted that 0.02% triton combined with 5 minutes of heating to 95°C resulted in the highest DNA yield, however, 0.02% triton alone resulted in a quantity of DNA that was above the previously determined analytic sensitivity of the assay. Given that detergent-based extraction is more easily deployable, we selected that as our method for extraction. We treated 23 clinical specimens with 0.02% triton, which we added to the Cas13a detection system. We ran all lateral flow detections in duplicate. The Cas13a-based assay detected 8 of 8 (100%) positive specimens, and 0 of 15 negative specimens.ConclusionUsing point-of-care DNA extraction, isothermal amplification, and Cas13a-based detection, our point-of-care lateral flowN. gonorrhoeaeassay correctly identified 23 clinical urine specimens as either positive or negative. Further evaluation of this assay among larger samples and more diverse sample types is warranted.
Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice
Authors: Shaw Dana C. , Kondabolu Krishnakanth , Walsh Katherine G. , Shi Wen , Rillosi Enrico , Hsiung Maxine , Eden Uri T. , Richardson Robert M. , Kramer Mark A. , Chu Catherine J. , Han Xue 
Published: March 2024

AbstractObjectiveInterictal epileptiform spikes, high-frequency ripple oscillations, and their co-occurrence (spike ripples) in human scalp or intracranial voltage recordings are well-established epileptic biomarkers. While clinically significant, the neural mechanisms generating these electrographic biomarkers remain unclear. To reduce this knowledge gap, we introduce a novel photothrombotic stroke model in mice that reproduces focal interictal electrographic biomarkers observed in human epilepsy.MethodsWe induced a stroke in the motor cortex of C57BL/6 mice unilaterally (N=7) using a photothrombotic procedure previously established in rats. We then implanted intracranial electrodes (2 ipsilateral and 2 contralateral) and obtained intermittent local field potential (LFP) recordings over several weeks in awake, behaving mice. We evaluated the LFP for focal slowing and epileptic biomarkers - spikes, ripples, and spike ripples - using both automated and semi-automated procedures.ResultsDelta power (1-4 Hz) was higher in the stroke hemisphere than the non-stroke hemisphere in all mice (p<0.001). Automated detection procedures indicated that compared to the non-stroke hemisphere, the stroke hemisphere had an increased spike ripple (p=0.006) and spike rates (p=0.039), but no change in ripple rate (p=0.98). Expert validation confirmed the observation of elevated spike ripple rates (p=0.008) and a trend of elevated spike rate (p=0.055) in the stroke hemisphere. Interestingly, the validated ripple rate in the stroke hemisphere was higher than the non-stroke hemisphere (p=0.031), highlighting the difficulty of automatically detecting ripples. Finally, using optimal performance thresholds, automatically detected spike ripples classified the stroke hemisphere with the best accuracy (sensitivity 0.94, specificity 0.94).SignificanceCortical photothrombosis-induced stroke in commonly used C57BL/6 mice produces electrographic biomarkers as observed in human epilepsy. This model represents a new translational cortical epilepsy model with a defined irritative zone, which can be broadly applied in transgenic mice for cell type specific analysis of the cellular and circuit mechanisms of pathologic interictal activity.Key PointsCortical photothrombosis in mice produces stroke with characteristic intermittent focal delta slowing.Cortical photothrombosis stroke in mice produces the epileptic biomarkers spikes, ripples, and spike ripples.All biomarkers share morphological features with the corresponding human correlate.Spike ripples better lateralize to the lesional cortex than spikes or ripples.This cortical model can be applied in transgenic mice for mechanistic studies.
Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease
Authors: Hector Audrey , da Costa Caiado Maria João , Leduc Tanya , Delignat-Lavaud Benoît , Dufort-Gervais Julien , Bourguignon Clément , Lina Jean-Marc , Fernandes Karl , Brouillette Jonathan , Mongrain Valérie 
Published: March 2024

ABSTRACTThe symptomatology of Alzheimer’s disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.
Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI
Authors: Stachowski Nicholas J. , Wheel Jaimena H. , Atoche Sebastian J. , Yao Lihua , Garcia-Ramirez D. Leonardo , Giszter Simon F. , Dougherty Kimberly J. 
Published: March 2024

SUMMARYVarious strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. In a mouse model of complete SCI, virally-delivered BDNF (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas sub-motor threshold epidural stimulation (ES) reduced BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory RORβ neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings revealed that the excitability of RORβ neurons was decreased in mice with poor locomotor function after SCI, but was similar between the uninjured and ‘best stepping’ SCI groups. Further, chemogenetic excitation of RORβ neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory RORβ neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.
Genome-wide association study between SARS-CoV-2 single nucleotide polymorphisms and virus copies during infections
Authors: Li Ke , Chaguza Chrispin , Stamp Julian , Chew Yi Ting , Chen Nicholas F.G. , Ferguson David , Pandya Sameer , Kerantzas Nick , Schulz Wade ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Hahn Anne M. , Ogbunugafor C Brandon , Pitzer Virginia E. , Crawford Lorin , Weinberger Daniel M. , Grubaugh Nathan D. 
Published: March 2024

AbstractSignificant variations have been observed in viral copies generated during SARS-CoV-2 infections. However, the factors that impact viral copies and infection dynamics are not fully understood, and may be inherently dependent upon different viral and host factors. Here, we conducted virus whole genome sequencing and measured viral copies using RT-qPCR from 9,902 SARS-CoV-2 infections over a 2-year period to examine the impact of virus genetic variation on changes in viral copies adjusted for host age and vaccination status. Using a genome-wide association study (GWAS) approach, we identified multiple single-nucleotide polymorphisms (SNPs) corresponding to amino acid changes in the SARS-CoV-2 genome associated with variations in viral copies. We further applied a marginal epistasis test to detect interactions among SNPs and identified multiple pairs of substitutions located in the spike gene that have non-linear effects on viral copies. We also analyzed the temporal patterns and found that SNPs associated with increased viral copies were predominantly observed in Delta and Omicron BA.2/BA.4/BA.5/XBB infections, whereas those associated with decreased viral copies were only observed in infections with Omicron BA.1 variants. Our work showcases how GWAS can be a useful tool for probing phenotypes related to SNPs in viral genomes that are worth further exploration. We argue that this approach can be used more broadly across pathogens to characterize emerging variants and monitor therapeutic interventions.Author SummaryOur study explores why viral load (copies measured by RT-qPCR) varies during SARS-CoV-2 infections by analyzing viral mutations and measuring viral copies in 9,902 individuals over two years. We aimed to understand how genetic differences in SARS-CoV-2 influence viral copies, considering host age and vaccination status. Using a genome-wide association study (GWAS), we identified several single-nucleotide polymorphisms (SNPs) in the virus linked to variations in viral levels. Notably, interactions between certain SNPs in the spike gene had non-linear effects on viral copies. Our analysis revealed that SNPs associated with higher viral copies were common in Delta and Omicron BA.2/BA.4/BA.5/XBB variants, while those linked to lower levels were mainly found in Omicron BA.1. This research highlights GWAS as a powerful tool for exploring virus genetics and suggests it can be broadly applied to monitor new variants of COVID-19 and other infectious diseases.
Monitoring of emerging nutritional factors impacting health outcomes: KOMPAS prospective family cohort study
Authors: Selinger Eliška , Heniková Marina , Světnička Martin , Ouřadová Anna , Cahová Monika , Potočková Jana , Dlouhý Pavel , Hrnčířová Dana , el-Lababidi Eva , Gojda Jan 
Published: March 2024

IntroductionThe dietary habits of the population are undergone dramatic changes in recent years, with an increasing proportion of people adopting different variants of plant-based diets, limiting their consumption of food of animal origin. Moreover, the shift toward a plant-based diet is supported by scientific reports promoting them as a more sustainable dietary option, which is necessary to adopt on a global scale to mitigate the human influence on climate change. However, despite their growing popularity, many questions regarding their safety and long-term health effects remain unanswered. One of the biggest concerns is the health impact during childhood and adolescence, due to the higher risk of development of severe nutritional deficiencies accompanied by the lack of good quality evidence to guide clinical recommendations and management in those groups. To close the knowledge gap, we decided to establish a family cohort study with increased representation of vegetarian and vegan families with the aim to describe not only adult and child-specific outcomes associated with plant-based diet, but also shared family risks. The aim of the presented manuscript is to introduce the background of the establishment of the family cohort study and provide a description of its protocol.MethodsTo investigate the long-term effect of these newly emerging dietary habits, a cohort of families with at least one child under 7 years of age and with the same diet followed by all members was established. The goal for the first year of the study was to recruit at least 40 vegetarian, 40 vegan, and 60-80 omnivore families. At the time of enrollment, biological samples, as well as medical history, together with 3 day dietary records, were taken. The initial active follow-up is planned for at least 5 years.Ethics and disseminationThe study was approved by the Institutional Review Board no. EK-VP/391012. The results of the study will serve as a basis for future research, as well as clinical guidelines and dietary recommendations in Czechia and neighboring regions.
Development of a clinical risk score to risk stratify for a serious cause of vertigo: A prospective cohort study
Authors: Ohle Robert , Savage David W. , Roy Danielle , McIsaac Sarah , Singh Ravinder , Lelli Daniel , Tse Darren , Johns Peter , Yadav Krishan , Perry Jeffrey J. 
Published: March 2024

AbstractObjectivesIdentify high-risk clinical characteristics for a serious cause of vertigo in patients presenting to the emergency department.DesignMulticentre prospective cohort study over 3 years.SettingThree university-affiliated tertiary care emergency departments.ParticipantsPatients presenting with vertigo, dizziness or imbalance. A total of 2078 of 2618 potentially eligible patients (79.4%) were enrolled (mean age 77.1 years; 59% women).Main outcome measurementsAn adjudicated serious diagnosis defined as stroke, transient ischemic attack, vertebral artery dissection or brain tumour.ResultsSerious events occurred in 111 (5.3%) patients. We used logistic regression to create a 7-item prediction model: male, age over 65, hypertension, diabetes, motor/sensory deficits, cerebellar signs/symptoms and benign paroxysmal positional vertigo diagnosis (C-statistic 0.96, 95% confidence interval [CI] 0.92–0.98). The risk of a serious diagnosis ranged from 0% for a score of <5, 2.1% for a score of 5-8, and 41% for a score >8. Sensitivity for a serious diagnosis was 100% (95% CI, 97.1-100%) and specificity 72.1% (95% CI, 70.1-74%) for a score <5.ConclusionsThe Sudbury Vertigo Risk Score identifies the risk of a serious diagnosis as a cause of a patient’s vertigo and can assist physicians in guiding further investigation, consultation and treatment decisions, improving resource utilization and reducing missed diagnoses.
Patient preferences and priorities for the design of an acute kidney injury prevention trial: Findings from a consensus workshop
Authors: Elliott Meghan J. , Fiest Kirsten M. , Love Shannan , Birdsell Dale , Loth Maureena , Dumka Heather , Rana Benny , Shommu Nusrat , Benterud Eleanor , Gil Sarah , Acharya Dilaram , Harrison Tyrone G. , Pannu Neesh , James Matthew T. 
Published: March 2024

ABSTRACTIntroductionHigh-quality clinical trials are needed to establish the safety, efficacy, and real-world use of potential therapies for acute kidney injury (AKI) prevention. In this consensus workshop, we identified patient and caregiver priorities for recruitment, intervention delivery, and outcomes of a clinical trial of cilastatin to prevent nephrotoxic AKI.MethodsWe included adults with lived experience of AKI, chronic kidney disease, or risk factors for AKI (e.g., critical care hospitalization), and their caregivers. Using a modified nominal group technique approach, we conducted a series of hybrid in-person/virtual discussions covering 3 clinical trial topic areas: (1) consent and recruitment; (2) intervention delivery; and (3) trial outcomes. Participants voted on their top preferences in each topic area, and discussion transcripts were analyzed inductively using conventional content analysis.ResultsThirteen individuals (11 patients, 2 caregivers) participated in the workshop. For consent and recruitment, participants prioritized technology enabled pre-screening and involvement of family members in the consent process. For intervention delivery, participants prioritized measures to facilitate intervention administration and return visits. For trial outcomes, participants identified kidney-related and other clinical outcomes (e.g., AKI, chronic kidney disease, cardiovascular events) as top priorities. Analysis of transcripts provided insight into care team and family involvement in trial-related decisions, implications of allocation to a placebo arm, and impact of participants’ experiences of AKI and critical illness.ConclusionFindings from our workshop will directly inform development of a clinical trial protocol of cilastatin for nephrotoxic AKI prevention and can assist others in patient-centered approaches to AKI trial design.
RegionScan: A comprehensive R package for region-level genome-wide association testing with integration and visualization of multiple-variant and single-variant hypothesis testing
Authors: Brossard Myriam , Roshandel Delnaz , Luo Kexin , Yavartanoo Fatemeh , Paterson Andrew D. , Yoo Yun J. , Bull Shelley B. 
Published: March 2024

AbstractSummaryRegionScan is an R package for comprehensive and scalable genome-wide association testing of region-level multiple-variant and single-variant statistics and visualization of the results. It implements various state-of-the-art region-level tests to improve signal detection under heterogeneous genetic architectures and facilitates comparison of multiple-variant region-level and single-variant test results. It exploits local linkage disequilibrium (LD) structure for genomic partitioning and LD-adaptive region definition. RegionScan is compatible with VCF input file formats for genotyped and imputed variants, and options are available for analysis of multi-allelic variants and unbalanced binary phenotypes. It accommodates parallel region-level processing and analysis to improve computational time and memory efficiency and provides detailed outputs and utility functions to assist results comparison, visualization, and interpretation.Availability and implementationRegionScan is freely available for download on GitHub (https://github.com/brossardMyriam/RegionScan).Contactbull@lunenfeld.ca,brossard@lunenfeld.ca.Supplementary informationSupplementary data are available at Bioinformatics online.