bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Lower-Grade Gliomas in MRI Through Segmentation and Genomic Cluster-Shape Feature Correlation
Authors: Paradkar Rohit , Paradkar Ria
Published: August 2022

Gliomas, which originate from glial cells, are considered the most aggressive type of brain tumors. Currently, glioma research efforts are focused mainly on high-grade gliomas. This project aims to analyze lower-grade gliomas (LGG) in MRI and extend the understanding of LGGs. LGG segmentation, which outlines tumors in MRIs, is crucial to developing effective treatment plans. However, segmentation performed manually by radiologists is tedious, time-consuming, and often leads to inter-observer variability. Another unexplored area of LGG research is genomic subtypes. These subtypes can play a large factor in how LGGs can be treated, however there is currently no noninvasive method of identifying these subtypes. Recent studies suggest that LGG shape features have a correlation with genomic subtypes and should be investigated as a viable factor in LGG treatment options. This presents a need for additional research as most LGGs eventually develop into high-grade gliomas. The specific aims of this project include analyzing LGGs through deep learning-based segmentation, shape feature extraction, and statistical analysis to identify correlation between selected shape features and genomic subtypes. To realize these goals, programs were written and run using a publicly available LGG dataset. In terms of automatic segmentation, two models were created using different convolutional neural networks (CNN). The highest performing model used U-Net with a ResNeXt-50 backbone and yielded a 91.4% accuracy in terms of mean intersection over union (IoU) after testing. Shape feature extraction included three geometric features and 4 radiomic features which quantified tumor shape in 2D and 3D. Angular Standard Deviation (ASD), Margin Fluctuation (MF), Bounding Ellipsoid Volume Ratio (BEVR), Elongation, Major and Minor Axis Length, and Volume were tested for correlation with genomic subtype data using 49 Pearson’s chi-squared tests. P-values less than or equal to 0.05 suggested correlation. Statistical analysis found 16 statistically significant associations. The strongest associations were between MF and the RNASeq cluster (p < 0.00003), ASD and the RNASeq Cluster (p < 0.0005), and volume and the RPPA cluster (p < 0.0035).
Detection of alternative isoforms of gene fusions from long-read RNA-seq with FLAIR-fusion
Authors: Felton Colette , Tang Alison D , Knisbacher Binyamin A , Wu Catherine J , Brooks Angela N
Published: August 2022

Gene fusions are important cancer drivers and drug targets, but are difficult to reliably identify with short-read RNA-sequencing. Long-read RNA sequencing data are more likely to span a fusion breakpoint and provide more sequence context around the breakpoint. This allows for more reliable identification of gene fusions and for detecting alternative splicing in gene fusions. Notably, alternative splicing of fusions has been shown to be a mechanism for drug resistance and altered levels of oncogenicity. Here, we present FLAIR-fusion, a computational tool to identify gene fusions and their isoforms from long-read RNA-sequencing data. FLAIR-fusion can detect fusions and their isoforms with high precision and recall, even with error-prone reads. We also investigated different library preparation methods and found that direct-cDNA has a higher incidence of artifactual chimeras than direct-RNA and PCR-cDNA methods. FLAIR-fusion is able to filter these technical artifacts from all of these library prep methods and consistently identify known fusions and their isoforms across cell lines. We ran FLAIR-fusion on amplicon sequencing from multiple tumor samples and cell lines and detected alternative splicing in the previously validated fusionGUCYA2-PIWIL4,which shows that long-read sequencing can detect novel splicing events from cancer gene panels. We also detect fusion isoforms from long-read sequencing in chronic lymphocytic leukemias with the splicing factor mutationSF3B1 K700E, and find that up to 10% of gene fusions had more than one unique isoform. We also compared long-read fusion detection tools with short-read fusion detection tools on the same samples and found greater consensus in the long-read tools. Our results demonstrate that gene fusion isoforms can be effectively detected from long-read RNA-sequencing and are important in the characterization of the full complexity of cancer transcriptomes.
Polymorphic short tandem repeats make widespread contributions to blood and serum traits
Authors: Margoliash Jonathan , Fuchs Shai , Li Yang , Zhang Xuan , Massarat Arya , Goren Alon , Gymrek Melissa
Published: August 2022

Short tandem repeats (STRs), genomic regions each consisting of a sequence of 1-6 base pairs repeated in succession, represent one of the largest sources of human genetic variation. However, many STR effects are not captured well by standard genome-wide association studies (GWAS) or downstream analyses that are mostly based on single nucleotide polymorphisms (SNPs). To study the involvement of STRs in complex traits, we imputed genotypes for 445,720 autosomal STRs into genotype array data from 408,153 White British UK Biobank participants and tested for association with 44 blood and serum biomarker phenotypes. We used two fine-mapping methods, SuSiE and FINEMAP, to identify 119 high-confidence STR-trait associations across 93 unique STRs predicted as causal variants under all fine-mapping settings tested. Using these results, we estimate that STRs account for 5.2-7.6% of causal variants identifiable from GWAS signals for these traits. Our high confidence STR-trait associations implicate STRs in some of the strongest hits for multiple phenotypes, including a CTG repeat inAPOBassociated with circulating apolipoprotein B levels, a CGG repeat in the promoter ofCBLassociated with multiple platelet traits and a poly-A repeat inTAOK1associated with mean platelet volume. Replication analyses in additional population groups and orthogonal expression data further support the role of a subset of the candidate STRs we identify. Together, our study suggests that polymorphic tandem repeats make widespread contributions to complex traits, provides a set of stringently selected candidate causal STRs, and demonstrates the need to routinely consider a more complete view of human genetic variation in GWAS.
Alveolar macrophage lipid burden correlates with clinical improvement in patients with Pulmonary Alveolar Proteinosis
Authors: Lee Elinor , Williams Kevin J. , McCarthy Cormac , Bridges James P. , Redente Elizabeth F. , de Aguiar Vallim Thomas Q. , Wang Tisha , Tarling Elizabeth J.
Published: August 2022

Pulmonary alveolar proteinosis (PAP) is a life-threatening rare lung syndrome characterized by the accumulation of surfactant and lipid-loaded macrophages within the alveoli for which there is no cure and no approved therapies. The clinical diagnosis of PAP, often made by invasive lung biopsies and/or cytology of bronchoalveolar lavage fluid does not identify the underlying cause of disease. In addition, no biomarkers exist to inform prognosis or therapeutic options in PAP. We now report on the use of comprehensive mass spectrometry to profile and define the lipid signature of alveolar macrophages obtained from PAP patients. In addition, we quantify how these macrophage-associated lipids change during clinical treatment. Our studies demonstrate that clinical improvement in treated PAP patients is associated with a decrease in total lipid content, indicating that levels of these macrophage-associated lipids correlate with the severity of the disease.
RELIEF: a structured multivariate approach for removal of latent inter-scanner effects
Authors: Zhang Rongqian , Oliver Lindsay D. , Voineskos Aristotle N. , Park Jun Young
Published: August 2022

Combining data collected from multiple study sites is becoming common and is advantageous to researchers to increase the generalizability and replicability of scientific discoveries. However, at the same time, unwantedinter-scanner biasesare commonly observed across neuroimaging data collected from multiple study sites or scanners, rendering difficulties in integrating such data to obtain reliable findings. While several methods for handling such unwanted variations have been proposed, most of them use univariate approaches that could be too simple to capture all sources of scanner-specific variations. To address these challenges, we propose a novel multivariate harmonization method, called RELIEF (REmoval ofLatentInter-scannerEffects throughFactorization) for estimating and removing both explicit and latent scanner effects. Our method is the first approach to introduce the simultaneous dimension reduction and factorization of interlinked matrices to a data harmonization context, which provides a new direction in methodological research for correcting inter-scanner biases. Analyzing diffusion tensor imaging (DTI) data from the Social Processes Initiative in Neurobiology of the Schizophrenia (SPINS) study and conducting extensive simulation studies, we show that RELIEF outperforms existing harmonization methods in mitigating inter-scanner biases and retaining biological associations of interest to increase statistical power. RELIEF is publicly available as an R package.
Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ
Authors: Milton Adrianna J. , Silver Daniel J. , Kwok Jessica , McClellan Jacob , Warren Philippa M. , Silver Jerry
Published: August 2022

Spinal cord injuries, for which there are limited effective clinical treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic modulation of the potently inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) can rapidly restore robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited rapid, albeit modest, improvements in upper arm function. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore gross as well as fine motor control of the forearm and digits at lengthy chronic stages post injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic, non-invasive combinatorial treatment strategy designed to both reduce and overcome inhibitory CSPGs simultaneously and spatially extensively. Following a three-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment has a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. Our exciting pre-clinical findings will begin to enhance our understanding of the basic mechanisms underlying functionally beneficial regenerative events occurring at chronic injury stages for clinically relevant translational benefits.

Significance statement

Overcoming the persistent axon inhibitory environment following a functionally debilitating incomplete spinal cord lesion has long proven to be an elusive dilemma, especially months to years after the initial spinal injury. Current therapeutic and rehabilitative techniques for patients suffering from chronic cervical spinal insults minimally, if at all, address this structural hindrance and support limited return of crucial behaviors such as voluntary use of the arms and hands. Our investigation into the behavioral and anatomical consequences of systemically perturbing the high-affinity binding interaction between the receptor PTPσ and the extracellular chondroitin sulfate proteoglycans highlight an underlying barrier to the restoration of forelimb/paw walking and eating behavior 12-weeks after a cervical spinal hemi-transection.
Characterization of enhancer fragments in Drosophila robo2
Authors: Hauptman Gina , Reichert Marie C. , Abdal Rhida Muna A. , Evans Timothy A.
Published: August 2022

Receptor proteins of the Roundabout (Robo) family regulate axon guidance decisions during nervous system development. Among the three Drosophila robo family genes (robo1, robo2, and robo3), robo2 displays a dynamic expression pattern and regulates multiple axon guidance outcomes, including preventing midline crossing in some axons, promoting midline crossing in others, forming lateral longitudinal axon pathways, and regulating motor axon guidance. The identity and location of enhancer elements regulating robo2’s complex and dynamic expression pattern in different neural cell types are unknown. Here, we characterize a set of 17 transgenic lines expressing GAL4 under the control of DNA sequences derived from noncoding regions in and around robo2, to identify enhancers controlling specific aspects of robo2 expression in the embryonic ventral nerve cord. We identify individual fragments that confer expression in specific cell types where robo2 is known to function, including early pioneer neurons, midline glia, and lateral longitudinal neurons. Our results indicate that robo2’s dynamic expression pattern is specified by a combination of enhancer elements that are active in different subsets of cells. We show that robo2’s expression in lateral longitudinal axons represents two genetically separable subsets of neurons, and compare their axon projections with each other and with Fasciclin II (FasII), a commonly used marker of longitudinal axon pathways. In addition, we provide a general description of each fragment’s expression in embryonic tissues outside of the nervous system, to serve as a resource for other researchers who may be interested in robo2 expression and its functional roles outside the CNS.
Multiple Intrinsic Membrane Properties are Modulated in a Switch from Single to Dual-Network Activity
Authors: Snyder Ryan R. , Blitz Dawn M.
Published: August 2022

Neural network flexibility extends to changes in neuronal participation between networks. This neuronal switching can include neurons moving between single- and dual-network activity. We previously identified an example in which bursting at a second frequency occurs due to modulation of intrinsic membrane properties instead of synaptic recruitment into a second network. However, the intrinsic properties that are modulated were not determined. Here, we use small networks in the Jonah crab (Cancer borealis) stomatogastric nervous system (STNS) to examine modulation of intrinsic properties underlying neuropeptide- (Gly1-SIFamide) elicited neuronal switching. The LPG neuron switches from exclusive participation in the fast pyloric (∼1 Hz) network, due to electrical coupling, to dual-network activity which includes periodic escapes from the fast rhythm via intrinsically-generated oscillations at the slower gastric mill network frequency (∼0.1 Hz). We isolated LPG from both networks using pharmacology and hyperpolarizing current injection. Gly1-SIFamide increased LPG intrinsic excitability and rebound from inhibition, and decreased spike frequency adaptation, which can all contribute to intrinsic bursting. Using ion substitution and channel blockers, we found that a hyperpolarization-activated current, a persistent sodium current, and a calcium or calcium-related current(s) appear to be primary contributors to Gly1-SIFamide-elicited LPG intrinsic bursting. However, this intrinsic bursting was more sensitive to blocking currents when LPG received rhythmic electrical coupling input from the fast network than in the isolated condition. Overall, a switch from single- to dual-network activity can involve modulation of multiple intrinsic properties, while synaptic input from a second network can shape the contributions of these properties.

New and Noteworthy

Neuropeptide-elicited intrinsic bursting was recently determined to switch a neuron from single to dual-network participation. Here we identified multiple intrinsic properties modulated in the dual-network state and candidate ion channels underlying the intrinsic bursting. Bursting at the second network frequency was more sensitive to blocking currents in the dual-network state than when neurons were synaptically isolated from their home network. Thus, synaptic input can shape the contributions of modulated intrinsic properties underlying dual-network activity.
V2b neurons act via multiple targets in spinal motor networks
Authors: Sengupta Mohini , Bagnall Martha W.
Published: August 2022

Within the spinal cord, interneurons shape motor neuron activity. These interneurons can project over long distances in the longitudinal axis, but systematic mapping of their connectivity has been limited. In this study, using larval zebrafish, we mapped local and long-range connectivity of a cardinal spinal population, the Gata3+ V2b class. V2b neurons are inhibitory and project ipsilateral, descending axons. We show that V2b neurons are active during fictive swimming, slightly leading the motor burst. Via optogenetic mapping of output in the rostrocaudal axis, we demonstrate that V2b neurons robustly inhibit motor neurons and other major spinal interneuron classes, including V2a, V1, commissural neurons and other V2b neurons. V2b inhibition is patterned along the rostrocaudal axis, providing long-range inhibition to motor and V2a neurons but more localized innervation of the V1 class. Furthermore, these results provide the first demonstration of reciprocal V1/V2b inhibition in axial circuits, potentially representing an ancestral motif of the limb control network.
USAG1 protein: An important drug target in teeth regeneration
Authors: Poorani R , Elakkiya E , Gupta Krishna Kant
Published: August 2022

The BMP antagonist and Wnt signaling modulator, USAG-1 (uterine sensitization associated gene-1) is mostly expressed in the kidneys and suppresses BMP7 bioactivity, which is crucial for tooth development. The homodimeric 35-kDa protein known as bone morphogenetic protein-7 is essential for the specification and patterning of the early embryo and controls apoptosis in a variety of developmental events. A single-gene knockout (KO) mouse model for Usag-1, also known as Sclerostin domain containing 1 (SOSTDC1), ectodin, Wnt modulator in surface ectoderm (WISE), CCAAT/enhancer-binding protein beta (CEBPB), Sprouty homolog 2 (SPRY2), Sprouty homolog 3 (SPRY3), or Epiprofin (EPFN), has demonstrated that Usag1 inhibition is important for teeth regeneration in mice. Anti Usag1 method was done by other scientists outside India. Tideglusib when placed at damaged teeth, it increases WNT signaling by inhibiting GSK-3.It results into teeth repair .Suginami et al proposed USAG-1 as a promising drug target for teeth regeneration .They proposed anti-USAG-1 approach to induce teeth regeneration but it has been associated with many sideaffects. This study aims to provide a natural lead molecule as a therapeutic drug for teeth regeneration.
Multiple pathways mediate chloroplast singlet oxygen stress signaling
Authors: Tano David W. , Kozlowska Marta A. , Easter Robert A. , Woodson Jesse D.
Published: August 2022

Chloroplasts can respond to stress and changes in the environment by producing reactive oxygen species (ROS). Aside from being cytotoxic, ROS also have signaling capabilities. For example, the ROS singlet oxygen (1O2) can initiate nuclear gene expression, chloroplast degradation, and cell death. To unveil the signaling mechanisms involved, researchers have used several 1O2-producing Arabidopsis thaliana mutants as genetic model systems, including plastid ferrochelatase two (fc2), fluorescent in blue light (flu), chlorina 1 (ch1), and accelerated cell death 2 (acd2). Here, we compare these 1O2-producing mutants to elucidate if they utilize one or more signaling pathways to control cell death and nuclear gene expression. Using publicly available transcriptomic data, we demonstrate fc2, flu, and ch1 share a core response to 1O2 accumulation, but maintain unique responses, potentially tailored to respond to their specific stresses. Subsequently, we used a genetic approach to determine if these mutants share 1O2 signaling pathways by testing the ability of genetic suppressors of one 1O2 producing mutant to suppress signaling in a different 1O2 producing mutant. Our genetic analyses revealed at least two different chloroplast 1O2 signaling pathways control cellular degradation: one specific to the flu mutant and one shared by fc2, ch1, and acd2 mutants, but with life-stage-specific (seedling vs. adult) features. Overall, this work reveals chloroplast stress signaling involving 1O2 is complex and may allow cells to finely tune their physiology to environmental inputs.
Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture
Authors: Basty Nicolas , Sorokin Elena P. , Thanaj Marjola , Whitcher Brandon , Liu Yi , Bell Jimmy D. , Thomas E. Louise , Cule Madeleine
Published: August 2022

Features extracted from cardiac MRI (CMR) are correlated with cardiovascular disease outcomes such as aneurysm, and have a substantial heritable component. To determine whether disease-relevant measurements are feasible in non-cardiac specific MRI, and to explore their associations with disease outcomes, and genetic and environmental risk factors. We segmented the heart, aorta, and vena cava from abdominal MRI scans using deep learning, and generated six image-derived phenotypes (IDP): heart volume, four aortic and one vena cava cross-sectional areas (CSA), from 44,541 UK Biobank participants. We performed genome- and phenome-wide association studies, and constructed a polygenic risk score for each phenotype. We demonstrated concordance between our IDPs and related IDPs from CMR, the current gold standard. We replicated previous findings related to sex differences and age-related changes in heart and vessel dimensions. We identified a significant association between infrarenal descending aorta CSA and incident abdominal aortic aneurysm, and between heart volume and several cardiovascular disorders. In a GWAS, we identified 72 associations at 59 loci (15 novel). We derived a polygenic risk score for each trait and demonstrated an association with TAA diagnosis, pointing to a potential screening method for individuals at high-risk of this condition. We demonstrated substantial genetic correlation with cardiovascular traits including aneurysms, varicose veins, dysrhythmia, and cardiac failure. Finally, heritability enrichment analysis implicated vascular tissue in the heritability of these traits. Our work highlights the value of non-specific MRI for exploring cardiovascular disease risk in cohort studies.
Archi-Prevaleat project. A National cohort of color-Doppler ultrasonography of the epi-aortic vessels in Patients Living with HIV
Authors: Maggi P. , Ricci E.D. , Muccini C. , Galli L. , Celesia B.M. , Ferrara S. , Salameh Y. , Basile R. , Di Filippo G. , Taccari F. , Tartaglia A. , Castagna A.
Published: August 2022

Objectives

To evaluate the prevalence of carotid intima-media thickness and plaques in a cohort of persons living with HIV, the role of cardiovascular risk factors, the impact of the antiretroviral regimens, and the difference between naïve and experienced patients in the onset of carotid lesions.

Methods

This project was initiated in 2019 and involves eight Italian Centers. Carotid changes were detected using a power color-Doppler ultrasonography with 7.5 MHz probes. The following parameters are evaluated: intima-media thickness of both the right and left common and internal carotids: Data regarding risk factors for CVD, HIV viral load, CD4+ cell counts, serum lipids, glycaemia, and body mass index. The associations between pathological findings and potential risk factors were evaluated by logistical regression, with odds ratios (OR) and 95% confidence intervals (95% CI).

Results

Among 1147 evaluated patients, aged 52 years on average, 347 (30.2%) had pathological findings (15.8% plaques and 14.5% IMT). Besides usual risk factors, such as older age, male sex, and dyslipidemia, CD4+ cell nadir <200 cells/mL (OR 1.51, 95% CI 1.14-1.99) and current use of raltegravir (OR 1.54, 95% CI 1.01-2.36) were associated with higher prevalence of pathological findings.

Conclusions

Our data show that the overall percentage of carotid impairments nowadays remains high. Color-Doppler ultrasonography could play a pivotal role in identifying and quantifying atherosclerotic lesions among persons living with HIV, even at a very premature stage, and should be included in the algorithms of comorbidity management of these patients.
A comprehensive evaluation of minimally invasive Achilles tendon reconstruction with hamstring graft indicates satisfactory long-term outcomes
Authors: Kiedrowski Bartosz , Bąkowski Paweł , Cisowski Paweł , Stołowski Łukasz , Kaszyński Jakub , Małecka Magdalena , Piontek Tomasz
Published: August 2022

Given the relevance of the Achilles tendon in proper function of the foot and ankle, the primary goal of the present study was to use a holistic approach for a comprehensive evaluation of Achilles tendon reconstruction results on multiple levels. 30 patients with partial or total Achilles tendon tears were subjected to the minimally invasive Achilles tendon reconstruction. Patients were then subjected to the clinical, functional and isokinetic tests 12 and 24 months after the treatment. The overall results of this extensive evaluation are highly satisfactory and patients returned to their normal physical activity.
Keeping on target during a low-calorie diet: The experiences of participants in a type 2 diabetes reversal pilot
Authors: Bartholomew Latoya , Unwin Nigel , Guell Cornelia , Murphy Madhuvanti M.
Published: August 2022

Rapid weight loss using a very low-calorie diet (VLCD) for 2 to 3 months followed by weight maintenance has been shown to lead to the restoration of normal glucose and insulin metabolism in people recently diagnosed with type 2 diabetes. We explored the barriers and facilitators of adhering to a VLCD for remission in an Afro-Caribbean population. Twenty-five participants completed an eight-week VLCD followed by a six-month structured weight maintenance phase. Semi-structured interviews and focus groups were thematically analysed. Cravings for ‘usual foods’ consumed by friends and family, stigma of diabetes and resulting lack of disclosure and the participants’ busy schedules were noted as predominant challenges throughout the study. In turn, social support and the participants’ internal drive were considered as key facilitators for success. VLCD is a feasible approach for type 2 diabetes remission. Self-motivation and supportive environments are however crucial in meeting and maintaining the weight loss goals.
Assessment of Joint and Interactive Effects of Multimorbidity and Chronic Pain on ADRD Risk in the Elder Population
Authors: Khalid Sumaira , Innes Kim E. , Umer Amna , Lilly Christa , Gross Diane , Sambamoorthi Usha
Published: August 2022

Objective

Multimorbidity and non-cancer chronic pain conditions (NCPC) are independently linked to elevated risk for cognitive impairment and incident Alzheimer’s Disease and Related Dementias (ADRD)-both - We present the study of potential joint and interactive effects of these conditions on the risk of incident ADRD in older population.

Methods

This retrospective-cohort study drew baseline and 2-year follow-up data from linked Medicare claims and Medicare Current Beneficiary Survey (MCBS). Baseline multimorbidity and NCPC were ascertained using claims data. ADRD was ascertained at baseline and follow-up.

Results

NCPC accompanied by multimorbidity (vs. absence of NCPC or multimorbidity) had a significant and upward association with incident ADRD (adjusted odds ratio (AOR): 1.72, 95% CI 1.38, 2.13, p<0.0001). Secondary analysis by number of comorbid conditions suggested that the joint effects of NCPC and multimorbidity on ADRD risk may increase with rising number contributing chronic conditions. Interaction analyses indicated significantly elevated excess risk for incident ADRD.
Cellular and humoral immunity towards parental SARS-CoV-2 and variants of concern after two doses of the NVX-CoV2373-vaccine in comparison to homologous BNT162b and mRNA1273 regimens
Authors: Hielscher Franziska , Schmidt Tina , Klemis Verena , Wilhelm Alexander , Marx Stefanie , Abu-Omar Amina , Ziegler Laura , Guckelmus Candida , Urschel Rebecca , Sester Urban , Widera Marek , Sester Martina
Published: August 2022

The NVX-CoV2373-vaccine has recently been licensed, although data on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to dual-dose mRNA-regimens are limited. In this observational study including 66 participants, we show that NVX-CoV2373-induced IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (n=22 each, p=0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. Interestingly, spike-specific CD8 T-cell levels after NVX-CoV2373-vaccination were significantly lower and were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals. However, CD4 T-cell levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFαα and IL-2 (p=0.0007) as compared to mRNA-vaccinated individuals. Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T cells cross-reacted to all tested VOCs from Alpha to Omicron, which may hold promise to protect from severe disease.
Adolescent binge drinking leads to long-lasting changes in cortical microcircuits in mice
Authors: Sicher Avery R. , Starnes William D. , Griffith Keith R. , Dao Nigel C. , Smith Grace C. , Brockway Dakota F. , Crowley Nicole A.
Published: August 2022

Adolescent drug consumption has increased risks to the individual compared to consumption in adulthood, due to the likelihood of long-term and permanent behavioral and neurological adaptations. However, little is known about how adolescent alcohol consumption influences the maturation and trajectory of cortical circuit development. Here, we explore the consequences of adolescent binge drinking on somatostatin (SST) neuronal function in superficial layers of the prelimbic (PL) cortex in male and female SST-Ai9 mice. We find that adolescent drinking-in-the-dark (DID) produces sex-dependent increases in intrinsic excitability of SST neurons, with no change in overall SST cell number, persisting well into adulthood. While we did not find evidence of altered GABA release from SST neurons onto other neurons within the circuit, we found a complementary reduction in layer II/III pyramidal neuron excitability immediately after binge drinking; however, this hypoexcitability rebounded towards increased pyramidal neuron activity in adulthood in females, suggesting long-term homeostatic adaptations in this circuit. Together, this suggests that binge drinking during key developmental timepoints leads to permanent changes in PL microcircuitry function, which may have broad behavioral implications.
HD-PTP/PTPN23 hypomorphic mice display lipodystrophy
Authors: Davies Brian A. , Payne Johanna A. , Martin Cole P. , Schultz Destiny , Childs Bennett G. , Zhang Cheng , Jeganathan Karthik , Sturmlechner Ines , White Thomas A. , de Bruin Alain , Chen Huiqin , Davies Michael A. , Jachim Sarah , LeBrasseur Nathan K. , Piper Robert C. , Li Hu , Baker Darren J. , van Deursen Jan , Katzmann David J.
Published: August 2022

Endosomal Sorting Complexes Required for Transport (ESCRTs) drive reverse topology membrane remodeling events including the formation of intralumenal vesicles within multivesicular bodies, the budding of retroviruses from the plasma membrane, and the scission of the cytokinetic bridge. It has been difficult to study the physiological relevance of this machinery in mammals because many contributing components are essential for viability. To bypass this problem we used combinations of knockout (−), hypomorphic (H) and wildtype (+) alleles to generate a series of mice with a gradual reduction of HD-PTP (product ofPTPN23), an ESCRT-associated protein known to cause embryonic lethality when fully depleted. WhereasPTPN23-/Hmice died shortly after birth,PTPN23H/Hmice developed into adulthood but had reduced size, lipodystrophy, and shortened lifespan. Analysis of 14-day inguinal adipose tissue indicated reduced expression of adipogenesis markers, andPTPN23knockout preadipocytes similarly display reduced adipogenesisin vitro.Defects in insulin-stimulated signaling were apparent in differentiatedPTPN23knockout adipocytes andPTPN23H/Hinguinal adipose tissuein vitro, correlating with reduced levels of insulin signaling hallmarks observed in adultPTPN23H/Hinguinal adipose tissuein vivo.Whereas the ESCRT machinery have been suggested to downregulate signaling, these results indicate that HD-PTP promotes insulin-induced signaling in, as well as differentiation of, inguinal adipose tissue. These results revealed unexpected roles for HD-PTP in promoting fat accumulation in mammalian cells through supporting insulin signaling, adipogenesis, and lipid droplet formation.
Occurrence and Antimicrobial Resistance Pattern of E. coli O157:H7 Isolated from Foods of Bovine Origin in Dessie and Kombolcha Towns, Ethiopia
Authors: Abebe Engidaw , Gugsa Getachew , Ahmed Meselu , Awol Nesibu , Tefera Yalew , Abegaz Shimelis , Sisay Tesfaye
Published: August 2022

E. coli are frequently isolated food-borne pathogens from meat, milk, and their products. Moreover, there has been a significant rise in the antimicrobial resistance patterns of E. coli O157:H7 to commonly used antibiotics. A cross-sectional study was conducted from October, 2019 to July, 2021 to estimate prevalence and identify associated factors of E. coli and E. coli O157:H7 and to determine antibiotic resistance pattern of E. coli O157:H7 from foods of bovine origin in Dessie and Kombolcha towns. A total of 384 samples were collected. Systematic and simple random sampling techniques were employed for sampling carcasses and milking cows, respectively. E. coli and E. coli O157:H7 were detected according to recommended bacteriological protocols. E. coli O157:H7 strains were evaluated for in vitro antimicrobial susceptibility using agar disk diffusion method. Both descriptive and inferential statistical techniques were applied to analyze the data. Overall prevalence rates of E. coli and E. coli O157:H7 were 54.7% and 6.5%, respectively. Highest prevalence rates of E. coli (79.6%) and E. coli O157:H7 (16.7%) were obtained from carcass swab and milk tank samples, respectively. Unlike E. coli O157:H7, a statistically significant difference in the E. coli prevalence (P<0.05) was observed among the different sample types. Multidrug resistance was observed among all isolates of E. coli O157:H7. All E. coli O157:H7 isolates (100.0%) were susceptible to Ampicillin, Sulfamethoxazole-trimethoprim, and Norfloxacin. On the contrary, all of the isolates (100%) were resistant to Penicillin G, Vancomycin, and Oxacillin. The current study indicated that different foods of bovine origin in the study area were unsafe for human consumption. Hence, good hygienic production methods should be employed to ensure the safety of foods of bovine origin.
Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSCs to microglia
Authors: Washer Sam J , Perez-Alcantara Marta , Chen Yixi , Steer Juliette , James William S , Bassett Andrew R , Cowley Sally A
Published: August 2022

There is increasing genetic evidence for the role of microglia in neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and motor neuron disease. Therefore, there is a need to generate authenticin vitromodels to study human microglial physiology. Various methods have been developed using human induced Pluripotent Stem Cells (iPSC) to generate microglia, however, systematic approaches to identify which media components are actually essential for functional microglia are mostly lacking. Here, we systematically assess medium components, coatings, and growth factors required for iPSC differentiation to microglia. Using single-cell RNA sequencing, qPCR, and functional assays, with validation across two labs, we have identified several medium components from previous protocols that are redundant and do not contribute to microglial identity. We provide an optimised, defined medium which produces both transcriptionally and functionally relevant microglia for modelling microglial physiology in neuroinflammation and for drug discovery.
Using language models and ontology topology to perform semantic mapping of traits between biomedical datasets
Authors: Liu Yi , Elsworth Benjamin L , Gaunt Tom R
Published: August 2022

Motivation

Human traits are typically represented in both the biomedical literature and large population studies as descriptive text strings. Whilst a number of ontologies exist, none of these perfectly represent the entire human phenome and exposome. Mapping trait names across large datasets is therefore time-consuming and challenging. Recent developments in language modelling have created new methods for semantic representation of words and phrases, and these methods offer new opportunities to map human trait names in the form of words and short phrases, both to ontologies and to each other. Here we present a comparison between a range of established and more recent language modelling approaches for the task of mapping trait names from UK Biobank to the Experimental Factor Ontology (EFO), and also explore how they compare to each other in direct trait-to-trait mapping.

Results

In our analyses of 1191 traits from UK Biobank with manual EFO mappings, the BioSentVec model performed best at predicting these, matching 40.3% of the manual mappings correctly. The BlueBERT-EFO model (finetuned on EFO) performed nearly as well (38.8% of traits matching the manual mapping). In contrast, Levenshtein edit distance only mapped 22% of traits correctly. Pairwise mapping of traits to each other demonstrated that many of the models can accurately group similar traits based on their semantic similarity.

Availability and Implementation

Our code is available at https://github.com/MRCIEU/vectology.
A minimum Bayes Factor based threshold for activation likelihood estimation
Authors: Costa Tommaso , Liloia Donato , Cauda Franco , Fox Peter , Mutta Francesca Dalla , Duca Sergio , Manuello Jordi
Published: August 2022

Activation likelihood estimation (ALE) is among the most used algorithms to perform neuroimaging meta-analysis. Since its first implementation, several thresholding procedures had been proposed, all referred to the frequentist framework, returning a rejection criterion for the null hypothesis according to the critical p-value selected. However, this is not informative in terms of probabilities of the validity of the hypotheses. Here, we describe an innovative thresholding procedure based on the concept of minimum Bayes factor (mBF). The use of the Bayesian framework allows to consider different levels of probability, each of these being equally significant. In order to simplify the translation between the common ALE practice and the proposed approach, we analised six task-fMRI/VBM datasets and determined the mBF values equivalent to the currently recommended frequentist thresholds based on Family Wise Error (FWE). Sensitivity and robustness toward spurious findings were also analyzed. Results showed that the cutoff log10(mBF)=5 is equivalent to the FWE threshold, often referred as voxel-level threshold, while the cutoff log10(mBF)=2 is equivalent to the cluster-level FWE (c-FWE) threshold. However, only in the latter case voxels spatially far from the blobs of effect in the c-FWE ALE map survived. Therefore, when using the Bayesian thresholding the cutoff log10(mBF)=5 should be preferred. However, being in the Bayesian framework, lower values are all equally significant, while suggesting weaker level of force for that hypothesis. Hence, results obtained through less conservative thresholds can be legitimately discussed without losing statistical rigor. The proposed technique adds therefore a powerful tool to the human-brain-mapping field.
FMRP-Regulated Alternative Splicing is Multifactorial and Resembles Splicing Control by MBNL1
Authors: Jung Suna , Shah Sneha , Han Geongoo , Richter Joel D.
Published: August 2022

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is often modeled inFmr1knockout mice where the RNA binding protein FMRP is absent. Here we show that inFmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted ofFmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation ofMbnl1mRNA as well asMbnl1RNA auto-splicing. ElevatedMbnl1auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This re-distribution of MBNL1 isoforms inFmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing distruptions resulting fromFmr1depletion could be rescued by overexpression of nuclear MBNL1. AlteredMbnl1auto-splicing also occurs in human FXS post-mortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing inFmr1-deficient cells.
SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons
Authors: Kotler Oron , Khrapunsky Yana , Shvartsman Arik , Dai Hui , Plant Leigh D. , Goldstein Steven A.N. , Fleidervish Ilya
Published: August 2022

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and backpropagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes backpropagation of APs to the soma. Here, we show the Small Ubiquitin-like Modifier (SUMO) pathway modulates persistent sodium current (INaP) generation at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

Significance Statement

Resolving a long-standing controversy, SUMOylation of NaV1.2 channels is revealed to regulate the excitability of cortical neurons by augmenting persistent sodium current at critical subthreshold voltages. SUMOylation increases the speed of action potential backpropagation from the axon initial segment to the soma, a phenomenon critical to long-term potentiation, spike-time dependent plasticity, and release of retrograde factors essential to synaptic plasticity and development.
Combining Sodium MRI, Proton MR Spectroscopic Imaging and Intracerebral EEG in Epilepsy
Authors: Azilinon Mikhael , Scholly Julia , Zaaraoui Wafaa , Villalon Samuel Medina , Viout Patrick , Roussel Tangi , El Mendili Mohamed Mounir , Ridley Ben , Ranjeva Jean-Philippe , Bartolomei Fabrice , Jirsa Viktor , Guye Maxime
Published: August 2022

Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. In this study we combined sodium MRI (23Na MRI) and 1H-MR Spectroscopic Imaging (1H-MRSI) and compared ionic/metabolic changes probed by this multimodal approach to intracerebral stereotactic-EEG (SEEG) recordings.

We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7T (23Na MRI) and a 3D echo planar spectroscopic imaging sequence at 3T (1H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated of with the short component of T2* decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho) and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls.

Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients’ regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ.

Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.
Spatial-temporal dynamics and recurrence of chikungunya virus in Brazil
Authors: de Souza William M. , Lima Shirlene T. S. , Simões Mello Leda M. , Candido Darlan S. , Buss Lewis , Whittaker Charles , Claro Ingra M. , Chandradeva Nilani , Granja Fabiana , de Jesus Ronaldo , Lemos Poliana S. , Toledo-Teixeira Daniel A. , Barbosa Priscilla P. , Firmino Antonio Carlos L. , Amorim Mariene R. , Duarte Larissa M. F. , Pessoa Ivan B. , Forato Julia , Vasconcelos Irihane L. , Maximo Ana Carolina B. M. , Araújo Emerson L. L. , Perdigão Mello Liana , Sabino Ester C. , Proença-Módena José Luiz , Faria Nuno R. , Weaver. Scott C.
Published: August 2022

Chikungunya virus (CHIKV) is an Aedes mosquito-borne virus that has caused explosive epidemics linked to acute, chronic, and severe clinical outcomes. Since 2014, Brazil has had the highest number of chikungunya fever (CHIKF) cases in the Americas. Here, we report and contextualize the spatiotemporal dynamic of CHIKF in Brazil and combine genomic, epidemiological, and vector analyses to investigate CHIKF recurrence in several Brazilian states. From 2013 to 2022, CHIKV caused seven epidemic waves across Brazil, affecting 59.5% (3,316 of 5,570) of the country’s municipalities. To date, Ceará State in the northeast has been the most affected, with 81,274 cases during the two largest epidemic waves in 2016 and 2017, and the ongoing third wave in 2022. The 2022 CHIKF recurrence was associated with a new introduction of an East/Central/South African strain. Also, the CHIKV recurrences in Ceará, Tocantins, and Pernambuco States were limited to municipalities with few or no prior reported cases in the previous epidemic waves, suggesting that spatial heterogeneity of CHIKV spread and population immunity may explain the recurrence pattern in the country. In addition, the population density metrics of main CHIKV vector in Brazil, Ae. aegypti, were not correlated spatially with locations of CHIKF recurrence in Ceará and Tocantins States. Also, we show that CHIKF disproportionally affected females, and we estimated the case-fatality ratio in Ceará at ∼1.3 deaths per 1,000 cases. These findings more comprehensively describe CHIKV epidemics in Brazil and contribute to understanding CHIKF recurrence in urban settings. Overall, this information may help guide public health policy to mitigate and reduce the burden of urban arboviruses.