bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial Intelligence-Based Clustering and Characterization of Parkinson’s Disease Trajectories
Authors: Birkenbihl Colin , Ahmad Ashar , Massat Nathalie J , Raschka Tamara , Avbersek Andreja , Downey Patrick , Armstrong Martin , Fröhlich Holger 
Published: August 2022

AbstractParkinson’s disease (PD) is a highly heterogeneous disease both with respect to arising symptoms and its progression over time. This hampers the design of disease modifying trials for PD as treatments which would potentially show efficacy in specific patient subgroups could be considered ineffective in a heterogeneous trial cohort. Establishing clusters of PD patients based on their progression patterns could help to entangle the exhibited heterogeneity, illuminate clinical differences among patient subgroups, and identify the biological pathways and molecular players which underlie the evident differences. Further, stratification of patients into clusters with distinct progression patterns could help to recruit more homogeneous trial cohorts. In the present work, we applied an artificial intelligence-based algorithm to model and cluster longitudinal PD progression trajectories from the Parkinson’s Progression Markers Initiative. Using a combination of six clinical outcome scores covering both motor and non-motor symptoms, we were able to identify specific clusters of PD that showed significantly different patterns of PD progression. The inclusion of genetic variants and biomarker data allowed us to associate the established progression clusters with distinct biological mechanisms, such as perturbations in vesicle transport or neuroprotection. Furthermore, we found that patients of identified progression clusters showed significant differences in their responsiveness to symptomatic treatment. Taken together, our work contributes to a better understanding of the heterogeneity encountered when examining and treating patients with PD, and points towards potential biological pathways and genes that could underlie those differences.
Applying a Socio-Ecological Model to Understand Factors Impacting Demand for Childhood Vaccinations in Nigeria, Uganda, and Guinea
Authors: Bell James , Lartey Belinda , Spickernell Gemma , Darrell Natasha , Salt Frances , Gardner Cassie , Richards Emily , Fasakin Lanre , Egbeniyi Shadrach , Odongo Emmanuel , Ssenkungu James , Kouadio Rigobert Kotchi , Cissé Mamadi , Rérambyah Axel Bruno Ayiya Igowa , Adou Maikol , West Rebecca , Sharma Sunny 
Published: August 2022

AbstractVaccines have reduced child mortality across the world, but low levels of demand for vaccination threatens to undermine progress. Existing frameworks to understand demand tend to prioritise caregivers’ decision-making processes. We aimed to build a wider understanding of vaccine demand by applying an adapted socio-ecological model to analyse 158 interviews with caregivers and fathers of young children, and community influencers in Nigeria, Uganda, and Guinea. We found that several factors come together to inform a caregiver’s demand for vaccination, including their familial and social relationships, their interactions with government and healthcare institutions, and the wider social and cultural norms in their communities. The study suggests that interventions targeted at families and communities instead of individuals could be effective. The results could be used to ensure that vaccine demand frameworks used by researchers and intervention designers are comprehensive and consider a wider range of influences on the caregiver.
Collateral impacts of pandemic COVID-19 drive the nosocomial spread of antibiotic resistance
Authors: Smith David R. M. , Shirreff George , Temime Laura , Opatowski Lulla 
Published: August 2022

AbstractCirculation of multidrug-resistant bacteria (MRB) in healthcare facilities is a major public health problem. These settings have been greatly impacted by the COVID-19 pandemic, notably due to surges in COVID-19 caseloads and the implementation of infection control measures. Yet collateral impacts of pandemic COVID-19 on MRB epidemiology remain poorly understood. Here, we present a dynamic transmission model in which SARS-CoV-2 and MRB co-circulate among patients and staff in a hospital population in an early pandemic context. Responses to SARS-CoV-2 outbreaks are captured mechanistically, reflecting impacts on factors relevant for MRB transmission, including contact behaviour, hand hygiene compliance, antibiotic prescribing and population structure. In a first set of simulations, broad parameter ranges are accounted for, representative of diverse bacterial species and hospital settings. On average, COVID-19 control measures coincide with MRB prevention, including fewer incident cases and fewer cumulative person-days of patient MRB colonization. However, surges in COVID-19 caseloads favour MRB transmission and lead to increased rates of antibiotic resistance, especially in the absence of concomitant control measures. In a second set of simulations, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase-producing Escherichia coli are simulated in specific hospital wards and pandemic response scenarios. Antibiotic resistance dynamics are highly context-specific in these cases, and SARS-CoV-2 outbreaks significantly impact bacterial epidemiology only in facilities with high underlying risk of bacterial transmission. Crucially, antibiotic resistance burden is reduced in facilities with timelier, more effective implementation of COVID-19 control measures. This highlights the control of antibiotic resistance as an important collateral benefit of robust pandemic preparedness.Significance StatementImpacts of COVID-19 on the spread of antibiotic resistance are poorly understood. Here, an epidemiological model accounting for the simultaneous spread of SARS-CoV-2 and antibiotic-resistant bacteria is presented. The model is tailored to healthcare settings during the first wave of the COVID-19 pandemic, and accounts for hand hygiene, inter-individual contact behaviour, and other factors relevant for pathogen spread. Simulations demonstrate that public health policies enacted to slow the spread of COVID-19 also tend to limit bacterial transmission. However, surges in COVID-19 cases simultaneously select for higher rates of antibiotic resistance. Selection for resistance is thus mitigated by prompt implementation of effective COVID-19 prevention policies. This highlights the control of antibiotic resistance as an important collateral benefit of pandemic preparedness.
Backscattering Mueller Matrix polarimetry on whole brain specimens shows promise for minimally invasive mapping of microstructural orientation features
Authors: Bonaventura Justina , Morara Kellys , Carlson Rhea , Comrie Courtney , Daigle Noelle , Hutchinson Elizabeth , Sawyer Travis W. 
Published: August 2022

ABSTRACTUnderstanding microscale physiology and microstructural cellular features of the brain is key to understanding the mechanisms of neurodegenerative diseases and injury, as well as the prominent changes that neurons and glia in the brain undergo in development and aging which reflect functional state. Non-invasive imaging modalities sensitive to the microscale - especially diffusion magnetic resonance imaging (dMRI) - are extremely promising for three-dimensional mapping of cellular microstructure of brain tissues and brain connectivity via tractography; however, there is a need for robust validation techniques to verify and improve the biological accuracy of fiber orientation information derived from these techniques. Recent advances in dMRI acquisition and modeling have moved toward probing of the more complex grey matter architecture, challenging current validation techniques, which are largely based on ex vivo staining and microscopy focusing on white matter. Polarized light imaging (PLI) has been shown to be a successful technique for high resolution, direct, microstructural imaging and has been applied to dMRI validation with clear advantages over conventional staining and microscopy techniques. Conventionally, PLI is applied to thin, sectioned samples in transmission mode, but unlike histologic staining, PLI can be extended to operate with high sensitivity in reflectance mode and even extended to 3D imaging to bridge the gap toward in vivo validation of dMRI measurements of orientation features in both gray and white matter of the brain. In this report we investigate the use of backscattering Mueller Matrix polarimetry to characterize the microstructural content of intact Ferret brain specimens. The experimental results show that backscattering polarimetry can probe white matter fiber coherence and fiber orientation in whole brain specimens, and show promise for probing grey matter microstructure. Ultimately, these preliminary results motivate further study to fully understand how backscattering polarimetry can best be used for validation of in vivo microstructural imaging of the brain.
Enhancement of vestibular motion discrimination by small stochastic whole-body perturbations in young healthy humans
Authors: Scaleia Barbara La , Lacquaniti Francesco , Zago Myrka 
Published: August 2022

ABSTRACTNoisy galvanic vestibular stimulation has been shown to improve vestibular perception in healthy subjects. Here, we sought to obtain similar results using more natural stimuli consisting of small-amplitude motion perturbations of the whole body. Thirty participants were asked to report the perceived direction of antero-posterior sinusoidal motion on a MOOG platform. We compared the baseline perceptual thresholds with those obtained by applying small, stochastic perturbations at different power levels along the antero-posterior axis, symmetrically distributed around a zero-mean. At the population level, we found that the thresholds for all but the highest level of noise were significantly lower than the baseline threshold. At the individual level, the threshold was lower with at least one noise level than the threshold without noise in 87% of participants. Thus, small, stochastic oscillations of the whole body can increase the probability of detecting subthreshold vestibular signals, possibly due to stochastic resonance mechanisms. We suggest that, just as the external noise of the present experiments, also the spontaneous random oscillations of the body associated with standing posture are beneficial by enhancing vestibular thresholds with a mechanism similar to stochastic resonance. The results are also relevant from a clinical perspective, since they raise the possibility of improving motion perception in people with elevated thresholds due to aging or vestibulopathy by means of small-amplitude motion perturbations.HIGHLIGHTSSmall-amplitude motion perturbations of the whole body improve vestibular perceptual thresholds of motion discrimination in young healthy peopleImprovements occur at optimal levels of noise amplitude, idiosyncratic to each subjectThe findings are consistent with the phenomenon of stochastic resonanceThe new method can applied to people with elevated thresholds due to aging or vestibulopathy
A Deep Redox Proteome Profiling Workflow and Its Application to Skeletal Muscle of a Duchene Muscular Dystrophy Model
Authors: Day Nicholas J. , Zhang Tong , Gaffrey Matthew J. , Zhao Rui , Fillmore Thomas L. , Moore Ronald J. , Rodney George G. , Qian Wei-Jun 
Published: August 2022

AbstractPerturbation to the redox state accompanies many diseases and its effects are viewed through oxidation of biomolecules, including proteins, lipids, and nucleic acids. The thiol groups of protein cysteine residues undergo an array of redox post-translational modifications (PTMs) that are important for regulation of protein and pathway function. To better understand what proteins are redox regulated following a perturbation, it is important to be able to comprehensively profile protein thiol oxidation at the proteome level. Herein, we report a deep redox proteome profiling workflow and demonstrate its application in measuring the changes in thiol oxidation along with global protein expression in skeletal muscle from mdx mice, a model of Duchenne Muscular Dystrophy (DMD). In depth coverage of the thiol proteome was achieved with >18,000 Cys sites from 5608 proteins in muscle being quantified. Compared to the control group, mdx mice exhibit markedly increased thiol oxidation, where ~2% shift in the median oxidation occupancy was observed. Pathway analysis for the redox data revealed that coagulation system and immune-related pathways were among the most susceptible to increased thiol oxidation in mdx mice, whereas protein abundance changes were more enriched in pathways associated with bioenergetics. This study illustrates the importance of deep redox profiling in gaining a greater insight into oxidative stress regulation and pathways/processes being perturbed in an oxidizing environment.Graphical AbstractHighlightsDeep redox profiling workflow results in stoichiometric quantification of thiol oxidation for > 18,000 Cys sites in muscleThiol redox changes were much more pronounced than protein abundance changes for the overlapping set of proteinsRedox changes are most significant in coagulation and immune response pathways while abundance changes on bioenergetics pathways
FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer
Authors: Wilde Blake R. , Chakraborty Nishma , Matulionis Nedas , Hernandez Stephanie , Ueno Daiki , Gee Michayla E. , Esplin Edward D. , Ouyang Karen , Nykamp Keith , Shuch Brian , Christofk Heather R. 
Published: August 2022

AbstractThe tricarboxylic citric acid cycle enzyme fumarate hydratase (FH) is a tumor suppressor. When lost in cells, its substrate fumarate accumulates to mM levels and drives oncogenic signaling and transformation. Germline alterations lead to an autosomal dominant condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to various benign tumors and an aggressive form of kidney cancer.FHalterations of unclear significance are frequently observed with germline testing; thus, there is an unmet need to classifyFHvariants by their cancer-associated risk, allowing for screening, early diagnosis and treatment. Here we quantify catalytic efficiency of 74 FH variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks purine biosynthesis, rendering FH-deficient cells reliant on purine salvage to maintain purine nucleotide pools. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growthin vivo. Together, these findings suggest pathogenicity of many patient-associatedFHvariants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.Statement of SignificanceThis study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers.
Architectural Groups of a Subtelomeric Gene Family Evolve Along Distinct Paths in Candida albicans
Authors: Dunn Matthew J. , Simonton Emily , Slot Jason C. , Anderson Matthew Z. 
Published: August 2022

ABSTRACTSubtelomeres are dynamic genomic regions shaped by elevated rates of recombination, mutation, and gene birth/death. These processes contribute to formation of lineage-specific gene family expansions that commonly occupy subtelomeres across eukaryotes. Investigating the evolution of subtelomeric gene families is complicated by the presence of repetitive DNA and high sequence similarity among gene family members that prevents accurate assembly from whole genome sequences. Here we investigated the evolution of the telomere-associated (TLO) gene family in Candida albicans using 189 complete coding sequences retrieved from 23 genetically diverse strains across the species. TLO genes conformed to the three major structural groups (α /β /γ) previously defined in the genome reference strain but significantly differed in the degree of within-group diversity and positional conservation. One group, TLOβ, was always found at the same chromosome arm with strong sequence similarity among all strains. In contrast, diverse Tloα sequences have proliferated among chromosome arms. Tloγ genes formed seven primary clades that included each of the previously identified Tloγ genes from the genome reference strain with limited mobility among chromosome arms. Structural groups displayed regions of high conservation that resolved newly identified functional motifs, providing insight into potential regulatory mechanisms that distinguish groups. Thus, by resolving intra-species subtelomeric gene variation, it is possible to identify previously unknown gene family complexity that may underpin adaptive functional variation.
Genetic silencing of AKT induces melanoma cell death
Authors: Parkman Gennie L. , Turapov Tursun , Kircher David A. , Burnett William J. , Stehn Christopher M. , O’Toole Kayla , Flaherty Ryan , Elmer Riley C. , Culver Katie M. , Foth Mona , Andtbacka Robert H. I. , Lum David H. , Judson-Torres Robert , VanBrocklin Matthew W. , Holmen Sheri L. , McMahon Martin 
Published: August 2022

ABSTRACTAberrant activation of the PI3K-AKT pathway is common in melanoma but efforts to drug this pathway have proven largely ineffective in patients. In this study, we observed that pharmacological inhibition of AKT was ineffective whereas genetic silencing of all three AKT paralogs significantly abrogated melanoma cell growth through effects on mTORC signaling. This phenotype could be rescued by overexpression of AKT but was dependent on kinase activity. Interestingly, expression of the serine/threonine kinase SGK1 was increased following genetic suppression of AKT but only expression of activated SGK1 could rescue the lethal effect of AKT knockdown. SGK1 also increases tumor growth and decreases survival in a BRAFV600E-driven mouse model of melanoma. Pharmacological inhibition of SGK and AKT reduced cell proliferation. These results demonstrate that SGK1 can compensate for AKT loss in this context and suggest that dual targeting of SGK1 and AKT may represent a novel therapeutic strategy in this disease.SIGNIFICANCEAlthough the AKT1, 2 & 3 genes encode: Bona fide oncoprotein kinases; well-validated downstream effectors of PI3’-lipids and: pleiotropic regulators of numerous aberrant properties of cancer cells, their role in melanoma progression and/or maintenance is poorly understood. Here we explore the effects of genetic or pharmacological inhibitors of AKT1-3 and conclude that combined inhibition of AKT plus the related SGK protein kinases may be required to inhibit melanomagenesis.
A near complete genome assembly of chia assists in identification of key fatty acid desaturases in developing seeds
Authors: Li Leiting , Song Jingjing , Zhang Meiling , Iqbal Shahid , Li Yuanyuan , Zhang Heng , Zhang Hui 
Published: August 2022

AbstractChia is an annual crop whose seeds have the highest content of α-linolenic acid (ALA) of any plant species. We generated a high-quality assembly of the chia genome using circular consensus sequencing of PacBio. The assembled six chromosomes are composed of 21 contigs and have a total length of 361.7 Mb. Genome annotation revealed a 53.5% repeat content and 35,850 protein-coding genes. Chia shared a common ancestor withSalvia splendens~6.1 million years ago. Utilizing the reference genome and two transcriptome datasets, we identified candidate fatty acid desaturases responsible for ALA biosynthesis during chia seed development. Because the seed ofS. splendenscontains significantly lower proportion of ALA but similar total contents of unsaturated fatty acids, we suggest that strong expression of twoShFAD3genes are critical for the high ALA content of chia seeds. This genome assembly will serve as a valuable resource for breeding, comparative genomics, and functional genomics studies of chia.
Cell Senescence-Independent Ageing of Human Skin
Authors: Wordsworth J. , Fullard N. , Welsh C. , Maltman V. , Bascom C. , Tasseff R. , Isfort R. , Costello L. , Scanlan R. , Przyborski S. , Shanley D. 
Published: August 2022

AbstractSkin ageing is defined in part by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that while increased collagen degradation with age might reflect senescent cell accumulation, the reduced collagen production that prevents the skin from maintaining homeostasis must reflect senescence-independent processes.
CRISPR-Cas9 editing induces Loss of Heterozygosity in the pathogenic yeast Candida parapsilosis
Authors: Lombardi Lisa , Bergin Sean A. , Ryan Adam , Butler Geraldine 
Published: August 2022

ABSTRACTGenetic manipulation is often used to study gene function. However, unplanned genome changes (including Single Nucleotide Polymorphisms (SNPs), aneuploidy and Loss of Heterozygosity (LOH)) can affect the phenotypic traits of the engineered strains. Here, we show that CRISPR-Cas9 editing can induce LOH in the diploid human pathogenic yeast Candida parapsilosis. We sequenced the genomes of ten isolates that were edited with CRISPR-Cas9 and found that the designed changes were present in nine. However, we also observed LOH in all isolates, and aneuploidy in two isolates. LOH occurred most commonly downstream of the Cas9 cut site and extended to the telomere in three isolates. In two isolates we observed LOH on chromosomes that were not targeted by CRISPR-Cas9. Two different isolates exhibited cysteine and methionine auxotrophy caused by LOH at a heterozygous site in MET10, approximately 11 and 157 kb downstream from the Cas9 target site, respectively. C. parapsilosis isolates have relatively low levels of heterozygosity. However, our results show that mutation complementation to confirm observed phenotypes is important even when using CRISPR-Cas9, which is now the gold standard of genetic engineering.IMPORTANCECRISPR-Cas9 has greatly streamlined gene editing, and is now the gold standard and first choice for genetic engineering. However, we show that in diploid species extra care should be taken in confirming the cause of any phenotypic changes observed. We show that the Cas9-induced double strand break is often associated with loss of heterozygosity in the asexual diploid human fungal pathogen Candida parapsilosis. This can result in deleterious heterozygous variants (e.g. stop gain in one allele) becoming homozygous resulting in unplanned phenotypic changes. Our results stress the importance of mutation complementation even when using CRISPR-Cas9.