bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter hyperintensities are common in midlife and already associated with cognitive decline
Authors: d’Arbeloff Tracy , Elliott Maxwell L. , Knodt Annchen R. , Melzer Tracy R. , Keenan Ross , Ireland David , Ramrakha Sandhya , Poulton Richie , Anderson Tim , Caspi Avshalom , Moffitt Terrie E. , Hariri Ahmad R. 
Published: July 2019

AbstractWhite matter hyperintensities (WMHs) proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimer’s disease and related dementias. As such, WMHs have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging WMHs begin to relate to cognition and if they may be a viable target for early prevention. In a population-representative birth cohort of 843 45-year-olds we measured WMHs using T2-weighted MRI, and we assessed cognitive decline from childhood to midlife. We found that WMHs were common at age 45 and that WMH volume was modestly associated with both lower childhood (ß=-0.08, p=0.013) and adult IQ (ß=-0.15, p<0.001). Moreover, WMH volume was associated with greater cognitive decline from childhood to midlife (ß=-0.09, p<0.001). Our results demonstrate that a link between WMHs and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, WMHs may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.
Trans- and cis-acting effects of the lncRNA Firre on epigenetic and structural features of the inactive X chromosome
Authors: Fang He , Bonora Giancarlo , Lewandowski Jordan P. , Thakur Jitendra , Filippova Galina N. , Henikoff Steven , Shendure Jay , Duan Zhijun , Rinn John L. , Deng Xinxian , Noble William S. , Disteche Christine M. 
Published: July 2019

AbstractFirre encodes a lncRNA involved in nuclear organization in mammals. Here we find that Firre RNA is transcribed from the active X chromosome (Xa) and exerts trans-acting effects on the inactive X chromosome (Xi). Allelic deletion of Firre on the Xa in a mouse hybrid fibroblast cell line results in a dramatic loss of the histone modification H3K27me3 and of components of the PRC2 complex on the Xi as well as the disruption of the perinucleolar location of the Xi. These features are measurably rescued by ectopic expression of a mouse or human Firre/FIRRE cDNA transgene, strongly supporting a conserved trans-acting role of the Firre transcript in maintaining the Xi heterochromatin environment. Surprisingly, CTCF occupancy is decreased on the Xi upon loss of Firre RNA, but is partially recovered by ectopic transgene expression, suggesting a functional link between Firre RNA and CTCF in maintenance of epigenetic features and/or location of the Xi. Loss of Firre RNA results in dysregulation of genes implicated in cell division and development, but not in reactivation of genes on the Xi, which retains its bipartite structure despite some changes in chromatin contact distribution. Allelic deletion or inversion of Firre on the Xi causes localized redistribution of chromatin contacts, apparently dependent on the orientation of CTCF binding sites clustered at the locus. Thus, the Firre locus and its RNA have roles in the maintenance of epigenetic features and structure of the Xi.
CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease
Authors: Wilson Edward N. , Swarovski Michelle S. , Linortner Patricia , Shahid Marian , Zuckerman Abigail J. , Wang Qian , Channappa Divya , Minhas Paras S. , Mhatre Siddhita D. , Plowey Edward D. , Quinn Joseph F. , Zabetian Cyrus P. , Tian Lu , Longo Frank M. , Cholerton Brenna , Montine Thomas J. , Poston Kathleen L. , Andreasson Katrin I. 
Published: July 2019

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD
Discovering functional sequences with RELICS, an analysis method for tiling CRISPR screens
Authors: Fiaux Patrick C. , Chen Hsiuyi V. , Chen Aaron R. , Chen Poshen B. , McVicker Graham 
Published: July 2019

AbstractCRISPR screens are a powerful new technology for the identification of genome sequences that affect cellular phenotypes such as gene expression, survival, and proliferation. By tiling single-guide RNA (sgRNA) target sites across large genomic regions, CRISPR screens have the potential to systematically discovery novel functional sequences, however, a lack of purpose-built analysis tools limits the effectiveness of this approach. Here we describe RELICS, a Bayesian hierarchical model for the discovery of functional sequences from tiling CRISPR screens. RELICS considers the overlapping effects of multiple nearby functional sequences, accounts for the ‘area of effect’ surrounding sgRNA target sites, models overdispersion in sgRNA counts, combines information across multiple pools, and estimates the number of functional sequences supported by the data. In simulations, RELICS outperforms existing methods and provides higher resolution predictions. We apply RELICS to published CRISPR interference and CRISPR activation screens and predict novel regulatory sequences, several of which we experimentally validate. In summary, RELICS is a powerful new analysis method for tiling CRISPR screens that enables the discovery of functional sequences with unprecedented resolution and accuracy.
Power series method for solving TASEP-based models of mRNA translation
Authors: Scott S , Szavits-Nossan J 
Published: July 2019

AbstractWe develop a method for solving mathematical models of messenger RNA (mRNA) translation based on the totally asymmetric simple exclusion process (TASEP). Our main goal is to demonstrate that the method is versatile and applicable to realistic models of translation. To this end we consider the TASEP with codon-dependent elongation rates, premature termination due to ribosome drop-off and translation reinitiation due to circularisation of the mRNA. We apply the method to the model organism Saccharomyces cerevisiae under physiological conditions and find excellent agreements with the results of stochastic simulations. Our findings suggest that the common view on translation as being rate-limited by initiation is oversimplistic. Instead we find theoretical evidence for ribosome interference and also theoretical support for the ramp hypothesis which argues that codons at the beginning of genes have slower elongation rates in order to reduce ribosome density and jamming.
Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph
Authors: Hubisz Melissa J. , Williams Amy L. , Siepel Adam 
Published: July 2019

AbstractThe sequencing of Neanderthal and Denisovan genomes has yielded many new insights about interbreeding events between extinct hominins and the ancestors of modern humans. While much attention has been paid to the relatively recent gene flow from Neanderthals and Denisovans into modern humans, other instances of introgression leave more subtle genomic evidence and have received less attention. Here, we present an extended version of the ARGweaver algorithm, ARGweaver-D, which can infer local genetic relationships under a user-defined demographic model that includes population splits and migration events. This Bayesian algorithm probabilistically samples ancestral recombination graphs (ARGs) that specify not only tree topology and branch lengths along the genome, but also indicate migrant lineages. The sampled ARGs can therefore be parsed to produce probabilities of introgression along the genome. We show that this method is well powered to detect the archaic migration into modern humans, even with only a few samples. We then show that the method can also detect introgressed regions stemming from older migration events, or from unsampled populations. We apply it to human, Neanderthal, and Denisovan genomes, looking for signatures of older proposed migration events, including ancient humans into Neanderthal, and unknown archaic hominins into Denisovans. We identify 3% of the Neanderthal genome that is putatively introgressed from ancient humans, and estimate that the gene flow occurred between 200-300kya. We find no convincing evidence that negative selection acted against these regions. We also identify 1% of the Denisovan genome which was likely introgressed from an unsequenced hominin ancestor, and note that 15% of these regions have been passed on to modern humans through subsequent gene flow.
Fecal Microbiota Transplantation Decreases Amyloid Load and Improves Cognition in Alzheimer’s
Authors: Elangovan Shalini , Borody Thomas J , Holsinger R M Damian 
Published: July 2019

AbstractThe efficacy of fecal microbiota transplantation (FMT) in Alzheimer’s disease has yet to be investigated. Here, we show that FMT is capable of providing neuroprotective effects in two groups of treated 5xFAD Alzheimer’s mice, old transgenic (Tg) mice fed fecal slurry from healthy, wild-type donors of similar age (Old Tg-FO) and old mice fed fecal slurry from younger healthy, wild-type donors (Old Tg-FY). Improved spatial and recognition memory in Old Tg-FY and enhanced recognition memory in Old Tg-FO were observed when compared to Old Tg-Control mice given saline. Crucially, there was significant decreases in cortical Aβ loading in all treated mice, demonstrating the therapeutic effects of FMT in improving cognition and reducing amyloid pathology in AD brains.One Sentence SummaryFecal microbial transplants reduce amyloid pathology and improve cognition in Alzheimer’s mice.
The Toxin Antitoxin MazEF DrivesStaphylococcus aureusChronic Infection
Authors: Ma Dongzhu , Mandell Jonathan B. , Donegan Niles P. , Cheung Ambrose L. , Ma Wanyan , Rothenberger Scott , Shanks Robert M. Q. , Richardson Anthony R. , Urish Kenneth L. 
Published: July 2019

AbstractStaphylococcus aureusis the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance ofS. aureusbiofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function inS. aureusis controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in threeS. aureusstrains to their corresponding strains with disruption ofmazFexpression. Strains lackingmazFproduction showed increased biofilm growth, and decreased biofilm antibiotic tolerance. Deletion oficaADBCin themazF::tn background suppressed the growth phenotype observed withmazF-disrupted strains, suggesting the phenotype wasica-dependent. We confirmed these phenotypes in our murine animal model. Loss ofmazFresulted in increased bacterial burden and decreased survival rate compared to its wild-type strain demonstrating that loss of themazFgene caused an increase inS. aureusvirulence. Although lack ofmazFgene expression increasedS. aureusvirulence, it was more susceptible to antibioticsin vivo. Combined, the ability ofmazFto inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone.ImportanceSurgical infections are one of the most common types of infections obtained in a hospital.Staphylococcus aureusis the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate as the bacteria form a biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria floating in liquid, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate thatmazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allowsS. aureusto transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.
Prevalence of Alcohol use during pregnancy and its association with partner alcohol use in East Africa: systematic review and meta-analysis
Authors: Dargie Abate , Eshetie Yossef , Asmare Yared , Shibabaw Wendimeneh , Dagne Kefyalew 
Published: July 2019

AbstractIntroductionmaternal alcohol beverages consumption (any amount) during pregnancy can result in multiple major health and social problems both for the mother and fetus; including miscarriage, stillbirth, low birth weight, and prematurity. At the regional and national level, alcohol use prevalence data is a use full indicator for maternal and child health.Methodsthe researchers were searched for studies using a computerized search engine, main electronic databases, and other applicable sources. Observational studies (case-control, crosssectional and cohort) which assess the prevalence of alcohol use and associated factors among pregnant mothers in East Africa were eligible. Data was extracted thoroughly by two authors independently and screened for eligibility. The Pooled prevalence of alcohol use during pregnancy and its association with partner alcohol use was determined by using Epi data version 14 statistical software.Resultsthe study included eighteen studies with the total sample size of 41,022 and The overall pooled prevalence of alcohol use during pregnancy from the random effects method was found to be 18.85% (95% CI; 11.26, 26.44). The overall weighted odds ration revealed that pregnant women partners’ alcohol use did not have a significant association with study subjects alcohol use during pregnancy; i.e. OR=0.32(95% CI: −0.39, 1.03).ConclusionsThe overall alcohol use (any amount) during pregnancy is higher in magnitude and pregnant mothers who had alcohol user partner had no association with their use of alcohol beverages. The prevalence of alcohol use during pregnancy may be underestimated in the current study due to social desirability bias. Since related study articles were found only in four East African countries, the region may be under-represented due to the limited number of studies included.
Seasonal diversity of soil microarthropods in two different vegetable plots of Aligarh-India
Authors: Abbas Mohammad Jalaluddin , Parwez Hina 
Published: July 2019

AbstractSoil microarthropods are intimately linked with health and fertility of soil as well as plant productivity. In India, despite their rich faunal diversity, information on soil microarthropods diversity and interactions with variety of edaphic factors is extremely limited. The present study has been carried out to observe seasonal diversity of soil microarthropods in two different vegetable plots at Aligarh. The two vegetable plots chosen in this study where predominantly Tomato (Lycopersicom esculentum) and Brinjal (Solanum melongena, family-Solaneceae) have been grown and sapling has been sown in the month of April when plants attained a height of approximately 6″. The samples were collected randomly from a depth of 5cm. @ of four samples per month for a period of one year. All microarthropods extracted with the help of Tullgren funnel apparatus. Among soil microarthropods collected, Collembolans have highest average monthly density (15.20 inds./sample) in brinjal plot and greatest abundance (18.7inds./sample) in tomato plot. A highly significant negative correlation was recorded between Collembolans population with reference to soil temperature (r = −0.867, P<0.05), whereas available nitrogen showed a positive correlation (r = 0.847, P>0.05). Interestingly, at neutral pH level, the highest population of Collembolans as well as Acari(mites) were recorded. During spring and winter months, there was a peak population buildup of Collembola and Acarina, whereas a sharp decline was recorded in summer months. So, this study clearly establishes that habitat difference as well as edaphic factors plays an important role along with seasonal parameters on their diversity.
Correlation between Retinal Ganglion Cell Loss and Nerve Crush Force-Impulse Established with Instrumented Tweezers in Mice
Authors: Liu Xiaorong , Feng Liang , Shinde Ishan , Cole James D. , Troy John B. , Saggere Laxman 
Published: July 2019

AbstractObjectivesRodent models of optic nerve crush (ONC) have often been used to study degeneration and regeneration of retinal ganglion cells (RGCs) and their axons as well as the underlying molecular mechanisms. However, ONC results from different laboratories exhibit a range of RGC injury with varying degree of axonal damage. We developed an instrumented tweezers to measure optic nerve (ON) crush forces in real time and studied the correlation between RGC axon loss and force-impulse, the product of force and duration, applied through the instrumented tweezers in mice.MethodsA pair of standard self-closing #N7 tweezers were instrumented with miniature foil strain gauges at optimal locations on both tweezer arms. The instrumented tweezers were capable of recording the tip closure forces in the form of voltages, which were calibrated through load cells to corresponding tip closure forces over the operating range. Using the instrumented tweezers, the ONs of multiple mice were crushed with varied forces and durations and the axons in the immunostained sections of the crushed ONs were counted.ResultsWe found that the surviving axon density correlated with crush force, with longer duration and stronger crush forces producing consistently more axon damage.DiscussionThe instrumented tweezers enable a simple technique for measurement of ONC forces in real-time for the first time. Using the instrumented tweezers, experimenters can quantify crush forces during ONC to produce consistent and predictable post-crush cell death. This should permit future studies a way to produce nerve damage more consistently than is available now.
A comprehensive genealogy of the replication associated protein of CRESS DNA viruses reveals a single origin of intron-containing Rep
Authors: Zhao Lele , Lavington Erik , Duffy Siobain 
Published: July 2019

AbstractAbundant novel circular Rep-encoding ssDNA viruses (CRESS DNA viruses) have been discovered in the past decade, prompting a new appreciation for the ubiquity and genomic diversity of this group of viruses. Although highly divergent in the hosts they infect or are associated with, CRESS DNA viruses are united by the homologous replication-associated protein (Rep). An accurate genealogy of Rep can therefore provide insights into how these diverse families are related to each other. We used a dataset of eukaryote-associated CRESS DNA RefSeq genomes (n=926), which included representatives from all six established families and unclassified species. To assure an optimal Rep genealogy, we derived and tested a bespoke amino acid substitution model (named CRESS), which outperformed existing protein matrices in describing the evolution of Rep. The CRESS model-estimated Rep genealogy resolved the monophyly of Bacilladnaviridae and the reciprocal monophyly of Nanoviridae and the alpha-satellites when trees estimated with general matrices like LG did not. The most intriguing, previously unobserved result is a likely single origin of intron-containing Reps, which causes several geminivirus genera to group with Genomoviridae (bootstrap support 55%, aLRT SH-like support 0.997, 0.91-0.997 in trees estimated with established matrices). This grouping, which eliminates the monophyly of Geminiviridae, is supported by both domains of Rep, and appears to be related to our use of all RefSeq Reps instead of subsampling to get a smaller dataset. In addition to producing a trustworthy Rep genealogy, the derived CRESS matrix is proving useful for other analyses; it best fit alignments of capsid protein sequences from several CRESS DNA families and parvovirus NS1/Rep sequences.
Label-retention expansion microscopy
Authors: Shi Xiaoyu , Li Qi , Dai Zhipeng , Tran Arthur A. , Feng Siyu , Ramirez Alejandro D. , Lin Zixi , Wang Xiaomeng , Chow Tracy T. , Chen Jiapei , Kumar Dhivya , McColloch Andrew R. , Reiter Jeremy F. , Huang Eric J. , Seiple Ian B. , Huang Bo 
Published: July 2019

AbstractExpansion microscopy (ExM) increases the effective resolving power of any microscope by expanding the sample with swellable hydrogel. Since its invention, ExM has been successfully applied to a wide range of cell, tissue and animal samples. Still, fluorescence signal loss during polymerization and digestion limits molecular-scale imaging using ExM. Here we report the development of label-retention ExM (LR-ExM) with a set of trifunctional anchors that not only prevent signal loss but also enable high-efficiency labeling using SNAP and CLIP tags. We have demonstrated multicolor LR-ExM for a variety of subcellular structures. Combining LR-ExM with super-resolution Stochastic Optical Reconstruction Microscopy (STORM), we have achieved molecular resolution in the visualization of polyhedral lattice of clathrin-coated pits in situ.
Natural selection shapes codon usage in the human genome
Authors: Dhindsa Ryan S , Copeland Brett R , Mustoe Anthony M , Goldstein David B 
Published: July 2019

AbstractSynonymous codon usage has been identified as an important determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, to date, population genetics studies have failed to observe evolutionary constraint on human codon usage, and synonymous variation has been largely overlooked as a component of human genetic diversity. Using genetic sequencing data from nearly 200,000 individuals, we uncover clear evidence that natural selection optimizes codon content in the human genome. We derive intolerance metrics to quantify gene-level constraint on synonymous variation and demonstrate that dosage-sensitive, DNA damage response, and cell cycle regulated genes are more intolerant to synonymous variation than other genes in the genome. Notably, we illustrate that reductions in codon optimality can attenuate the function of BRCA1. Our results reveal that synonymous mutations likely play an important and underappreciated role in human variation.