bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heroin self-administration and extinction increases prelimbic cortical astroglia-synapse proximity and alters dendritic spine morphometrics that are reversed by N-acetylcysteine
Authors: Siemsen BM , Denton AR , Hooker KN , Carpenter EA , Prescott ME , Brock AG , Leath MN , McFaddin JA , McGinty JF , Scofield MD 
Published: May 2020

AbstractClinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astroglial glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observed increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astroglial plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astroglial complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at synapses. Additionally, these data demonstrate, for the first time, that NAC reverses PrL cortical heroin SA and extinction-induced adaptations in both astrocytes and corticostriatal neurons.
Immunoglobulin T genes in Neopterygii
Authors: Mirete-Bachiller Serafin , Olivieri David N. , Gambón-Deza Francisco 
Published: May 2020

AbstractIn teleost fishes there are three immunoglobulin isotypes named immunoglobulin M (IgM), D (IgD) and T (IgT). IgT has been the last to be described and is considered a teleosts-fish specific isotype. From the recent availability of genome sequences of fishes, an in-depth analysis of Actinopterygii immunoglobulin heavy chain genes was undertaken. With the aid of a bioinformatics pipeline, a machine learning software, CHfinder, was developed that identifies the coding exons of the CH domains of fish immunoglobulins. Using this pipeline, a high number of such sequences were obtained from teleosts and holostean fishes. IgT was found in teleost and holostean fishes that had not been previously described. A phylogenetic analysis reveals that IgT CH1 exons are similar to the IgM CH1. This analysis also demonstrates that the other three domains (CH2, CH3 and CH4) were not generated by recent duplication processes of IgM in Actinopterygii, indicating it is an immunoglobulin with an earlier origin.
Genetic Risk Scores for Cardiometabolic Traits in Sub-Saharan African Populations
Authors: Ekoru Kenneth , Adeyemo Adebowale A. , Chen Guanjie , Doumatey Ayo P. , Zhou Jie , Bentley Amy R. , Shriner Daniel , Rotimi Charles N. 
Published: May 2020

AbstractThere is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. Here, we evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF;n=5200), African Americans (AA;n=9139), and European Americans (EA;n=9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and increase in discriminatory ability over traditional risk factors (age, sex and BMI), with adjustment for ancestry-derived principal components. Across all traits, GRS showed upto a 5-fold and 20-fold greater predictive utility in EA relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percent increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EA, 26.6% to 65.8% among AA, and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EA relative to AA and up to 44-fold greater in EA relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EA. This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiethnic populations in genomic studies to ensure equitable clinical translation of GRS.Key MessagesGenetic Risk Score (GRS) prediction is markedly poorer in sub-Saharan Africans compared with African Americans and European AmericansTo ensure equitable clinical translation of GRS, there is need need to improve representation of multiethnic populations in genomic studies
Defective folate metabolism causes germline epigenetic instability and distinguishesHiraas a phenotype inheritance biomarker
Authors: Blake Georgina E.T. , Zhao Xiaohui , Yung Hong wa , Burton Graham J. , Ferguson-Smith Anne C. , Hamilton Russell S. , Watson Erica D. 
Published: May 2020

ABSTRACTThe mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by theMtrrgthypomorphic mutation results in TEI of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. In this work, we use a genome-wide approach to reveal genetic stability in theMtrrgtmodel and epigenome-wide differential DNA methylation in the germline ofMtrr+/gtmaternal grandfathers. While epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional memory of germline methylation defects. One region encompasses theHiragene, which is misexpressed in embryos at least until the F3 generation in a manner that distinguishesHiratranscript expression as a biomarker of maternal phenotypic inheritance.
Rolling Signal-based Ripley’s K: A new algorithm to identify spatial patterns in histological specimens
Authors: Healy Connor P. , Adler Frederick R. , Deans Tara L. 
Published: May 2020

SUMMARYThe spatial distribution of cells within a tissue underlies organ function. However, these spatial distributions are often difficult to identify, making it challenging to evaluate how cells establish these patterns during development or how diseases may disrupt these patterns and impair function. To address this, we developed an image analysis tool based on a novel algorithm that identifies spatial patterns within tissues. This analytical tool was used to study the bone marrow, a specialized microenvironment in which spatial patterning of regulatory cells may influence the differentiation and survival of hematopoietic stem cells. Using this algorithm, we discovered clusters of regulatory cells within the bone marrow that suggest an organization of micro-niches, which may form the basis of the hematopoietic stem cell microenvironment. This work provides a new tool for the detection and analysis of tissue morphology that enables identification of spatial patterns within tissues that can lead to a deeper understanding of tissue function, provide clues for early onset of disease, and be used as a tool for studying the impact of pharmaceutics on tissue development and regeneration.In BriefThis work introduces a new statistic to analyze the patterning of cells and physiological features in histological images. This statistic was used on a published set of immunofluorescent images of murine bone to identify novel spatial structures within the bone marrow that may provide new inisghts to the organization of the hematopoietic stem cell microenvironment.HighlightsRSRK, a statistical tool for analyzing the spatial distribution of features in histological images, is introduced.RSRK incorporates the quantification of signal distribution to identify unique spatial patterns.Spatial patterns in hematopoietic stem cell microenvironments are identified.Graphical Abstract
How cells determine the number of polarity sites
Authors: Chiou Jian-geng , Moran Kyle D. , Lew Daniel J. 
Published: May 2020

AbstractThe diversity of cell morphologies arises, in part, through regulation of cell polarity by Rho-family GTPases. A poorly understood but fundamental question concerns the regulatory mechanisms by which different cells can generate different numbers of polarity sites. Theoretical models of polarity circuits develop multiple initial polarity sites, but then those sites engage in competition, leaving a single winner. The timescale of competition slows dramatically as GTPase concentrations at polarity sites approach a “saturation point”, allowing multiple sites to coexist. Here, we show that these principles hold in more complex mechanistic models of theSaccharomyces cerevisiaepolarity machinery, and confirm model predictionsin vivo. Further, we elucidate a novel design principle whereby cells can switch from competition to equalization among polarity sites. These findings provide insight into how cells determine the number of polarity sites.
Reconstruction of Fur pan-regulon uncovers the complexity and diversity of transcriptional regulation inE. coli
Authors: Gao Ye , Bang Ina , Seif Yara , Nam Gayoung , Sastry Anand V. , Chen Ke , Monk Jonathan M. , Choudhary Kumari Sonal , Seo Sang Woo , Lee Eun-Yeol , Kim Donghyuk , Palsson Bernhard O. 
Published: May 2020

AbstractRegulons for many transcription factors have been elucidated in model strains leading to an understanding of their role in producing physiological states. Comparative analysis of a regulon and its target genes between different strains of the same species is lacking. Ferric uptake regulator (Fur), involved in iron homeostasis, is one of the most conserved TFs, and is present in a wide range of bacteria. Using ChIP-exo experiments, we performed a comprehensive study of Fur binding sites in nineEscherichia colistrains with different lifestyles. 79 of the 431 target genes (18%) found belong to Fur core regulon, comprising genes involved in ion transport and metabolism, energy production and conversion, and amino acid metabolism and transport. 179 of the target genes (42%) comprise the accessory regulon, most of which were related to cell wall structure and biogenesis, and virulence factor pathways. The remaining target genes (173 or 40%) were in the unique regulon, with gene functions that were largely unknown. Furthermore, deletion of thefurgene led to distinct phenotypes in growth, motility, antibiotic resistance, and the change of siderophore production. These results provide a more complete understanding of how Fur regulates a set of target genes with surprising variation in closely related bacteria.
Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity
Authors: Teng Shaolei , Sobitan Adebiyi , Rhoades Raina , Liu Dongxiao , Tang Qiyi 
Published: May 2020

ABSTRACTThe spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.
Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles
Authors: Zhang Jiyuan , Guan Xin , Yan Jiusheng 
Published: May 2020

SUMMARYNicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+-mobilizing second messenger which uniquely mobilizes Ca2+from acidic endolysosomal organelles. However, the molecular identity of the NAADP receptor remains unknown. Given the necessity of the endolysosomal two-pore channel (TPC1 or TPC2) in NAADP signaling, we performed affinity purification and quantitative proteomic analysis of the interacting proteins of NAADP and TPCs. We identified an Sm-like protein Lsm12 complexed with NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, whereas TPC-containing membranes and isolated TPCs lose their affinities to NAADP in the absence of Lsm12. Lsm12 is essential and directly involved in NAADP-evoked TPC2 activation and Ca2+mobilization. These findings reveal a putative RNA-binding protein to function as an NAADP receptor and a TPC regulatory protein and provides a molecular basis for understanding the mechanisms of NAADP signaling.
Congregate Shelter Characteristics and Prevalence of Asymptomatic SARS-CoV-2
Authors: Samuels Elizabeth A. , Karb Rebecca , Vanjani Rahul , Trimbur M. Catherine , Napoli Anthony 
Published: May 2020

AbstractBackgroundIndividuals experiencing homelessness residing in congregate shelters have increased risk for SARS-CoV-2 infection. Prevalence of asymptomatic SARS-CoV-2 in congregate shelters is high, but shelter characteristics associated with SARS-CoV-2 transmission are currently unknown.MethodsWe conducted a cross-sectional, multicenter cohort study across five congregate shelters in Rhode Island. We tested people 18 years of age and older staying in Rhode Island congregate shelters in April 2020 during the COVID-19 pandemic. A survey instrument was designed and implemented based on an a priori sample size. All consented participants reported basic demographics, recent travel, duration of time at the shelter, any symptomatology, and had their temperature and pulse oximetry measured. Each participant was tested for COVID-19 using nasopharyngeal swabbing. Shelter characteristics about location, occupancy, resident length of stay, and COVID-19 mitigation strategies were collected through structured phone questionnaire with shelter staff.ResultsA total of 302 individuals were screened and 299 participated across five homeless shelters. The median age was 47.9 (range 18-85) and 20% were female. Of the 299 participants, 35 (11.7%) were positive for SARS-CoV-2; rates varied among shelters, ranging from 0% to 35%. Among the participants in the study, 5% had a new cough, 4% shortness of breath, and 3% reported loss of taste or smell. Symptom prevalence did not vary significantly between positive and negative SARS-CoV-2 groups. Regular symptom screening was not associated with lower infection rates. Shelters with higher rates of positivity were in more densely populated areas, cared for a more transient populations, and instituted fewer social distancing practices for sleeping arrangements or mealtimes.Conclusions and RelevanceResidents of congregate shelters are at increased risk for asymptomatic transmission of SARS-CoV-2. To reduce transmission and enable continuation of low-threshold shelter services, there is a need for universal testing, implementation of infection control and physical distancing measures within congregate shelters, and expansion of non-congregate supportive housing.
A bipartite element with allele-specific functions safeguards DNA methylation imprints at theDlk1-Dio3locus
Authors: Aronson BE , Scourzic L , Shah V , Swanzey E , Kloetgen A , Polyzos A , Sinha A , Azziz A , Caspi I , Li J , Pelham-Webb B , Wichterle H , Tsirigos A , Stadtfeld M , Apostolou E 
Published: May 2020

SUMMARYDysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essentialDlk1-Dio3locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternalGtl2lncRNA by precludingde novoDNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entireDlk1-Dio3locus. Although the targeted repression of either IG-DMR orGtl2promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control ofDlk1-Dio3imprinting by allele-specific restriction of the DNA (de)methylation machinery.HIGHLIGHTSThe IG-DMR is a bipartite element with distinct allele-specific functionsA non-canonical enhancer within the IG-DMR prevents DNA methyltransferase activityTargeted epigenome editing allows induction of specific imprinting phenotypesCRISPRi reveals a functional hierarchy between DMRs that dictates imprint stability
Translocation of an arctic seashore plant reveals signs of maladaptation to altered climatic conditions
Authors: Hällfors M.H. , Lehvävirta S. , Aandahl T.R. , Lehtimäki I.-M. , Nilsson L.O. , Ruotsalainen A.L. , Schulman L.E. , Hyvärinen M.-T. 
Published: May 2020

AbstractOngoing anthropogenic climate change alters the local climatic conditions to which species may be adapted. Information on species’ climatic requirements and their intraspecific variation is necessary for predicting the effects of climate change on biodiversity. We used a climatic gradient to test whether populations of two allopatric varieties of an arctic seashore herb (Primula nutansssp.finmarchica) show adaptation to their local climates and how a future warmer climate may affect them. Our experimental set-up combined i) a reciprocal translocation within the distribution range of the species with ii) an experiment testing performance of the sampled populations in warmer climatic conditions south of their range. We monitored survival, size, and flowering over four growing seasons as measures of performance and, thus, proxies of fitness. We found that both varieties performed better in experimental gardens towards the north. Interestingly, highest up in the north, the southern variety outperformed the northern one. Supported by weather data, this suggests that the climatic optima of both varieties has moved at least partly outside their current range. Further warming would make the current environments of both varieties even less suitable. We conclude thatPrimula nutansssp.finmarchicais already suffering from adaptation-lag due to climate change, and that further warming may be increase this maladaptation, especially for the northern variety. The study also highlights that it is not sufficient to run only reciprocal translocation experiments. Climate change is already shifting the optimum conditions for many species and adaptation needs also to be tested outside the current range of the focal taxon in order to include both historic conditions and future conditions.
Single-particle cryo-EM at atomic resolution
Authors: Nakane Takanori , Kotecha Abhay , Sente Andrija , McMullan Greg , Masiulis Simonas , Brown Patricia M.G.E. , Grigoras Ioana T. , Malinauskaite Lina , Malinauskas Tomas , Miehling Jonas , Yu Lingbo , Karia Dimple , Pechnikova Evgeniya V. , de Jong Erwin , Keizer Jeroen , Bischoff Maarten , McCormack Jamie , Tiemeijer Peter , Hardwick Steven W. , Chirgadze Dimitri Y. , Murshudov Garib , Aricescu A. Radu , Scheres Sjors H.W. 
Published: May 2020

AbstractThe three-dimensional positions of atoms in protein molecules define their structure and provide mechanistic insights into the roles they perform in complex biological processes. The more precisely atomic coordinates are determined, the more chemical information can be derived and the more knowledge about protein function may be inferred. With breakthroughs in electron detection and image processing technology, electron cryo-microscopy (cryo-EM) single-particle analysis has yielded protein structures with increasing levels of detail in recent years1,2. However, obtaining cryo-EM reconstructions with sufficient resolution to visualise individual atoms in proteins has thus far been elusive. Here, we show that using a new electron source, energy filter and camera, we obtained a 1.7 Å resolution cryo-EM reconstruction for a prototypical human membrane protein, the β3 GABAAreceptor homopentamer3. Such maps allow a detailed understanding of small molecule coordination, visualisation of solvent molecules and alternative conformations for multiple amino acids, as well as unambiguous building of ordered acidic side chains and glycans. Applied to mouse apo-ferritin, our strategy led to a 1.2 Å resolution reconstruction that, for the first time, offers a genuine atomic resolution view of a protein molecule using single particle cryo-EM. Moreover, the scattering potential from many hydrogen atoms can be visualised in difference maps, allowing a direct analysis of hydrogen bonding networks. Combination of the technological advances described here with further approaches to accelerate data acquisition and improve sample quality provide a route towards routine application of cryo-EM in high-throughput screening of small molecule modulators and structure-based drug discovery.