bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative and molecular differences distinguish adult human medullary and extramedullary haematopoietic stem and progenitor cell landscapes
Authors: Mende Nicole , Bastos Hugo P , Santoro Antonella , Sham Kendig , Mahbubani Krishnaa T. , Curd Abbie , Takizawa Hitoshi , Wilson Nicola K , Göttgens Bertie , Saeb-Parsy Kourosh , Laurenti Elisa 
Published: January 2020

ABSTRACTIn adults, the bone marrow (BM) is the main site of haematopoietic stem and progenitor cells (HSPCs) maintenance and differentiation. It is known that other anatomical sites can contribute significantly to blood production under stress conditions. However limited tissue availability restricts our knowledge on the cellular, molecular and functional composition of extramedullary HSPC pools in humans at steady state or under stress. Here we describe the landscape of human HSPC differentiation across the three major haematopoietic anatomical sites: BM, spleen and peripheral blood (PB), using matched tissues isolated from the same individuals. Single cell RNA-seq of 30,000 HSPCs and 700 phenotypic haematopoietic stem cells and multipotent progenitors (HSC/MPP) demonstrates significantly different dynamics of haematopoiesis between BM and extramedullary tissues. Lineage-committed progenitors of spleen and PB do not actively divide, whereas BM is the primary site of progenitor proliferation. The balance of differentiation in spleen and PB is skewed towards the lymphoid and erythroid lineages, whereas in BM it is tilted towards megakaryocytic and myeloid progenitors. Extramedullary tissues also harbour a molecularly defined subset of HSC/MPP not found in the BM, which is marked by a specific acto-myosin cytoskeletal signature and transcriptional priming for division and lineage differentiation. Collectively, our findings define a unique cellular and molecular structure of the haematopoietic landscape in extramedullary organs, positioned for rapid lineage-primed demand-adapted haematopoiesis. These data also provide a framework for better understanding of human extramedullary haematopoiesis in health and disease.
Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2
Authors: Zhao Yu , Zhao Zixian , Wang Yujia , Zhou Yueqing , Ma Yu , Zuo Wei 
Published: January 2020

AbstractA novel coronavirus SARS-CoV-2 was identified in Wuhan, Hubei Province, China in December of 2019. According to WHO report, this new coronavirus has resulted in 76,392 confirmed infections and 2,348 deaths in China by 22 February, 2020, with additional patients being identified in a rapidly growing number internationally. SARS-CoV-2 was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-CoV. Here based on the public database and the state-of-the-art single-cell RNA-Seq technique, we analyzed the ACE2 RNA expression profile in the normal human lungs. The result indicates that the ACE2 virus receptor expression is concentrated in a small population of type II alveolar cells (AT2). Surprisingly, we found that this population of ACE2-expressing AT2 also highly expressed many other genes that positively regulating viral entry, reproduction and transmission. This study provides a biological background for the epidemic investigation of the COVID-19, and could be informative for future anti-ACE2 therapeutic strategy development.
“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”
Authors: Alić Ivan , Goh Pollyanna A , Murray Aoife , Portelius Erik , Gkanatsiou Eleni , Gough Gillian , Mok Kin Y , Koschut David , Brunmeir Reinhard , Yeap Yee Jie , O’Brien Niamh L , Groet Jurgen , Shao Xiaowei , Havlicek Steven , Dunn N Ray , Kvartsberg Hlin , Brinkmalm Gunnar , Hithersay Rosalyn , Startin Carla , Hamburg Sarah , Phillips Margaret , Pervushin Konstantin , Turmaine Mark , Wallon David , Rovelet-Lecrux Anne , Soininen Hilkka , Volpi Emanuela , Martin Joanne E , Foo Jia Nee , Becker David L , Rostagno Agueda , Ghiso Jorge , Krsnik Željka , Šimić Goran , Kostović Ivica , Mitrečić Dinko ,   LonDownS Consortium, Francis Paul T , Blennow Kaj , Strydom Andre , Hardy John , Zetterberg Henrik , Nižetić Dean 
Published: January 2020

AbstractA population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grownin vitrofrom non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-geneBACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role ofBACE2as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ∼30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
Eating breakfast and avoiding the evening snack sustains lipid oxidation
Authors: Kelly Kevin Parsons , McGuinness Owen P. , Buchowski Maciej , Hughey Jacob J. , Chen Heidi , Powers James , Page Terry , Johnson Carl Hirschie 
Published: January 2020

SUMMARYCircadian (daily) regulation of metabolic pathways implies that food may be metabolized differentially over the daily cycle. To test that hypothesis, we monitored the metabolism of older subjects in a whole-room respiratory chamber over two separate 56-h sessions in a random crossover design. In one session, one of the three daily meals was presented as breakfast whereas in the other session, a nutritionally equivalent meal was presented as a late-evening snack. The duration of the overnight fast was the same for both sessions. Whereas the two sessions did not differ in overall energy expenditure, the respiratory exchange ratio (RER) was different during sleep between the two sessions. Unexpectedly, this difference in RER due to daily meal timing was not due to daily differences in physical activity, sleep disruption, or core body temperature. Rather, we found that the daily timing of nutrient availability coupled with daily/circadian control of metabolism drives a switch in substrate preference such that the late-evening snack session resulted in significantly lower lipid oxidation compared to the breakfast session. Therefore, the timing of meals during the day/night cycle affects how ingested food is oxidized or stored in humans with important implications for optimal eating habits.
The activity of chloroplast NADH dehydrogenase-like complex influences the photosynthetic activity of the mossPhyscomitrella patens
Authors: Storti Mattia , Puggioni Maria Paola , Segalla Anna , Morosinotto Tomas , Alboresi Alessandro 
Published: January 2020

ABSTRACTAlternative electron pathways contribute to the regulation of photosynthetic light reactions to meet metabolic demands in a dynamic environment. Understanding the molecular mechanisms of their activity is seminal to decipher their role in response to environmental cues and in plant adaptation. The chloroplast NADH dehydrogenase-like (NDH) complex mediates cyclic electron transport pathway around photosystem I (PSI) in different organisms like cyanobacteria, algae and various plant species but has a discontinuous distribution in the green lineage. In order to assess how its activity and physiological role changed during plant evolution, we isolatedPhyscomitrella patenslines knocked out of the geneNDHMwhich encodes for a subunit fundamental for the stability and activity of the whole complex.P. patens ndhmKO mosses showed high PSI acceptor side limitation upon illumination leading to PSI photoinhibition. Flavodiiron proteins (FLV) have similar and particularly important role in preventing PSI overreduction when plants are exposed to light fluctuations. Theflva ndhmdouble KO mosses alteration in photosynthetic parameters leaded to a defect in plant growth under fluctuating light as compared to WT and single KO mutants. Results evidenced that, while FLV sustain strong electron transport after an abrupt change in light intensity, NDH contribution to electron transport is small. NDH still participate in modulating PSI activity and it is seminal to prevent PSI photoinhibition especially when FLV are inactive. In plants the functional overlap between NDH- and FLV-dependent electron transport systems sustains PSI activity and to prevent its photoinhibition.
Cortical surface alterations in cingulate and frontal regulatory areas underlie insensitive mothering
Authors: León Inmaculada , Rodrigo María José , Quiñones Ileana , Andrés Hernández-Cabrera Juan , García-Pentón Lorna 
Published: January 2020

AbstractThis study focuses on severe insensitive or neglectful mothering, the most prevalent type of child maltreatment, to examine cortical surface feature alterations underlying maternal functioning and their impact on mother-child interactive bonding. High-resolution 3D volumetric images were obtained on 24 neglectful (NM) and 21 non-neglectful control (CM) mothers. Using surface-based morphometry, we compared differences in cortical thickness and surface area. Mothers completed alexithymia and cortical integrity measures and participated with their children in a play task (Emotional Availability Scale). We found cortical thinning for NM in the right rostral middle frontal gyrus and the right anterior/medial cingulate cortex, and also increased surface area in the right occipital lingual and fusiform areas and the caudal middle frontal area. Mediation analyses showed that cognitive integrity and alexithymia mediated, respectively, the positive and negative effect of the rostral middle frontal gyrus on Emotional Availability. The findings suggest cortical thinning in the rostral frontal area underlying high-order regulatory functioning as being critical for poor maternal self-awareness of emotions and the organization of coordinated actions during mother-child interactive bonding.
Reconstituted Mining Effluent Reduces Neuronal Proliferation in the Developing Brain and Slows Growth of Body and Facial Features in Wild-Caught Wood Frog Tadpoles
Authors: Sturgeon Hannah G. , Kitchen Jeremy P. , Dahora Lara I. , Sweeten Sara E. , Thompson Christopher K. 
Published: January 2020

AbstractMining, whether current or inactive, generally increases salt concentrations in catchment watersheds due to precipitation on and through exposed rock surfaces. Practices like mountaintop removal mining have exacerbated this issue, with measurements of salt concentrations in nearby catchment systems well above normal levels. Nevertheless, the impact of the ionic composition of mining effluent on aquatic animal health is not well understood. This is a particularly important issue in Appalachia because it is home to an enormous diversity of organisms, including a huge array of amphibians that live in streams that receive mining effluent from operating and abandoned mines. To investigate this issue, we examined the effects of reconstituted mining effluent on the development of wild-caught wood frog (Lithobates sylvaticus) tadpoles. We collected day-old fertilized eggs from a creek near Blacksburg, VA in early March, 2018 and raised them to hatch. Tadpoles were then assigned to either sulfate or chloride-based reconstituted mining effluent diluted to six different conductivities (100 μS/cm - 2,400 μS/cm). After 7 or 14 days of treatment, tadpoles were euthanized and fixed in paraformaldehyde. We imaged the heads and bodies of tadpoles for morphometric analysis before dissecting out brains and immunostaining them for phospho-histone H3, which labels dividing progenitor cells in the brain. We found that sulfate-based reconstituted mining effluent significantly lowered progenitor cell division at 1200 μS/cm at Day 7 and at 600 μS/cm at Day 14 relative to control. Chloride-based reconstituted mining effluent was less impactful, with no significant differences observed at Day 7 and significantly lowered progenitor cell division at 2400 μS/cm at Day 14. In addition, both treatments slowed growth of some head morphological features, including head size and interocular distance. Chloride treatment slowed growth of body length at Day 14 at 600 μS/cm, whereas sulfate-based reconstituted mining effluent had no effect on body length. These data show that sulfate-based mining effluent has a substantial impact on aspects of neural development, whereas chloride-based reconstituted mining effluent had less effect. In contrast, chloride-based reconstituted mining effluent had a much greater impact than sulfate on body morphology and growth. These experiments demonstrate that the chemical composition of salts in mining effluent can have divergent effects on the development of amphibians.
Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts
Authors: Báez-Becerra Cindy Tatiana , Valencia-Rincón Estefania , Velásquez-Méndez Karen , Ramírez-Suárez Nelson J. , Guevara Claudia , Sandoval-Hernandez Adrian , Arboleda-Bustos Carlos E. , Olivos-Cisneros Leonora , Gutiérrez-Ospina Gabriela , Arboleda Humberto , Arboleda Gonzalo 
Published: January 2020

ABSTRACTRecently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein. In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.
Clustering of dispersal corridors in metapopulations leads to higher rates of recovery following subpopulation extinction
Authors: Kurkjian Helen M. 
Published: January 2020

AbstractUnderstanding how spatially divided populations are affected by the physical characteristics of the landscapes they occupy is critical to their conservation. While some metapopulations have dispersal corridors spread relatively evenly through space in a homogeneous arrangement such that most subpopulations are connected to a few neighbors, others may have corridors clustered in a heterogeneous arrangement, creating a few highly connected subpopulations and leaving most subpopulations with only one or two neighbors. Graph theory and empirical data from other biological and non-biological networks suggest that heterogeneous metapopulations should be the most robust to subpopulation extinction. Here, I usedPseudomonas syringaepv.syringaeB728a in metapopulation microcosms to compare the recovery of metapopulations with homogeneous and heterogeneous corridor arrangements following small, medium, and large subpopulation extinction events. I found that while metapopulations with heterogeneous corridor arrangements had the fastest rates of recovery following extinction events of all sizes and had the shortest absolute time to recovery following medium-sized extinction events, metapopulations with homogeneous corridor arrangements had the shortest time to recovery following the smallest extinction events.
VARIATION AND SELECTION IN AXON NAVIGATION THROUGH MICROTUBULE-DEPENDENT STEPWISE GROWTH CONE ADVANCE
Authors: Turney Stephen G , Chandrasekar Indra , Ahmed Mostafa , Rioux Robert M , Whitesides George M , Bridgman Paul C 
Published: January 2020

ABSTRACTMyosin II (MII) activity is required for elongating mammalian sensory axons to change speed and direction in response to Nerve Growth Factor (NGF) and laminin-1 (LN). NGF signaling induces faster outgrowth on LN through regulation of actomyosin restraint of microtubule advance into the growth cone periphery. It remains unclear whether growth cone turning on LN works through the same mechanism and, if it does, how the mechanism produces directed advance. Using a novel method for substrate patterning, we tested how directed advance occurs on LN by creating a gap immediately in front of a growth cone advancing on a narrow LN path. The growth cone stopped until an actin-rich protrusion extended over the gap, adhered to LN, and became stabilized. Stepwise advance over the gap was triggered by microtubule +tip entry up to the adhesion site of the protrusion and was independent of traction force pulling. We found that the probability of microtubule entry is regulated at the level of the individual protrusion and is sensitive to the rate of microtubule polymerization and the rate of rearward actin flow as controlled by adhesion-cytoskeletal coupling and MII. We conclude that growth cone navigation is an iterative process of variation and selection. Growth cones extend leading edge actin-rich protrusions that adhere transiently (variation). Microtubule entry up to an adhesion site stabilizes a protrusion (selection) leading to engorgement, consolidation, protrusive activity distal to the adhesion site, and stepwise growth cone advance. The orientation of the protrusion determines the direction of advance.
Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain
Authors: Noch Evan K. , Yim Isaiah , Milner Teresa A. , Cantley Lewis C. 
Published: January 2020

AbstractPhosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. PI-4,5-P2can be generated by two families of kinases: type 1 phosphatidylinositol-4-phosphate 5-kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol-5-phosphate 4-kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kß, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kß is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kß is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co-localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kß co-localizes with the neuronal marker, NeuN. Immunohistochemical subcellular distribution studies demonstrate that PI5P4Kα and PI5P4Kß are expressed in the early endosome system. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunohistochemical analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kß. These results highlight the diverse cell-autonomous expression of PI5P4Kα and PI5P4Kß and support further exploration into their role in synaptic function in the brain.
Redundant and additive functions of the four Lef/Tcf transcription factors in lung epithelial progenitors
Authors: Gerner-Mauro Kamryn N. , Akiyama Haruhiko , Chen Jichao 
Published: January 2020

ABSTRACTIn multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multi-member paralogs, as exemplified by the 4 obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the dauntingly complex genetics involved. Using the developing mouse lung as a model system, we generate 2 quadruple conditional knockouts and myriad triple and double combinations, and show that the 4 Lef/Tcf genes function redundantly in the presence of at least 2 Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Pre-lung-specification, pan-epithelial double knockouts have no lung phenotype, triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas, and the quadruple knockout barely forms a lung, resembling theCtnnb1mutant. Post-lung-specification deletion of all 4 Lef/Tcf genes leads to branching defects, downregulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the correspondingCtnnb1mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors and represents, to our knowledge, the first in vivo analysis of cell-type-specific genetic redundancy among the 4 Lef/Tcf paralogs.SIGNIFICANCE STATEMENTParalogs represent genetic redundancy and survive purifying selection by evolving overlapping and distinct functions. In multicellular organisms, such functional diversification can manifest as tissue and cell type specific expression, which masks possible selective pressure for genetic redundancy within a single cell type. Using in vivo genetic and genomic analyses, we show that although the 4 mammalian Lef/Tcf transcription factors have evolved organ-specific functions, they function additively and redundantly, depending on gene dosage, to promote lung epithelial progenitors and do so in a monotonic, positive manner with beta-Catenin in the canonical Wnt signaling pathway.