bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Sea Change in Microbial Enzymes: Heterogeneous latitudinal and depth-related gradients in bulk water and particle-associated enzymatic activities from 30°S to 59°N in the Pacific Ocean
Authors: Balmonte John Paul , Simon Meinhard , Giebel Helge-Ansgar , Arnosti Carol 
Published: October 2020

AbstractHeterotrophic microbes initiate organic matter degradation using extracellular enzymes. Our understanding of differences in microbial enzymatic capabilities, especially among particle-associated taxa and in the deep ocean, is limited by a paucity of hydrolytic enzyme activity measurements. Here, we measured the activities of a broad range of hydrolytic enzymes (glucosidases, peptidases, polysaccharide hydrolases) in epipelagic to bathypelagic bulk water (non-size fractionated), and on particles (≥ 3 μm) along a 9,800 km latitudinal transect from 30°S in the South Pacific to 59°N in the Bering Sea. Individual enzyme activities showed heterogeneous latitudinal and depth-related patterns, with varying biotic and abiotic correlates. With increasing latitude and decreasing temperature, lower laminarinase activities sharply contrasted with higher leucine aminopeptidase (leu-AMP) and chondroitin sulfate hydrolase activities in bulk water. Endopeptidases (chymotrypsins, trypsins) exhibited patchy spatial patterns, and their activities can exceed rates of the widely-measured exopeptidase, leu-AMP. Compared to bulk water, particle-associated enzymatic profiles featured a greater relative importance of endopeptidases, a broader spectrum of polysaccharide hydrolases, and latitudinal and depth-related trends that paralleled variations in particle fluxes. As water depth increased, enzymatic spectra on particles and in bulk water became narrower, and diverged more from one another. These distinct latitudinal and depth-related gradients of enzymatic activities underscore the biogeochemical consequences of emerging global patterns of microbial community structure and function, from surface to deep waters, and among particle-associated taxa.
The impact of life stage and pigment source on the evolution of novel warning signal traits
Authors: Lindstedt Carita , Bagley Robin , Calhim Sara , Jones Mackenzie , Linnen Catherine 
Published: October 2020

ABSTRACTOur understanding of how novel color traits evolve in aposematic taxa is based largely on studies of reproductive stages and organisms with endogenously produced pigmentation. In these systems, genetic drift is often required for novel alleles to overcome strong purifying selection stemming from frequency-dependent predation and positive assortative mating. Here we show that the importance of these mechanisms can differ if selective processes are considered in larval stage instead. By integrating population genomic data, predation experiments and phenotypic measurements of larvae and their host plants, we show that novel white alleles inNeodiprion lecontei(pine sawfly) larvae spread via selection rather than drift. The cost of being rare was not offset by an enhanced aposematic display or immune function. Instead, bottom-up selection via host plants may drive divergence among populations as white larvae were disproportionately abundant on a pine species with a reduced carotenoid content relative to other pine hosts.
Cortical inhibitory network selects cerebellar signals for movement initiation
Authors: Nashef Abdulraheem , Cohen Oren , Perlmutter Steve I. , Prut Yifat 
Published: October 2020

SUMMARYThe onset of voluntary movements is driven by coordinated firing across a large population of motor cortical neurons. This pattern of activity is determined by both local interactions and long-range corticocortical and subcortical inputs. The way remote areas of the brain communicate to effectively drive movement is still unclear. We addressed this question by studying an important pathway through which the cerebellum communicates, via the motor thalamus, with the motor cortex. We found that similar to the sensory cortices, thalamic input to the motor cortex triggers feedforward inhibition by directly contacting inhibitory cells via particularly effective GluR2- lacking AMPA receptors blocked by NASPM. Based on these results, we constructed a classifier for SCP-responsive cortical cells to identify pyramidal and PV interneurons and study their role in controlling movements. The findings indicate that PV and pyramidal cells are co-driven by TC input in response to activation of the CTC pathway. During task performance, PV and pyramidal cells had comparable relations to movement parameters (directional tuning and movement duration). However, PV interneurons exhibited stronger movement-related activity that preceded the firing of pyramidal cells. This seemingly counterintuitive sequence of events where inhibitory cells are recruited more strongly and before excitatory cells may in fact enhance the signal-to-noise ratio of cerebellar signals by suppressing other inputs and prioritizing the excitatory synchronized volley from the TC system which occurs at the right time to overcome the inhibitory signal. In this manner, the CTC system can shape cortical activity in a way that exceeds its sheer synaptic efficacy.
Genetic characterization of a mild isolate of papaya ringspot virus type-P (PRSV-P) and assessment of its cross-protection potential under greenhouse and field conditions
Authors: Medina-Salguero Andres X. , Cornejo-Franco Juan F. , Grinstead Sam , Mowery Joseph , Mollov Dimitre , Quito-Avila Diego F. 
Published: October 2020

AbstractA mild isolate ofPapaya ringspot virustype-P, abbreviated as PRSV-mild, from Ecuador was sequenced and characterized. The most distinguishing symptom induced by PRSV-mild was gray powder-like leaf spots radiating from secondary veins. In greenhouse experiments, PRSV-mild did not confer durable protection against a severe isolate of the virus (PRSV-sev), obtained from the same field. Furthermore, isolate specific detection in cross-protected plants showed that PRSV-sev becomes dominant in infections, rendering PRSV-mild undetectable at 90 - 120 days post superinfection. Virus testing using isolate-specific primers detected PRSV-mild in two out of five surveyed provinces, with 10% and 48% of incidence in Santo Domingo and Los Ríos, respectively. Comparative genomics showed that PRSV-mild lacks two amino acids from the coat protein region, whereas amino acid determinants for asymptomatic phenotypes were not identified. Recombination events were not predicted in the genomes of the Ecuadorean isolates. Phylogenetic analyses placed both PRSV-mild and PRSV-sev in a clade that includes an additional PRSV isolate from Ecuador and others from South America.
Expression analysis of photosynthesis-related genes in albinoArtocarpus heterophyllusseedlings leaves
Authors: Cai Zeping , Dong Junna , Zhang Xi , Qu Qian , Wu Fanhua , Cao Lu , Li Shidong , Wang Zixuan , Zhou Dan , Luo Jiajia , Yu Xudong 
Published: October 2020

AbstractAlbinoArtocarpus heterophyllusSeedlings (AAS) were found in the preliminary investigation by our group and were used as materials for researching. The phenotype of AAS leaves were observed and measured. In parallel, the photosynthetic physiological parameters were determined under different photosynthetically active radiations (PAR). The results suggested that the length, width, area and thickness of AAS leaves were less than normal seedings. Likewise, the net photosynthetic rate, intercellular CO2concentration, stomatal conductance and transpiration rate of AAS leaves were not susceptible to PAR in contrast to normal individuals. Furthermore, the transcriptome sequencing technology was performed to clarify the expression of genes related to photosynthesis. It is as expected that numerous down-regulated genes were found in the synthesis of photosynthetic pigments, as well as the pathways of photosynthesis - antenna proteins, photoreaction and carbon fixation reaction of AAS leaves. Compared to other albino plants, AAS have a longer life span and more stable phenotypic traits with larger leaves, which could provide ideal materials for investigating photosynthesis of woody plants.
Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action
Authors: Hallakou-Bozec Sophie , Kergoat Micheline , Fouqueray Pascale , Bolze Sébastien , Moller David E. 
Published: October 2020

ABSTRACTPancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that Imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool – potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+conversion to a second messenger, cyclic ADP ribose (cADPR), via cyclic ADP ribose hydrolase (CD38) is required for Imeglimin’s effects in islets, thus representing a potential link between increased NAD+and enhanced glucose-induced Ca2+ mobilization which - in turn - is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for Imeglimin that explains its ability to effectively restore β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.
Local adaptation in populations ofMycobacterium tuberculosisendemic to the Indian Ocean Rim
Authors: Menardo Fabrizio , Rutaihwa Liliana K. , Zwyer Michaela , Borrell Sonia , Comas Iñaki , Conceição Emilyn Costa , Coscolla Mireia , Cox Helen , Joloba Moses , Dou Horng-Yunn , Feldmann Julia , Fenner Lukas , Fyfe Janet , Gao Qian , de Viedma Darío García , Garcia-Basteiro Alberto L. , Gygli Sebastian M. , Hella Jerry , Hiza Hellen , Jugheli Levan , Kamwela Lujeko , Kato-Maeda Midori , Liu Qingyun , Ley Serej D. , Loiseau Chloe , Mahasirimongkol Surakameth , Malla Bijaya , Palittapongarnpim Prasit , Rakotosamimanana Niaina , Rasolofo Voahangy , Reinhard Miriam , Reither Klaus , Sasamalo Mohamed , Duarte Rafael Silva , Sola Christophe , Suffys Philip , Lima Karla Valeria Batista , Yeboah-Manu Dorothy , Beisel Christian , Brites Daniela , Gagneux Sebastien 
Published: October 2020

AbstractLineage 1 (L1) and 3 (L3) are two lineages of theMycobacterium tuberculosiscomplex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the world’s new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at theesxHlocus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.
A lamin A/C variant causing striated muscle disease provides insights into filament organization
Authors: Kronenberg-Tenga Rafael , Tatli Meltem , Eibauer Matthias , Wu Wei , Shin Ji-Yeon , Bonne Gisele , Worman Howard J. , Medalia Ohad 
Published: October 2020

AbstractTheLMNAgene encodes the A-type lamins that polymerize into ~3.5 nm thick filaments, and together with B-type lamins and lamin binding proteins form the nuclear lamina. Mutations inLMNAare associated with a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts fromLmnaH222P/H222Pmice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filamentsin situ, and using a nuclear extraction protocol. Averaging of individual segments of filaments inLmnaH222P/H222Pmouse fibroblasts resolved two-polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.
The Halastavi árva virus intergenic region IRES promotes translation by the simplest possible initiation mechanism
Authors: Abaeva Irina S. , Vicens Quentin , Bochler Anthony , Soufari Heddy , Simonetti Angelita , Pestova Tatyana V. , Hashem Yaser , Hellen Christopher U. T. 
Published: October 2020

ABSTRACTDicistrovirus intergenic region internal ribosomal entry sites (IGR IRES) do not require initiator tRNA, an AUG codon or initiation factors, and jumpstart translation from the middle of the elongation cycle via formation of IRES/80S complexes resembling the pre-translocation state. eEF2 then translocates the [codon-anticodon]-mimicking pseudoknot I (PKI) from ribosomal A to P sites, bringing the first sense codon into the decoding center. Halastavi árva virus (HalV) contains an IGR that is related to previously described IGR IRESs, but lacks domain 2, which enables these IRESs to bind to individual 40S ribosomal subunits. By employingin vitroreconstitution and cryo-electron microscopy, we now report that the HalV IGR IRES functions by the simplest initiation mechanism that involves binding to 80S ribosomes such that PKI is placed in the P site, so that the A site contains the first codon that is directly accessible for decoding without prior eEF2-mediated translocation of PKI.
Control of archetype BK polyomavirus miRNA expression
Authors: Zou Wei , Vue Gau Shoua , Assetta Benedetta , Manza Heather , Atwood Walter J. , Imperiale Michael J. 
Published: October 2020

AbstractBK polyomavirus (BKPyV) is a ubiquitous human pathogen, with over 80% of adults worldwide persistently infected. BKPyV infection is usually asymptomatic in healthy people; however, it causes polyomavirus-associated nephropathy in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. BKPyV has a circular, double-stranded DNA genome that is divided genetically into three parts: an early region, a late region, and a non-coding control region (NCCR). The NCCR contains the viral DNA replication origin and cis-acting elements regulating viral early and late gene expression. It was previously shown that a BKPyV miRNA expressed from the late strand regulates viral large T antigen expression and limits the replication capacity of archetype BKPyV. A major unanswered question in the field is how expression of the viral miRNA is regulated. Typically, miRNA is expressed from introns in cellular genes but there is no intron readily apparent in the BKPyV from which the miRNA could derive. Here we provide evidence for primary RNA transcripts that circle the genome more than once and include the NCCR. We identified splice junctions resulting from splicing of primary transcripts circling the genome more than once, and Sanger sequencing of RT-PCR products indicates that there are viral transcripts that circle the genome up to four times. Our data suggest that the miRNA is expressed from the intron of these greater-than-genome size primary transcripts.
P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
Authors: Tian Xiaobing , Ahsan Nagib , Lulla Amriti , Lev Avital , Abbosh Philip , Dicker David T. , Zhang Shengliang , El-Deiry Wafik S. 
Published: October 2020

AbstractA long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.
Membrane-Dependent Amyloid Aggregation of Human BAX α9 (173-192)
Authors: Price David A. , Hill Tayler D. , Hutson Kaitlyn A. , Rightnowar Blaze W. , Moran Sean D. 
Published: October 2020

ABSTRACTMitochondrial outer membrane permeabilization, which is a critical step in apoptosis, is initiated upon transmembrane insertion of the C-terminal α-helix (α9) of the pro-apoptotic Bcl-2 family protein BAX. The isolated α9 fragment (residues 173-192) is also competent to disrupt model membranes, and the structures of its membrane-associated oligomers are of interest in understanding the potential roles of this sequence in apoptosis. Here, we used ultrafast two-dimensional infrared (2D IR) spectroscopy, thioflavin T binding, and transmission electron microscopy to show that the synthetic BAX α9 peptide (α9p) forms amyloid aggregates in solution and on the surfaces of anionic small unilamellar vesicles (SUVs). Its inherent amyloidogenicity was predicted by sequence analysis, and 2D IR spectra reveal that SUVs modulate the β-sheet structures of the resulting amyloid species. These results contradict prior models of transmembrane α9p pores and motivate further examination of the formation or suppression of BAX amyloids in apoptosis.
Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure
Authors: Amitai Assaf 
Published: October 2020

AbstractThe evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.
High throughput measurements of BMP/BMP receptors interactions using bio-layer interferometry
Authors: Khodr Valia , Machillot Paul , Migliorini Elisa , Reiser Jean-Baptiste , Picart Catherine 
Published: October 2020

AbstractBone morphogenetic proteins (BMP) are an important family of growth factors playing a role in a large number of physiological and pathological processes, including bone homeostasis, tissue regeneration and cancers.In vivo, BMPs bind successively to both BMP receptors (BMPR) of type I and type II, and a promiscuity has been reported. In this study, we used bio-layer interferometry to perform parallel real-time biosensing and to deduce the kinetic parameters (ka, kd) and the equilibrium constant (KD) for a large range of BMPs/BMPR combinations in similar experimental conditions. We selected four members of the BMP family (BMP-2, 4, 7, 9) known for their physiological relevance and studied their interactions with five type-I BMP receptors (ALK1, 2, 3, 5, 6) and three type-II BMP receptors (BMPR-II, ACTR-IIA, ACTR-IIB). We reveal that BMP-2 and BMP-4 behave differently, especially regarding their kinetic interactions and affinities with the type-II BMPR. We found that BMP-7 has a higher affinity for ACTR-IIA and a tenfold lower affinity with the type-I receptors. While BMP-9 has a high and similar affinity for all type-II receptors, it can interact with ALK5 and ALK2, in addition to ALK1. Interestingly, we also found that all BMPs can interact with ALK5. The interaction between BMPs and both type-I and type II receptors immobilized on the same surface did not reveal further cooperativity. Our work provides a synthetic view of the interactions of these BMPs with their receptors and paves the way for future studies on their cell-type and receptor specific signaling pathways.
Mechanosensitive calcium signaling in filopodia
Authors: Efremov Artem K. , Yao Mingxi , Sheetz Michael P. , Bershadsky Alexander D. , Martinac Boris , Yan Jie 
Published: October 2020

AbstractFilopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+channels localized to filopodia play an important role in regulation of their formation and since some Ca2+channels are known to possess mechanosensing properties, activity of filopodial Ca2+channels might be tightly interlinked with the filopodia mechanosensing function. We tested this hypothesis by monitoring changes in the intra-filopodial Ca2+level in response to application of stretching force to individual filopodia of several cell types. It has been found that stretching forces of tens of pN strongly promote Ca2+influx into filopodia, causing persistent Ca2+oscillations that last for minutes even after the force is released. Most of the known mechanosensitive Ca2+channels, such as Piezo 1, Piezo 2 and TRPV4, were found to be dispensable for the observed force-dependent Ca2+influx. In contrast, L-type Ca2+channels appear to be a key component in the discovered phenomenon. Since previous studies have shown that intra-filopodial transient Ca2+signals play an important role in guidance of cell migration, our results suggest that the force-dependent activation of L-type Ca2+channels may contribute to this process. Overall, our study reveals an intricate interplay between mechanical forces and Ca2+signaling in filopodia, providing novel mechanistic insights for the force-dependent filopodia functions in guidance of cell migration.Significance statementWe found that tensile forces of tens of pN applied to individual filopodia trigger Ca2+influx through L-type Ca2+channels, producing persistent Ca2+oscillations inside mechanically stretched filopodia. Resulting elevation of the intra-filopodial Ca2+level in turn leads to downstream activation of calpain protease, which is known to play a crucial role in regulation of the cell adhesion dynamics. Thus, our work suggests that L-type channel-dependent Ca2+signaling and the mechanosensing function of filopodia are coupled to each other, synergistically governing cell adhesion and motion in a force-dependent manner. Since L-type Ca2+channels have been previously found in many different cell types, such as neural or cancer cells, the above mechanism is likely to be widespread among various cell lines.