bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circuit Analysis of the Drosophila Brain using Connectivity-based Neuronal Classification Reveals Organization of Key Communication Pathways
Authors: Mehta Ketan , Goldin Rebecca F. , Ascoli Giorgio A. 
Published: March 2022

ABSTRACTWe present a functionally relevant, quantitative characterization of the neural circuitry of Drosophila melanogaster at the mesoscopic level of neuron types as classified exclusively based on potential network connectivity. Starting from a large neuron-to-neuron brain-wide connectome of the fruit fly, we use stochastic block modeling and spectral graph clustering to group neurons together into a common “cell class” if they connect to neurons of other classes according to the same probability distributions. We then characterize the connectivity-based cell classes with standard neuronal biomarkers, including neurotransmitters, developmental birthtimes, morphological features, spatial embedding, and functional anatomy. Mutual information indicates that connectivity-based classification reveals aspects of neurons that are not adequately captured by traditional classification schemes. Next, using graph-theoretic and random walk analyses to identify neuron classes as hubs, sources, or destinations, we detect pathways and patterns of directional connectivity that potentially underpin specific functional interactions in the Drosophila brain. We uncover a core of highly interconnected dopaminergic cell classes functioning as the backbone communication pathway for multisensory integration. Additional predicted pathways pertain to the facilitation of circadian rhythmic activity, spatial orientation, fight-or-flight response, and olfactory learning. Our analysis provides experimentally testable hypotheses critically deconstructing complex brain function from organized connectomic architecture.AUTHOR SUMMARYThe potential synaptic circuitry of a neural system constitutes the fundamental architectural underpinning of its in vivo dynamics, plasticity, and functions. The fruit fly neural circuit presented here captures the latent stochastic patterns of network connectivity and provides a fundamental parts list for reverse-engineering brain computation. Mapping the interactions among connectivity-based neuronal classes to development, morphology, physiology, and transcriptomics result in testable hypotheses on the relationship between whole-brain neural architecture and behavior.
High axial-resolution optical stimulation of neurons in vivo via two-photon optogenetics with speckle-free beaded-ring pattern
Authors: Jin Cheng , Liu Chi , Kong Lingjie 
Published: March 2022

AbstractTwo-photon optogenetics has become an indispensable technology in neuroscience, due to its capability in precise and specific manipulation of neural activities. Scanless holographic approach is generally adopted to meet the requirement of stimulating neural emsembles simultaneously. However, the commonly used disk patterns fail in achieving single-neuron resolution, especially in axial dimension, and its inherent speckles decrease the stimulation efficiency. Here, we propose a novel speckle-free, beaded-ring pattern for high axial-resolution optical stimulation of neurons in vivo. Using a dye pool and a fluorescent thin-film as samples, we verify that, compared to those with disk patterns, higher axial resolution and better localization ability can be achieved with beaded-ring patterns. Furthermore, we perform two-photon based all-optical physiology with neurons in mouse S1 cortex in vivo, and demonstrate that the axial resolution obtained by beaded-ring patterns can be improved by 24% when stimulating multiple neurons, compared with that of disk patterns.
Minor differences in peptide presentation between chicken MHC class I molecules can explain differences in disease susceptibility
Authors: Han Lingxia , Wu Shaolian , Peng Weiyu , Zhao Min , Yue Can , Wen Wanxin , Cai Wenbo , Zhang Ting , Wallny Hans-Joachim , Avila David W. , Mwangi William , Nair Venugopal , Ternette Nicola , Guo Yaxin , Zhao Yingze , Chai Yan , Qi Jianxun , Liang Hao , Gao George F. , Kaufman Jim , Liu William J. 
Published: March 2022

ABSTRACTThe highly polymorphic classical major histocompatibility complexes (MHCs) can confer resistance or susceptibility to diseases. The chicken MHC is known to confer decisive resistance or susceptibility to various economically-important pathogens, including the iconic oncogenic herpesvirus that causes Marek’s disease (MD). Only one classical class I gene, BF2, is expressed at a high level in chickens, so it was relatively easy to discern a hierarchy from well-expressed thermostable fastidious specialist alleles to promiscuous generalist alleles that are less stable and expressed less on the cell surface. The BF2*1901 is more highly expressed and more thermostable than the closely-related BF2*1501, but the data for peptide repertoire available did not obviously correlate as expected. Here, we confirm for newly-developed chicken lines that the chicken haplotype B15 confers resistance to MD compared to B19. Using gas phase sequencing of peptide pools, and using immunopeptidomics involving mass spectroscopy, we find that the BF2*1901 binds a greater variety of amino acids in some anchor positions than BF2*1501. However, by X-ray crystallography, we find that the peptide-binding groove of BF2*1901 is narrower and shallower. Though the self-peptides bound to BF2*1901 may appear more various than those of BF2*1501, the structures show that the wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, correlating with the expected hierarchies for expression level, thermostability and MD resistance. Moreover, the α2 helix of BF2*1901 is higher than BF2*1501, potentially reducing the number of T cell clones that can recognize this fastidious class I molecule.IMPORTANCEDisease susceptibility mechanism is complicated, but chicken infection of Marek’s disease (MD) is one of ideal models, considering the only one highly expressed classical MHC class I, BF2. The different susceptibility of the two close alleles BF2*1901 and BF2*1501 with minor difference of expression and thermostability is still unfathomed. Here, we confirm B15 chicken confers resistance to MD compared to B19. But the BF2*1901 binds a broader variety of anchoring peptides than BF2*1501. This mystery was solved by the structural determination of the two molecules with one similar peptide. The wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, which is concordant to the expected hierarchies for expression level, thermostability and MD resistance.
Did COVID-19 Vaccines Go to the Whitest Neighborhoods First? Racial Inequities in Six Million Phase 1 Doses Shipped to Pennsylvania
Authors: Holtzman Geoffrey S. , Yang Yukun , Louis Pierce 
Published: March 2022

AbstractResearch on racial disparities in COVID-19 vaccination rates has focused primarily on vaccine hesitancy. However, vaccine hesitancy research is increasingly unable to account for racial disparities in vaccination rates in the U.S., which have shrunk rapidly over the past year. This and other evidence suggests that inequities in vaccine allocation and access may have contributed to vaccination rate disparities in the U.S. But to our knowledge, no previously published research has examined whether the geographic distribution of COVID-19 vaccines has led to greater access for White Americans than for Black Americans.Here, we link neighborhood-level data on vaccine allocation to data on racial demographics to show that in the first 17 weeks of Pennsylvania’s COVID-19 vaccine rollout (Phase 1), White people were 25% more likely than Black people to live in neighborhoods (census tracts) that received vaccine shipments. In the 17 weeks of Pennsylvania’s de jure restrictions on vaccine eligibility, de facto geographic restrictions on vaccine access disproportionately disadvantaged Black people and favored White people. In revealing these vaccine inequities, our work builds on prior work to develop a theory-driven, evidence-based, reproducible framework for studying racial inequities in the distribution of COVID-19 vaccines.
Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients
Authors: Zhou Zhen , Ding Zhengping , Yuan Jie , Shen Shengping , Jian Hong , Tan Qiang , Yang Yunhai , Chen Zhiwei , Luo Qingquan , Cheng Xinghua , Yu Yongfeng , Niu Xiaomin , Qian Liqiang , Chen Xiaoke , Gu Linping , Liu Ruijun , Ma Shenglin , Huang Jia , Chen Tianxiang , Li Ziming , Ji Wenxiang , Song Liwei , Shen Lan , Jiang Long , Yu Zicheng , Zhang Chao , Tai Zaixian , Wang Changxi , Chen Rongrong , Lu Shun 
Published: March 2022

AbstractBackgroundNeoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer but the study to prioritize effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between patients with distinct response to neoadjuvant immunotherapy in non-small-cell lung cancer (NSCLC) for the derive of biomarkers with indicative capability in predicting outcomes.MethodsIn this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimen followed by surgical resection. Pre-therapy FFPE or fresh tissues and blood samples were analyzed by whole-exome sequencing (WES). Genetic alternation comparisons were conducted between differently-responded patients. Multiple public cohorts were selected for validation.ResultsDNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e. major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percent of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings.ConclusionsWe innovatively associated the HRD event with enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multi-facet public cohorts. We propose the inspection of HR pathway gene status could serve as novel and additional indicators directing immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.
A self-adjusting, progressive shock strength procedure to investigate resistance to punishment: characterization in male and female rats
Authors: Desmercieres Stevenson , Lardeux Virginie , Longueville Jean-Emmanuel , Hanna Myriam , Panlilio Leigh V. , Thiriet Nathalie , Solinas Marcello 
Published: March 2022

ABSTRACTIndifference to harmful consequences is one of the main characteristics of compulsive behaviors and addiction. Animal models that provide a rapid and effective measure of resistance to punishment could be critical for the investigation of mechanisms underlying these maladaptive behaviors. Here, analogous to the progressive ratio (PR) procedure widely used to evaluate appetitive motivation as the response requirement is increased, we developed a self-adjusting, progressive shock strength (PSS) procedure. The PSS provides, within a single session, a break point that quantifies the propensity to work for a reward in spite of receiving electric footshock that progressively increases in duration. In both male and female rats, the PSS break point was sensitive to 1) hunger; and 2) changes in the qualitative, but not quantitative, incentive value of the reward. In systematic comparisons between PSS and PR procedures in the same rats, we found that both measures are sensitive to manipulations of motivational states, but they are not intercorrelated, suggesting that they measure overlapping but partially distinct processes. Importantly, the PSS procedure represents a refinement in the 3Rs principles of animal research because animals can control the strength of shock that they are willing to tolerate. This self-adjusting PSS procedure may represent a useful tool to investigate mechanisms underlying maladaptive behavior that persists in certain individuals despite harmful consequences.
Revisiting Ancient Polyploidy in Leptosporangiate Ferns
Authors: Chen Hengchi , Fang Yuhan , Zwaenepoel Arthur , Huang Sanwen , Van de Peer Yves , Li Zhen 
Published: March 2022

AbstractFerns, and particularly homosporous ferns, have long been assumed to have experienced recurrent whole-genome duplication (WGD) events because of their substantially large genome sizes, surprisingly high chromosome numbers, and high degrees of polyploidy among many extant members. Although, consequently, the number of sequenced fern genomes is very limited, recent studies using transcriptome data to find evidence for WGDs in ferns reached conflicting results concerning the occurrence of ancient polyploidy, for instance, in the lineage of leptosporangiate ferns. Because identifying WGDs in a phylogenetic context is the foremost step in studying the contribution of ancient polyploidy to evolution, we revisited earlier identified WGDs in leptosporangiate ferns, mainly the core leptosporangiate ferns, by building age distributions and applying substitution rate corrections and by conducting statistical gene tree – species tree reconciliation analyses. Our integrative analyses confidently identified four ancient WGDs in the sampled core leptosporangiates and suggest both false positives and false negatives for the WGDs that recent studies have reported earlier. In conclusion, we underscore the significance of substitution rate corrections and uncertainties in gene tree – species tree reconciliations in calling WGD events, and that failing to do so likely leads to incorrect conclusions.
Organellar transcripts dominate the cellular mRNA pool across plants of varying ploidy levels
Authors: Forsythe Evan S. , Grover Corrinne E. , Miller Emma R. , Conover Justin L. , Arick Mark A. , Chavarro M. Carolina F. , Leal-Bertioli Soraya C. M. , Peterson Daniel G. , Sharbrough Joel , Wendel Jonathan F. , Sloan Daniel B. 
Published: March 2022

ABSTRACTMitochondrial and plastid functions depend on coordinated expression of proteins encoded by genomic compartments that have radical differences in copy number of organellar and nuclear genomes. In polyploids, doubling of the nuclear genome may add challenges to maintaining balanced expression of proteins involved in cytonuclear interactions. Here, we use ribo-depleted RNA-seq to analyze transcript abundance for nuclear and organellar genomes in leaf tissue from four different polyploid angiosperms and their close diploid relatives. We find that, even though plastid genomes contain <1% of the number of genes in the nuclear genome, they generate the majority (69.9–82.3%) of mRNA transcripts in the cell. Mitochondrial genes are responsible for a much smaller percentage (1.3–3.7%) of the leaf mRNA pool but still produce much higher transcript abundances per gene compared to nuclear genome. Nuclear genes encoding proteins that functionally interact with mitochondrial or plastid gene products exhibit mRNA expression levels that are consistently more than ten-fold lower than their organellar counterparts, indicating an extreme cytonuclear imbalance at the RNA level despite the predominance of equimolar interactions at the protein level. Nevertheless, interacting nuclear and organellar genes show strongly correlated transcript abundances across functional categories, suggesting that the observed mRNA stoichiometric imbalance does not preclude coordination of cytonuclear expression. Finally, we show that nuclear genome doubling does not alter the cytonuclear expression ratios observed in diploid relatives in consistent or systematic ways, indicating that successful polyploid plants are able to compensate for cytonuclear perturbations associated with nuclear genome doubling.
Automated patch clamp screening of amiloride and 5-N,N-hexamethyleneamiloride (HMA) analogs identifies 6-iodoamiloride as a potent acid-sensing ion channel inhibitor
Authors: Finol-Urdaneta Rocio K. , McArthur Jeffrey R. , Aboelela Ashraf , Bujaroski Richard S. , Majed Hiwa , Rangel Alejandra , Adams David J. , Ranson Marie , Kelso Michael J. , Buckley Benjamin J. 
Published: March 2022

ABSTRACTAcid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K+-sparing diuretic amiloride is a moderate non-specific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch-clamp protocol and identified 6-iodoamiloride as a more potent ASIC1 inhibitor. Follow-up IC50 determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 97 (hASIC1 97 IC50 88 nM cf. amiloride 11 IC50 1.7 μM). A similar improvement in activity was observed in ASIC3-mediated currents from rat small diameter dorsal root ganglion neurons (rDRG single-concentration 97 IC50 230 nM cf. 11 IC50 2.7 μM). 6-iodoamiloride represents the amiloride analogue of choice for studying the effects of ASIC inhibition on cell physiology.
Identification of the gene coding for seed cotyledon albumin SCA in the pea (Pisum L.) genome
Authors: Mglinets Anatoliy V. , Bogdanova Vera S. , Kosterin Oleg E. 
Published: March 2022

AbstractAlbumins SCA and SAA are short, highly hydrohylic proteins accumulated in large quantity in the cotyledons and seed axes, respectively, of a dry pea (Pisum sativum L.) seed. SCA was earlier shown to have two allelic variants differing in mobility in polyacrylamide gel electrophoresis in acid medium. Using them the corresponding gene SCA was mapped on Linkage Group V. This gene was used as a useful genetic and phylogeographical marker that still required electrophoretic analysis of the protein while the DNA sequence of the corresponding SCA gene remained unknown. Based the length, the positive charge in acid conditions and the number of lysine residues of SCA and SAA albumins, estimated earlier electrophoretically, the high throughput sequencing data available in public databases were searched for the respective candidates for the corresponding genes SCA and SAA genes among coding sequences residing in the region of the pea genome corresponding to the map position of SCA. Then we sequenced them in a number of pea accessions. Concordance of the earlier electrophoretic data and sequence variation indicated the sequence Psat0s797g0160 of the reference pea genome to be the SCA gene. The sequence Psat0s797g0240 could encode a minor related albumin SA-a2, while a candidate gene for albumin SAA is still missing (as well as electrophoretic variation of both latter albumins). DNA amplification using original primers SCA1_3f and SCA1_3r from genomic DNA and restriction by endonuclease Hind II made SCA a convenient CAPS marker in peas. Thus, the gene encoding the highly hydrophilic albumin SCA accumulated in pea seeds, with its alleles useful classification of pea wild relatives, is now identified in the pea genome and a convenient CAPS marker is worked out on its base.
Nementin is a Nematode-Selective Small Molecule Agonist of Neurotransmitter Release
Authors: Harrington Sean , Knox Jessica J. , Burns Andrew R. , Choo Ken-Loon , Au Aaron , Kitner Megan , Haeberli Cecile , Pyche Jacob , D’Amata Cassandra , Kim Yong-Hyun , Volpatti Jonathan R. , Guiliani Maximillano , Snider Jamie , Wong Victoria , Palmeira Bruna M. , Redman Elizabeth M. , Vaidya Aditya S. , Gilleard John S. , Stagljar Igor , Cutler Sean R. , Kulke Daniel , Dowling James J. , Yip Christopher M. , Keiser Jennifer , Zasada Inga , Lautens Mark , Roy Peter J. 
Published: March 2022

AbstractNematode parasites of humans, livestock and crops pose a significant burden on human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we present a pipeline that exploits multiple motor outputs of the model nematode C. elegans for nematicide discovery. This pipeline yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call Nementin. We find that Nementin agonizes neuronal dense core vesicle release, which in turn agonizes cholinergic signaling. Consequently, Nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase inhibitors (AChEIs), but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChEI pesticides used to control nematode infections and infestations.Significance StatementParasitic nematodes pose a considerable burden to human health and food security. Small molecules that have traditionally been used to control these parasites have either been banned because of toxicity concerns or are being rendered ineffective because of the evolution of resistance. Significant gaps in our nematicidal toolkit are therefore becoming an alarming problem. Here, we describe our discovery of Nementin, a small molecule that disrupts the nematode nervous system but is ineffective against non-targeted organisms. We find that Nementin also enhances the activity of non-selective pesticides but does so in a nematode-selective manner. Hence, Nementin is an innovative solution to combat parasitic nematodes in a safe and phylum-selective manner.One-Sentence SummaryA C. elegans-based screening pipeline identifies a selective nematicide that also potentiates acetylcholinesterase inhibitors.
Phyllochron duration and changes through rice development shape the vertical leaf size profile
Authors: Pablo Janet P. , Clerget Benoit , Bueno Crisanta , Dionora Jacqueline , Domingo Abigail J. , De Guzman Constancio C. , Aguilar Edna A. , Cadiz Nina M. , Sta Cruz Pompe C. 
Published: March 2022

SummaryWell-irrigated aerobic rice (Oryza sativa L.) plants are often shorter with smaller leaves, and the leaf appearance rate is slower in well-irrigated than in flooded environments. This observation questions the functional relationship between the leaf appearance rate, which is correlated with the apical cell production rate, and leaf length that is in turn correlated with the leaf division zone length.Meristem size, blade size, and appearance were monitored for all leaves from leaf 6 on the main stem of rice plants in field experiments using two varieties, two watering systems, and three sowing dates.Leaf blade and division zone lengths were correlated in all leaves of the main stem of rice plants. New stable linear relationships were found between the leaf division zone growth duration and internal cell production rate, which changed after leaf 11. These stable relationships imply a stable link between the rates of cell production in the stem apex and leaf meristem, explaining the vertical leaf size profile.Overall, faster leaf appearance leads to shorter leaves and organs in rice because of a functional link, which is counterbalanced by additional acclimation in transplanted plants.