bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of HIV-1 Envelope Mutations that Enhance Entry Using Macaque CD4 and CCR5
Authors: Roop Jeremy I. , Cassidy Noah A. , Dingens Adam S. , Bloom Jesse D. , Overbaugh Julie 
Published: December 2019

AbstractAlthough Rhesus macaques are an important animal model for HIV-1 vaccine development research, most transmitted HIV-1 strains replicate poorly in macaque cells. A major genetic determinant of this species-specific restriction is a non-synonymous mutation in macaque CD4 that results in reduced HIV-1 Envelope (Env)-mediated viral entry compared to human CD4. Recent research efforts employing either laboratory evolution or structure-guided design strategies have uncovered several mutations in Env’s gp120 subunit that enhance binding of macaque CD4 by transmitted/founder HIV-1 viruses. In order to identify additional Env mutations that promote infection of macaque cells, we utilized deep mutational scanning to screen thousands of Env point mutants for those that enhance HIV-1 entry via macaque receptors. We identified many uncharacterized amino acid mutations in the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) regions of gp41 that increased entry into cells bearing macaque receptors by up to 38-fold. Many of these mutations also modestly increased infection of cells bearing human CD4 and CCR5 (up to 13-fold). NHR/CHR mutations identified by deep mutational scanning that enhanced entry also increased sensitivity to neutralizing antibodies targeting the MPER epitope, and to inactivation by cold-incubation, suggesting that they promote sampling of an intermediate trimer conformation between closed and receptor bound states. Identification of this set of mutations can inform future macaque model studies, and also further our understanding of the relationship between Env structure and function.ImportanceAlthough Rhesus macaques are the favored non-human primate animal model used in HIV-1 research, most circulating HIV-1 strains poorly infect macaque cells. Studies using macaques to model HIV-1 infection often use evolved, or mutant HIV-1 variants that are able to utilize macaque CD4, but these HIV-1 variants poorly model infection by circulating strains. In this work, we sought to identity HIV-1 mutations that would allow entry into macaque cells, but that would maintain critical characteristics of circulating HIV-1 strains. We employed a powerful experimental method to simultaneously assess the effects of thousands of individual HIV-1 mutations on infection of cells bearing macaque receptors. We identified many previously uncharacterized mutations that enhance infection of circulating HIV-1 strains into cells bearing macaque receptors by up to 38-fold. Identification of these mutations may be of use in future macaque model studies.
SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
Authors: Rothenburger Tamara , McLaughlin Katie-May , Herold Tobias , Schneider Constanze , Oellerich Thomas , Rothweiler Florian , Feber Andrew , Fenton Tim R. , Wass Mark N. , Keppler Oliver T. , Michaelis Martin , Cinatl Jindrich 
Published: December 2019

AbstractThe nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.
NON-EQUILIBRIUM BELOUSOV–ZHABOTINSKY REACTION DESCRIBES THE SPONTANEOUS ACTIVITY OF THE BRAIN
Authors: Zhang Y-idi , Guo Shan , Sun Mingzhu , Tozzi Arturo , Zhao Xin 
Published: December 2019

ABSTRACTBelousov–Zhabotinsky (BZ) reactions describe chemical patterns in terms of non-equilibrium thermodynamics, chaotic evolution of nonlinear oscillators, excitability under the influence of peculiar chemical stimulations. In touch with this chemical model, we hypothesized that the nonlinear brain electric activity at the edge of the chaos could be triggered by neural oscillation equipped with BZ dynamics, and that changes in neural activity might be correlated with the transient occurrence of (either short and long-range) BZ-like reactions in cortical subareas. To prove our hypothesis of neuronal waves driven by BZ-like processes, we evaluated fMRI movies that assess in vivo BOLD resting state activity of the human brain. We found that the spontaneous activity of the brain display features fully overlapping the recently-introduced local circuits based on BZ chemical reaction. Therefore, neuronal paths during spontaneous activity of the brain match BZ dynamics’ previsions. Our results point towards the brain as crossed by diffusive nonlinear neural oscillations patterns that are predictable. Furthermore, our results suggest that chaotic dynamics arise from nothing else than the network arrangements subtending physical and biological systems.
Gene swamping alters evolution during range expansions in the protist Tetrahymena thermophila
Authors: Moerman Felix , Fronhofer Emanuel A. , Wagner Andreas , Altermatt Florian 
Published: December 2019

AbstractAt species’ range edges, individuals often face novel environmental conditions that may limit range expansion until populations adapt. The potential to adapt depends on genetic variation upon which selection can act. However, populations at species’ range edges are often genetically depauperated. One mechanism to increase genetic variation is to reshuffle existing variation through sex. During range expansions, sex can, however, act as a double-edged sword. The gene swamping hypothesis predicts that for populations expanding along an abiotic gradient, sex can hinder adaptation if asymmetric dispersal leads to numerous maladapted dispersers from the range core swamping the range edge. In this study, we experimentally tested the gene swamping hypothesis by performing replicated range expansions in landscapes with or without an abiotic pH-gradient, using the ciliate Tetrahymena thermophila, while simultaneously manipulating the occurrence of gene flow and sex. We show that sex accelerated evolution of local adaptation in the absence of gene flow, but hindered it in the presence of gene flow. The effect of sex, however, was independent of the pH-gradient, indicating that not only abiotic gradients but also the biotic gradient in population density leads to gene swamping. Overall, our results show that gene swamping can affect adaptation in life-history strategies.
Functional role of Polymerase IV during pollen development inCapsella
Authors: Wang Zhenxing , Butel Nicolas , Santos-González Juan , Borges Filipe , Yi Jun , Martienssen Robert A , Martinez German , Köhler Claudia 
Published: December 2019

AbstractInArabidopsis thaliana,the DNA-dependent RNA polymerase IV (Pol IV) is required for the formation of transposable element (TE)-derived small RNA (sRNA) transcripts. These transcripts are processed by DICER-LIKE 3 into 24-nt small interfering RNAs (siRNAs) that guide RNA-dependent DNA methylation. In the pollen grain, Pol IV is also required for the accumulation of 21/22-nt epigenetically-activated siRNAs (easiRNAs) that likely silence TEs by post-transcriptional mechanisms. Despite this proposed functional role, loss of Pol IV function inArabidopsisdoes not cause a discernable pollen defect. Here, we show that loss ofNRPD1,encoding the largest subunit of Pol IV in the BrassicaceaeCapsella rubella,causes post-meiotic arrest of pollen development at the microspore stage. As inArabidopsis,all TE-derived siRNAs were depleted inCapsella nrpd1microspores. In wild-type background, we found that the same TEs produced 21/22-nt and 24-nt siRNAs, leading us to propose that Pol IV is generating the direct precursors for 21-24-nt siRNAs, which are targeted by different DICERs. Arrest ofCapsella nrpd1microspores was accompanied by deregulation of genes targeted by Pol IV-dependent siRNAs. The distance of TEs to genes was much closer inCapsella rubellacompared toArabidopsis thaliana,providing a possible explanation for the essential role of Pol IV for pollen development inCapsella.Our study inCapsellauncovers a functional requirement of Pol IV in microspores, emphasizing the relevance of investigating different plant models.One-sentence summaryLoss of Polymerase IV function inCapsella rubellacauses microspore arrest, revealing an important functional role of Polymerase IV during pollen development.The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: Claudia Kohler (Claudia.Kohler@slu.se)
Individual differences in successful self-regulation of the dopaminergic midbrain
Authors: Hellrung Lydia , Kirschner Matthias , Sulzer James , Sladky Ronald , Scharnowski Frank , Herdener Marcus , Tobler Philippe N. 
Published: December 2019

AbstractThe dopaminergic midbrain is associated with brain functions, such as reinforcement learning, motivation and decision-making that are often disturbed in neuropsychiatric disease. Previous research has shown that activity in the dopaminergic midbrain can be endogenously modulated via neurofeedback, suggesting potential for non-pharmacological interventions. However, the robustness of endogenous modulation, a requirement for clinical translation, is unclear. Here, we examined how self-modulation capability relates to regulation transfer. Moreover, to elucidate potential mechanisms underlying successful self-regulation, we studied individual prediction error coding, and, during an independent monetary incentive delay (MID) task, individual reward sensitivity. Fifty-nine participants underwent neurofeedback training either in a veridical or inverted feedback group. Successful self-regulation was associated with post-training activity within the cognitive control network and accompanied by decreasing prefrontal prediction error signals and increased prefrontal reward sensitivity in the MID task. The correlative link of dopaminergic self-regulation with individual differences in prefrontal prediction error and reward sensitivity suggests that reinforcement learning contributes to successful self-regulation. Our findings therefore provide new insights in the control of dopaminergic midbrain activity and pave the way to improve neurofeedback training in neuropsychiatric patients.
Uncharacteristic task-evoked pupillary responses implicate atypical locus coeruleus activity in autism
Authors: Granovetter Michael C. , Burlingham Charlie S. , Blauch Nicholas M. , Minshew Nancy J. , Heeger David J. , Behrmann Marlene 
Published: December 2019

AbstractAutism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, such as hypersensitivity to environmental stimuli. Attentional engagement is known to be regulated by the locus coeruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether individuals with ASD exhibit a different profile of LC activity compared to typically developing controls under different attentional task demands. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses—an established inverse correlate for baseline LC activity—were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared to controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed only in response to task-relevant and not to task-irrelevant stimuli, providing confirmation that the group differences are specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.Significance StatementIndividuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, such as environmental hypersensitivity and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus coeruleus (LC) activity, as the LC has a critical role in attentional modulation. Elevated LC activity is associated with environmental exploration, while moderate LC activity is associated with focused attention on relevant stimuli. This study shows that, under tightly controlled conditions, task-evoked pupil responses—an LC activity proxy—are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.
Novel ankyrin-repeat mutant and modifiers of a kafirin mutant improve sorghum protein digestibility
Authors: Diatta-Holgate Elisabeth , Tuinstra Mitchell , Addo-Quaye Charles , Cisse Ndiaga , Danquah Agyemang , Tongoona Pangirayi , Danquah Eric , Weil Clifford F. 
Published: December 2019

ABSTRACTSorghum is a staple food for over 500 million people in Sub-Saharan Africa and Asia, however, sorghum proteins are poorly digested when wet-cooked. Three sorghum mutants were identified in a mutagenized population of the inbred line BTx623 that showed a 23-37% increase in wet-cooked protein digestibility compared to their unmutagenized parent. Furthermore, in comparison to the known high lysine, highly digestible sorghum mutant, P721Q, these mutants had 9% more protein overall that was 10% more digestible, had 12% more lysine, as well as better seed hardness. Using bulked segregant analysis based on whole genome sequencing data, we identified unique genomic regions on chromosome 5 of each EMS mutant that are associated with the increase in protein digestibility. Analyzing shared mutations in candidate genes, the high protein digestibility phenotype in one mutant is linked to a point mutation in a novel, ankyrin repeat protein. In another, the increase is associated with a mutation in a kafirin gene and suggests novel genetic modifiers. This study provides material and molecular markers that can be used to enhance sorghum nutritional value, contribute to fighting malnutrition and elucidate new roles for ankyrin-repeat proteins in plants.One sentence summaryMutations in a novel, ankyrin domain protein and genetic modifiers of a known mutation in a seed storage protein lead to increased digestibility of seed proteins in sorghum after wet cooking.
Identification of evolutionarily conserved nuclear matrix proteins and their prokaryotic origins
Authors: Sureka Rahul , Mishra Rakesh 
Published: December 2019

AbstractCompared to prokaryotic cells, a typical eukaryotic cell is much more complex along with its endomembrane system and membrane-bound organelles. Although the endosymbiosis theories convincingly explain the evolution of membrane-bound organelles such as mitochondria and chloroplasts, very little is understood about the evolutionary origins of the nucleus, the defining feature of eukaryotes. Most studies on nuclear evolution have not been able to take into consideration the underlying structural framework of the nucleus, attributed to the nuclear matrix (NuMat), a ribonucleoproteinaceous structure. This can largely be attributed to the lack of annotation of its core components. Since, NuMat has been shown to provide a structural platform for facilitating a variety of nuclear functions such as replication, transcription, and splicing, it is important to identify its protein components to better understand these processes. In this study, we address this issue using the developing embryos ofD. melanogasterandD. rerioand identify 362 core NuMat proteins that are conserved between the two organisms. We find that of them, 132 protein groups have originated from pre-existing proteins in prokaryotes. While 51 were conserved across all eukaryotic supergroups, 17 new proteins evolved before the evolution of the last eukaryotic common ancestor and together these 68 proteins out of the 362 core conserved NuMat proteins are conserved across all eukaryotes indicating their indispensable nature for nuclear function for over 1.5 billion years of eukaryotic history. Our analysis paves the way to understand the evolution of the complex internal nuclear architecture and its functions.
Quantifying the heterogeneity of macromolecular machines by mass photometry
Authors: Sonn-Segev Adar , Belacic Katarina , Bodrug Tatyana , Young Gavin , VanderLinden Ryan T. , Schulman Brenda A. , Schimpf Johannes , Friedrich Thorsten , Dip Phat Vinh , Schwartz Thomas U. , Bauer Benedikt , Peters Jan-Michael , Struwe Weston B. , Benesch Justin L. P. , Brown Nicholas G. , Haselbach David , Kukura Philipp 
Published: December 2019

AbstractSample purity is central to in vitro studies of protein function and regulation, as well as to the efficiency and success of structural studies requiring crystallization or computational alignment of individual molecules. Here, we show that mass photometry (MP) accurately reports on sample heterogeneity using minimal volumes with molecular resolution within minutes. We benchmark our approach by negative stain electron microscopy (nsEM), including workflows involving chemical crosslinking and multi-step purification of a multi-subunit ubiquitin ligase. When applied to proteasome stability, we detect and quantify assemblies invisible to nsEM. Our results illustrate the unique advantages of MP for rapid sample characterization, prioritization and optimization.
Slo2 potassium channel function depends on a SCYL1 protein
Authors: Niu Long-Gang , Liu Ping , Wang Zhao-Wen , Chen Bojun 
Published: December 2019

AbstractSlo2 potassium channels play important roles in neuronal function, and their mutations in humans cause epilepsies and cognitive defects. However, little is known how Slo2 function is regulated by other proteins. Here we found that the function of C. elegans Slo2 (SLO-2) depends on adr-1, a gene important to RNA editing. However, slo-2 transcripts have no detectable RNA editing events and exhibit similar expression levels in wild type and adr-1 mutants. In contrast, mRNA level of scyl-1, which encodes an orthologue of mammalian SCYL1, is greatly reduced in adr-1 mutants due to deficient RNA editing at a single adenosine in its 3’-UTR. SCYL-1 physically interacts with SLO-2 in neurons. Single-channel open probability of SLO-2 in neurons is reduced by ∼50% in scyl-1 knockout whereas that of human Slo2.2/Slack is doubled by SCYL1 in a heterologous expression system. These results suggest that SCYL-1/SCYL1 is an evolutionarily conserved regulator of Slo2 channels.
Smallholder farmers’ engagement in non-certified organic farming: a case from Southern China
Authors: Zhu Bing , Habisch André 
Published: December 2019

Purpose
The purpose of this paper is to investigate the influences of smallholder farmers’ motivations, opportunities and abilities on their satisfactions of non-certified organic farming practices in Southern China based on the motivation–opportunity–ability (MOA) model.

Design/methodology/approach
The sample covers 314 smallholders from Nanning region in Southern China who have engaged in non-certified organic farming. Judgmental and convenient sampling are applied to collect data. Data analysis consists of confirmatory factor analysis, structural equation modelling and mediation test.

Findings
The results show opportunity as dominant impact factor of smallholder farmers’ satisfaction followed by motivation and ability. Also, their commitment to further non-certified organic farming is positively influenced by their satisfactory level. Mediation test reveals that satisfaction partially mediates the relationships between motivation, ability and commitment.

Research limitations/implications
First, due to the limited sample size in a single region, the findings cannot represent even Southern Chinese farmers as an entirety. Second, the study only limited itself in the scope of the MOA model.

Practical implications
Apart from providing updated empirical results for existing studies, this study also highlights the importance of farmer association, supporting scheme as well as the relevant training for the smallholder farmers to size the opportunities, promote their motivations and strengthen their abilities.

Originality/value
As little attention has been given to small-scale farmer who are involved in organic farming practice in China, this paper presents findings based on the MOA framework.