bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Specification to Implementation: Assume-Guarantee Contracts for Synthetic Biology
Authors: Pandey Ayush , Incer Inigo , Sangiovanni-Vincentelli Alberto , Murray Richard M. 
Published: April 2022

AbstractWe provide a new perspective on using formal methods to model specifications and synthesize implementations for the design of biological circuits. In synthetic biology, design objectives are rarely described formally. We present an assume-guarantee contract framework to describe biological circuit design objectives as formal specifications. In our approach, these formal specifications are implemented by circuits modeled by ordinary differential equations, yielding a design framework that can be used to design complex synthetic biological circuits at scale. We describe our approach using the design of a biological AND gate as a motivating, running example.
Population-level hypertension control rate in India: A systematic review and meta-analysis of community based non-interventional studies, 2001-2020
Authors: Koya Shaffi Fazaludeen , Pilakkadavath Zarin , Wilson Tom , Chandran Praseeda , Kuriakose Serin , Akbar Suni K , Ali Althaf 
Published: April 2022

AbstractBackgroundHypertension is a significant contributor to mortality in India. Adequate control of hypertension is important to prevent cardiovascular morbidity and mortality.MethodsWe conducted a systematic review and meta-analysis of community-based, non-interventional studies published between 2001 and 2020. We screened records from PubMed, Embase, and Web of Science databases, extracted data, and assessed risk of bias. We conducted random-effects meta-analysis to provide overall summary estimates and subgroup estimates, and mixed-effects meta-regression with sex, region, and study period as covariates. The risk of bias was assessed using modified New Castle-Ottawa scales. This study is registered with PROSPERO, CRD42021267973.ResultsThe systematic review included 37 studies (n=170,631 hypertensive patients). Twelve studies (32%) reported poorer control rates among males than females, four studies (11%) reported poorer control rates among rural patients, while very few studies reported differences across socioeconomic variables. The overall control rate was 33.2% (n=84,485, 95% CI=27.9,38.6) with substantial heterogeneity (I2=99.1%, \chi^2= 3003.91, 95% CI=98.9,99.2; p <0.001). Unadjusted sub-group analysis showed significantly different hypertension control rates across regions (n=12,938, p=0.003) but not across study periods (n= 84,485, p=0.22), or sex (n= 81,197, p=0.22). Meta-regression showed that control rates increased by 14.7% during 2011-2020 compared to 2001-2010 (95%CI=5.8, 23.5, p=0.0021), and was 26.3% higher in the south (95%CI=12.6, 39.9, p=0.0005) and 15.9% higher in the west (95%CI=3.4, 31.4, p=0.0456) compared to the east. The control rates did not differ by sex.ConclusionHypertension is adequately controlled only among one-third of patients in India. The control rate has improved during 2011-2020 compared to 2001-2010, but substantial differences exist across regions. Very few studies examined relevant socioeconomic factors relevant to hypertension control. India needs more studies at the community level to understand the health system and socioeconomic factors that determine uncontrolled hypertension in India.
Inferring microRNA regulation: A proteome perspective
Authors: Ofer Dan , Linial Michal 
Published: April 2022

AbstractPost-transcriptional regulation in multicellular organisms is mediated by microRNAs. However, the mechanisms that determine if a gene is regulated by miRNAs are poorly understood. Previous works focused mostly on miRNA seed matches and other features of the 3’-UTR of transcripts. These common approaches relied on knowledge of the miRNA families, and computational approaches still yield poor, inconsistent results, with many false positives. In this work, we present a different paradigm for predicting miRNA-regulated genes based on proteins. In a novel, automated machine learning framework, we use sequence as well as diverse functional annotations to train models on multiple organisms using experimentally validated data. We present insights from tens of millions of features extracted and ranked from different modalities. We show high predictive performance per organism and in generalization across species. We provide a list of novel predictions for Danio rerio (zebrafish) and Arabidopsis thaliana (mouse-ear cress). We compare genomic models, and observe that our protein model outperforms genomics, while a unified model improves on both. While most membranous and disease related proteins are regulated by miRNAs, we observe the G-protein coupled receptor (GPCR) family is an exception, being mostly unregulated by miRNAs, and we raise possible explanations for this. We further show that the evolutionary conservation among duplicated genes does not imply a coherence in miRNA regulation. We conclude that duplicated genes diverge in their tendency to be miRNA regulated. However, protein function is informative across species in predicting post-transcriptional miRNA regulation in living cells.
Quantum chemical elucidation of a sevenfold symmetric bacterial antenna complex
Authors: Cupellini Lorenzo , Qian Pu , Nguyen-Phan Cam Tu , Gardiner Alastair T. , Cogdell Richard J. 
Published: April 2022

AbstractThe light-harvesting complex 2 (LH2) of purple bacteria is one of the most studied photosynthetic antenna complexes. Its symmetric structure and ring-like bacteriochlorophyll arrangement make it an ideal system for theoreticians and spectroscopists. LH2 complexes from most bacterial species are thought to have eightfold or ninefold symmetry, but recently a sevenfold symmetric LH2 structure from the bacterium Mch. purpuratum was solved by Cryo-Electron microscopy. This LH2 also possesses unique nearinfrared absorption and circular dichroism (CD) spectral properties. Here we use an atomistic strategy to elucidate the spectral properties of Mch. purpuratum LH2 and understand the differences with the most commonly studied LH2 from Rbl. acidophilus. Our strategy exploits a combination of molecular dynamics simulations, multiscale polarizable quantum mechanics/molecular mechanics calculations, and lineshape simulations. Our calculations reveal that the spectral properties of LH2 complexes are tuned by site energies and exciton couplings, which in turn depend on the structural fluctuations of the bacteriochlorophylls. Our strategy proves effective in reproducing the absorption and CD spectra of the two LH2 complexes, and in uncovering the origin of their differences. This work proves that it is possible to obtain insight into the spectral tuning strategies of purple bacteria by quantitatively simulating the spectral properties of their antenna complexes.
Intrinsically photosensitive retinal ganglion cells evade temporal filtering to encode environmental light intensity
Authors: Sabbah Shai , Papendorp Carin , Behrendt Inbar , Rasras Hala , Cann Jesse , Leyrer Megan L. , Koplas Elizabeth , Beltoja Marjo , Etebari Cameron , Gunesch Ali Noel , Carrete Luis , Kim Min Tae , Manoff Gabrielle , Bhatia-Lin Ananya , Zhao Tiffany , Dowling Henry , Briggman Kevin L. , Berson David M. 
Published: April 2022

SummaryThe retina encodes environmental light intensity to drive innate physiological responses. The synaptic basis of such coding remains obscure. Intrinsically photosensitive retinal ganglion cells (ipRGCs) are the only retinal output neurons stably encoding intensity. They do so even without their melanopsin photopigment, so specializations in their synaptic drive from bipolar cells (BCs) must also contribute. Here, we shed new light on mechanisms responsible for this unique intensity-coding drive. By ultrastructural reconstruction, we show that specific BC types and unusual ribbon synapses carry photoreceptor signals to ipRGCs. By glutamate imaging and electrophysiology, we show that their light responses are unusually persistent. Still, we find that virtually all BCs encode intensity. Intensity coding becomes restricted to ipRGCs primarily because other RGCs filter out steady-state intensity signals postsynaptically. Thus, neural “pinholes” in global, persistent neural “masking” allow intensity signals to be encoded by ipRGCs and sent to specific centers of the visual brain.
Ecological and evolutionary drivers of phenotypic and genetic variation in the European crabapple (Malus sylvestris (L.) Mill.), a wild relative of the cultivated apple
Authors: Chen X. , Avia K. , Forler A. , Remoué C. , Venon A. , Rousselet A. , Lucas G. , Kwarteng A.O. , Rover R. , Le Guilloux M. , Belcram H. , Combes V. , Corti H. , Vazquez S. , Falque M. , Alins G. , Kirisits T. , Ursu T.M. , Roman A. , Volk G.M. , Bazot Stéphane , Cornille A 
Published: April 2022

AbstractCharacterizing the phenotypic and genetic variation among populations of crop wild relatives help understanding the ecological and evolutionary processes involved in population divergence, and better harness their diversity to mitigate the impact of climate change on crops. We assessed genetic and phenotypic diversity of the European crabapple, Malus sylvestris, a main contributor to the cultivated apple genome (Malus domestica), and investigated for ecological divergence.We assessed variation in growth rate and traits related to carbon uptake between seedlings measured in a common garden, and related it to the genetic ancestry of the seedlings, assessed using 13 microsatellite loci and Bayesian clustering method. The occurrence of patterns of isolation-by-distance, -by-climate and -by-adaptation that might have caused genetic and phenotypic differentiation among M. sylvestris populations was also tested.Seedlings belonged to seven M. sylvestris populations in Europe, with 11.6% of seedlings introgressed by M. domestica. Significant trait variation among M. sylvestris populations was observed, which for some was of moderate to high heritability. Lack of association between trait and genetic divergence suggests that this significant phenotypic variation is not adaptive, but strong association between genetic variation and the climate during the last glacial maximum suggests local adaptation of M. sylvestris to past climates.This study provides an insight into the ecological and evolutionary drivers of phenotypic and genetic differentiation among populations of a wild apple species and relative of cultivated apples, which is a starting point for future breeding programs.Societal impact StatementApple is a major fruit crop worldwide and a model species for understanding the evolutionary processes underlying perennial crop domestication. Several wild species have contributed to the genetic make-up of the cultivated apple, yet phenotypic and genetic diversity data across their natural distribution is lacking. This study revealed phenotypic variation between populations of the European crabapple, and showed that both geography, and surprisingly, past but not current climate, shaped its genetic structure. We provide a starting point for harnessing wild apple diversity for apple breeding programs to mitigate the impact of climate change on this perennial crop.
Integrated Systems-Level Proteomics and Metabolomics Reveals the Diel Molecular Landscape of Diverse Kale Cultivars
Authors: Scandola Sabine , Mehta Devang , Castillo Brigo , Boyce Nicholas , Uhrig R. Glen 
Published: April 2022

ABSTRACTKale are a group of diverseBrassicaceaespecies that are nutritious leafy greens consumed for their abundance of vitamins and micronutrients. Typified by their curly, serrated and/or wavy leaves, kale varieties have been primarily defined based on their leaf morphology and geographic origin, despite having complex genetic backgrounds. Kale is a very promising crop for vertical farming due to its high nutritional content; however, being a non-model organism, foundational, systems-level analyses of kale are lacking. Previous studies in kale have shown that time-of-day harvesting can affect its nutritional composition. Therefore, to gain a systems-level diel understanding of kale across its wide-ranging and diverse genetic landscape, we selected nine publicly available and commercially grown kale cultivars for growth under near-sunlight LED light conditions ideal for vertical farming. We then analyzed changes in morphology, growth and nutrition using a combination of phenomics, proteomics and metabolomics. As the diel molecular activities of plants drive their daily growth and development, ultimately determining their productivity as a crop, we harvested kale leaf tissue at both end-of-day (ED) and end-of-night (EN) time-points for all molecular analyses. Our results reveal that diel proteome and metabolome signatures divide the selected kale cultivars into two distinct groups, defined by their amino acid and sugar content, along with significant proteome differences involving carbon and nitrogen metabolism, mRNA splicing, protein translation and light harvesting. Together, our multi-cultivar, multi-omic analysis provides robust quantitative insights into the molecular underpinnings of the diel growth and development landscape of kale, significantly advancing our fundamental understanding of this nutritious leafy green super-food for next-generation horticulture / vertical farming applications.
TIGER: A Web Portal of Tumor Immunotherapy Gene Expression Resource
Authors: Chen Zhihang , Luo Ziwei , Zhang Di , Li Huiqin , Liu Xuefei , Zhu Kaiyu , Zhang Hongwan , Wang Zongping , Zhou Penghui , Ren Jian , Zhao An , Zuo Zhixiang 
Published: April 2022

AbstractImmunotherapy is a promising cancer treatment method, but only a few patients benefit from it. Developing new immunotherapy strategies and effective biomarkers of response and resistance is urgent. Recent high-throughput bulk and single-cell gene expression profiling technologies have generated valuable resources in these regards. However, these resources are not well organized and systematic analysis is difficult. Here, we present TIGER, a tumor immunotherapy gene expression resource, which contains bulk transcriptome data of 1508 tumor samples with immunotherapy clinical outcome and 11,057 tumor/normal samples without immunotherapy clinical outcome, as well as single-cell transcriptome data of 2,116,945 immune cells of 655 samples. TIGER provides many useful modules to analyze the collected data and user-provided data. Using the resource in TIGER, we identified a tumor enriched subset of CD4+ T cells. Melanoma patients with higher signature score of this subset have significantly better response and survival under immunotherapy. We believe that TIGER will be helpful for understanding anti-tumor immunity mechanisms and discovering effective biomarkers. TIGER is freely accessible at http://tiger.canceromics.org/.
Heterogeneity in the size of the apical surface of cortical progenitors
Authors: Badouel Caroline , Audouard Christophe , Davy Alice 
Published: April 2022

ABSTRACTThe apical surface of epithelial cells is highly specialized, it is important for morphogenetic processes that are essential to shape organs and tissues and it plays a role in morphogen and growth factor signaling. Apical progenitors in the mammalian neocortex are pseudoepithelial cells whose apical surface lines the ventricle. Whether changes in their apical surface sizes are important for cortical morphogenesis and/or other aspects of neocortex development after neurulation has not been thoroughly addressed. Here we show that apical progenitors are heterogeneous with respect to their apical surface area. In Efnb1 mutants, the size of the apical surface is modified and this correlates with discrete alterations of tissue organization without impacting proliferation or differentiation. Altogether, our data reveal heterogeneity in apical progenitors AS area in the developing neocortex and shows a role for Ephrin B1 in controlling AS size. Our study also indicates that changes in AS size does not have strong repercussion on apical progenitor behavior.
Saccades are locked to the phase of alpha oscillations during natural reading
Authors: Pan Yali , Popov Tzvetan , Frisson Steven , Jensen Ole 
Published: April 2022

AbstractWe saccade three to five times per second when reading. However, little is known about the neuronal mechanisms coordinating the oculomotor and visual system during such rapid processing. Here we ask if brain oscillations play a role in the temporal coordination of the visuomotor integration. We simultaneously acquired MEG and eye-tracking data while participants read sentences silently. Every sentence was embedded with target words of either high or low lexical frequency. Our key finding demonstrated that saccade onsets were locked to the phase of alpha oscillations (8 – 13 Hz); in particular, for saccades towards low-frequency words. Source modelling demonstrated that the alpha oscillations to which the saccades were locked, were generated in the right-associative visual cortex (BA 19). Our findings suggest that the alpha oscillations serve to time the processing between the oculomotor and visual systems during natural reading, and that this coordination becomes more pronounced for demanding words.Significance StatementReading is an essential skill in modern society that allows us to acquire information from written language. While we effortlessly can acquire the meaning of a text, the task of reading requires precisely timed saccades as our eyes jump from word to word. By using a natural reading task, we demonstrate that the coordination between saccades and visual processing is clocked by ongoing ~10 Hz alpha oscillations in the visual cortex. The clocking of the saccades by brain oscillations became particularly pronounced when the participants made saccades to demanding words.
Peptide-RNA Coacervates as a Cradle for the Evolution of Folded Domains
Authors: Seal Manas , Weil-Ktorza Orit , Despotović Dragana , Tawfik Dan S. , Levy Yaakov , Metanis Norman , Longo Liam M. , Goldfarb Daniella 
Published: April 2022

AbstractPeptide-RNA coacervates can result in the concentration and compartmentalization of simple biopolymers. Given their primordial relevance, peptide-RNA coacervates may have also been a key site of early protein evolution. However, the extent to which such coacervates might promote or suppress the exploration of novel peptide conformations is fundamentally unknown. To this end, we used electron paramagnetic resonance (EPR) spectroscopy to characterize the structure and dynamics of an ancient and ubiquitous nucleic acid binding element, the helix-hairpin-helix (HhH) motif, alone and in the presence of RNA, with which it forms coacervates. Double electron-electron resonance (DEER) spectroscopy applied to singly labeled peptides containing one HhH motif reveals the presence of dimers, even in the absence of RNA, and transient α-helical character. Moreover, dimer formation is promoted upon RNA binding and was detectable within peptide-RNA coacervates. The distance distributions between spin labels are consistent with the symmetric (HhH)2-Fold, which is generated upon duplication and fusion of a single HhH motif and traditionally associated with dsDNA binding. These results support the hypothesis that coacervates are a unique testing ground for peptide oligomerization and that phase-separating peptides could have been a resource for the construction of complex protein structures via common evolutionary processes, such as duplication and fusion.
WDR47 facilitates ciliogenesis by modulating intraflagellar transport
Authors: Song Chun-Xue , Zeng Xian-Ting , Zeng Wan-Xin , Tong Xia-Jing , Li Qian 
Published: April 2022

ABSTRACTCilia are conserved organelles found in many cell types in eukaryotes, and their dysfunction causes defects in environmental sensing and signaling transduction; such defects are termed ciliopathies. Distinct cilia have cell-specific morphologies and exert distinct functions. However, the underlying mechanisms of cell-specific ciliogenesis and regulation are unclear. Here we identified a WD40-repeat (WDR) protein, WDR47/NMTN-1, and show that it is specifically required for ciliogenesis of AWB chemosensory neurons in C. elegans. WDR47/NMTN-1 is expressed in the AWB chemosensory neuron pair, and is localized at the basal body (BB) of the AWB cilia. Knockout of wdr47/nmtn-1 causes abnormal AWB neuron cilia morphology, structural integrity, and induces aberrant AWB-mediated aversive behaviors. We further demonstrate that wdr47/nmtn-1 deletion affects movement of intraflagellar transport (IFT) particles and their cargo delivery in AWB neurons. Our results indicate that WDR47/NMTN-1 is essential for AWB neuron ciliary morphology and function, which reveal a novel mechanism for cell-specific ciliogenesis. Since WDR47/NMTN-1 is conserved in mammals, our findings may help understand the process of cell-specific ciliogenesis and provide insights for treating ciliopathies.
Type One Protein Phosphatase Regulates Fixed-Carbon Starvation-Induced Autophagy by Dephosphorylating ATG13a to Facilitate ATG1a-ATG13a Formation in Arabidopsis
Authors: Wang Qiuling , Hou Suiwen 
Published: April 2022

ABSTRACTAutophagy, a conserved pathway which carries out the bulk degradation of cytoplasmic material in eukaryotic cells, is critical in plant physiology and development. It is tightly regulated by ATG13, a core component of ATG1 kinase complex which initiates autophagy. Although it has been reported that ATG13 is dephosphorylated immediately after nutrient starvation, the phosphatase regulating this process is poorly understood. Here, we demonstrated that the septuple mutant (topp-7m) and octuple mutant (topp-8m) of type one protein phosphatase (TOPP) exhibited significantly reduced tolerance to fixed-carbon (C) starvation due to compromised autophagy activity. Genetic analysis placed TOPP upstream of autophagy. Interestingly, ATG13a was found to be an interactor of TOPP. And TOPP directly dephosphorylated ATG13a in vitro and in vivo. Meanwhile, eighteen phosphorylation sites of ATG13a were identified by LC-MS. Mimic dephosphorylation of ATG13a at these 18 sites significantly promoted autophagy and increased the atg13ab mutant tolerance to fixed-C starvation. Further study showed that the dephosphorylation of ATG13a facilitated ATG1a-ATG13a complex formation. Consistently, the recruitment of ATG13a for ATG1a was markedly inhibited in topp-7m-1. In addition, TOPP-controlled dephosphorylation of ATG13a boosted ATG1a phosphorylation. Taken together, our study reveals the crucial role of TOPP in regulating autophagy by stimulating the formation of ATG1a-ATG13a complex through dephosphorylating ATG13a in Arabidopsis.
MPI region of interest (ROI) analysis and quantification of iron in different volumes
Authors: Sehl Olivia C. , Tiret Brice , Berih Maryam A. , Makela Ashley V. , Goodwill Patrick W. , Foster Paula J. 
Published: April 2022

AbstractMPI directly detects superparamagnetic iron oxides (SPIONs), which should enable precise, accurate, and linear quantification. However, selecting a region of interest (ROI) has strong effects on MPI quantification results. Ideally, ROI selection should be simple, user-independent, and widely applicable. In this work, we describe and compare four MPI ROI selection methods and assess their performance in vitro and in vivo. To explore the effect of ROI selection, ten ferucarbotran phantoms were imaged, each contained the same amount of iron but varied in volume. Three users tested the accuracy of the ROI methods for quantification of these samples. Lastly, the four ROI methods were applied to quantify ferucarbotran in vivo after intravenous, intramuscular, and subcutaneous injections in mice. We demonstrate that each ROI method has strengths. We conclude there is an important trade-off between ROI size and the accuracy of iron quantification, therefore the choice of ROI selection method for each study must be carefully informed.