bluuebunny/crossref_metadata_2025_split huggingface dataset:
Orthogonal neural codes for phonetic features in the infant brain
Authors: Gennari Giulia , Marti Sébastien , Palu Marie , Fló Ana , Dehaene-Lambertz Ghislaine 
Published: March 2021

ABSTRACTCreating invariant representations from an ever-changing speech signal is a major challenge for the human brain. Such an ability is particularly crucial for preverbal infants who must discover the phonological, lexical and syntactic regularities of an extremely inconsistent signal in order to acquire language. Within visual perception, an efficient neural solution to overcome signal variability consists in factorizing the input into orthogonal and relevant low-dimensional components. In this study we asked whether a similar neural strategy grounded on phonetic features is recruited in speech perception.Using a 256-channel electroencephalographic system, we recorded the neural responses of 3-month-old infants to 120 natural consonant-vowel syllables with varying acoustic and phonetic profiles. To characterize the specificity and granularity of the elicited representations, we employed a hierarchical generalization approach based on multivariate pattern analyses. We identified two stages of processing. At first, the features of manner and place of articulation were decodable as stable and independent dimensions of neural responsivity. Subsequently, phonetic features were integrated into phoneme-identity (i.e. consonant) neural codes. The latter remained distinct from the representation of the vowel, accounting for the different weights attributed to consonants and vowels in lexical and syntactic computations.This study reveals that, despite the paucity of articulatory motor plans and productive skills, the preverbal brain is already equipped with a structured phonetic space which provides a combinatorial code for speech analysis. The early availability of a stable and orthogonal neural code for phonetic features might account for the rapid pace of language acquisition during the first year.SIGNIFICANCE STATEMENTFor adults to comprehend spoken language, and for infants to acquire their native tongue, it is fundamental to perceive speech as a sequence of stable and invariant segments despite its extreme acoustic variability. We show that the brain can achieve such a critical task thanks to a factorized representational system which breaks down the speech input into minimal and orthogonal components: the phonetic features. These elementary representations are robust to signal variability and are flexibly recombined into phoneme-identity percepts in a secondary processing phase. In contradiction with previous accounts questioning the availability of authentic phonetic representations in early infancy, we show that this neural strategy is implemented from the very first stages of language development.
Numerosity tuning in human association cortices and local image contrast representations in early visual cortex
Authors: Paul Jacob M. , van Ackooij Martijn , ten Cate Tuomas C. , Harvey Ben M. 
Published: March 2021

AbstractHuman early visual cortex response amplitudes monotonically increase with numerosity (object number), regardless of object size and spacing. However, numerosity is typically considered a high-level visual or cognitive feature, while early visual responses follow image contrast in the spatial frequency domain. We found that, at fixed contrast, aggregate Fourier power (at all orientations and spatial frequencies) followed numerosity closely but nonlinearly with little effect of object size, spacing or shape. This would allow straightforward numerosity estimation from spatial frequency domain image representations. Using 7T fMRI, we showed monotonic responses originate in primary visual cortex (V1) at the stimulus’s retinotopic location. Responses here and in neural network models followed aggregate Fourier power more closely than numerosity. Truly numerosity tuned responses emerged after lateral occipital cortex and were independent of retinotopic location. We propose numerosity’s straightforward perception and neural responses may have built on behaviorally beneficial spatial frequency analyses in simpler animals.
Stand-alone lipoylated H-protein of the glycine cleavage system enables glycine cleavage and the synthesis of glycine from one-carbon compounds in vitro
Authors: Xu Yingying , Li Yuchen , Zhang Han , Nie Jinglei , Ren Jie , Wang Wei , Zeng An-Ping 
Published: March 2021

AbstractH-protein, one of the four component proteins (H, T, P and L) of glycine cleavage system (GCS), is generally considered a shuttle protein interacting with the other three GCS-proteins via a lipoyl swinging arm. We report that without P-, T- and L-proteins, lipoylated H-protein (Hlip) enables GCS reactions in both glycine cleavage and synthesis directions in vitro. This apparent catalytic activity is closely related to the cavity on the H-protein surface where the lipoyl arm is attached. Heating or mutation of selected residues in the cavity destroys or reduces the stand-alone activity of Hlip, which can be restored by adding the other three GCS-proteins. Systematic study of the Hlip-catalyzed overall GCS reactions and the individual reaction steps provides a first step towards understanding the stand-alone function of Hlip. The results in this work provide some inspiration for further understanding the mechanism of the GCS and give some interesting implications on the evolution of the GCS.Significance statementGlycine cleavage system (GCS) plays central roles in C1 and amino acids metabolisms and the biosynthesis of purines and nucleotides. Manipulations of GCS are desired to promote plant growth or to treat serious pathophysiological processes such as aging, obesity and cancers. Reversed GCS reactions form the core of the reductive glycine pathway (rGP), one of the most promising pathway for the assimilation of formate and CO2 in the emerging C1-synthetic biology. H-protein, one of the four GCS component proteins (H, T, P and L) is generally considered a shuttle protein interacting with the other three proteins via a lipoyl swinging arm. Here, we discovered that without P-, T- and L-proteins, H-protein alone can catalyze GCS reactions in both glycine cleavage and synthesis directions in vitro. The surprising catalytic activities are related to a structural region of H-protein which can be manipulated. The results have impacts on engineering GCS to treat related diseases, to improve photorespiration, and to efficiently use C1-carbon for biosynthesis.
Extended-Ensemble Docking to Probe Evolution of Ligand Binding Sites During Large-Scale Structural Changes of Proteins
Authors: Kapoor Karan , Thangapandian Sundar , Tajkhorshid Emad 
Published: March 2021

AbstractProteins can sample a broad landscape as they undergo conformational transition between different functional states. As key players in almost all cellular processes, proteins are important drug targets. Considering the different conformational states of a protein is therefore central for a successful drug-design strategy. Here we introduce a novel docking protocol, termed as extended-ensemble docking, pertaining to proteins that undergo large-scale (global) conformational changes during their function. In its application to multidrug ABC-transporter P-glycoprotein (Pgp), extensive non-equilibrium molecular dynamics simulations employing system-specific collective variables capturing the alternate access mechanism of Pgp, are first used to construct the transition cycle of the transporter. An extended set of conformational states representing the full transition between the inward- and the outward-facing states of Pgp, is then used to seed high-throughput docking calculations of a set of known substrates, non-substrates, and modulators of the transporter. Large differences are observed in the predicted binding affinities to the conformational ensemble, with compounds showing stronger binding affinities to intermediate conformations compared to the starting crystal structure. Hierarchical clustering of the individual binding modes of the different compounds shows all ligands preferably bind to the large central cavity of the protein, formed at the apex of the transmembrane domain (TMD), whereas only small binding populations are observed in the previously described R and H sites present within the individual TMD leaflets. Based on the results, the central cavity is further divided into two major subsites: first subsite preferably binds smaller substrates and high-affinity inhibitors, whereas the second one shows preference for larger substrates and low-affinity modulators. These central sites along with the low-affinity interaction sites present within the individual TMD leaflets may respectively correspond to the proposed high- and low-affinity binding sites in Pgp. We propose further optimization strategy for developing more potent inhibitor of Pgp, based on increasing its specificity to the extended ensemble of the protein instead of using a single protein structure, as well as its selectivity for the high-affinity binding site. In contrast to earlier in-silico studies using single static structures of Pgp, our results show better agreement with experimental studies, pointing to the importance of incorporating the global conformational flexibility of proteins in future drug-discovery endeavors.
Differential expression of single-cell RNA-seq data using Tweedie models
Authors: Mallick Himel , Chatterjee Suvo , Chowdhury Shrabanti , Chatterjee Saptarshi , Rahnavard Ali , Hicks Stephanie C. 
Published: March 2021

SummaryThe performance of computational methods and software to identify differentially expressed genes in single-cell RNA-sequencing (scRNA-seq) has been shown to be influenced by several factors, including the choice of the normalization method used and the choice of the experimental platform (or library preparation protocol) to profile gene expression in individual cells. Currently, it is up to the practitioner to choose the most appropriate differential expression (DE) method out of over 100 DE tools available to date, each relying on their own assumptions to model scRNA-seq data. Here, we propose to use generalized linear models with the Tweedie distribution that can flexibly capture a large dynamic range of observed scRNA-seq data across experimental platforms induced by heavy tails, sparsity, or different count distributions to model the technological variability in scRNA-seq expression profiles. We also propose a zero-inflated Tweedie model that allows zero probability mass to exceed a traditional Tweedie distribution to model zero-inflated scRNA-seq data with excessive zero counts. Using both synthetic and published plate- and droplet-based scRNA-seq datasets, we performed a systematic benchmark evaluation of more than 10 representative DE methods and demonstrate that our method (Tweedieverse) outperforms the state-of-the-art DE approaches across experimental platforms in terms of statistical power and false discovery rate control. Our open-source software (R package) is available athttps://github.com/himelmallick/Tweedieverse.
Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition
Authors: Johnson Noah R. , Wang Athena C.-J. , Coughlan Christina , Sillau Stefan , Lucero Esteban , Viltz Lisa , Markham Neil , Allen Cody , Dhanasekaran A. Ranjitha , Chial Heidi J. , Potter Huntington 
Published: March 2021

AbstractThe apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer’s disease (AD) besides age itself, but the mechanism(s) underlying this risk are debated. The critical test of any proposed AD mechanism is whether it leads to effective treatments. We developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of the amyloid β (Aβ) peptide into neurotoxic fibrils. Screening a human drug library, we identified five non-toxic, blood-brain-barrier-permeable hit compounds that reduced apoE4-promoted Aβ and tau neuropathology in cultured neurons. Two hit compounds, imipramine and olanzapine, but not other (non-hit) antipsychotics or antidepressants, when prescribed to AD patients for their normal clinical indications, led to improvements in cognition and clinical diagnosis. Imipramine and olanzapine have no structural, functional, or clinical similarities other than their ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.One Sentence SummaryHigh-throughput drug screens, studies in Alzheimer’s disease cell culture models, and analyses of human clinical data identified inhibitors of the apoE4-Aβ interaction as a novel class of Alzheimer’s disease therapeutics.
A Deep Reinforcement Learning based approach for movement training of neuro-musculoskeletal systems
Authors: Iyengar Raghu Sesha , Mallampalli Kapardi , Raghavan Mohan 
Published: March 2021

AbstractMechanisms behind neural control of movement have been an active area of research. Goal-directed movement is a common experimental paradigm used to understand these mechanisms and relevant neural pathways. In this paper, we attempt to build an anatomically and physiologically realistic model of spinal cord along with the relevant circuitry and interface it with a musculoskeletal model of an upper limb, using the NEUROiD platform. The neuronal model (simulated on NEURON) and the musculoskeletal model (simulated on OpenSim) are cosimulated on NEUROiD. We then use Deep Reinforcement Learning to obtain a functionally equivalent model of the supraspinal components and the descending cortical activations feeding into the last-order interneurons and motoneurons. Uniplanar goal directed movement of the elbow joint was used as the goal for the learning algorithm. Key aspects of our work are: (1) Our solution converges naturally to the triphasic response observed in goal directed tasks (2) Gradually increasing the complexity of task helped in faster learning (3) In response to corticospinal inputs, our model could produce movements on which it was not explicitly trained, but were close to the trained movements. Being able to generate movements on which the model was not explicitly trained, implies that the movement repertoire that a biomimetic model needs to learn, could be much smaller than the complete set of movements it can execute. We hope that this will lead to building larger and complex biomimetic systems, one block at a time.
Maxent modeling for predicting the potential distribution of global talaromycosis
Authors: Wei Wudi , He Jinhao , Ning Chuanyi , Xu Bo , Wang Gang , Lai Jingzhen , Jiang Junjun , Ye Li , Liang Hao 
Published: March 2021

AbstractTalaromycosis, an invasive mycosis caused by Talaromyces marneffei (Tm), has rapidly increased in recent years, becoming an emerging pathogenic fungal disease. However, The driving factors and potential distribution of global talaromycosis is still unclear. Here, we developed maxent ecology model using environmental variables, Rhizomys distribution and HIV/AIDS epidemic to forecast ecological niche of talaromycosis worldwhile, as well as Identify the drivering factors. The constructed model had excellent performance with the area under the curve (AUC) of the receiver operating curve (ROC) of 0.997 in training data and 0.991 in testing data. Our model revealed that Rhizomys distribution, mean temperature of warmest quarter, precipitation of wettest month, HIV/AIDS epidemic and mean temperature of driest quarter were the top 5 important variables affecting talaromycosis distribution. In addition to traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), our model also identified other potential epidemic regions, inculding parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our findings has redefined global talaromycosis, discovered hidden high-risk areas and prorvided insights about driving factors of talaromycosis distribution, which will help inform surveillance strategies and improve the effectiveness of public health interventions against Tm infections.Author SummaryOur study aims to explore the spatial ecology of talaromycosis worldwhile. The diseases burden of Talaromycosis, a neglected zoonotic disease, is continuously rising in recent years because of the sheer size of susceptible population in the setting of increased globalization, rising HIV prevalence, and emerging iatrogenic immunodeficiency conditions. Here, we used historic reported talaromycosis cases from 1964 to 2017, combined with environmental factors, Rhizomys distribution and HIV/AIDS epidemic to build an maxent ecology model to define the ecological niche of talaromycosis, then predicting the potential distribution of the disease. The ecological niche of talaromycosis is characterized by a concentrated distribution, which can be cognitively divided into two regions: traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), while other potential epidemic regions were predicted in parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our model also identified 5 driving factors affecting talaromycosis distribution. These findings will help demonstrate the global distribution of talaromycosis, discover hidden high-risk areas, and improve the effectiveness of public health interventions against Tm infections.
Sulfate adenylyl transferase kinetics and mechanisms of metabolic inhibitors of microbial sulfate respiration
Authors: Carlson Hans K. , Youngblut Matthew D. , Redford Steven A. , Williamson Adam J. , Coates John D. 
Published: March 2021

AbstractSulfate analog oxyanions that function as selective metabolic inhibitors of dissimilatory sulfate reducing microorganisms (SRM) are widely used in ecological studies and industrial applications. As such, it is important to understand the mode of action and mechanisms of tolerance or adaptation to these compounds. Different oxyanions vary widely in their inhibitory potency and mechanism of inhibition, but current evidence suggests that the sulfate adenylyl transferase/ATP sulfurylase (Sat) enzyme is an important target. We heterologously expressed and purified the Sat from the model SRM,Desulfovibrio alaskensisG20. With this enzyme we determined the turnover kinetics (kcat, KM) for alternative substrates (molybdate, selenate, arsenate, monofluorophosphate, and chromate) and inhibition constants (KI) for competitive inhibitors (perchlorate, chlorate, and nitrate). These measurements enable the first quantitative comparisons of these compounds as substrates or inhibitors of a purified Sat from a respiratory sulfate reducer. We compare predicted half-maximal inhibitory concentrations (IC50) based on Sat kinetics with measured IC50values againstD. alaskensisG20 growth and discuss our results in light of known mechanisms of sensitivity or resistance to oxyanions. This analysis helps with the interpretation of recent adaptive laboratory evolution studies and illustrates the value of interpreting gene-microbe-environment interactions through the lens of enzyme kinetics.
A novel domain within the CIL regulates egress of IFITM3 from the Golgi and prevents its deleterious accumulation in this apparatus
Authors: Zhong Li , Uzbekov Rustem , Journo Chloé , Roingeard Philippe , Cimarelli Andrea 
Published: March 2021

AbstractThe InterFeron-Induced TransMembrane proteins (IFITMs) are broad viral inhibitors that protect cells by preventing viral-to-cellular membrane fusion and they belong to the dispanin/CD225 family that includes vesicle trafficking regulators and proteins of unknown functions into four subfamilies (A-D). In this study, we uncover a novel domain that regulates the egress of IFITM3 from the Golgi and that is required to prevent IFITM3-driven v- to t-SNAREs membrane fusion inhibition and Golgi dysfunctions.The S-x-K-x-R-D domain is conserved among vertebrate members of the dispanin/CD225 A subfamily that regroups all IFITMs and through the study of mutations identified in patients affected by paroxysmal kinesigenic dyskinesia (PKD), we determine that it is functionally conserved also in PRRT2, member of the B subfamily.Overall, our study defines a novel domain that regulates the egress of dispanin/CD225 members from the Golgi and stresses the importance that regulation of this process bears to preserve the functions of this apparatus.
A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
Authors: Robertson Nic , Shchepachev Vadim , Wright David , Turowski Tomasz W. , Spanos Christos , Helwak Aleksandra , Zamoyska Rose , Tollervey David 
Published: March 2021

AbstractRMRPencodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex. Mutations cause Cartilage Hair Hypoplasia (CHH), characterized by skeletal abnormalities and impaired T cell activation. Yeast RNase MRP cleaves a specific site in the pre-ribosomal RNA (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption ofRMRPin human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations inRMRPimpair mouse T cell activation and delay pre-rRNA processing. Patient-derived human fibroblasts with CHH-linked mutations showed similar pre-rRNA processing delay. Human cells engineered with the most common CHH mutation (70AGinRMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70AGmutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy, and the first processing-specific human disorder to be described.HighlightsMutations inRMRPlncRNA impair pre-rRNA processing and T cell activationPatient derived fibroblasts show impaired pre-rRNA processingCells with the most common disease-linked mutation have specific processing defectsCytoplasmic ribosomes and intact RNase MRP complexes are also reduced in these cells
The institutional logic of the sustainable organisation: the case of a chocolate supply network
Authors: McLoughlin Kate , Meehan Joanne 
Published: March 2021

PurposeThe purpose of this paper is to examine how, and by whom, institutional logics are determined in the action of sustainable organisation. The authors analyse a supply chain network structure to understand how multiple stakeholders' perceptions of sustainability emerge into a dominant logic and diffuse across an organisational field.Design/methodology/approachStakeholder network theory provides novel insights into emerging logics within a chocolate supply chain network. Semi-structured interviews with 35 decision-makers were analysed alongside 269 company documents to capture variations in emergent logics. The network was mapped to include 63 nodes and 366 edges to analyse power structure and mechanisms.FindingsThe socio-economic organising principles of sustainable organisation, their sources of power and their logics are identified. Economic and social logics are revealed, yet the dominance of economic logics creates risks to their coexistence. Logics are largely shaped in pre-competitive activities, and resource fitness to collaborative clusters limits access for non-commercial actors.Research limitations/implicationsPowerful firms use network structures and collaborative and concurrent inter-organisational relationships to define and diffuse their conceptualisation of sustainability and restrict competing logics.Originality/valueThis novel study contributes to sustainable supply chain management (SSCM) through presenting the socio-economic logic as a new conceptual framework to understand the action of sustainable organisation. The identification of sophisticated mechanisms of power and hegemonic control in the network opens new research agendas.