bluuebunny/crossref_metadata_2025_split huggingface dataset:
SBML to bond graphs: from conversion to composition
Authors: Shahidi Niloofar , Pan Michael , Tran Kenneth , Crampin Edmund J , Nickerson David P 
Published: May 2022

AbstractThe Systems Biology Markup Language (SBML) is a popular software-independent XML-based format for describing models of biological phenomena. The BioModels Database is the largest online repository of SBML models. Several tools and platforms are available to support the reuse and composition of SBML models. However, these tools do not explicitly assess whether models are physically plausibile or thermodynamically consistent. This often leads to ill-posed models that are physically impossible, impeding the development of realistic complex models in biology. Here, we present a framework that can automatically convert SBML models into bond graphs, which imposes energy conservation laws on these models. The new bond graph models are easily mergeable, resulting in physically plausible coupled models. We illustrate this by automatically converting and coupling a model of pyruvate distribution to a model of the pentose phosphate pathway.Graphical AbstractHighlightsA framework to convert suitable SBML models of biochemical networks into bond graphs is developed.The framework is applied here to two interconnecting models of metabolism pathways.We automatically integrate the generated bond graph modules.We qualitatively illustrate the functionality of the composed model.
Prioritizing virtual screening with interpretable interaction fingerprints
Authors: Fassio Alexandre V. , Shub Laura , Ponzoni Luca , McKinley Jessica , O’Meara Matthew J. , Ferreira Rafaela S. , Keiser Michael J. , de Melo Minardi Raquel C. 
Published: May 2022

AbstractMachine learning-based drug discovery success depends on molecular representation. Yet traditional molecular fingerprints omit both the protein and pointers back to structural information that would enable better model interpretability. Therefore, we propose LUNA, a Python 3 toolkit that calculates and encodes protein-ligand interactions into new hashed fingerprints inspired by Extended Connectivity Finger-Print (ECFP): EIFP (Extended Interaction FingerPrint), FIFP (Functional Interaction FingerPrint), and Hybrid Interaction FingerPrint (HIFP). LUNA also provides visual strategies to make the fingerprints interpretable. We performed three major experiments exploring the fingerprints’ use. First, we trained machine learning models to reproduce DOCK3.7 scores using 1 million docked Dopamine D4 complexes. We found thatEIFP-4,096performed (R2= 0.61) superior to related molecular and interaction fingerprints. Secondly, we used LUNA to support interpretable machine learning models. Finally, we demonstrate that interaction fingerprints can accurately identify similarities across molecular complexes that other fingerprints over-look. Hence, we envision LUNA and its interface fingerprints as promising methods for machine learning-based virtual screening campaigns. LUNA is freely available athttps://github.com/keiserlab/LUNA.
NeRFax: An efficient and scalable conversion from the internal representation to Cartesian space
Authors: Dutton Oliver , Hoffmann Falk , Tamiola Kamil 
Published: May 2022

AbstractMotivationAccurate modelling of protein ensembles requires sampling of a large number of 3D conformations. A number of sampling approaches that use internal coordinates have been proposed, yet poor performance in the conversion from internal to Cartesian coordinates limits their applicability.ResultsWe describe here NeRFax, an efficient method for the conversion from internal to Cartesian coordinates that utilizes the platform-agnostic JAX Python library. The relative benefit of NeRFax is demonstrated here, on peptide chain reconstruction tasks. Our novel approach offers 35-175x times performance gains compared to previous state-of-the-art methods, whereas >10,000x speedup is reported in a reconstruction of a biomolecular condensate of 1,000 chains.AvailabilityNeRFax has purely open-source dependencies and is available at https://github.com/PeptoneLtd/nerfax.Contactoliver@peptone.io
Undermatching is a consequence of policy compression
Authors: Bari Bilal A. , Gershman Samuel J. 
Published: May 2022

AbstractThe matching law describes the tendency of agents to match the ratio of choices allocated to the ratio of rewards received when choosing among multiple options (Herrnstein, 1961). Perfect matching, however, is infrequently observed. Instead, agents tend to undermatch, or bias choices towards the poorer option. Overmatching, or the tendency to bias choices towards the richer option, is rarely observed. Despite the ubiquity of undermatching, it has received an inadequate normative justification. Here, we assume agents not only seek to maximize reward, but also seek to minimize cognitive cost, which we formalize as policy complexity (the mutual information between actions and states of the environment). Policy complexity measures the extent to which an agent’s policy is state-dependent. Our theory states that capacity-constrained agents (i.e., agents that must compress their policies to reduce complexity), can only undermatch or perfectly match, but not overmatch, consistent with the empirical evidence. Moreover, we validate a novel prediction about which task conditions exaggerate undermatching. Finally, we argue that a reduction in undermatching with higher dopamine levels in patients with Parkinson’s disease is consistent with an increased policy complexity.Significance statementThe matching law describes the tendency of agents to match the ratio of choices allocated to different options to the ratio of reward received. For example, if option A yields twice as much reward as option B, matching states that agents will choose option A twice as much. However, agents typically undermatch: they choose the poorer option more frequently than expected. Here, we assume that agents seek to simultaneously maximize reward and minimize the complexity of their action policies. We show that this theory explains when and why undermatching occurs. Neurally, we show that policy complexity, and by extension undermatching, is controlled by tonic dopamine, consistent with other evidence that dopamine plays an important role in cognitive resource allocation.
A comparison of software for analysis of rare and common short tandem repeat (STR) variation using human genome sequences from clinical and population-based samples
Authors: Oketch John W. , Wain Louise V. , Hollox Edward J. 
Published: May 2022

AbstractShort tandem repeat (STR) variation is an often overlooked source of variation between genomes. STRs comprise about 3% of the human genome and are highly polymorphic. Some cause Mendelian disease, and others affect gene expression. Their contribution to common disease is not well-understood, but recent software tools designed to genotype STRs using short read sequencing data are beginning to address this. Here, we compare software that genotypes common STRs and rarer STR expansions genome-wide, with the aim of applying them to population-scale genomes. By using the Genome-In-A-Bottle (GIAB) consortium and 1000 Genomes Project sequencing data, we compare performance in terms of sequence length, depth, computing resources needed, genotyping accuracy and number of STRs genotyped. To ensure broad applicability of our findings, we also measure genotyping performance against a set of genomes from clinical samples with known STR expansions, and a set of STRs commonly used for forensic identification. We find that HipSTR, ExpansionHunter and GangSTR perform well in genotyping common STRs, including the CODIS 13 core STRs used for forensic analysis. GangSTR and ExpansionHunter outperform HipSTR for genotyping call rate and memory usage. ExpansionHunter denovo (EHdn), STRling and GangSTR outperformed STRetch for detecting expanded STRs, and EHdn and STRling used considerably less processor time compared to GangSTR. Analysis on shared genomic sequence data provided by the GIAB consortium allows future performance comparisons of new software approaches on a common set of data, facilitating comparisons and allowing researchers to choose the best software that fulfils their needs.
PACeR: a bioinformatic pipeline for the analysis of chimeric RNA-seq data
Authors: Mills William T , Jaffe Andrew E. , Meffert Mollie K 
Published: May 2022

ABSTRACTMicroRNAs (miRNAs) are small non-coding RNAs that function in post-transcriptional gene regulation through imperfect base pairing with mRNA targets which results in inhibition of translation and often destabilization of bound transcripts. Sequence-based algorithms historically used to predict miRNA targets face inherent challenges in reliably reflecting in vivo interactions. Recent strategies have directly profiled miRNA-target interactions by cross-linking and ligation of miRNAs to their targets within the RNA-induced silencing complex (RISC), followed by high throughput sequencing of the chimeric RNAs. Despite the strength of these direct chimeric miRNA:target profiling approaches, standardized pipelines for analyzing the resulting chimeric RNA sequencing data are not readily available. Here we present PACeR, a robust bioinformatic pipeline for the analysis of chimeric RNA sequencing data. PACeR consists of two parts, each of which are optimized for the distinctive characteristics of chimeric RNA sequencing reads: first, read processing and alignment and second, peak calling and motif analysis. We apply PACeR to chimeric RNA sequencing data generated in our lab as well as a published benchmark dataset. PACeR has minimal computational power requirements and contains extensive annotation to broaden accessibility for processing chimeric RNA sequencing data and enable insights to be gained about the targets of small non-coding RNAs in regulating diverse biological systems.
G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis
Authors: Bielczyk-Maczynska Ewa , Zhao Meng , Zushin Peter-James H. , Schnurr Theresia M. , Kim Hyun-Jung , Li Jiehan , Nallagatla Pratima , Sangwung Panjamaporn , Park Chong , Cornn Cameron , Stahl Andreas , Svensson Katrin J. , Knowles Joshua W. 
Published: May 2022

AbstractHuman genetics has been instrumental in identification of genetic variants linked to type 2 diabetes (T2D). Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for T2D, but the mechanism behind this association has remained elusive. Here for the first time we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. Our findings establish a previously unknown role of Gpr151 in the liver and provides an explanation to the lowered T2D risk in individuals with nonsynonymous mutations in GPR151. This study highlights the therapeutic potential of targeting GPR151 for treatment of metabolic disease.
REM Sleep Movements in Parkinson’s Disease: Is the Basal Ganglia Engaged?
Authors: Verma Ajay K. , Acosta Lenis Sergio Francisco , Aman Joshua E. , Sanabria David Escobar , Wang Jing , Pearson Amy , Hill Meghan , Patriat Remi , Schrock Lauren E. , Cooper Scott E. , Park Michael C. , Harel Noam , Howell Michael J. , MacKinnon Colum D. , Vitek Jerrold L. , Johnson Luke A. 
Published: May 2022

AbstractTo elucidate the role of the basal ganglia during REM sleep movements in Parkinson’s disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.
Postural analysis reveals persistent vigilance in paper wasps after conspecific challenge
Authors: Legan Andrew W. , Vogt Caleb C. , Sheehan Michael J. 
Published: May 2022

ABSTRACTVigilant animals detect and respond to threats in the environment, often changing posture and movement patterns. In social animals vigilance is modulated not only by predators but also by threatening conspecifics. Precisely how social interactions alter vigilance behavior over time is not well understood. We report persistent effects of a simulated social challenge on the vigilance behavior of wild northern paper wasp foundresses,Polistes fuscatus. During the founding phase of the colony cycle conspecific wasps may usurp nests from the resident foundress, representing a severe threat. Using postural tracking, we found that after simulated intrusions wasps displayed increased vigilance during the minutes after the threat was removed. Sustained vigilance elicited after social threat manifested as increased movement, greater bilateral wing extension, and reduced antennal separation. However, no postural changes were observed after a control stimulus presentation. By rapidly adjusting individual vigilance behavior after fending off a conspecific intruder, paper wasp foundresses invest in surveillance of potential social threats, even when such threats are no longer immediately present. The prolonged state of vigilance observed here is relevant to plasticity of recognition processes as a result of conspecific threats.
Nucleotide-decoupled G proteins reveal the role of G protein conformation in receptor-G protein selectivity
Authors: Jang Wonjo , Lu Sumin , Lambert Nevin A. 
Published: May 2022

AbstractG protein-coupled receptors (GPCRs) selectively activate at least one of the four families of heterotrimeric G proteins to transduce environmental cues, but the mechanistic basis of coupling selectivity remains unclear. Structural studies have emphasized structural complementarity of GPCR complexes with nucleotide-free G proteins, but it has also been suggested that selectivity may be determined by intermediate activation processes that occur prior to nucleotide release. To test these ideas we have studied coupling to nucleotide- decoupled G protein variants, which can adopt conformations similar to receptor-bound G proteins without the need for nucleotide release. We find that selectivity is significantly degraded when nucleotide release is not required for GPCR-G protein complex formation, to the extent that most GPCRs interact with most nucleotide-decoupled G proteins. These findings demonstrate the absence of absolute structural incompatibility between most GPCRs and G proteins, and are consistent with the hypothesis that high-energy intermediate state complexes are involved in coupling selectivity.
Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient
Authors: Klich John H. , Kasse Catherine M. , Mann Joseph L. , Huang Yaoqi , d’Aquino Andrea I. , Grosskopf Abigail K. , Baillet Julie , Fuller Gerald G. , Appel Eric A. 
Published: May 2022

AbstractMonoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, we demonstrate the ability of a simple “drop-in”, amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically-relevant monoclonal antibodies without altering their pharmacokinetics or injectability. Through interfacial rheology and surface tension measurements, we demonstrate that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity through stressed aging, we show that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, we demonstrate that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as a simple formulation additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route-of-administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.
First Report of Susceptibility Status of the Invasive Vector:Aedes albopictusto insecticides used in vector control in Morocco
Authors: Aboulfadl Souhail , Mellouki Fouad , Ameur Btissam , Faraj Chafika 
Published: May 2022

AbstractAedes albopictushas been newly recorded in Agdal district at Rabat in Morocco. The establishment of this invasive mosquito could affect the public health by causing serious epidemics despite of its high nuisance in urban and sub-urban areas. Vector control is mainly based on environmental management but chemical insecticides can be used to reduce adult mosquito densities during peak periods. However, the level of susceptibility of this mosquito to insecticides has not been studied yet in Morocco.This paper reports the results of the first study conducted to monitor the insecticide resistance of adult and larvaAe. albopictusto the insecticides currently used in the vector control. The study was carried out during May-June 2018 at Rabat from the north-west of the country. Adult susceptibility tests were performed following the WHO test procedures. One organochlorate (DDT 4%), one pyrethroids (cyfluthrin 0.15%), one carbamate (bendiocarb 0.1%) and one organophosphate (fenithrothion 1%) were tested at diagnostic doses (DD). The five-fold DD of bendiocarb were also used to yield information on the intensity of mosquito adult resistance. The results of the performed susceptibility bioassay showed that the vector is susceptible to cyfluthrin and resistant to DDT, bendiocarb and fenithrothion.Larval bioassays to temephos were conducted according to WHO standard operating protocol to establish the dose-mortality relationship and deduct the LC50 and LC90 then resistance ratios. We show that larval populations ofAe. albopictusare still sensible to this insecticide. This information could help policy-makers to plan insecticide resistance management.
Masked Inverse Folding with Sequence Transfer for Protein Representation Learning
Authors: Yang Kevin K. , Yeh Hugh , Zanichelli Niccolò 
Published: May 2022

AbstractSelf-supervised pretraining on protein sequences has led to state-of-the art performance on protein function and fitness prediction. However, sequence-only methods ignore the rich information contained in experimental and predicted protein structures. Meanwhile, inverse folding methods reconstruct a protein’s amino-acid sequence given its structure, but do not take advantage of sequences that do not have known structures. In this study, we train a masked inverse folding protein masked language model parameterized as a structured graph neural network. During pretraining, this model learns to reconstruct corrupted sequences conditioned on the backbone structure. We then show that using the outputs from a pretrained sequence-only protein masked language model as input to the inverse folding model further improves pretraining perplexity. We evaluate both of these models on downstream protein engineering tasks and analyze the effect of using information from experimental or predicted structures on performance.
Clinical characterization of human monkeypox infections in the Democratic Republic of the Congo
Authors: Pittman Phillip R. , Martin James W. , Kingebeni Placide Mbala , Tamfum Jean-Jacques Muyembe , Wan Qingwen , Reynolds Mary G. , Quinn Xiaofei , Norris Sarah , Townsend Michael B. , Satheshkumar Panayampalli S. , Soltis Bryony , Honko Anna , Güereña Fernando B. , Korman Lawrence , Huggins John W. 
Published: May 2022

AbstractWe describe the results of a prospective observational study of the clinical natural history of human monkeypox virus (MPXV) infections at the remote General Reference Hospital of Kole (Kole hospital), the rainforest of the Congo River basin of the Democratic Republic of the Congo (DRC) from March 2007 until August 2011. The research was conducted jointly by the Institute National de Recherche Biomedical (INRB) and the US Army Medical Research Institute of Infectious Diseases (USAMRIID). The Kole hospital was one of the two previous WHO Monkeypox (MPX) study sites (1981-1986). The hospital is staffed by a Spanish Order of Catholic Nuns from La Congregation Des Seours Missionnaires Du Christ Jesus including two Spanish physicians, who were members of the Order as well, were part of the WHO study on human monkeypox. Of 244 patients admitted with a clinical diagnosis of MPXV infection, 216 were positive in both the Pan-Orthopox and MPXV specific PCR. The cardinal observations of these 216 patients are summarized in this report. There were three deaths (3/216) among these hospitalized patients; fetal death occurred in 4 of 5 (80%) patients who were pregnant at admission. The most common complaints were rash (96.8%), malaise (85.2%), sore throat (78.2%), and lymphadenopathy/adenopathy (57.4%). The most common physical exam findings were MPX rash (99.5%) and lymphadenopathy (98.6%). Age group of less than 5 years had the highest lesion count. Primary household cases tended to have higher lesion counts than secondary or later same household cases. Of the 216 patients, 200 were tested for IgM & IgG antibodies (Abs) to Orthopoxviruses. All 200 patients had anti-orthopoxvirus IgG Abs; whereas 189/200 were positive for IgM. Patients with hypoalbuminemia had a high risk of severe disease. Patients with fatal disease had significantly higher maximum geometric mean values than survivors for the following variables, respectively: viral DNA in blood (DNAemia, p=0.0072); maximum lesion count (p=0.0025); day of admission mean AST and ALT (p=0.0002 and p = 0.0224, respectively, adjusted p-values).Author SummaryThis is a prospective observational study of Human monkeypox disease, an emerging infectious disease in parts of the continent of Africa. There are certain differential characteristics when compared to other pox diseases. This paper describes the presenting symptoms and signs of human monkeypox disease, laboratory findings and makes recommendation for the medical treatment of patients with monkeypox disease.
A single-cell atlas of bobtail squid visual and nervous system highlights molecular principles of convergent evolution
Authors: Gavriouchkina Daria , Tan Yongkai , Ziadi-Künzli Fabienne , Hasegawa Yuko , Piovani Laura , Zhang Lin , Sugimoto Chikatoshi , Luscombe Nicholas , Marlétaz Ferdinand , Rokhsar Daniel S. 
Published: May 2022

AbstractAlthough the camera-type eyes of cephalopods and vertebrates are a canonical example of convergent morphological evolution, the cellular and molecular mechanisms underlying this convergence remain obscure. We used genomics and single cell transcriptomics to study these mechanisms in the visual system of the bobtail squid Euprymna berryi, an emerging cephalopod model. Analysis of 98,537 cellular transcriptomes from the squid visual and nervous system identified dozens of cell types that cannot be placed in simple correspondence with those of vertebrate or fly visual systems, as proposed by Ramón y Cajal and J.Z. Young. Instead, we find an unexpected diversity of neural types, dominated by dopamine, and previously uncharacterized glial cells. Surprisingly, we observe changes in cell populations and neurotransmitter usage during maturation and growth of the visual systems from hatchling to adult. Together these genomic and cellular findings shed new light on the parallel evolution of visual system complexity in cephalopods and vertebrates.