bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simplest Model of Nervous System. III. Partial Optimization
Authors: Sinitskiy Anton V. 
Published: June 2024

AbstractThis paper extends our previous work on the simplest model of a nervous system by providing an asymptotic analysis of the evolutionarily optimal solution in this model. Building on the formalism and principles established earlier, we derive an asymptotic solution to the Fokker-Planck-Kolmogorov equation for a given dynamical equation for the state of the neuron. This solution provides the stationary probability distribution for the position of an organism in its environment and the state of its nervous system. Next, exact and asymptotic solutions for the optimal motor and sensory responses to the approach of a predator are derived. These results align with biological expectations and provide a robust mathematical framework for predicting the behavior of simple nervous systems.
LooMS: a novel peptide identification tools for data independent acquisition
Authors: Zhong Jiancheng , Wu Jia Rong , Zeng Xiangyuan , Moran Michael , Ma Bin 
Published: June 2024

AbstractAdvancements in mass spectrometry (MS)-based proteomics have produced large-scale datasets, necessitating the development of effective tools for peptide identification. Here, we present LooMS, a novel tool specifically designed for identifying peptides in data-independent acquisition (DIA) datasets. LooMS employs an innovative approach, using an unbiased generation strategy for positive and negative samples, which reduces the risk of overfitting in peptide identification with deep learning models. Additionally, LooMS addresses various critical aspects of DIA mass spectra data analysis, constructing a comprehensive set of 43 features for training deep learning models, which cover different stages of DIA data analysis. Notably, we propose a false discovery rate (FDR) control strategy that integrates results from both LooMS and DiaNN, another leading peptide identification tool. Our results demonstrate significant improvements in peptide identification performance, with enhancements of 40.61% and 26.60% at the unique peptide level for human and mouse datasets, respectively.HighlightsLooMS is a novel tool for identifying peptides in DIA datasets that adopts an innovative unbiased positive and negative sample generation strategy, which aim to avoid the overfilling in peptide identification with deep learning model.LooMS comprehensively considers various aspects of data analysis for DIA mass spectra and builds 43 useful features for training deep learning models, which involve different stages of DIA data analysis.A FDR control strategy for integration of results from both LooMS and DiaNN is proposed, which can significantly improve the identification of peptides due to the differences in the features involved in peptide detection during their respective design.
The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects ofCOL3A1mutations that cause vascular Ehlers Danlos Syndrome
Authors: Omar Ramla , Lee Michelle , Gonzalez-Trueba Laura , Lianos Spyridonas , Hazarika Snoopy , Ammar Malak A , Cassels Jennifer , Michie Alison M. , Bulleid Neil J , Malfait Fransiska , Agtmael Tom Van 
Published: June 2024

AbstractPurposeVascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused byCOL3A1mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to address this critical knowledge gap, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach.MethodsWe performed a mechanistic analysis of two novelCOL3A1glycine mutations, G189S and G906R, using primary patient fibroblast cultures, and performed pre-clinical proof-of-concept treatments using FDA-approved chemical chaperones targeting protein folding and/or degradation.ResultsCOL3A1mutations caused secretion of misfolded collagen III and intracellular collagen retention, leading to matrix defects and endoplasmic reticulum (ER) stress, with increased severity for the more C-terminal mutation. Promoting ER protein folding capacity through the chemical chaperone 4-phenylbutyric acid rescued the ER stress, thermostability of secreted collagen, matrix defects and apoptosis. Optimising treatment duration and dosage helped overcome allele-dependent treatment efficacy. In contrast, protein degradation alone or combined with targeting protein folding did not increase efficacy.ConclusionER stress is a molecular mechanism in vEDS that can be influenced by the position ofCOL3A1mutation, and promoting protein folding is a putative mechanism-based therapeutic approach that can rescue intra- and extracellular defects.
Keetia magassoubiana sp.nov. (Rubiaceae - Vanguerieae) a threatened evergreen forest climber of West Africa
Authors: Cheek Martin , Bowden-Pickstock Joel 
Published: June 2024

SummaryKeetia magassoubianaCheek, an evergreen rainforest climber, is described and illustrated from the Republic of Guinea, Sierra Leone, Liberia and Ivory Coast. Previously indicated as being close to but different fromKeetia tenuiflora(Hiern) Bridson, it differs in the glossy black, glabrous, epidermis of the distal stem internodes, the first internode rarely with very sparse red adpressed hairs (vs epidermis pale white-brown, dense pale yellow spreading hairs) and abaxial leaf surface with domed domatia with a central aperture (vs domatia absent or obscure), the secondary stem leaf bases acute (vs obtuse to truncate), the bracts forming a laciniate sheath on the distal peduncle (vs two opposite triangular bracts), the pyrene surface honeycombed with pits (vs entire). The species was earlier included withinCanthium multiflorum(Schum. & Thonn.) Hiern (nowK. multiflora(Schum. & Thonn.) Bridson) in the Flora of West Tropical Africa second edition. An updated key is presented to the 16 species of the genus from West Africa.Keetia magassoubianais provisionally assessed using the IUCN standard as Endangered EN B1ab(iii) due to only five of the recorded 14 locations having extant forest habitat, and because of ongoing threats of habitat clearance mainly for agriculture, but also mining.
Identifying conservation priorities of a pantropical plant lineage: a case study in Scleria (Cyperaceae)
Authors: Díaz Javier Galán , Bachman Steven P. , Forest Félix , Escudero Marcial , Rotton Hannah , Larridon Isabel 
Published: June 2024

AbstractScleriais a pantropical genus of annual and perennial herbs and the sixth largest genus in the Cyperaceae family with around 261 species. In this study, we produced preliminary extinction risk assessments for the ∼30% ofScleriaspecies that do not yet have a global Red List assessment and followed the Evolutionarily Distinct and Globally Endangered (EDGE2) and Ecologically Distinct and Globally Endangered (EoDGE) protocols to identify evolutionary and ecologically uniqueScleriaspecies at greatest risk of extinction and hotspots of rare and endangered species. Our results indicate that 38 of the 78Scleriaspecies not yet included in the Red List, and 26% of species in the genus, are potentially threatened with extinction. The risk of extinction is not equally distributed across the phylogeny, and the Afrotropics and the Neotropics accumulate most threatened species. Eleven ecoregions mostly from four African (Madagascar, D.R. Congo, Zambia and Tanzania) and two South American (Brazil, Venezuela) countries accumulate almost half ofScleriaspecies and stand out in terms of their sum of EDGE2 scores. Phylogenetic and functional distinctiveness metrics were largely uncorrelated, and the EcoDGE metric mostly points towards South American countries as reservoirs of ecologically distinctive and endangered species: Brazil, Venezuela, Bolivia, Peru, Colombia, Guyana and Dominican Republic. Recent methodological advances in the identification of species at-risk of extinction and the novel EDGE2 framework emerge as powerful tools to identify conservation priorities.
Digital Immunoassay for Rapid Detection of SARS-CoV-2 Infection in a Broad Spectrum of Animals
Authors: Li Siyan , Wang Weijing , Liu Weinan , Chen Chi , Shephard Skye , Yuan Fangfeng , Reinhart Jennifer M. , Diel Diego , Cunningham Brian T. , Fang Ying 
Published: June 2024

ABSTRACTThe ability of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to infect a wide-range of species raises significant concerns regarding both human-to-animal and animal-to-human transmission. There is an increasing demand for highly sensitive, rapid, and simple diagnostic assays that can detect viral infection across various species. In this study, we developed a biosensor assay that adapted a monoclonal-antibody (mAb)-based blocking ELISA format into an Activate Capture + Digital Counting (AC + DC)-based immunoassay. The assay employs a photonic crystal (PC) biosensor, gold-nanoparticle (AuNP) tags, SARS-CoV-2 nucleocapsid (N) protein, and specific anti-N mAb to detect antibody responses in animals exposed with SARS-CoV-2. We demonstrated a simple 2-step 15-min test that was capable of detecting as low as 12.5 ng of antibody in controlled standard serum samples. Based on an evaluation of 176 cat serum samples with known antibody status, an optimal percentage of inhibition (PI) cut-off value of 0.588 resulted in a diagnostic sensitivity of 98.3% and a diagnostic specificity of 96.5%. The test is highly repeatable with low variation coefficients of 2.04%, 2.73%, and 4.87% across different runs, within a single run, and on a single chip, respectively. The test was further employed to detect antibody responses in multiple animal species as well as investigate dynamics of antibody response in experimentally infected cats. This test platform provides an important tool for rapid field surveillance of SARS-CoV-2 infection across multiple species.
Stable platelet production via the bypass pathway explains the long-term reconstitution capacity of hematopoietic stem cells
Authors: Iwanami Shoya , Sato Toshiko , Haeno Hiroshi , Xu Longchen , Imamura Keimyo , Ooehara Jun , Lan Xun , Nakauchi Hiromitsu , Iwami Shingo , Yamamoto Ryo 
Published: June 2024

AbstractPrecise understanding how hematopoietic stem cells (HSCs) differentiate in vivo is difficult because we can not trace the in vivo differentiation of HSCs. The single-cell transplantation assay and our own paired daughter cell assay of phenotypic HSCs has revealed the presence of HSCs with reconstitution capacity whose differentiation potential is restricted to the myeloid lineage (MySCs) and the presence of novel direct differentiation pathway form HSCs to MySCs (named myeloid bypass pathway). However, how HSCs differentiate in vivo during hematopoiesis has remained unclear since the paired daughter cell assay was performed partially ex vivo. Aiming to characterize HSCs, including the myeloid bypass pathway, we examined the kinetics of HSC differentiation using a mathematical model. We analyzed data from single-cell transplantation assays in which five blood cell lineages were followed successively after transplantation. An age-related skewing to the myeloid lineage was quantitatively indicated as the production of B cells reduced with age. Dependence on platelet bypass increased with aging and consistently high dependence was associated with long-term reconstitution capacity of the HSCs. Focusing on the ratio of chimerism among cell lineages, the characteristics of dependence on platelet bypass can be accurately determined by the ratio of erythrocyte to platelet chimerism at 8 weeks after transplantation. This new identification criterion is an indicator of long-term reconstitution of HSCs that does not rely on observation of long-term transplantation experiments. These findings reveal the novel characteristics of HSCs related to aging and stemness and highlight the importance of the bypass pathway in HSC differentiation.Significance statementIn vivo differentiation of hematopoietic stem cells (HSCs) is important for understanding blood cell production. Here we investigated the differentiation kinetics of HSCs in single-cell transplantation assays by using a mathematical model. Our findings demonstrate the importance of the bypass pathway in platelet production for the long-term reconstitution capacity of HSCs. These results also suggest the utility of studying time changes in HSC differentiation. The new HSC characteristics and its detection criteria identified in this study are expected to be useful in understanding HSC diversity and aging.
Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors
Authors: Bosetti Chiara , Kampasis Dionisis , Galera-Prat Albert , Brinch Shoshy A. , Karelou Maria , Dhakar Saurabh S. , Alaviuhkola Juho , Waaler Jo , Lehtiö Lari , Kostakis Ioannis 
Published: June 2024

AbstractHuman diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and some small molecule inhibitors have already been developed. These inhibitors typically interact with the nicotinamide binding site and extend along the NAD+binding groove of the catalytic domain. Quinazolin-4-ones have been explored as promising scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both nitro- and diol-substituents exhibit intriguing inhibition of TNKS2, with compound49displaying an IC50of 65 nM, while compound40’s IC50value is 14 nM. Both analogues show efficacy in cell assays and attenuate the tankyrase-controlled Wnt/β-catenin signaling with sub-micromolar IC50. When tested against a wider panel of enzymes, compound40displayed high selectivity towards tankyrases, whereas49also inhibited other PARPs. The results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.
Time is Brain: Detection of Nonconvulsive Seizures and Status Epilepticus During Acute Stroke Evaluation Using Point-of-Care Electroencephalography
Authors: Gururangan Kapil , Kozak Richard , Dorriz Parshaw J. 
Published: June 2024

ABSTRACTObjectivesSeizures are both a common mimic and a potential complication of acute stroke. Although EEG can be helpful to evaluate this differential diagnosis, conventional EEG infrastructure is resource- intensive and unable to provide timely monitoring to match the emergent context of a stroke code. We aimed to evaluate the real-world use and utility of a point-of-care EEG device as an adjunct to acute stroke evaluation.Materials and MethodsWe performed a retrospective observational cohort study at a tertiary care community teaching hospital by identifying patients who underwent point-of-care EEG monitoring using Rapid Response EEG system (Ceribell Inc., Sunnyvale, CA) during stroke code evaluation of acute neurological deficits during the study period from January 1, 2020 to December 31, 2020. We assessed the frequency of seizures and highly epileptiform patterns among patients with either confirmed strokes or stroke mimics.ResultsPoint-of-care EEG monitoring was used in the wake of a stroke code in 70 patients. Of these, neuroimaging and clinical information resulted in a diagnosis of stroke in 38 patients (28 ischemic, 6 hemorrhagic, 4 transient ischemic attack; median NIHSS score of 6.5 [IQR 2.0-12.0]) and absence of any stroke in 32 patients. Point-of-care EEG detected seizures and highly epileptiform patterns in 6 (15.8%) stroke patients and 11 (34.4%) stroke-mimic patients, including 2 patients with persistent expressive aphasia due to repeated focal seizures.ConclusionsPoint-of-care EEG has utility for detecting nonconvulsive seizures in patients undergoing acute stroke evaluations.
tame: An R package for identifying clusters of medication use based on dose, timing and type of medication
Authors: Laksafoss Anna , Wohlfahrt Jan , Hviid Anders 
Published: June 2024

ABSTRACTSimplified exposure classifications, such as ever exposed versus never exposed, are commonly used in pharmacoepidemiology. However, this simplification may obscure complex use patterns relevant to researchers. We introduce tame, an R package that offers a novel method for classifying medication use patterns, capturing complexities such as timing, dose, and concurrent medication use in real-world data. The core innovation of tame is its bespoke distance measure, which identifies complex clusters in medication use and is highly adaptable, allowing customization based on the Anatomical Therapeutic Chemical (ATC) Classification System, medication timing, and dose. By prioritizing a robust distance measure, tame ensures accurate and meaningful clustering, enabling researchers to uncover intricate patterns within their data. The package also includes tools for visualizing and applying these clusters to new datasets. In a national Danish cohort study, tame identified nuanced antidepressant use patterns before and during pregnancy, demonstrating its capability to detect complex trends. tame is available on the Comprehensive R Archive Network at [https://CRAN.R-project.org/package=tame] under an MIT license, with a development version on GitHub at [https://github.com/Laksafoss/tame]. tame enhances medication use classification by detecting complex interactions and offering insights into real-world medication usage, thus improving stratification in epidemiological studies.
Milliseconds matter: Biomechanical inverse dynamics analysis is highly sensitive to imperfect data synchronization
Authors: Lemaire Koen K. , Kuo Arthur D. 
Published: June 2024

AbstractInverse dynamics analysis is the primary means of quantifying joint moments and powers from biomechanical data. The data are often combined from force plates, motion capture cameras, and perhaps body-worn inertial sensors, and must be temporally synchronized to avoid potentially large inverse dynamics errors. The principles behind the errors, and the sensitivities for movements such as human walking, have yet to be demonstrated. Here we quantify how inverse dynamics computations of joint moments, powers, and work are highly sensitive to temporal mis-synchronization. We do this with (1) a theoretical examination of inverse dynamics, supported by (2) a simulated multi-body jumping movement, and (3) experimental human walking data. The theoretical analysis shows that root-mean-square errors in joint powers increase linearly with temporal mis-synchronization, and increase more for faster movements. With the other analyses we quantify the specific amount. For example, for human walking at 1.25 m/s, an artificially induced 5 ms lag of force relative to motion resulted in a 29% root-mean-square error of the ankle joint moment. The corresponding error in ankle joint power was 58%, and five times as much for walking at 2.2 m/s. The residual force, a measure of internal inconsistency in the data, increased by almost 1% body weight for each millisecond of mis-synchronization for walking. These sensitivities are relevant because standard experimental equipment usually synchronizes only the recording of data, but not processing latencies internal to equipment, which can and do cause mis-synchronization on the order of ten milliseconds. Biomechanical data should be synchronized to within a few milliseconds, and with respect to physical stimulus, to yield accurate inverse dynamics analysis.
The role of two major nucleoid associated proteins in Streptomyces, HupA and HupS, in stress survival and gene expression regulation
Authors: Strzałka Agnieszka , Mikołajczyk Jakub , Kowalska Klaudia , Skurczyński Michał , Holmes Neil , Jakimowicz Dagmara 
Published: June 2024

AbstractStreptomycesare sporulating soil bacteria with enormous potential for secondary metabolites biosynthesis. Regulatory networks governingStreptomyces coelicolordifferentiation and secondary metabolites production are complex and composed of numerous regulatory proteins ranging from specific transcriptional regulators to sigma factors. Nucleoid associated proteins (NAPs) are also believed to contribute to regulation of gene expression. Upon DNA binding these proteins impact DNA accessibility. Among NAPs HU proteins are the most widespread and abundant. Unlike other bacteria, theStreptomycesgenome encodes two HU homologs: HupA and HupS, differing in structure and expression profile. In this study, we explore whether HupA and HupS affectS. coelicolorgrowth under optimal and stressful conditions and how they control global gene expression. By testing both single and double mutants we address the question of both HU homologs complementarity. The lack of bothhupgenes led to growth and sporulation inhibition, as well as increased spore fragility. Our data indicate a synergy between the functions of HupA and HupS duringS. coelicolorgrowth. We also demonstrate, that both HU homologs can be considered global transcription regulators influencing expression of numerous genes encoding proteins linked to chromosome topology, secondary metabolites production and transcription. We identify the independent HupA and HupS regulons as well as genes under the control of both HupA and HupS proteins. Our data indicate some extent of redundancy as well as independent function of both homologs.ImportanceStreptomycesbelong to the bacterial family widely used in the production of antibiotics as well as research for new bioactive substances with antimicrobial properties. Gene expression inStreptomyces, and consequently the production of secondary metabolites, is controlled by a vast and complex network of transcriptional regulators. Our data indicate that two proteins, HupA and HupS, involved in the maintenance of chromosome structure, also participate in this regulatory network. Their presence appears to important forS. coelicolor’s adaptation for survival in unfavorable conditions such as high temperature. The lack of one or both HU proteins affects the expression of many genes, indicating that they act as global transcriptional regulators.