bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seamless, rapid and accurate analyses of outbreak genomic data using Split K-mer Analysis (SKA)
Authors: Derelle Romain , von Wachsmann Johanna , Mäklin Tommi , Hellewell Joel , Russell Timothy , Lalvani Ajit , Chindelevitch Leonid , Croucher Nicholas J. , Harris Simon R. , Lees John A. 
Published: March 2024

AbstractSequence variation observed in populations of pathogens can be used for important public health and evolution genomic analyses, especially outbreak analysis and transmission reconstruction. Identifying this variation is typically achieved by aligning sequence reads to a reference genome, but this approach is susceptible to reference biases and requires careful filtering of called genotypes. Additionally, while the volume of bacterial genomes continues to grow, tools which can accurately and quickly call genetic variation between sequences have not kept pace. There is a need for tools which can process this large volume of data, providing rapid results, but remain simple so they can be used without highly trained bioinformaticians, expensive data analysis, and long term storage and processing of large files.Here we describe Split K-mer Analysis (SKA2), a method which supports both reference-free and reference-based mapping to quickly and accurately genotype populations of bacteria using sequencing reads or genome assemblies. SKA2 is highly accurate for closely related samples, and in outbreak simulations we show superior variant recall compared to reference-based methods, with no false positives. We also show that within bacterial strains, where it is possible to construct a clonal frame, SKA2 can also accurately map variants to a reference, and be used with recombination detection methods to rapidly reconstruct vertical evolutionary history. SKA2 is many times faster than comparable methods and can be used to add new genomes to an existing call set, allowing sequential use without the need to reanalyse entire collections. Given its robust implementation, inherent absence of reference bias and high accuracy, SKA2 has the potential to become the tool of choice for genotyping bacteria and can help expand the uses of genome data in evolutionary and epidemiological analyses. SKA2 is implemented in Rust and is freely available athttps://github.com/bacpop/ska.rust.
A NOVEL APPROACH TO RECOVERING OFF-TRACK ALIGNER TREATMENT THROUGH HYPER-ELASTIC POLYMER INNOVATION
Authors: Phan Loc X. , Mora Carla , Klucinska Agnieszka 
Published: March 2024

ABSTRACTClear plastic aligners are becoming an increasingly popular choice for patients seeking orthodontic treatment. However, Industry Standard Aligners lack material properties that sustain tooth movement throughout the typical wear time for aligners.In a study compiling force data from existing Industry Standard Aligners and the OrthoFX Rescue Aligner, data points were plotted to compare the force profiles of each product. The Rescue Aligner aims to eliminate the mid-course correction process and provide consistent forces to improve treatment times and patient satisfaction.
Chilean brush-tailed mouse (Octodon degus): a diurnal precocial rodent as a new model to study visual receptive field properties of superior colliculus neurons
Authors: Márquez N.I. , Fernández-Aburto P.F. , Deichler A. , Perales I. , Letelier J.-C. , Marín G. J. , Mpodozis J. , Pallas S.L. 
Published: March 2024

ABSTRACTLab rodent species used to study the visual system and its development (hamsters, rats, and mice) are nocturnal, altricial, and possess simpler visual systems than carnivores and primates. To widen the spectra of studied species, here we introduce an alternative model, the Chilean degu (Octodon degus), a diurnal, precocial Caviomorph rodent with a cone enriched, well-structured retina, and well-developed central visual projections. To assess degus’ visual physiological properties, we characterized the visual responses and receptive field (RF) properties of isolated neurons in the superficial layers of the superior colliculus (sSC). To facilitate comparison with studies in other rodent species, we used four types of stimuli: (1) a moving white square, (2) sinusoidal gratings, (3) an expanding black circle (looming), and (4) a stationary black circle. We found that as in other mammalian species, RF size increases from superficial to deeper SC layers. Interestingly, compared to other lab rodents, degus have smaller RF sizes, likely indicating higher acuity. sSC neurons displayed spatial frequency tuning to grating stimuli from 0.08 to 0.24 cycles/degree. Additionally, neurons from sSC showed transient ON, OFF, or ON-OFF responses to stationary stimuli but increased their firing rates as a looming object increased in size. Our results suggests that degus have higher visual acuity, higher frequency tuning, and lower contrast sensitivity than commonly used nocturnal lab rodents, positioning degus as a well-suited model for studies of diurnal vision that are more relevant to humans.
Comparative CNS Pharmacology of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis
Authors: Turner Timothy J. , Brun Priscilla , Gruber Ross , Ofengeim Dimitry 
Published: March 2024

AbstractTolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS, employingin vitrokinase, cellular activation assays, and pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS.In vitrokinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a Kivalue of 4.7 nM and slow off-rate (1.54 x 10−5s-1), also had an association rate 1760-fold slower (3.28 x 103M-1* s-1). Estimates of cellular potency were largely consistent with thein vitrokinase assays, with an estimated IC50 of 0.7 nM for tolebrutinib against 34.5 nM for evobrutinib and 2.9 nM for fenebrutinib. We then observed that evobrutinib, fenebrutinib, and tolebrutinib achieved similar levels of exposure in non-human primate CSF after oral doses of 10 mg/kg. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp,uu CSF=0.40) exceeded the IC90 (the estimated concentration inhibiting 90% of kinase activity) value, while evobrutinib (3.2 ng/mL) (kp,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the estimated IC90 values. We conclude that tolebrutinib is the only candidate that attained relevant CSF exposure in non-human primates.DISCLOSURESTT, PB, DO:Employees of Sanofi (may hold shares and/or stock options in the company).RGnone.
Rationalizing diverse binding mechanisms to the same protein fold: insights for ligand recognition and biosensor design
Authors: Leonard Alison C. , Friedman Anika J. , Chayer Rachel , Petersen Brian M. , Kaar Joel , Shirts Michael R. , Whitehead Timothy A. 
Published: March 2024

ABSTRACTThe engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem which could enable many practical applications of protein biosensors. In this work, we analyzed two engineer ed biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.
GenoTools: An Open-Source Python Package for Efficient Genotype Data Quality Control and Analysis
Authors: Vitale Dan , Koretsky Mathew , Kuznetsov Nicole , Hong Samantha , Martin Jessica , James Mikayla , Makarious Mary B , Leonard Hampton , Iwaki Hirotaka , Faghri Faraz , Blauwendraat Cornelis , Singleton Andrew B. , Song Yeajin , Levine Kristin , Sreelatha Ashwin Ashok Kumar , Fang Zih-Hua , Nalls Mike 
Published: March 2024

AbstractGenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control (QC), and genome-wide association studies (GWAS) capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools’ “Ancestry” module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization, specified to the user’s genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIH’s Center for Alzheimer’s and Related Dementias (CARD) and the Global Parkinson’s Genetics Program (GP2). GenoTools was used to process and analyze the UK Biobank and major Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) datasets with over 400,000 genotypes from arrays and 5000 sequences and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous QC, and conducted genetic ancestry-specific GWAS to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotype data with reproducible and scalable ancestry, QC, and GWAS pipelines.
Conserved DNA Methylation Signatures in The Prefrontal Cortex of Newborn and Juvenile Guinea Pigs Following Antenatal Corticosteroid Exposure
Authors: Kim Bona , Kostaki Alisa , Matthews Stephen G. 
Published: March 2024

ABSTRACTAntenatal corticosteroids (ACS) are provided to improve perinatal survival when there is risk of preterm birth. Though evidence suggests increased risk of developing neurobehavioural disorders in exposed offspring, the mechanisms that mediate this relationship remain largely unknown. Here, we investigated the DNA methylation patterns in the prefrontal cortex (PFC) of exposed offspring. We hypothesized that differential methylation will be evident at both newborn and juvenile ages.Pregnant guinea pigs were administered saline or betamethasone (1mg/kg) on gestational days 50/51 to mimic a single course of ACS. gDNA was isolated from the PFC of term-born offspring on postnatal day 1 (PND1) and PND14 to identify differentially methylated CpG sites (DMCs) using reduced representative bisulfite sequencing.In the PND1 PFC, 1521 DMCs, annotating to 145 genes were identified following ACS. Identified genes were involved in pathways regulating ‘developmental cellular process’. In the PND14 PFC, 776 DMCs representing 46 genes were identified, and were enriched in ‘synaptic signalling’ pathways. Though no individual DMCs were identified at both PND1 and PND14, differential methylation was consistently observed at the binding sites of transcription factors PLAGL1, TFAP2C, ZNF263, and SP1 at both ages.In this study, we identified an altered DNA methylome in the PFC of ACS-exposed guinea pig offspring at both newborn and juvenile ages. Notably, a unique methylation signature was consistently observed at four key transcription factor binding sites at multiple post-natal time points, indicating a persistent change which may predispose the development of altered neurobehavioural phenotypes that have been described in exposed offspring.
Emergent Collective Behavior Evolves More Rapidly Than Individual Behavior Among Ant Species
Authors: Doering Grant Navid , Prebus Matthew M. , Suresh Sachin , Greer Jordan N. , Bowden Reilly , Linksvayer Timothy A. 
Published: March 2024

AbstractEmergence is a fundamental concept in biology and other disciplines, but whether emergent phenotypes evolve similarly to non-emergent phenotypes is unclear. The hypothesized process ofemergent evolutionposits that evolutionary change in collective behavior is irreducible to evolutionary change in the intrinsic behaviors of isolated individuals. As a result, collective behavior might evolve more rapidly and diversify more between populations compared to individual behavior. To test if collective behavior evolves emergently, we conducted a large comparative study using 22 ant species and gathered over 1,500 behavioral rhythm time series from hundreds of colonies and isolated individuals, totaling over 1.5 years of behavioral data. We show that analogous traits measured at individual and collective levels exhibit distinct evolutionary patterns. The estimated rates of phenotypic evolution for the rhythmicity of activity in ant colonies were faster than the evolutionary rates of the same behavior measured in isolated individual ants, and total variation across species in collective behavior was higher than variation in individual behavior. We hypothesize that more rapid evolution and higher variation is a general feature of emergent phenotypes relative to lower-level phenotypes across complex biological systems.
Complement activation by IgG subclasses is governed by their ability to oligomerize upon antigen binding
Authors: Frischauf Nikolaus , Strasser Jürgen , Borg Ellen G.F. , Labrijn Aran F. , Beurskens Frank J. , Preiner Johannes 
Published: March 2024

AbstractComplement activation through antibody-antigen complexes is crucial in various pathophysiological processes such as infections, inflammation, and autoimmunity, but is also utilized in immunotherapies to eliminate infectious agents, regulatory immune cells, or cancer cells. Although the tertiary structures of the four IgG antibody subclasses are largely identical, complement recruitment and further activation depend strongly on subclass, which is commonly explained by the respective affinity for C1, the first component of the classical complement pathway. Contradicting this established view, we here demonstrate that complement activation by different IgG subclasses is determined by their varying ability to form IgG oligomers on antigenic surfaces large enough to multivalently bind and activate C1. We directly visualize the resulting IgG oligomer structures and characterize their distribution by means of high-speed atomic force microscopy (HS-AFM), quantify their complement recruitment efficiency from quartz crystal microbalance (QCM) experiments, and characterize their ability to activate complement on tumor cell lines as well as in vesicle-based complement lysis assays. We present a mechanistic model of the multivalent interactions that govern C1 binding to IgG oligomers and use this model to extract affinities and kinetic rate constants from real-time interaction QCM data. Together, our detailed characterization yields a comprehensive view on the parameters that govern complement activation by the different IgG subclasses, which may inform the design of future antibody therapies.
Thalamic blood flow and EEG frequency band power during hyperventilation in idiopathic generalized epilepsy
Authors: Debatisse Justine , Yaakub Siti N , De Vita Enrico , Charles-Edwards Geoff , Jeljeli Sami , Stirling James , Flaus Anthime , Dunn Joel , Koutroumanidis Michalis , Hammers Alexander , McGinnity Colm J 
Published: March 2024

AbstractAbsence seizures in idiopathic generalised epilepsy (IGE) involve thalamo-cortical circuits. Hyperventilation (HV) is a standard technique to trigger epileptiform discharges and absence seizures in IGE. HV also increases electroencephalography (EEG) delta band power and decreases global cerebral blood flow (CBF). The relationships between HV, EEG band power, and regional CBF have not been investigated in the same patients at the same time.We compared the effects of hyperventilation between 13 individuals with IGE and 18 healthy controls on thalamic CBF assessed with pseudo-continuous Arterial Spin Labelling (pCASL) simultaneously to EEG frequency band power during three periods of hyperventilation interleaved with three periods of rest, normalised to each participant’s pre-HV values.Pre-HV, there were no differences between patients and controls. During the three rest periods combined, patients had higher normalised respiratory rates but no difference in CBF or EEG band power compared with controls.During HV, CBF decreases were similar in controls and IGE patients in cortical gray matter (37.1±1.3% in controls, 37.9±2.0% in patients) and basal ganglia (35.6±2.0% in controls, 33.3±2.3% in patients). In the thalamus, CBF decreased by 35.5±1.9% in controls, but only by 27.1±2.5% in patients (p=0.011). Delta band power increased by 42% in patients, but only by 27% in patients (p<0.045).Both controls’ and patients’ thalamic CBF significantly decreased as a function of respiratory rate, but the relationship was weaker in patients (rho –0.38 [0.95 confidence interval lower limit −0.629; upper limit −0.059] vs –0.51 [-0.698; −0.255] in controls). Delta power correlated with thalamic CBF only in controls (rho −0.21 [-0.388; −0.017]) but not in patients (rho −0.1 [-0.345; 0.157]). EEG power and respiratory rate were not significantly correlated in either group.This first study of the interrelationships between HV, blood flow, and EEG band power suggests that regional thalamic abnormalities of blood flow regulation, or a neurophysiological abnormality leading to smaller reactive blood flow changes, may underlie HV-associated EEG activation.Graphical abstract textIn this first investigation of combined hyperventilation, blood flow and EEG band power measurements in idiopathic generalised epileptic patients and healthy subjects, we revealed that localized thalamic blood flow regulatory problems or neurophysiological disorders caused minor reactive blood flow variations and may cause hyperventilation-associated EEG activation.
Crude extract ofRuellia tuberosaL. flower induces intracellular ROS, promotes DNA damage and apoptosis in Triple Negative Breast Cancer Cells
Authors: Guha Subhabrata , Talukdar Debojit , Mandal Gautam Kumar , Mukherjee Rimi , Ghosh Srestha , Naskar Rahul , Saha Prosenjit , Murmu Nabendu , Das Gaurav 
Published: March 2024

AbstractEthnophamacological relevanceIn the traditional folklore medicine system, the primary uses ofRuellia tuberosaL. include as a diuretic, anti-hypertensive, antipyretic, anti-diabetic, analgesic, and gastroprotective agent. Some reports also demonstrated that it has been used to treat gonorrhea-like diseases.PurposeExploring the anti-cancer potential of the methanolic extract ofRuellia tuberosaL. flower (RTME) with special emphasis on human triple-negative breast cancer (TNBC) and investigating the possible signaling networks and regulatory pathways underlying it.MethodsPreparation of RTME and identifying the possible phytochemicals through GC-MS analysis. The anti-cancer potential of RTME was executed throughin-vitrocytotoxicity assay, clonogenic assay, wound healing assay, ROS generation assay, cell cycle arrest, apoptotic nuclear morphology study, cellular apoptosis study, mitochondrial membrane potential (MMP) alteration study, protein and gene expressions alteration study. Apart from this, toxicological status andin-silicomolecular docking studies were also conducted.ResultsFrom this study, it was obvious that several phytochemicals within RTME have the potential to act as anti-cancerous agents. RTME was found to exhibit significantin-vitrocytotoxicity along with a reduction in colony formation and inhibition of cell migratory potential in MDA-MB-231 cells. RTME also induced intracellular ROS, promoted G0/G1 cell cycle arrest, caused mitochondrial membrane potential (MMP) alteration, and promoted cell death. From the pro- and anti-apoptotic marker study through the western blot and the qRT-PCR analysis, it was revealed that RTME promoted the intrinsic pathway of apoptosis. Furthermore, blood parameters and histological analysis revealed that RTME doesn’t exhibit any toxic effect on female Balb/C mice. Finally, anin-silicomolecular docking study revealed that the three identified lead phytochemicals in RTME show strong receptor-ligand interactions with the anti-apoptotic Bcl-2 and give a clue to the possible molecular mechanism of the RTME extract.ConclusionFrom the findings, it was concluded that RTME has a significant therapeutic potential against TNBC which could be an alternative option for anti-cancer drug development.Graphical AbstractHighlightsPreparation of methanolic extract ofRuellia tuberosaL. flower,Identification of phytochemicals from the methanolic extract ofRuellia tuberosaL. flower,Methanolic extract ofRuellia tuberosaL. (RTME) flower exhibited significant anti-cancer potential in triple-negative breast cancer (TNBC) cells, MDA-MB-231 through induction of intracellular ROS, G0/G1 cell cycle arrest, and apoptosis,Toxicological assessments of RTME on female Balb/C mice,In-silicoassessments of lead phytochemicals with the target anti-apoptotic protein, bcl-2
Holding glycolysis in check though Alox15 activity is required for macrophage M2 commitment and function in tissue repair and anti-helminth immunity
Authors: Doolan R. , Moyat M. , Coakley G. , Wickramasinghe L. , Daunt C. , Volpe B.. , Henkel F. , Trefzer V. , Ubags N. , Butler A. , Chatzis R. , Marsland B. , Smith A. , Deveson Lucas D. , McGowan E.N.S. , Binger K.J. , Esser-von-Bieren J. , Bouchery T. , Harris N. 
Published: March 2024

AbstractMacrophage polarization by type-2 cytokines is central to anti-helminth immunity and tissue repair. While some hallmark changes in macrophages are well-characterized and associated with protection against helminths, it is still unclear how macrophages exert their anti-helminth effects. In this context, we investigated Arachidonate 15-lipoxygenase (Alox15), a lipoxygenase well known for its role in macrophage polarization in the context of metabolic diseases, and a hallmark of type-2 macrophage (M2) human polarization. We show that in the absence of Alox15, M2 cannot trap and kill helminths. Surprisingly, expression of M2 markers was normal despite a loss of function. Instead, we found a concomitant increase in pro-inflammatory responses due to an uncontrolled activation of glycolysis. We further show that activation of Peroxisome proliferator-activated receptor-delta (PPAR-δ) by lipids downstream of Docosapentaenoic acid (DPA) can restore normal glycolysis control, highlighting a novel role for lipids in the fine-tuning of the metabolic support required for optimal macrophage polarization.