bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid and Stimulus-Specific Deviance Detection in the Human Inferior Colliculus
Authors: Wetekam Johannes , Gotta Nell , López-Jury Luciana , Hechavarría Julio , Kössl Manfred 
Published: June 2024

AbstractAuditory deviance detection, the neural process by which unexpected stimuli are identified within repetitive acoustic environments, is crucial for survival. While this phenomenon has been extensively studied in the cortex, recent evidence indicates that it also occurs in subcortical regions, including the inferior colliculus (IC). However, compared to animal studies, research on subcortical deviance detection in humans is often constrained by methodological limitations, leaving several important questions unanswered. This study aims to overcome some of these limitations by employing auditory brainstem responses (ABRs) to investigate the earliest neural correlates of deviance detection in humans, with a focus on the IC. We presented healthy participants of either sex with low- and high-frequency chirps in an oddball paradigm and observed significant deviance detection effects in the ABR, specifically when low-frequency chirps were used as deviants within a context of high-frequency standards. These effects manifested as larger and faster ABRs to deviant stimuli, with the strongest responses occurring at higher stimulation rates. Our findings suggest that the human IC exhibits rapid, stimulus-specific deviance detection with differential modulation of response amplitude and latency. The data indicate that the temporal dynamics of novelty detection in humans align well with the data reported in animals, helping to bridge the gap between animal and human research. By uncovering previously unknown characteristics of subcortical deviance detection in humans, this study highlights the value of ABR recordings with excellent temporal resolution in investigating subcortical deviance detection processes.Significance statementAuditory deviance detection enables the brain to identify unexpected stimuli in a repetitive environment, but its subcortical mechanisms in humans remain comparatively underexplored. Using auditory brainstem responses (ABRs), our study reveals two key findings about deviance detection in the human inferior colliculus (IC). First, we show subcortical deviance detection at latencies under 10 ms, bridging a longstanding gap between human and animal research. Second, deviance detection in the IC is rapid, emerging within three or fewer standard repetitions, with differential modulation of ABR amplitude and latency. These findings improve our understanding of the temporal dynamics of auditory processing in the human IC and highlight the value of ABR recordings in studying subcortical deviance detection mechanisms.
Hyperporous encapsulation of microbes for whole cell biocatalysis and biomanufacturing
Authors: Zhang Jingyi , Chang Keziah , Tay Joyce , Tiong Elaine , Heng Elena , Seah Theresa , Lim Yi Wee , Peh Guangrong , Lim Yee Hwee , Wong Fong Tian , Beh Cyrus W. 
Published: June 2024

AbstractCompared to traditional synthetic chemical processes, biocatalysts offer a more sustainable and eco-friendly approach to producing complex molecules. In particular, whole-cell biocatalysts boast numerous advantages, including scalable, self-containing co-factor recycling systems, the use of cost-effective raw materials, and reduced purification costs. However, challenges arise when working with microbial consortia for biotransformation cascades. Our encapsulation strategy addresses these challenges by controlling microbial cell populations through physical constraints, offering a promising approach in biomanufacturing.In this work, we describe the immobilization of cells in a hyper-porous hydrogel block, which provides ample nutrient access while simplifying media changes. We encapsulatedE. colicells in a hydrogel matrix with suitable mechanical properties, effectively limiting their proliferation while sustaining recombinant GFP production. Furthermore, we successfully maintained different microbial strains spatially in a single porous hydrogel block for at least 10 days, demonstrating the potential of this method for achieving stable co-culture. Finally, we demonstrated the application of immobilizedE. colifor co-culture fermentation. The immobilization ofE. coliheterologously expressing RadH halogenase significantly improved the efficiency of genistein halogenation in a co-culture with genistein-producingStreptomycescompared to its non-immobilized counterpart.
Rituximab-IgG2 is a phagocytic enhancer in antibody-based immunotherapy of B-cell lymphoma by altering CD47 expression
Authors: Nguyen Oanh T.P. , Lara Sandra , Ferro Giovanni , Peipp Matthias , Kleinau Sandra 
Published: June 2024

AbstractAntibody-dependent phagocytosis (ADP) by monocytes and macrophages contributes significantly to the efficacy of many therapeutic monoclonal antibodies (mAbs), including anti-CD20 rituximab (RTX) targeting CD20+B-cell non-Hodgkin lymphomas (NHL). However, ADP is constrained by various immune checkpoints, notably the anti-phagocytic CD47 molecule, necessitating strategies to overcome this resistance.The IgG2 isotype of RTX induces CD20-mediated apoptosis in B-cell lymphoma cells, and significantly enhances Fc receptor-mediated phagocytosis when used in combination with RTX-IgG1 or RTX-IgG3 mAbs, as previously described. Here, we report that the apoptotic effect of RTX-IgG2 on lymphoma cells contributes to changes in the tumor cell’s CD47 profile by reducing its overall expression and altering its surface distribution. Furthermore, when RTX-IgG2 is combined with other lymphoma-targeting mAbs, such as anti-PD-L1 or anti-CD59, it significantly enhances the ADP of lymphoma cells compared to single mAb treatment.In summary, RTX-IgG2 acts as a potent phagocytic enhancer by promoting Fc-receptor mediated phagocytosis through apoptosis and reduction of CD47 in malignant CD20+B-cells. RTX-IgG2 represents a valuable therapeutic component in enhancing the effectiveness of different mAbs targeting B-cell NHL.
Highly-sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies
Authors: Groen Kevin , Kuratli Roger , Vasou Andri , Huber Michael , Hughes David J. , Hale Benjamin G. 
Published: June 2024

AbstractInterferons (IFNs) are a critical component of innate immune defenses and limit viral disease severity. To advance studies on IFNs and their neutralization by pathogenic autoantibodies, we generated a Renilla luciferase-based reporter cell line capable of detecting the activities of IFN-Is, IFN-II, and IFN-IIIs. The reporter cell line exhibits a 125-to 2000-fold higher sensitivity to IFNs than a commonly-used alternative biological reporter system, and allows for a rapid and simple live-cell workflow for detecting low titer amounts of neutralizing anti-IFN antibodies.
TheDlk1-Dio3noncoding RNA cluster coordinately regulates mitochondrial respiration and chromatin structure to establish proper cell state for muscle differentiation
Authors: Pinheiro Amanda , Petty Christopher A. , Cabrera Kevin , Tost Eric P. , Gower Adam C. , Marano Madison , Leviss Ethan M. , Boberg Matthew J. , Mahendran Jawahar , Bock Payton M. , Stephens Chelsea E. , Fetterman Jessica L. , Naya Francisco J. 
Published: June 2024

AbstractThe coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprintedDlk1-Dio3noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that theDlk1-Dio3ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable muscle cell lines were generated harboring two distinct deletions in the proximal promoter region resulting in either greatly upregulated or downregulated expression of the entireDlk1-Dio3ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with altered mitochondrial respiration and genome-wide changes in chromatin accessibility and histone methylation. Global gene expression patterns and pathway analyses indicated a reprogramming of myogenic cell state creating a differentiated-like phenotype in proliferating myoblasts. Our results strongly suggest theDlk1-Dio3ncRNA locus is a nodal regulator coordinating metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage.Summary statementMuscle cell state is regulated by the imprintedDlk1-Dio3noncoding RNA locus through its coordinate control of mitochondrial activity and histone modifications.
The persistence of locally adapted polymorphisms under mutation swamping
Authors: Sakamoto Takahiro , Whiting James R. , Yeaman Samuel 
Published: June 2024

AbstractLocally adapted traits can exhibit a wide range of genetic architectures, from pronounced divergence at a few loci to small allele frequency shifts at many loci. The type of architecture that evolves depends strongly on migration rate, as weakly selected loci experience swamping and do not make stable contributions to divergence. Simulations from previous studies showed that even when mutations are strongly selected and should resist migration swamping, the architecture of adaptation can collapse and become transient at high mutation rates. Here, we use an analytical two-population model to study how this “mutation swamping” phenomenon depends upon population size, strength of selection, and parameters determining mutation effects. To do this, we developed a mathematical theory based on the diffusion approximation to predict the threshold mutation rate above which swamping occurs, and find that this performs well across wide range of parameter space, based on comparisons with individual-based simulations. The mutation swamping threshold depends most strongly on the average effect size of mutations, and weakly on the strength of selection, but is only minimally affected by population size. Across a wide range of parameter space, we observe that mutation swamping occurs when the trait-wide mutation rate is 10−3–10−2, suggesting that this phenomenon is potentially relevant to complex traits with a large mutational target. On the other hand, based on the apparent stability of genetic architecture in many classic examples of local adaptation, our theory suggests that per-trait mutation rates are often relatively low.
AAV-mediated gene transfer of WDR45 corrects neurologic deficits in the mouse model of beta-propeller protein-associated neurodegeneration
Authors: Carisi Maria Carla , Shamber Claire , Bishop Martha , Sangster Madison , Chandrachud Uma , Meyerink Brandon , Pilaz Louis Jean , Grishchuk Yulia 
Published: June 2024

AbstractBeta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodegenerative disease caused by loss-of-function mutations in theWDR45gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurologic decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia.WDR45encodes β-propeller-shaped scaffold protein, or WIPI4, which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurologic decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurologic disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, WDR45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue inWDR45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurologic symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether AAV-mediated CNS-targeted gene transfer ofWDR45can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of humanWDR45transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers in the brain tissue. This data demonstrates thatWDR45gene transfer can be a promising therapeutic strategy for BPAN.
Drugs targeting microRNAs that regulate DNA damage sensing and repair mechanisms:A computational drug discovery approach
Authors: Ravindranath S.B , Vratin S. , Lakshmi B.S. , Ramirez D.C. , Gomez Mejiba S.E. 
Published: June 2024

ABSTRACTDNA damage-sensing (DDS) and DNA damage-repair (DDR) mechanisms are essential for the fidelity of genetic information transmission. Failure to accomplish an effective DDS/DDR mechanism can lead to cell death or otherwise to cell transformation and cancer development. microRNAs (miRs) are short noncoding RNAs that primarily function as micromanagers of gene expression. Herein, we aimed to investigate the links between miRs and the translation of specific mRNAs encoding proteins involved in genomic DDS and DDR and to screen drugs that have high binding affinity to the selected miRs, which may serve as cancer therapeutics. To accomplish these aims, we used a variety of computational methods spanning data analysis, molecular modeling, and simulation tools (i.e.,PyRx, Biopython, ViennaRNA, RNAComposer, AutoDock Vina, OpenBabel, PyMOL, Discovery Studio, MarvinSketch). The genes and miRNAs involved in the DDS and DDR mechanisms were retrieved from either the literature or various online databases (e.g.,miRDB). miR data were further cleaned and prepared using scripts, and various libraries were used to obtain their 3-D structures. Genes interacting with miRs were enriched based on multiple database annotations using Enrichr KG. Then, we used docking analyses to virtually screen compounds to serve as ligands for the miRs. Finally, we generated gene-disease-miR-drug networks to study the linkages between the compounds and miR molecules under investigation. For the first time, we were able to identify five compounds that could be repurposed for downregulating miRs that are linked to inhibition of translation of mRNA involved in the DDS and DDR processes. The gathered candidate drugs can be useful for preventing cell transformation and cancer development.
Amniotic fluid stem cell extracellular vesicles promote lung development via TGF-beta modulation in a fetal rat model of oligohydramnios
Authors: Doktor Fabian , Figueira Rebeca Lopes , Fortuna Victoria , Biouss George , Stasiewicz Kaya , Obed Mikal , Khalaj Kasra , Antounians Lina , Zani Augusto 
Published: June 2024

AbstractOligohydramnios (decreased amniotic fluid volume for gestational age) is a severe condition associated with high morbidity and mortality mainly due to fetal pulmonary hypoplasia. Currently, there are limited treatment options to promote fetal lung development. Administration of stem cells and their derivates have shown promising regenerative properties for several fetal and neonatal diseases related to arrested lung development. Herein, we first characterized pulmonary hypoplasia secondary to oligohydramnios in a surgical rat model. Experimental induction of oligohydramnios led to impaired lung growth, branching morphogenesis (fewer airspaces with decreasedFgf10,Nrp1,Ctnnb1expression), proximal/distal progenitor cell patterning (decreased Sox2 and Sox9 expression), and TGF-β signaling. We then tested antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC- EVs). In oligohydramnios lungs, AFSC-EV administration improved lung branching morphogenesis and airway progenitor cell patterning at least in part through the release of miR-93-5p. Our experiments suggest that AFSC-EV miR-93-5p blocked SMAD 7, resulting in upregulation of pSMAD2/3 and restoration of TGF-β signaling. Conversely, oligohydramnios lungs treated with antagomir 93-5p transfected AFSC- EVs had decreased branching morphogenesis and TGF-β signaling. This is the first study reporting that antenatal administration of stem cell derivatives could be a potential therapy to rescue lung development in fetuses with oligohydramnios.HighlightsPulmonary hypoplasia secondary to oligohydramnios in fetal rats is characterized by impaired TGF-β signaling.AFSC-EV administration improves fetal lung branching morphogenesis and airway progenitor cell patterning.AFSC-EV effects are mediated at least in part via modulation of TGF-β signaling by the release of miR-93-5p from AFSC-EVs.
Designing a novel Scaffold-Based Multi-Epitope Vaccine to Combat Melioidosis Caused by Burkholderia pseudomallei: AnIn-silicoand Immunoinformatics approach
Authors: Rahman Shakilur , Das Ardhendu , Das Amit Kumar , Hazra Ditipriya , Roychowdhury Amlan 
Published: June 2024

ABSTRACTBurkholderia pseudomallei, the gram-negative bacteria causing melioidosis, is becoming a serious threat to healthcare settings. In recent years,B. pseudomalleihas been identified as an emerging and significant etiological agent responsible for localized pyogenic infections primarily observed in India and South Asia. At present, no vaccine against melioidosis is available in the treatment system. This study has undertaken anin-silicoreverse vaccinology approach to design a novel multi-epitope vaccine for treatingB. pseudomallei-mediated infections. B-cell and T-cell epitopes have been predicted and stitched to develop a multi-epitope vaccine. The predicted vaccine is found to be non-toxic, non-allergic, and immunogenic in nature. Immune simulation results indicate that the designed vaccine can generate an immune response resembling a real-life scenario. The 610 amino-acid long vaccine construct has been codon-optimized and could be cloned in the E. coli K12 system. These findings from this immunoinformatics study offer a foundation for developing a tailored, safe, and potent vaccine targetingB. pseudomallei.
Emergence of alternative stable states in microbial communities undergoing horizontal gene transfer
Authors: Hong Juken , Xue Wenzhi , Wang Teng 
Published: June 2024

AbstractMicrobial communities living in the same environment often display alternative stable states, each characterized by a unique composition of species. Understanding the origin and determinants of microbiome multistability has broad implications in environments, human health and microbiome engineering. However, despite its conceptual importance, how multistability emerges in complex communities remains largely unknown. Here, we focused on the role of horizontal gene transfer (HGT), one important aspect mostly overlooked in previous studies, on the stability landscape of microbial populations. Combining mathematical modeling and numerical simulations, we demonstrate that, when mobile genes only affect bacterial growth rates, increasing HGT rate in general promote the emergence of alternative stable states in complex microbiota. We further extend our analysis to scenarios where HGT changes interspecies interactions, microbial communities are subjected to strong environmental selections and microbes live in metacommunities consisting of multiple local habitats. We also discuss the role of different mechanisms, including interspecies interaction strength, the growth rate effects of MGEs, MGE epistasis and microbial death rates in shaping the multistability of microbial communities undergoing HGT. These results reveal how different dynamic processes collectively shape community multistability and diversity. Our results provide key insights for the predictive control and engineering of complex microbiota.
Optimizing Cost-Effective Gene Expression Phenotyping Approaches in Cattle Using 3′ mRNA Sequencing
Authors: Mohamed Ruwaa I. , Ault-Seay Taylor B. , Moisa Sonia , Beever Jonathan , Ríus Agustín G. , Rowan Troy 
Published: June 2024

AbstractBackgroundGenetic and genomic selection programs require large numbers of phenotypes observed for animals in shared environments. Direct measurements of phenotypes like meat quality, methane emission, and disease susceptibility are difficult and expensive to measure at scale but are critically important to livestock production. Our work leans on our understanding of the “Central Dogma” of molecular genetics to leverage molecular intermediates as cheaply-measured proxies of organism-level phenotypes. The rapidly declining cost of next-generation sequencing presents opportunities for population-level molecular phenotyping. While the cost of whole transcriptome sequencing has declined recently, its required sequencing depth still makes it an expensive choice for wide-scale molecular phenotyping. We aim to optimize 3′ mRNA sequencing (3′ mRNA-Seq) approaches for collecting cost-effective proxy molecular phenotypes for cattle from easy-to-collect tissue samples (i.e., whole blood). We used matched 3′ mRNA-Seq samples for 15 Holstein male calves in a heat stress trail to identify the 1) best library preparation kit (Takara SMART-Seq v4 3′ DE and Lexogen QuantSeq) and 2) optimal sequencing depth (0.5 to 20 million reads/sample) to capture gene expression phenotypes most cost-effectively.ResultsTakara SMART-Seq v4 3′ DE outperformed Lexogen QuantSeq libraries across all metrics: number of quality reads, expressed genes, informative genes, differentially expressed genes, and 3′ biased intragenic variants. Serial downsampling analyses identified that as few as 8.0 million reads per sample could effectively capture most of the between-sample variation in gene expression. However, progressively more reads did provide marginal increases in recall across metrics. These 3′ mRNA-Seq reads can also capture animal genotypes that could be used as the basis for downstream imputation. The 10 million read downsampled groups called an average of 104,386 SNPs and 20,131 INDELs, many of which segregate at moderate minor allele frequencies in the population.ConclusionThis work demonstrates that 3′ mRNA-Seq with Takara SMART-Seq v4 3′ DE can provide an incredibly cost-effective (<$25/sample) approach to quantifying molecular phenotypes (gene expression) while discovering sufficient variation for use in genotype imputation. Ongoing work is evaluating the accuracy of imputation and the ability of much larger datasets to predict individual animal phenotypes.