bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age- and sex-related changes in motor functions: A Comprehensive Assessment and Component Analysis
Authors: Wunderle Veronika , Kuzu Taylan D. , Tscherpel Caroline , Fink Gereon R. , Grefkes Christian , Weiss Peter H. 
Published: April 2024

AbstractAge-related motor impairments often cause caregiver dependency or even hospitalization. However, comprehensive investigations of the different motor abilities and the changes thereof across the adult lifespan remain sparse.We, therefore, extensively assessed essential basic and complex motor functions in 444 healthy adults covering a wide age range (range 21 to 88 years). Basic motor functions, here defined as simple isolated single or repetitive movements in one direction, were assessed by means of maximum grip strength (GS) and maximum finger-tapping frequency (FTF). Complex motor functions, comprising composite sequential movements involving both proximal and distal joints/muscle groups, were evaluated with the Action Research Arm Test (ARAT), the Jebsen-Taylor Hand Function Test (JTT), and the Purdue Pegboard Test.Men achieved higher scores than women concerning GS and FTF, whereas women stacked more pins per time than men during the Purdue Pegboard Test. There was no significant sex effect regarding JTT. We observed a significant but task-specific reduction of basic and complex motor performance scores across the adult lifespan. Linear regression analyses significantly predicted the participants’ ages based on motor performance scores (R2= .502). Of note, the ratio between the left- and right-hand performance remained stable across ages for all tests. Principal Component Analysis (PCA) revealed threemotor componentsacross all tests that represented dexterity, force, and speed. These components were consistently present in young (21 – 40 years), middle-aged (41 – 60 years), and older (61 – 88 years) adults, as well as in women and men. Based on the threemotor components, K-means clustering analysis differentiated high- and low-performing participants across the adult life span.The rich motor data set of 444 healthy participants revealed age- and sex-dependent changes in essential basic and complex motor functions. Notably, the comprehensive assessment allowed for generating robustmotor componentsacross the adult lifespan. Our data may serve as a reference for future studies of healthy subjects and patients with motor deficits. Moreover, these findings emphasize the importance of comprehensively assessing different motor functions, including dexterity, force, and speed, to characterize human motor abilities and their age-related decline.
A HYBRID INTEGRO-DIFFERENTIAL EQUATION AND NETWORK BASED MODEL OF EPIDEMICS
Authors: Duclos Ted , Reichert Tom 
Published: April 2024

AbstractA closed form solution of the full Kermack and McKendrick integro-differential equations (Kermack and McKendrick 1927), called the KMES, is presented and verified. The solution is derived by combining network concepts with the integro-differential equations.This solution has two parameters: one describing disease transmissibility and a second characterizing population interactions. The verified solution leads directly to useful, previously unknown, analytical expressions which characterize an epidemic. These include novel expressions for the effective reproduction number, time to peak in new infections, and the final size.Using COVID -19 data from six countries, the transmissibility parameter is estimated and subsequently used to estimate the normalized contagiousness of an individual, a close approximation to viral shedding measured in infected persons. The population interaction parameter is estimated using the Google Residential Mobility Measure. With these parameter estimations, the KMES accurately projects case data from the COVID-19 pandemic in six countries over a 60-day period with R2values above 0.85.As to performance over longer periods, the KMES projects the Covid-19 total case data from the United States 21 days in advance over an 18-month period with a Mean Absolute Percentage Error of 4.1%. The KMES also accurately identifies the beginnings and peaks of outbreaks within multi month periods in case data from 4 countries.
α-Aminooxyacetic acid derivatives acting as pro-drugs againstMycobacterium tuberculosis
Authors: Vill Kristin , van Geelen Lasse , Michel Oliver , Kiffe-Delf Anna-Lene , Berger Alexander , Podlesainski David , Stenzel Katharina , Kovacic Filip , Lungerich Beate , Burkhardt Björn , Crooks Taylor A. , Howe Michael D. , Ostrer Lev , Jia Ziyi , Ioerger Thomas R. , Kaschani Farnusch , Kaiser Markus , Baughn Anthony D. , Kurz Thomas , Kalscheuer Rainer 
Published: April 2024

ABSTRACTTuberculosis (TB), a significant cause of mortality globally, continues to claim 1.5 million lives each year. Despite recent advances in TB management, the emergence of multidrug-resistant strains of TB is exacerbating the treatment of TB. Therefore, there is an immediate necessity to uncover new anti-TB compounds with unprecedented targets. This study introduces novel antimycobacterial molecules that are based on α-aminooxyacetic acid core structures. The lead compounds KSK-104 and KSK-106 displayed potent sub-micromolar antibacterial activity againstMycobacterium tuberculosisH37Rv and XDR clinical isolates, while exhibiting virtually no cytotoxicity against various human cells. Complementation experiments following whole genome sequencing of spontaneously resistant mutants generated against these bactericidal compounds suggested that they are pro-drugs that are intracellularly hydrolyzed by one or both of two specific amidohydrolases, Rv0552 and AmiC. Furthermore, proteomic and transcriptomic analyses of stressed cells and genetic interaction mapping employing transposon insertion sequencing suggest a “dirty drug” mechanism that involves the simultaneous attack of the various drug cleavage products on multiple intracellular targets. Our results suggest a primary role of the pyridoxal 5’-phosphate (PLP) synthesis and salvage pathway and/or PLP-dependent enzymes, the oxidative stress network, and the largely uncharacterizedRv3092c-Rv3095gene cluster in the mode of action.
Massively parallel identification of single-cell immunophenotypes
Authors: Cienciala Martin , Alvarez Laura , Berne Laura , Chena David , Fikar Pavel , Holubova Monika , Kasl Hynek , Lysak Daniel , Luo Mona , Novackova Zuzana , Ordonez Sheyla , Sramkova Zuzana , Vlas Tomas , Georgiev Daniel 
Published: April 2024

AbstractTranslating insights from single-cell analysis into actionable indicators of health and disease requires large-scale confirmatory studies. We introduce biocytometry, a novel method utilizing engineered bioparticles for multiparametric immunophenotyping in suspension, enabling simultaneous measurement across thousands of assays with single-cell sensitivity and a wide dynamic range (1 to 1,000 target cells/sample). The technical validation of biocytometry revealed strong alignment with established technologies (mean bias = 0.25%, LoA = −1.83% to 2.33%) for low-sensitivity settings. Biocytometry excelled in high-sensitivity settings, consistently showcasing superior sensitivity and specificity (LoB = 0), irrespective of the sample type. By employing multiparametric target cell identification, we harnessed the homogeneous assay workflow to discern cell-specific apoptosis in mixed cell cultures. Potential applications include monitoring rare premalignant subpopulations in indications such as smoldering multiple myeloma (SMM), enhancing the detection of circulating tumor cells (CTCs), advancing pharmacokinetic assessments in chimeric antigen receptor (CAR) T-cell therapies, and improving the accuracy of minimal residual disease (MRD) evaluations. Additionally, the high throughput and cell-specific readout capabilities might provide substantial value in drug development, especially for the analysis of complex sample matrices, such as primary cell cultures and organoids.
Transcriptional cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription
Authors: Goldberg Dana , Buchshtab Nufar , Charni-Natan Meital , Goldstein Ido 
Published: April 2024

AbstractBackground & AimsDuring fasting, bodily homeostasis is maintained due to hepatic production of glucose (gluconeogenesis) and ketone bodies (ketogenesis). The main hormones governing hepatic fuel production are glucagon and glucocorticoids that initiate transcriptional programs aimed at supporting gluconeogenesis and ketogenesis.MethodsUsing primary mouse hepatocytes as an ex vivo model, we employed transcriptomic analysis (RNA-seq), genome-wide profiling of enhancer dynamics (ChIP-seq), perturbation experiments (inhibitors, shRNA), hepatic glucose production measurements and computational analyses.ResultsWe found that in addition to the known metabolic genes transcriptionally induced by glucagon and glucocorticoids, these hormones induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Upon activation by glucocorticoids, the glucocorticoid receptor (GR) induced the genes encoding two TFs: CCAAT/enhancer-binding protein beta (C/EBPβ) and peroxisome proliferator-activated receptor alpha (PPARα). We found that C/EBPβ mainly serves as an amplifier of hormone-induced gene programs in hepatocytes. C/EBPβ augmented gluconeogenic gene expression and hepatic glucose production. Conversely, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. The cascade led to synergistic induction of ketogenic genes which is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers were proximal to ketogenic genes, enriched for the PPARα response element and showed increased PPARα binding.ConclusionThis study reveals abundant transcriptional cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the primary gluconeogenic transcriptional program and the induction of a secondary gene program aimed at enhancing ketogenesis.
Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15
Authors: Ebenwaldner Carmen , García Saura Antonio Ginés , Ekström Simon , Bernfur Katja , Schüler Herwig 
Published: April 2024

AbstractPARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship with PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization to stress granules point to functions in the regulation of translation. PARP15 also modifies itself and other proteins using its ADP-ribosyltransferase (ART) domain and contains two macrodomains predicted to bind ADP-ribosyl on targets. We used biochemical and biophysical analysis to study how the ADP-ribosyltransferase activity of PARP15 is regulated. Here we show that the catalytic domain of PARP15 dimerizes with mid-nanomolar affinity, forming the same dimer interface in solution that had already been captured by X-ray crystallography of the domain. Furthermore, we show that the formation of dimers is a prerequisite for catalytic activity and that monomeric mutant variants of the domain were catalytically inactive. Our findings suggest a regulatory mechanism by which dimerization is linked to either target engagement or placement of a catalytic residue, rather than NAD+ co-substrate binding, and by which the two protomers of the dimer operate independent of one another. Together, our results uncover a novel mechanism of regulation in a PARP family enzyme, which might inspire new avenues of pharmacological intervention.
Mapping the Human Proteome with Physical Access to DNA
Authors: Trendel Jakob , Trendel Simon , Sha Shuyao , Küster Bernhard 
Published: April 2024

AbstractIn a human cell, DNA is packed in histones, RNA, and chromatin-associated proteins, forming a cohesive gel. At any given moment, only a specific subset of the proteome has physical access to the DNA and organizes its structure, transcription, replication, repair and other molecular functions essential to the way the genome is read and maintained. We have developed a ‘zero-distance’ photo-crosslinking approach to quantify proteins in direct contact with DNA in living cells. Collecting DNA interactomes from human breast cancer cells, we present an atlas of over one thousand proteins with physical access to DNA, and hundreds of peptide-nucleotide crosslinks pinpointing protein-DNA interfaces with single amino-acid resolution. Differential comparisons of DNA interactomes from cells undergoing treatment with estrogen or genotoxic chemotherapy recapitulated the recruitment of key transcription factors and DNA damage proteins. This opens a direct way to explore genomic regulation in a hypothesis-free manner, applicable to many organisms and systems.
Distinct genetic pathways to music enjoyment
Authors: Bignardi Giacomo , Wesseldijk Laura W. , Mas-Herrero Ernest , Zatorre Robert. J. , Ullén Fredrik , Fisher Simon E. , Mosing Miriam A. 
Published: April 2024

AbstractHumans engage with music for various reasons that range from emotional regulation and relaxation to social bonding. While there are large inter-individual differences in how much humans enjoy music, little is known about the origins of those differences. Here, we disentangled the genetic factors underlying such variation. We collected behavioural data on several facets of music reward sensitivity, music perceptual ability, and general reward sensitivity from a large sample of Swedish twins (N= 9,169). We found that genetic factors substantially explain variance in music reward sensitivity above and beyond genetic influences shared with music perception and general reward sensitivity. Furthermore, multivariate analyses showed that genetic influences on the different facets of music reward sensitivity are partly distinct, uncovering distinct pathways to music enjoyment and different patterns of genetic associations with objectively assessed music perceptual abilities. These results paint a complex picture in which partially distinct sources of genetic variation contribute to different aspects of musical enjoyment and open up new possibilities for using inter-individual differences to gain insights into the biology of a key aspect of human behaviour.
A conserved phenylalanine motif among Teleost fish provides insight for improving electromagnetic perception
Authors: Ricker Brianna , Castellanos Franco E. Alejandro , de los Campos Gustavo , Pelled Galit , Gilad Assaf A. 
Published: April 2024

AbstractMagnetoreceptive biology as a field remains relatively obscure; compared to the breadth of species believed to sense magnetic fields, it remains under-studied. Here, we present grounds for the expansion of magnetoreception studies among Teleosts. We begin with the electromagnetic perceptive gene (EPG) fromKryptopterus vitreolusand expand to identify 72 Teleosts with homologous proteins containing a conserved three-phenylalanine (3F) motif. Phylogenetic analysis provides insight as to how EPG may have evolved over time, and indicates that certain clades may have experienced a loss of function driven by different fitness pressures. One potential factor is water type with freshwater fish significantly more likely to possess the functional motif version (FFF), and saltwater fish to have the non-functional variant (FXF). It was also revealed that when the 3F motif from the homolog ofBrachyhypopomus gauderio(B.g.) is inserted into EPG – EPG(B.g.) – the response (as indicated by increased intracellular calcium) is faster. This indicates that EPG has the potential to be engineered to improve upon its response and increase its utility to be used as a controller for specific outcomes.
SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment
Authors: Pereyra Guadalupe , Mateo María Inés , Martin-Bermejo María Jesús , Miaja Pablo , Klaassen Remco , Gruart Agnès , Rueda-Carrasco Javier , Fernández-Rodrigo Alba , López-Merino Esperanza , Esteve Pilar , Esteban José A. , Smit August B. , Delgado-García José M. , Bovolenta Paola 
Published: April 2024

AbstractDecreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimer’s disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpressSfrp1in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.
Disinhibition enables vocal repertoire expansion after a critical period
Authors: Heim Fabian , Mendoza Ezequiel , Koparkar Avani , Vallentin Daniela 
Published: April 2024

ABSTRACTThe efficiency of motor skill acquisition is age-dependent, making it increasingly challenging to learn complex maneuvers later in life1–6. Zebra finches, for instance, acquire a complex vocal motor program during a developmental critical period7,8after which the learned song is essentially impervious to modification9. Although inhibitory interneurons are implicated in critical period closure10–13, it is unclear whether manipulating them can reopen heightened motor plasticity windows. Using pharmacology and a novel cell-type specific optogenetic approach, we manipulated inhibitory neuron activity in a premotor area of adult zebra finches beyond their critical period. When exposed to auditory stimulation in the form of novel song, manipulated birds added new vocal syllables to their stable song sequence. By lifting inhibition in a premotor area during sensory experience, we reintroduced vocal plasticity, promoting an expansion of the syllable repertoire without compromising pre-existing song production. Our findings provide insights into motor skill learning capacities, offer potential for motor recovery after injury, and suggest avenues for treating neurodevelopmental disorders involving inhibitory dysfunctions.
Detailed phenotyping ofTbr1-2A-CreERknock-in mice demonstrates significant impacts on TBR1 protein levels and axon development
Authors: Co Marissa , O’Brien Grace K. , Wright Kevin M. , O’Roak Brian J. 
Published: April 2024

ABSTRACTSpatiotemporal control of Cre-mediated recombination has been an invaluable tool for understanding key developmental processes. For example, knock-in ofCreinto cell type marker gene loci drivesCreexpression under endogenous promoter and enhancer sequences, greatly facilitating the study of diverse neuronal subtypes in the cerebral cortex. However, insertion of exogenous DNA into the genome can have unintended effects on local gene regulation or protein function that must be carefully considered. Here, we analyze a recently generatedTbr1-2A-CreERknock-in mouse line, where a2A-CreERcassette was inserted in-frame just before the stop codon of the transcription factor geneTbr1. HeterozygousTBR1mutations in humans and mice are known to cause autism or autism-like behavioral phenotypes accompanied by structural brain malformations, most frequently a reduction of the anterior commissure. Thus, it is critical for modified versions ofTbr1to exhibit true wild-type-like activity. We evaluated theTbr1-2A-CreERallele for its potential impact onTbr1function and complementation toTbr1loss-of-function alleles. In mice with one copy of theTbr1-2A-CreERallele, we identified reduction of TBR1 protein in early postnatal cortex along with thinning of the anterior commissure, suggesting hypersensitivity of this structure to TBR1 dosage. ComparingTbr1-2A-CreERandTbr1-null heterozygous and homozygous mice toTbr1-null complementation crosses showed reductions of TBR1 dosage ranging from 28.4% to 95.9%. Using these combinatorial genotypes, we found that low levels of TBR1 protein (∼16%) are sufficient to establish cortical layer positioning, while greater levels (>50%) are required for normal suppression of layer 5 identity. In total, these results strongly support the conclusion thatTbr1-2A-CreERis a hypomorphic allele. We advise caution when interpreting experiments using this allele, such as transcriptomic studies, considering the sensitivity of various corticogenic processes to TBR1 dosage and the association of heterozygousTBR1mutations with complex neurodevelopmental disorders.
The Flexible, Versatile and Fast GreGT Platform of Fully Deleted Helper-Virus Independent Adenoviral Vectors
Authors: Qi Yan , Zhang Xianghua , Cull Janae Wheeler , Wall Charles , Maslanik William , Staerz Uwe D. 
Published: April 2024

ABSTRACTGene transfer (GT) vectors have diverse applications. They have been used to restore cellular activities by reconstituting normal cellular functions, by delivering therapeutic compounds, and by priming immune responses as genetic vaccines. Viruses, nature’s gene delivery vehicles, have formed the basis of most GT vectors. The biology of the underlying virus may, however, hamper their use. For instance, retroviral vectors with their ability to integrate into the genome, may cause malignant transformations. Vectors designed as minor variants of the relatively benign, yet complex adenovirus (Ad) excite vigorous immune responses, thus limiting their therapeutic effects. Deleting Ad vectors of all endogenous Ad genes brought their beneficial features to the front, such as their ability to transduce cells of many types with high efficiency and to deliver large genetic payloads. Earlier production schemes of fully deleted Ad (fdAd) vectors depended on helper virus constructs to deliver the vector production informationin trans. They suffered from contaminations with the helper virus or the recombination of replication competent adenoviruses (RCA). We previously developed a novel transfection-based helper virus-independent Ad vector encapsidation technology that avoided these pitfalls. It was built on a vector genome and a vector packaging module. We have now optimized our approach into the GreGTplug-and-playplatform so that a new vector can be delivered in about four weeks. The GreGT system is built upon a set of base vector genome modules that can be quickly loaded with a new application, and a set of packaging modules that allow their encapsidation into capsids of different Ad serotypes. As both components can be freely combined, the GreGT platform is endowed with high degrees of flexibility and versatility. Finally, the deletion of all endogenous Ad genes from the vector genome limits the interference by anti-Ad immune responses. It also increases the genetic payload capacity to levels unique to this system.