bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Updated Mouse Universal Genotyping Array Bioinformatic Pipeline Improves Genetic QC in Laboratory Mice
Authors: Blanchard Matthew W , Sigmon John Sebastian , Brennan Jennifer , Ahulamibe Chidima , Allen Michelle E , Baric Ralph S , Bell Timothy A , Farrington Joeseph , Ciavatta Dominic , Cruz Cisneros Marta , Drushal Madison , Ferris Martin T , Fry Rebecca , Gaines Christiann , Gu Bin , Heise Mark T , Hodges Richard Austin , Kafri Tal , Lynch Rachel , Magnuson Terry , Miller Darla , Murphy Caroline E Y , Nguyen David Truong , Noll Kelsey E , Proulx Megan , Sassetti Chris , Shaw Ginger D , Simon Jeremy M , Smith Clare , Styblo Myrek , Tarantino Lisa , Woo Joyce , Pardo Manuel de Villena Fernando 
Published: March 2024

ABSTRACTThe MiniMUGA genotyping array is a popular tool for genetic QC of laboratory mice and genotyping of samples from most types of experimental crosses involving laboratory strains, particularly for reduced complexity crosses. The content of the production version of the MiniMUGA array is fixed; however, there is the opportunity to improve array’s performance and the associated report’s usefulness by leveraging thousands of samples genotyped since the initial description of MiniMUGA in 2020. Here we report our efforts to update and improve marker annotation, increase the number and the reliability of the consensus genotypes for inbred strains and increase the number of constructs that can reliably be detected with MiniMUGA. In addition, we have implemented key changes in the informatics pipeline to identify and quantify the contribution of specific genetic backgrounds to the makeup of a given sample, remove arbitrary thresholds, include the Y Chromosome and mitochondrial genome in the ideogram, and improve robust detection of the presence of commercially available substrains based on diagnostic alleles. Finally, we have made changes to the layout of the report, to simplify the interpretation and completeness of the analysis and added a table summarizing the ideogram. We believe that these changes will be of general interest to the mouse research community and will be instrumental in our goal of improving the rigor and reproducibility of mouse-based biomedical research.
Redox regulation by the CDSP32 thioredoxin of ATP-synthase activity and enzymatic antioxidant network inSolanum tuberosum
Authors: Rey Pascal , Henri Patricia , Alric Jean , Blanchard Laurence , Viola Stefania 
Published: March 2024

AbstractPlant thioredoxins (TRXs) form a complex family involved in numerous metabolic and signalling pathways, such as the regulation of photosynthetic metabolism in relation with light conditions. The atypical CDSP32, chloroplastic drought-induced stress protein of 32 kDa, TRX includes two TRX-fold domains, one of which has an atypical redox-active HCGPC motif, and has been initially reported to participate in responses to oxidative stress as an electron donor to peroxiredoxins and methionine sulfoxide reductases. Here, we further characterized potato lines modified forCDSP32expression to clarify the physiological roles of the TRX. Upon high salt treatments, modified lines displayed changes in the abundance and redox status of CDSP32 antioxidant partners, and exhibited sensitivity to NaHCO3, but not to NaCl. In non-stressed plants overexpressing CDSP32, a lower abundance of photosystem II PsbO and D1 subunits and ATP-synthase γ subunit was noticed. The CDSP32 co-suppressed line showed altered chlorophyllafluorescence induction and modified regulation of the plastidial ATP-synthase activity during dark/light and light/dark transitions, revealing the involvement of CDSP32 in the control of the photosynthetic machinery. In agreement with the previously reported interactionin plantabetween CDSP32 and the ATP-synthase γ subunit, our data show that CDSP32 participates in the regulation of the transthylakoid membrane potential. Consistently, modeling of protein complex 3-D structure indicates that the CDSP32 TRX constitutes a suitable partner of ATP-synthase γ subunit. We discuss the roles of CDSP32 in chloroplast redox homeostasis through the regulation of both photosynthetic activity and enzymatic antioxidant network.
Sexually dimorphic renal expression ofKlothois directed by a kidney-specific distal enhancer responsive to HNF1b
Authors: Jankowski Jakub , Lee Hye Kyung , Liu Chengyu , Wilflingseder Julia , Hennighausen Lothar 
Published: March 2024

ABSTRACTTranscription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression.Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation ofKlothois not understood. Here, we characterize two candidateKlothoenhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causingKlothoexpression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism ofKlothoas evidenced by qPCR and RNA- seq. Despite the sharp reduction ofKlothomRNA, unlike germlineKlothoknockouts, mutant mice presented normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolatedKlotholoss, especially in female E1 knockouts, retaining renoprotection despite over 80%Klothoreduction.
Dynamics of morphogen source formation in a growing tissue
Authors: Ho Richard D. J. G. , Kishi Kasumi , Majka Maciej , Kicheva Anna , Zagorski Marcin 
Published: March 2024

AbstractA tight regulation of morphogen production is key for morphogen gradient formation and thereby for reproducible and organised organ development. Although many genetic interactions involved in the establishment of morphogen production domains are known, the biophysical mechanisms of morphogen source formation are poorly understood. Here we addressed this by focusing on the morphogen Shh in the vertebrate neural tube. Shh is produced by the adjacently located notochord and by the floor plate of the neural tube. Using a data-constrained computational screen, we identified different possible mechanisms by which floor plate formation can occur, only one of which is consistent with experimental data. In this mechanism, the floor plate is established rapidly in response to Shh from the notochord and the dynamics of regulatory interactions within the neural tube. In this process, uniform activators and Shh-dependent repressors are key for establishing the floor plate size. Subsequently, the floor plate becomes insensitive to Shh and increases in size due to tissue growth, leading to scaling of the floor plate with neural tube size. In turn, this results in scaling of the Shh amplitude with tissue growth. Thus, this mechanism ensures a separation of time scales in floor plate formation, so that the floor plate domain becomes growth dependent after an initial rapid establishment phase. Our study raises the possibility that the time scale separation between specification and growth might be common strategy for scaling the morphogen gradient amplitude in growing organs. The model that we developed provides a new opportunity for quantitative studies of morphogen source formation in growing tissues.
Non-linear transcriptional responses to gradual modulation of transcription factor dosage
Authors: Domingo Júlia , Minaeva Mariia , Morris John A , Ghatan Sam , Ziosi Marcello , Sanjana Neville E , Lappalainen Tuuli 
Published: March 2024

AbstractGenomic loci associated with common traits and diseases are typically non-coding and likely impact gene expression, sometimes coinciding with rare loss-of-function variants in the target gene. However, our understanding of how gradual changes in gene dosage affect molecular, cellular, and organismal traits is currently limited. To address this gap, we induced gradual changes in gene expression of four genes using CRISPR activation and inactivation. Downstream transcriptional consequences of dosage modulation of three master trans-regulators associated with blood cell traits (GFI1B, NFE2, and MYB) were examined using targeted single-cell multimodal sequencing. We showed that guide tiling around the TSS is the most effective way to modulatecisgene expression across a wide range of fold-changes, with further effects from chromatin accessibility and histone marks that differ between the inhibition and activation systems. Our single-cell data allowed us to precisely detect subtle to large gene expression changes in dozens oftransgenes, revealing that many responses to dosage changes of these three TFs are non-linear, including non-monotonic behaviours, even when constraining the fold-changes of the master regulators to a copy number gain or loss. We found that the dosage properties are linked to gene constraint and that some of these non-linear responses are enriched for disease and GWAS genes. Overall, our study provides a straightforward and scalable method to precisely modulate gene expression and gain insights into its downstream consequences at high resolution.
ADP-dependent platelet activation is required for thrombus formation during a long-distance flight
Authors: Tourn Julie , Carminita Estelle , Crescence Lydie , Bruzzese Laurie , Adjriou Nabil , Guieu Regis , Dubois Christophe , Panicot-Dubois Laurence 
Published: March 2024

AbstractThe association between venous thromboembolism (VTE) and air travel is well documented. Prolonged exposure to reduced atmospheric pressure and low oxygen levels during flights triggers coagulation disorders, representing the primary risk factor for Deep Vein Thrombosis (DVT), surpassing immobility. In our study, we investigated how long-distance flight conditions affect VTE development in mice exposed to 6h of hypobaric hypoxia or normobaric normoxia after inferior vena cava (IVC) ligation. We observed a pro-thrombotic profile under flight-simulated conditions, characterized by larger thrombi with higher neutrophil and fibrin densities. However, no difference was observed in neutrophil extracellular traps (NETs) or fibrin-positive neutrophils in thrombi between groups, indicating that neutrophils/NETs may not be involved in DVT development during flight. Considering the elevated ADP levels observed at high altitudes, we further assessed thrombus formation in wild-type andP2RY12-deficient mice. Remarkably, thrombus formation was no longer affected by aircraft conditions inP2RY12-deficient or wild type mice treated with clopidogrel. We conclude that ADP-induced platelet activation is involved in the development of DVT during flight, suggesting that the use of P2RY12inhibitors may be of interest to prevent DVT in susceptible patients.
Fabrication of elastomeric stencils for patterned stem cell differentiation
Authors: Lehr Stefanie , Merrin Jack , Kulig Monika , Minchington Thomas , Kicheva Anna 
Published: March 2024

AbstractStem cell differentiation with controlled geometry results in reproducible pattern formation. In contrast to constraining differentiating cells on micropatterned surfaces, we initialise colony formation using elastomeric stencils that adhere to culture dishes and create microwells with defined sizes and shapes. After colony formation, stencils are removed to allow colony growth and cell migration. Stencil fabrication involves mould production by photolithography followed by replica-moulding polydimethylsiloxane (PDMS). This approach produces reproducible two-dimensional organoids tailored for quantitative studies of growth control and pattern formation.
Exposure to HIV alters the composition of maternal microchimeric T cells in infants
Authors: Armistead Blair , Peters M. Quinn , Houck John , Carlson Marc , Balle Christina , Mulugeta Nolawit , Gray Clive M. , Jaspan Heather B. , Harrington Whitney E. 
Published: March 2024

AbstractInfants exposed to HIV but uninfected (iHEU) display altered cellular immunity and are at increased risk of infection through poorly understood mechanisms. We previously reported that iHEU have lower levels of maternal microchimerism (MMc), maternal cells transferred to the offspring in utero/during breastfeeding. We evaluated MMc levels in T cell subsets in iHEU and HIV unexposed infants (iHU) to determine whether a selective deficiency in MMc may contribute to altered cellular immunity. Across all infants, MMc levels were highest in CD8+ T cells; however, the level of MMc in the CD8 T cell subset was significantly lower in iHEU compared to iHU.
Unlocking Herbal Potentials: Novel Shikimate Kinase Inhibitors in the Fight Against Antibiotic Resistance
Authors: Nirgudkar Siddharth , Chai Yurong 
Published: March 2024

AbstractAgainst a backdrop of stagnant antibiotic innovation, the escalating prevalence of antibiotic-resistant pathogens forecasts a challenging future [6]. Traditionally, antibiotics, predominantly derived from fungal sources, employ a limited set of mechanisms to inhibit bacterial growth [6, 16]. Shikimate Kinase has emerged as a promising antibacterial target due to its exclusivity to bacteria and the lethality of its inhibition [4, 13, 14, 15, 28, 29, 30]. Although synthetic inhibitors have been developed, the exploration of plant-derived alternatives remains untapped. Naturally derived plant-based compounds provide a more viable option because of the high cost of creating synthetic compounds. This study examines the Goldenrod plant, reputed in Native American Ethno-medicine for its antimicrobial properties [3, 12, 17]. Employing Liquid Chromatography - Mass Spectrometry (LC-MS) and Quantitative Structure Activity Relationship (QSAR) models, the study evaluates the plant’s compounds for their potential as antibacterial agents. Antibacterial activity againstBacillus Subtiliswas assessed using the Kirby-Bauer Disk Diffusion assay, and genetic sequencing was performed on mutants that overcame the initial inhibition zone. By comparing the parent and mutant strains, the mode of inhibition by the plant antibiotic was determined by backtracking. The study identified Shikimate Kinase as the inhibitory target of the plant-derived compounds. Molecular docking revealed a binding affinity of -8.9 kcal/mol for the most effective compound, which is statistically significant compared to Shikimate Acid, the enzyme’s natural substrate. Through Pymol visualization, competitive inhibition was confirmed, with the compound’s binding pocket exhibiting a druggability score of 0.84, approaching the threshold of clinical drugs. This research suggests new antibiotic classes targeting the Shikimate Kinase pathway, offering an alternative approach to tackling ESKAPE pathogens and enhancing health outcomes.
Self-organization of modular activity in immature cortical networks
Authors: Mulholland Haleigh N. , Kaschube Matthias , Smith Gordon B. 
Published: March 2024

AbstractDuring development, cortical activity is organized into distributed modular patterns that are a precursor of the mature columnar functional architecture. Theoretically, such structured neural activity can emerge dynamically from local synaptic interactions through a recurrent network with effective local excitation with lateral inhibition (LE/LI) connectivity. Utilizing simultaneous widefield calcium imaging and optogenetics in juvenile ferret cortex prior to eye opening, we directly test several critical predictions of an LE/LI mechanism. We show that cortical networks transform uniform stimulations into diverse modular patterns exhibiting a characteristic spatial wavelength. Moreover, patterned optogenetic stimulation matching this wavelength selectively biases evoked activity patterns, while stimulation with varying wavelengths transforms activity towards this characteristic wavelength, revealing a dynamic compromise between input drive and the network’s intrinsic tendency to organize activity. Furthermore, the structure of early spontaneous cortical activity – which is reflected in the developing representations of visual orientation – strongly overlaps that of uniform opto-evoked activity, suggesting a common underlying mechanism as a basis for the formation of orderly columnar maps underlying sensory representations in the brain.
Expanding the genetic toolbox for the obligate human pathogenStreptococcus pyogenes
Authors: Lautenschläger Nina , Schmidt Katja , Schiffer Carolin , Wulff Thomas F. , Hahnke Karin , Finstermeier Knut , Mansour Moïse , Elsholz Alexander K. W. , Charpentier Emmanuelle 
Published: March 2024

AbstractGenetic tools form the basis for the study of molecular mechanisms. Despite many recent advances in the field of genetic engineering in bacteria, genetic toolsets remain scarce for non-model organisms, such as the obligatory human pathogenStreptococcus pyogenes.In this study, we set out to develop a comprehensive set of plasmids, promoters and reporters forS. pyogenes. We present an expansion to the current genetic toolbox that comprises new replicative and site-specific integrative plasmids. Moreover, we established a collection of constitutive promoters with a wide variety of strengths as well as a set of novel inducible regulatory elements, including a zinc-inducible promoter, an erythromycin-inducible riboswitch and an IPTG-inducible promoter that outperform previously described inducible systems in terms of tightness and inducibility. In addition, we demonstrated the applicability of two codon-optimized fluorescent proteins, mNeongreen and mKate2, as reporters inS. pyogenes. For this, we adapted a novel chemically defined medium called RPMI4Spy. This medium showed a highly reduced autofluorescence compared to other growth media and allowed efficient signal detection in plate reader assays and fluorescence microscopy. Finally, we developed a plasmid-based system for genome engineering inS. pyogenesfeaturing the counterselection markerpheS*, which improved the generation of scarless gene deletions.This new toolbox simplifies previously laborious genetic manipulation procedures and lays the foundation for new methodologies to study gene functions inS. pyogenes,leading to a better understanding of its virulence mechanisms and physiology.
Sex differences in early human fetal brain development
Authors: Buonocore Federica , Suntharalingham Jenifer P , Ogunbiyi Olumide K , Jones Aragorn , Moreno Nadjeda , Niola Paola , Brooks Tony , Solanky Nita , Dattani Mehul T. , del Valle Ignacio , Achermann John C. 
Published: March 2024

AbstractThe influence of sex chromosomes and sex hormones on early human brain development is poorly understood. We therefore undertook transcriptomic analysis of 46,XY and 46,XX human brain cortex samples (n=64) at four different time points between 7.5 and 17 weeks post conception (wpc), in two independent studies. This developmental period encompasses the onset of testicular testosterone secretion in the 46,XY fetus (8wpc). Differences in sex chromosome gene expression included X-inactivation genes (XIST,TSIX) in 46,XX samples; core Y chromosome genes (n=18) in 46,XY samples; and two Y chromosome brain specific genes,PCDH11YandRP11-424G14.1.PCDH11Y(protocadherin11 Y-linked)regulates excitatory neurons; this gene is unique to humans and is implicated in language development.RP11-424G14.1is a novel long non-coding RNA. Fewer differences in sex hormone pathway-related genes were seen. The androgen receptor (AR, NR4A2) showed cortex expression in both sexes, which decreased with age. Global cortical sex hormone effects were not seen, but more localized AR mechanisms may be important with time (e.g., hypothalamus). Taken together, our data suggest that limited but potentially important sex differences occur during early human fetal brain development.
Lepton universality in a model with three generations of sterile Majorana neutrinos
Authors: Dubinin M. N. , Kazarkin D. M. 
Published: March 2024

The extension of the Standard Model lepton sector by three right-handed Majorana neutrinos [heavy neutral leptons (HNLs)] with masses up to GeV scale is considered. While the lightest heavy neutral lepton is the dark matter particle with mass of the order of 5 keV, the remaining two HNLs ensure standard (active) neutrino mass generation by means of the seesaw type I mechanism. Two heavy sterile neutrinos with quasidegenerate masses up to 5 GeV can induce the deviation of lepton universality violation parameter in the decays of π+ and K+ mesons from the Standard Model value. Contours are obtained for the permissible values of this parameter within the framework of two mixing scenarios, taking into account the lifetime boundary for heavy neutral lepton from big bang nucleosynthesis in the Universe. When calculating the HNL decay width in the framework of the model with six Majorana neutrinos, three active and three heavy, both two-particle and three-particle lepton decays, essential for masses below the mass of the pion, were taken into account. When calculating the decay widths, the limiting case known as the “Dirac limit” is not used. The results based on the explicit form of mixing matrices for three HNL generations and the diagram technique for Majorana neutrinos, which explicitly take into account the interference terms for diagrams with identical mass states, can lead to some differences in lifetime from the results using the Dirac limit and the displacement of the corresponding experimental exclusion contours of the “mass-mixing” type. For the second mixing scenario, a mass region of 460  MeV<M<485  MeV has been found that allows violation of lepton universality in charged kaon decays at the level observed in the experiment.

Published by the American Physical Society
2024
95 GeV excess in a
CP
-violating
μ
-from-
ν
SSM
Authors: Liu Chang-Xin , Zhou Yang , Zheng Xiao-Yu , Ma Jiao , Feng Tai-Fu , Zhang Hai-Bin 
Published: March 2024

The CMS and ATLAS Collaborations have recently reported their results searching for a light Higgs boson with mass around 95 GeV, based on the full run 2 dataset. In the framework of the CP-violating (CPV) μ-from-ν supersymmetric standard model (SSM), we discuss an ∼2.9σ (local) excess at 95 GeV in the light Higgs boson search in the diphoton decay mode as reported by ATLAS and CMS, together with an ∼2σ excess (local) in the bb¯ final state at LEP in the same mass range. By introducing CPV phases as well as by mixing CP-even Higgs and CP-odd Higgs, a lighter Higgs boson in the μ-from-ν SSM can be produced, which can account for the “diphoton excess.”

Published by the American Physical Society
2024
Do my accents matter? Examining the relationship between English language teachers’ linguistic profiling and career development
Authors: Chen Ning , Ironsi Chinaza Solomon 
Published: March 2024

PurposeThis paper examines the relationship between linguistic profiling and English language teachers’ career development.Design/methodology/approachThis paper collected data from 20 participants using a qualitative approach. Semi-structured interview guides were used to collect qualitative data on this topic.FindingsAfter collecting and analyzing the data, the results showed that linguistic profiling results in demotivation and low self-esteem and can spur career development among non-native English teachers.Originality/valueThis paper advances scientific knowledge by providing empirical evidence showing that while linguistic profiling has some negative influences, it can spur career development among non-native English teachers.