bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activator-blocker model of transcriptional regulation by pioneer-like factors
Authors: Riesle Aileen Julia , Gao Meijiang , Rosenblatt Marcus , Hermes Jacques , Hass Helge , Gebhard Anna , Veil Marina , Grüning Björn , Timmer Jens , Onichtchouk Daria 
Published: January 2023

AbstractZygotic genome activation (ZGA) in the development of flies, fish, frogs and mammals depends on pioneer-like transcription factors (TFs). Those TFs create open chromatin regions, promote histone acetylation on enhancers, and activate transcription. Here, we use the panel of single, double and triple mutants for zebrafish genome activators Pou5f3, Sox19b and Nanog, multi-omics and mathematical modeling to investigate the combinatorial mechanisms of genome activation. We show that Pou5f3 and Nanog act differently on synergistic and antagonistic enhancer types. Pou5f3 and Nanog both bind as pioneer-like TFs on synergistic enhancers, promote histone acetylation and activate transcription. Antagonistic enhancers are activated by binding of one of these factors. The other TF binds as non-pioneer-like TF, competes with the activator and blocks all its effects, partially or completely. This activator-blocker mechanism mutually restricts widespread transcriptional activation by Pou5f3 and Nanog and prevents premature expression of late developmental regulators in the early embryo.
Pressure and ultrasound activate mechanosensitive TRAAK K+channels through increased membrane tension
Authors: Sorum Ben , Docter Trevor , Panico Vincent , Rietmeijer Robert A. , Brohawn Stephen G. 
Published: January 2023

AbstractTRAAK is a mechanosensitive two-pore domain K+(K2P) channel found in nodes of Ranvier within myelinated axons. It displays low leak activity at rest and is activated up to one hundred-fold by increased membrane tension. Structural and functional studies have led to physical models for channel gating and mechanosensitivity, but no quantitative analysis of channel activation by tension has been reported. Here, we use simultaneous patch-clamp recording and fluorescent imaging to determine the tension response characteristics of TRAAK. TRAAK shows high sensitivity and a broad response to tension spanning nearly the entire physiologically relevant tension range. This graded response profile distinguishes TRAAK from similarly low-threshold mechanosensitive channels Piezo1 and MscS, which activate in a step-like fashion over a narrow tension range. We further use patch imaging to show that ultrasonic activation of TRAAK and MscS is due to increased membrane tension. Together, these results provide mechanistic insight into TRAAK tension gating, a framework for exploring the role of mechanosensitive K+channels at nodes of Ranvier, and biophysical context for developing ultrasound as a mechanical stimulation technique for neuromodulation.
Uptake-independent killing of macrophages by extracellular aggregates ofMycobacterium tuberculosisis ESX-1 and PDIM-dependent
Authors: Toniolo Chiara , Dhar Neeraj , McKinney John D. 
Published: January 2023

AbstractMycobacterium tuberculosis(Mtb) infection is initiated by inhalation of small numbers of bacteria into lung alveoli, where they are phagocytosed by resident macrophages. Intracellular replication ofMtbleads to death of the infected macrophages, release of bacterial aggregates, and rapid growth of the extracellular aggregates on host-cell debris. Here, we show that extracellularMtbaggregates can evade phagocytosis by killing macrophages in a contact-dependent but uptake-independent manner. We use single-cell time-lapse fluorescence microscopy to show that contact with extracellularMtbaggregates triggers macrophage plasma membrane perturbation, cytoplasmic calcium accumulation, and pyroptotic cell death. These effects depend on theMtbtype VII secretion system ESX-1, however, this system alone cannot induce calcium accumulation and macrophage death in the absence of theMtbsurface-exposed lipid phthiocerol dimycocerosate. Unexpectedly, we found that ESX-1-mediated secretion of the EsxA/EsxB virulence factors is not required for uptake-independent killing of macrophages after contact with extracellularMtbaggregates. In the absence of EsxA/EsxB secretion, killing is mediated by the 50-kDa isoform of the ESX-1-secreted protein EspB, while blocking secretion of both EsxA/EsxB and processed EspB reduces killing to background levels. Treatment with a small-molecule ESX-1 inhibitor reduces uptake-independent killing of macrophages byMtbaggregates, suggesting that novel therapies targeting this anti-phagocytic mechanism could prevent the propagation of extracellular bacteria within the lung.Significance statementMycobacterium tuberculosis(Mtb) can survive inside the lung macrophages that normally provide the first line of defense against bacterial infections. Intracellular replication ofMtbultimately results in the death and lysis of infected macrophages, allowing the bacteria to spread to other cells and propagate the infection. Our study shows that extracellularMtbaggregates that form on the debris of dead host cells can induce macrophage death in a contact-dependent but uptake-independent manner, allowing the bacteria to evade the host defenses associated with uptake by macrophages. Killing of macrophages by extracellularMtbaggregates is driven by theMtbESX-1 secretion system and the surface-exposed lipid phthiocerol dimycocerosate. Our results suggest that novel drugs targetingMtbfactors required for host-cell killing by extracellularMtbaggregates may reduce bacterial spreading and expansion of necrotic tuberculosis lesions, which are known to be poorly penetrated by conventional antibiotics.
Modulation and Neural Correlates of Postmating Sleep Plasticity inDrosophilaFemales
Authors: Duhart José M. , Buchler Joseph R. , Inami Sho , Kennedy Kyle J. , Jenny B. Peter , Afonso Dinis J.S. , Koh Kyunghee 
Published: January 2023

SummarySleep is essential, but animals may forgo sleep to engage in other critical behaviors, such as feeding and reproduction. Previous studies have shown that female flies show decreased sleep after mating, but our understanding of the process is limited. Here, we report that postmating nighttime sleep loss is modulated by diet and sleep deprivation, demonstrating a complex interaction among sleep, reproduction, and diet. We also report that female-specific pC1 neurons and sleep-promoting dorsal fan-shaped body (dFB) neurons are required for postmating sleep plasticity. Activating pC1 neurons leads to sleep suppression on standard fly culture media but has little sleep effect on sucrose-only food. Published connectome data suggest indirect, inhibitory connections among pC1 subtypes. Using calcium imaging, we show that activating the pC1e subtype inhibits dFB neurons. We propose that pC1 and dFB neurons integrate the mating status, food context, and sleep drive to modulate postmating sleep plasticity.HighlightsDiet and sleep drive modulate female nighttime postmating sleep lossFemale-specific pC1 neurons are required for postmating sleep lossSleep-promoting dFB-projecting neurons are required for postmating sleep lossActivating pC1 subtypes promotes wakefulness and inhibits dFB-projecting neuronseTOC blurbAnimals evaluate environmental conditions and internal states to make behavioral choices. Duhart et al. show that the decision to stay awake after mating inDrosophilafemales is modulated by food composition and sleep history and mediated by female-specific pC1 neurons acting upstream of the dFB sleep center.
Population demographic history and evolutionary rescue: influence of a bottleneck event
Authors: Olazcuaga Laure , Lincke Beatrice , Delacey Sarah , Durkee Lily F. , Melbourne Brett A. , Hufbauer Ruth A. 
Published: January 2023

AbstractRapid environmental change presents a significant challenge to the persistence of natural populations. Rapid adaptation that increases population growth, enabling populations that declined following severe environmental change to grow and avoid extinction, is called evolutionary rescue. Numerous studies have shown that evolutionary rescue can indeed prevent extinction. Here, we extend those results by considering the demographic history of populations. To evaluate how demographic history influences evolutionary rescue, we created 80 populations of red flour beetle,Tribolium castaneum, with three classes of demographic history: diverse populations that did not experience a bottleneck, and populations that experienced either an intermediate or a strong bottleneck. We subjected these populations to a new and challenging environment for six discrete generations and tracked extinction and population size. Populations that did not experience a bottleneck in their demographic history avoided extinction entirely, while more than 20% of populations that experienced an intermediate or strong bottleneck went extinct. Similarly, among the extant populations at the end of the experiment, adaptation increased the growth rate in the novel environment the most for populations that had not experienced a bottleneck in their history. Taken together, these results highlight the importance of considering the demographic history of populations to make useful and effective conservation decisions and management strategies for populations experiencing environmental change that pushes them toward extinction.
Urinary Glycosaminoglycans are Associated with Recurrent UTI and Urobiome Ecology in Postmenopausal Women
Authors: Neugent Michael L. , Hulyalkar Neha V. , Kumar Ashwani , Xing Chao , Zimmern Philippe E. , Shulaev Vladimir , De Nisco Nicole J. 
Published: January 2023

AbstractGlycosaminoglycans (GAGs) are linear, negatively charged polysaccharides composed of repeating disaccharide units of uronic acid and amino sugars. The luminal surface of the bladder epithelium is coated with a GAG layer. These urothelial GAGs are thought to provide a protective barrier and serve as a potential interaction site with the urinary microbiome (urobiome). Previous studies have profiled urinary GAG composition in mixed cohorts, but the urinary GAG composition in postmenopausal women remains undefined. To investigate the relationship between GAGs and recurrent UTI (rUTI), we profiled urinary GAGs in a controlled cohort of postmenopausal women. We found that chondroitin sulfate (CS) is the major urinary GAG in postmenopausal women and that urinary CS was elevated in women with active rUTI. We also associated urinary GAGs with urobiome composition and identified bacterial species that significantly associated with urinary GAG concentration.Corynebacterium amycolatum, Porphyromonas somerae, andStaphylococcus pasteuriwere positively associated with heparin sulfate or hyaluronic acid and bacterial species associated with vaginal dysbiosis were negatively correlated to urinary CS. Altogether, this work defines changes in urinary GAG composition associated with rUTI and identifies new associations between urinary GAGs and the urobiome that may play a role in rUTI pathobiology.
DNA metabarcoding using newrbcLandITS2metabarcodes collectively enhance detection efficiency of medicinal plants in single and polyherbal formulations
Authors: Travadi Tasnim , Shah Abhi P. , Pandit Ramesh , Sharma Sonal , Joshi Chaitanya , Joshi Madhvi 
Published: January 2023

AbstractWith the widespread adoption of barcoding and next-generation sequencing, metabarcoding is emerging as a potential tool for detecting labelled and unlabelled plant species in herbal products. In this study, newly designedrbcLandITS2metabarcode primers were validated for metabarcoding using in-house mock controls of medicinal plant gDNA pools and biomass pools. The applicability of the multi-barcode sequencing approach was evaluated on 17 single drugs and 15 polyherbal formulations procured from the Indian market. TherbcLmetabarcode demonstrated detection efficiencies of 86.7% and 71.7% in gDNA plant pools and biomass mock controls, respectively, while theITS2metabarcode demonstrated 82.2% and 69.4%. In the gDNA plant pool and biomass pool mock controls, the cumulative detection efficiency increased by 100% and 90%, respectively. A total of 79% cumulative detection efficiency of both metabarcodes was observed in single drugs, while 76.3% was observed in polyherbal formulations. An average fidelity of 83.6% was observed for targeted plant species present within mock controls as well as in herbal formulations. Our results demonstrated the applicability of multilocus strategies in metabarcoding as a potential tool for detecting labelled and unlabelled plant species in herbal formulations.
Candida albicansoropharyngeal infection is an exception to iron-based nutritional immunity
Authors: Solis Norma V. , Wakade Rohan S. , Filler Scott G. , Krysan Damian J. 
Published: January 2023

AbstractCandida albicansis a commensal of the human gastrointestinal tract and one of the most causes of human fungal disease, including mucosal infections such as oropharyngeal candidiasis and disseminated infections of the bloodstream and deep organs. We directly compared the in vivo transcriptional profile ofC. albicansduring oral infection and disseminated infection of the kidney to identify niche specific features. Although the expression of a set of environmentally responsive genes were correlated in the two infection sites (Pearson R2, 0.6), XXX genes were differentially expressed. Virulence associated genes such as hyphae-specific transcripts were expressed similarly in the two sites. Genes expressed during growth in a poor carbon source (ACS1andPCK1) were upregulated in oral tissue relative to kidney. Most strikingly,C. albicansin oral tissue shows the transcriptional hallmarks of an iron-replete state while in the kidney it is in the expected iron starved state. Interestingly,C. albicansexpresses genes associated with a low zinc environment in both niches. Consistent with these expression data, deletion of two transcription factors that activate iron uptake genes (SEF1,HAP5) have no effect on virulence in a mouse model of oral candidiasis. During microbial infection, the host sequesters iron and other metal nutrients to suppress growth of the pathogen in a process called nutritional immunity. Our results indicate thatC. albicansis subject to iron and zinc nutritional immunity during disseminated infection but is exempted from iron nutritional immunity during oral infection.
Family Vulnerability Scale: evidence of content and internal structure validity
Authors: de Souza Evelyn Lima , Eshriqui Ilana , Rebustini Flávio , Masuda Eliana Tiemi , de Paiva Neto Francisco Timbó , Lima Ricardo Macedo , Bonfim Daiana 
Published: January 2023

AbstractIntroductionterritory view based on families’ vulnerability strata allows identifying different health needs that, in their turn, can guide healthcare at primary care scope. Although there are instruments aimed at measuring family vulnerability, they still need robust validity evidences; therefore, they represent a limitation for usability in a country showing multiple socioeconomic and cultural realities, such as Brazil. The present study introduces the development and search for evidences about the validity of the Family Vulnerability Scale for Brazil, known as EVFAM-BR.Methodsitems were generated through exploratory qualitative study carried out with 123 professionals. Collected data subsidized the generation of 92 initial items that were subjected to a panel of multi-regional and multi-disciplinary judges (n = 73) to calculate the Content Validity Ratio (CVR) – this process resulted in a version of the scale comprising 38 items. Subsequently, it was applied to 1,255 individuals to find evidences about the internal-structure validity by using the Exploratory Factor Analysis (EFA). Dimensionality was assessed through Robust Parallel Analysis and the model was tested through cross-validation to find EVFAM-BR’s final version.Resultsthe final version comprised 14 items distributed into four domains, with explained variance of 79.02%. All indicators were within adequate and satisfactory limits, without any cross-loading and Heywood Case issues. Reliability indices also reached adequate levels (α= 0.71;ω= 0.70; glb = 0.83 and ORION ranging from 0.80 to 0.93, between domains). Instrument’s score was subjected to normalization, and it pointed towards three vulnerability strata (0 to 4 – Low; 5 to 6 – Moderate; 7 to 14 - High).Conclusionthe scale showed satisfactory validity evidences, which were consistent, reliable ad robust; it led to a synthesized instrument capable of accurately measuring and differentiating family vulnerability in the primary care territory, in Brazil.
Flat clathrin lattices are linked to metastatic potential in colorectal cancer
Authors: Cresens Charlotte , Solis-Fernandez Guillermo , Tiwari Astha , Nuyts Rik , Hofkens Johan , Barderas Rodrigo , Rocha Susana 
Published: January 2023

AbstractClathrin assembles at the cells’ plasma membrane in a multitude of clathrin-coated structures (CCSs). Among these are flat clathrin lattices (FCLs), alternative clathrin structures that have been found in specific cell types, including cancer cells. Here we show that these structures are also present in different colorectal cancer (CRC) cell lines, and that they are extremely stable with lifetimes longer than 8 hours. By combining cell models representative of CRC metastasis with advanced fluorescence imaging and analysis, we discovered that the metastatic potential of CRC is associated with an aberrant membranous clathrin distribution, resulting in a higher prevalence of FCLs in cells with a higher metastatic potential. These findings suggest that clathrin organization might play an important yet unexplored role in cancer metastasis.
The autism-associated loss of δ-catenin functions disrupts social behaviors
Authors: Mendez-Vazquez Hadassah , Roach Regan L. , Nip Kaila , Sathler Matheus F. , Garver Tyler , Danzman Rosaline A. , Moseley Madeleine C. , Roberts Jessica P. , Koch Olivia N. , Steger Ava A. , Lee Rahmi , Arikkath Jyothi , Kim Seonil 
Published: January 2023

Abstractδ-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in theδ-cateningene is found in autism spectrum disorder (ASD) patients and induces loss of δ-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3β (GSK3β). This promotes δ-catenin degradation and causes the reduction of δ-catenin levels, which likely contributes to the loss of δ-catenin functions. Synaptic δ-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. δ-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3β activity reverses the G34S-induced loss of δ-catenin function effects in cells and mice. Finally, using δ-catenin knockout mice, we confirm that δ-catenin is required for GSK3β inhibition-induced restoration of normal social behaviors in δ-catenin G34S mutant animals. Taken together, we reveal that the loss of δ-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3β inhibition can reverse δ-catenin G34S-induced synaptic and behavioral deficits.Significance Statementδ-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in theδ-cateningene is found in autism patients and results in the loss of δ-catenin functions. δ-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the autism pathophysiology. Importantly, social dysfunction is a key characteristic of autism. Nonetheless, the links between δ-catenin functions and social behaviors are largely unknown. The significance of the current research is thus predicated on filling this gap by discovering the molecular, cellular, and synaptic underpinnings of the role of δ-catenin in social behaviors.
FOXM1 acts sexually dimorphically to regulate functional β-cell mass
Authors: Peng Guihong , Mosleh Elham , Yuhas Andrew , Katada Kay , Cherry Christopher , Golson Maria L. 
Published: January 2023

AbstractThe transcription factor FOXM1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1*) in β cells increases β-cell proliferation and mass in aged male mice. Additionally, FOXM1* enhances β-cell function even in young mice, in which no β-cell mass elevation occurs. Here, we demonstrate that FOXM1 acts in a sexually dimorphic manner in the β cell. Expression of FOXM1* in female mouse β cells does not affect β-cell proliferation or glucose tolerance. Transduction of male but not female human islets with FOXM1* enhances insulin secretion in response to elevated glucose. Estrogen contributes to diabetes susceptibility differences between males and females, and the estrogen receptor (ER)α is the primary mediator of β-cell estrogen signaling. We show that FOXM1* can rescue impaired glucose tolerance in female mice with a pancreas-wide ERα deletion. Further, FOXM1 and ERα binding sites overlap with each other and with other β-cell-enriched transcription factors, including ISL1, PAX6, MAF, and GATA. These data indicate that FOMX1 and ERα cooperate to regulate β-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.