bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis
Authors: Li Yang , Li Chuhan , Sun Qiang , Chen Fengyuan , Cheung Yeelo , Zhao Yu , Xie Ting , Chazaud Bénédicte , Sun Hao , Wang Huating 
Published: January 2024

AbstractStem cell activity is known to be tightly regulated by both intrinsic and extrinsic pathways but less is known about whether and how stem cells modulate their niche microenvironment. Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and also tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in the niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here in this study we demonstrate that intrinsic deletion of transcription factor YY1 in MuSCs exacerbates dystrophic pathologies by altering the cellular composition and heterogeneity of MPs and FAPs. Further analysis reveals that the YY1 loss induces the expression of immune genes in MuSCs, includingCcl5. Augmented secretion of CCL5 from MuSCs promotes the recruitment of MPs via CCL5/CCR5 mediated crosstalk, which subsequently hinders the apoptosis and clearance of FAPs through elevated TGFβ1 accumulation. Maraviroc mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we further demonstrate that YY1 repressesCcl5transcription in MuSCs by directly binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study has demonstrated the previously unappreciated role of MuSCs in actively shaping their niche microenvironment through secreting immunomodulatory cytokines, and has also provided novel insight into the therapeutic intervention of muscle dystrophy.
Dyrk1a is required for craniofacial development inXenopus laevis
Authors: Johnson H. Katherine , Wahl Stacy E , Sesay Fatmata , Litovchick Larisa , Dickinson Amanda JG 
Published: January 2024

AbstractLoss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model,Xenopus laevis.Dyrk1amRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, usingdyrk1amorpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators,sox9andpax3are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.
Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron
Authors: Porter Aidan , Vorndran Hannah E. , Marciszyn Allison , Mutchler Stephanie M. , Subramanya Arohan R. , Kleyman Thomas R. , Hendershot Linda M. , Brodsky Jeffrey L. , Buck Teresa M. 
Published: January 2024

ABSTRACTThe maintenance of fluid and electrolyte homeostasis by the kidney requires proper folding and trafficking of ion channels and transporters in kidney epithelia. Each of these processes requires a specific subset of a diverse class of proteins termed molecular chaperones. One such chaperone is GRP170, which is an Hsp70-like, endoplasmic reticulum (ER)-localized chaperone that plays roles in protein quality control and protein folding in the ER. We previously determined that loss of GRP170 in the mouse nephron leads to hypovolemia, electrolyte imbalance, and rapid weight loss. In addition, GRP170-deficient mice develop an AKI-like phenotype, typified by tubular injury, elevation of clinical kidney injury markers, and induction of the unfolded protein response (UPR). By using an inducible GRP170 knockout cellular model, we confirmed that GRP170 depletion induces the UPR, triggers an apoptotic response, and disrupts protein homeostasis. Based on these data, we hypothesized that UPR induction underlies hyponatremia and volume depletion in rodents, but that these and other phenotypes might be rectified by supplementation with high salt. To test this hypothesis, control and GRP170 tubule-specific knockout mice were provided with a diet containing 8% sodium chloride. We discovered that sodium supplementation improved electrolyte imbalance and reduced clinical kidney injury markers, but was unable to restore weight or tubule integrity. These results are consistent with UPR induction contributing to the kidney injury phenotype in the nephron-specific GR170 knockout model, and that the role of GRP170 in kidney epithelia is essential to both maintain electrolyte balance and cellular protein homeostasis.
Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations
Authors: Clusella Pau , Manubens-Gil Linus , Garcia-Ojalvo Jordi , Dierssen Mara 
Published: January 2024

AbstractCognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.Author summaryThe structural integrity of individual brain neurons and the intricate networks they form are fundamental to all brain functions, with structural anomalies directly linked to neurological disorders. Deciphering these links is a leading question in developmental disorders such as Down syndrome. Our work sheds light on the pivotal role that the structure of complex neural systems plays in shaping emergent network activity. In particular, our anatomically informed network modeling enables determining the extent to which specific deficits in neuronal architecture and connectivity perturb oscillatory patterns of activity.
FoxO transcription factors actuate the formative pluripotency specific gene expression programme
Authors: Santini Laura , Kowald Saskia , Sestini Giovanni , Rivron Nicolas , Leeb Martin 
Published: January 2024

ABSTRACTNaïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, ES cells transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage-choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localization of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for transition from the naïve to the formative pluripotent state. Our work uncovers a pivotal role for FoxO TFs and AKT signalling in mechanisms establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.
Pivotal roles ofPlasmodium falciparumlysophospholipid acyltransferase 1 in cell cycle progression and cytostome internalization
Authors: Fukumoto Junpei , Yoshida Minako , Tokuoka Suzumi M. , Hayakawa Eri Saki H. , Miyazaki Shinya , Sakura Takaya , Inaoka Daniel Ken , Kita Kiyoshi , Usukura Jiro , Shindou Hideo , Tokumasu Fuyuki 
Published: January 2024

AbstractThe rapid intraerythrocytic replication ofPlasmodium falciparum, a deadly species of malaria parasite, requires a quick but constant supply of phospholipids to support marked cell membrane expansion. In the malarial parasite, many enzymes functioning in phospholipid synthesis pathway have not been identified or characterized. Here, we identifiedP. falciparumlysophospholipid acyltransferase 1 (PfLPLAT1) and showed that PfLPLAT1 is vital for asexual parasite cell cycle progression and cytostome internalization. Deficiency in PfLPLAT1 resulted in decreased parasitemia and prevented transition to the schizont stage. Parasites lacking PfLPLAT1 also exhibited distinctive omega-shaped vacuoles, indicating disrupted cytostome function. Transcriptomic analyses suggested that this deficiency impacted DNA replication and cell cycle regulation. Mass spectrometry-based enzyme assay and lipidomic analysis demonstrated that recombinant PfLPLAT1 exhibited lysophospholipid acyltransferase activity with a preference for unsaturated fatty acids as its acyl donors and lysophosphatidic acids as an acceptor, with its conditional knockout leading to abnormal lipid composition and marked morphological and developmental changes including stage arrest. These findings highlight PfLPLAT1 as a potential target for antimalarial therapy, particularly due to its unique role and divergence from human orthologs.
The PCM scaffold enables RNA localization to centrosomes
Authors: Fang Junnan , Tian Weiyi , Quintanilla Melissa A. , Beach Jordan R. , Lerit Dorothy A. 
Published: January 2024

AbstractAs microtubule-organizing centers, centrosomes direct assembly of the bipolar mitotic spindle required for chromosome segregation and genome stability. Centrosome activity requires the dynamic assembly of pericentriolar material (PCM), the composition and organization of which changes throughout the cell cycle. Recent studies highlight the conserved localization of several mRNAs encoded from centrosome-associated genes enriched at centrosomes, includingPericentrin-like protein(Plp) mRNA. However, relatively little is known about how RNAs localize to centrosomes and influence centrosome function. Here, we examine mechanisms underlying the subcellular localization ofPlpmRNA. We find thatPlpmRNA localization is puromycin-sensitive, and thePlpcoding sequence is both necessary and sufficient for RNA localization, consistent with a co-translational transport mechanism. We identify regions within thePlpcoding sequence that regulatePlpmRNA localization. Finally, we show that protein-protein interactions critical for elaboration of the PCM scaffold permit RNA localization to centrosomes. Taken together, these findings inform the mechanistic basis ofPlpmRNA localization and lend insight into the oscillatory enrichment of RNA at centrosomes.
Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
Authors: Arnold Moriah R. , Cohn Gabriel M. , Oxe Kezia Catharina , Elliott Somarr N. , Moore Cynthia , Laraia Peter V. , Shekoohi Sahar , Brownell Dillon , Meshul Charles K. , Witt Stephan N. , Larsen Dorthe H. , Unni Vivek K. 
Published: January 2024

AbstractAlthough an increased risk of the skin cancer melanoma in people with Parkinson’s Disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important. Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in the SK-MEL28 melanoma cell line, where it colocalizes with DNA damage markers and DSBs. Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases αSyn levels near sites of damage. αSyn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage. αSyn is important downstream of ATM signaling to facilitate 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.
Genome-aware annotation of CRISPR guides validates targets in variant cell lines and enhances discovery in screens
Authors: Lam Simon , Thomas John C. , Jackson Stephen P. 
Published: January 2024

AbstractPooled CRISPR-Cas9 genetic knockout screens are powerful high-throughput tools for identifying chemo-genetic, synthetic-lethal and synthetic-viability interactions and are used as a key step towards identifying disease-modifying knockout candidates and informing drug design and therapeutic regimens. CRISPR guide libraries are commercially available for purchase and have been widely applied in different cell lines. However, discrepancies between the genomes used to design CRISPR libraries and the genomes of the cells subjected to CRISPR screens lead to loss of signal or introduction of bias towards the most conserved genes. Here, we present an algorithm, EXOme-guided Reannotation of nuCleotIde SEquences (Exorcise), which uses sequence search and CRISPR target annotation to adapt existing CRISPR libraries to user-defined genomes and exomes. Applying Exorcise on 55 commercially available CRISPR-spCas9 knockout libraries for human and mouse, we found that all libraries have mis-annotations, and that design strategy affects off-target effects and targeting accuracy relative to a standard reference sequence. In simulations on synthetic data, we modelled common mis-annotations in CRISPR libraries and found that they adversely affected recovery of the ground truth for all genes except for those with the strongest signals. Finally, we reanalysed DepMap and DDRcs CRISPR screens with Exorcise annotations and found that strong hits were retained, and lower-confidence hits were strengthened. Use of Exorcise on DepMap with exomes inferred from transcriptomic expression data demonstrated that cell-line–aware reannotation is possible without whole-genome sequencing. Taken together, our results show that Exorcise is a powerful reannotation tool that focuses existing CRISPR libraries towards the cell line genome under investigation and allows post-hoc reanalysis of completed CRISPR screens. Exorcise is open-source software licenced under a Creative Commons Zero Universal 1.0 licence and is available at <https://github.com/SimonLammmm/exorcise>.
NRX-101 (D-Cycloserine + Lurasidone), a Qualified Infectious Disease Product, is Active Against Drug-Resistant Urinary PathogensIn Vitro
Authors: Sapko Michael T. , Manyak Michael , Panicucci Riccardo , Javitt Jonathan C. 
Published: January 2024

AbstractBackgroundD-Cycloserine (DCS) is a broad-spectrum antibiotic that is currently FDA-approved to treat tuberculosis (TB) disease and urinary tract infection. Despite numerous reports showing good clinical efficacy, DCS fell out of favor as a UTI treatment because of its propensity to cause side effects. NRX-101, a fixed dose combination of DCS and lurasidone, has been awarded Qualified Infectious Disease Product and Fast Track Designation by the US Food and Drug Administration and is being developed for various CNS indications because of its unique synergistic effect; each component mitigates side effects of the other.MethodsIn this study, we tested NRX-101 against the urinary tract pathogensE. coli, P. aeruginosa, K. pneumoniae, andA. baumanniiin Mueller Hinton broth (caMHB) and artificial urine media (AUM). Several strains were multidrug resistant. Test compounds were serially diluted in broth/media. Minimum inhibitory concentration (MIC) was defined as the lowest concentration of test compound at which no bacterial growth was observed.ResultsDCS exhibited antibacterial efficacy against all strains tested while lurasidone did not appreciably affect the antibacterial action of DCSin vitro. In AUM, the MICs ranged from 128 to 512 mcg/ml for both DCS and NRX-101. In caMHB, MICs ranged from 8 to 1024 mcg/ml for NRX-101 and 32 to 512 mcg/ml for DCS alone.ConclusionsOur data confirm that DCS as antibacterial activity against reference and drug-resistant urinary pathogens. Furthermore, lurasidone does not interfere with DCS’s anti-microbial actionin vitro. These results support the clinical development of NRX-101 as a treatment for complicated urinary tract infection.
TheStreptococcusphage protein paratox is an intrinsically disordered protein
Authors: Asakereh Iman , Rutbeek Nicole R. , Singh Manvir , Davidson David , Prehna Gerd , Khajehpour Mazdak 
Published: January 2024

ABSTRACTThe bacteriophage protein paratox blocks quorum sensing in its streptococcal host by directly binding the signal receptor and transcription factor ComR. This reduces ability ofStreptococcusto uptake environmental DNA and protects phage DNA from damage by recombination. Past work characterizing the paratox:ComR molecular interaction revealed that paratox adopts a well-ordered globular fold when bound to ComR. However, solution-state biophysical measurements suggested that paratox may be conformationally dynamic. To address this discrepancy, we investigated the stability and dynamic properties of paratox in solution using circular dichroism, nuclear magnetic resonance, and several fluorescence-based protein folding assays. Our work shows that under dilute buffer conditions paratox is intrinsically disordered. We also show that the addition of kosmotropic salts or protein stabilizing osmolytes induces paratox folding. However, only the addition of ComR was able to induce paratox to adopt its previously characterized globular fold. Furthermore, as we can induce different paratox folding-states we characterize Prx folding thermodynamics and folding kinetics using stopped flow measurements. Based upon the kinetic results, paratox is a highly dynamic protein in dilute solution, folding and refolding within the 10 ms timescale. Overall, our results demonstrate that the streptococcal phage protein paratox is an intrinsically disordered protein in a two-state equilibrium with a solute-stabilized folded form. Furthermore, the solute-stabilized paratox fold is likely the predominant form of paratox in a solute-crowded bacterial cell. Finally, our work suggests that Prx binds and inhibits ComR, and thus quorum sensing inStreptococcus, by a combination of conformational selection and induced-fit binding mechanisms.
Stopping the Vicious Cycle: Equitable Enforcement Strategies to Achieve Safe, Stable, and Accessible Housing for People with Disabilities
Authors: MICHEL KATIE HANNON , WATTS MAYA HAZARIKA , BRESLIN JESSICA , TOBIN‐TYLER ELIZABETH 
Published: January 2024

Policy Points
People with disabilities experience a vicious cycle of poverty, poor health, and marginalization partly because of the inequitable implementation and enforcement of laws, including underenforcement of civil rights and housing laws and overenforcement of punitive nuisance and criminal laws.
Inequitable enforcement reflects policy choices that prioritize powerful entities (e.g., landlords, developers) to the detriment of people who experience intersectional structural discrimination based on, for example, race, disability, and income.
Equitable enforcement, a process of ensuring compliance with the law while considering and minimizing harms to marginalized people, can promote health and disability justice by increasing access to safe, stable, and accessible housing.
Mapping the Lobbying Footprint of Harmful Industries: 23 Years of Data From OpenSecrets
Authors: CHUNG HOLLY , CULLERTON KATHERINE , LACY‐NICHOLS JENNIFER 
Published: January 2024

Policy Points
Our research reveals the similarities and differences among the lobbying activities of tobacco, alcohol, gambling, and ultraprocessed food industries, which are often a barrier to the implementation of public health policies.
Over 23 years, we found that just six organizations dominated lobbying expenses in the tobacco and alcohol sectors, whereas the gambling sector outsourced most of their lobbying to professional firms.
Databases like OpenSecrets are a useful resource to monitor the commercial determinants of health.
ContextCommercial lobbying is often a barrier to the development and implementation of public health policies. Yet, little is known about the similarities and differences in the lobbying practices of different industry sectors or types of commercial actors. This study compares the lobbying practices of four industry sectors that have been the focus of much public health research and advocacy: tobacco, alcohol, gambling, and ultraprocessed foods.MethodsData on lobbying expenditures and lobbyist backgrounds were sourced from the OpenSecrets database, which monitors lobbying in the United States. Lobbying expenditure data were analyzed for the 1998–2020 period. We classified commercial actors as companies or trade associations. We used Power BI software to link, analyze, and visualize data sets.FindingsWe found that the ultraprocessed food industry spent the most on lobbying ($1.15 billion), followed by gambling ($817 million), tobacco ($755 million), and alcohol ($541 million). Overall, companies were more active than trade associations, with associations being least active in the tobacco industry. Spending was often highly concentrated, with two organizations accounting for almost 60% of tobacco spending and four organizations accounting for more than half of alcohol spending. Lobbyists that had formerly worked in government were mainly employed by third‐party lobby firms.ConclusionsOur study shows how comparing the lobbying practices of different industry sectors offers a deeper appreciation of the diversity and similarities of commercial actors. Understanding these patterns can help public health actors to develop effective counterstrategies.