bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome profiling of the dorsomedial prefrontal cortex in suicide victims
Authors: Dóra Fanni , Renner Éva , Keller Dávid , Palkovits Miklós , Dobolyi Árpád 
Published: April 2022

AbstractThe default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA-sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. Most of the data variance (79%) was associated with expression changes between suicide and control samples. 1400 genes differed using log2FC > ± 1 and adjustedp-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Gene set enrichment and protein-protein interaction network analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated while glutamatergic synaptic signaling in upregulated genes in suicide individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding proteins 2 (NECAB2).In situhybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in 2 different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.
Peer presence elicits task-independent changes within and beyond the mentalizing network across children and adults
Authors: Tricoche Leslie , Pélisson Denis , Longo Léa , Koun Eric , Poisson Alice , Prado Jérôme , Meunier Martine 
Published: April 2022

AbstractThere is ample behavioral evidence that others’ mere presence can affect any behavior in human and non-human animals, generally facilitating the expression of mastered responses while impairing the acquisition of novel ones. Much less is known about i) how the brain orchestrates the modulation of such a wide array of behaviors by others’ presence and ii) when these neural underpinnings mature during development. To address these issues, fMRI data were collected in children and adults alternately observed and unobserved by a familiar peer. Subjects performed two tasks. One, numerosity comparison, depends on number-processing brain areas, the other, phonological comparison, on language-processing areas. Consistently with previous behavioral findings, peer observation facilitated both tasks, and children’s improvement was comparable to adults’. Regarding brain activation, we found virtually no evidence of observation-driven changes within the number- or language-related areas specific to each task. Rather, we observed the same task-independent changes for both numerosity and phonological comparisons. This unique neural signature encompassed a large brain network of domain-general areas involved in social cognition, especially mentalizing, attention, and reward. It was also largely shared by children and adults. The one exception was children’s right temporoparietal junction, which failed to show the observation- driven lesser deactivation seen in adults. These findings indicate that social facilitation of some human education-related skills is i) primarily orchestrated by domain-general brain networks, rather than by task-selective substrates, and ii) relatively mature early in the course of education, thus having a protracted impact on academic achievements that may have heretofore been underestimated.HighlightBasic math and reading skills were measured in children and adults.Participants were alternately observed and unobserved by a familiar peer.Behavior showed that children were as facilitated by peer observation as adults.fMRI data showed task-independent, observation-driven changes in mentalizing, attention, and reward brain regions.All adults’ neural changes were also found in children, except one located in right temporo- parietal junction.
Cryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae
Authors: Kishikawa Jun-ichi , Ishikawa Moe , Masuya Takahiro , Murai Masatoshi , Kitazumi Yuki , Butler Nicole L. , Kato Takayuki , Barquera Blanca , Miyoshi Hideto 
Published: April 2022

SUMMARYThe Na+-pumping NADH-ubiquinone oxidoreductase (Na+-NQR) couples electron transfer from NADH to ubiquinone with Na+-pumping, generating an electrochemical Na+ gradient that is essential for energy-consuming reactions in bacteria. Since Na+-NQR is exclusively found in prokaryotes, it is a promising target for highly selective antibiotics. However, the molecular mechanism of inhibition is not well-understood for lack of the atomic structural information about an inhibitor-bound state. Here we present cryo-electron microscopy structures of Na+- NQR from Vibrio cholerae with or without a bound inhibitor at 2.5- to 3.1-Å resolution. The structures reveal the arrangement of all six redox cofactors including riboflavin, whose position has been under debate, and a newly assigned 2Fe-2SNqrD/E cluster located between the membrane embedded NqrD and NqrE subunits. A large part of the hydrophilic NqrF near the cytoplasmic membrane surface is barely visible in the density map, suggesting a high degree of flexibility. This flexibility may be responsible to reducing the long distance between the 2Fe- 2S centers in NqrF and NqrD/E, consistent with physiologically relevant electron transfer. Two different types of specific inhibitors (korormicin A and aurachin D-42) bind to the N-terminal region of NqrB, which is disordered in the absence of inhibitors. The current inhibitor-bound structures reasonably explain our previous biochemical findings obtained by different chemistry-based experiments. This study provides a definite foundation for understanding the function of Na+-NQR and the molecular mechanism of its specific inhibitors to support molecular design of new antibiotics targeting the enzyme.
Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators
Authors: Selvakumar Purushotham , Fernández-Mariño Ana I. , Khanra Nandish , He Changhao , Paquette Alice J. , Wang Bing , Huang Ruiqi , Smider Vaughn V. , Rice William J. , Swartz Kenton J. , Meyerson Joel R. 
Published: April 2022

ABSTRACTThe Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. We determined structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer’s voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine induces an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.
High-resolution transcriptomics of bovine purified protein derivative-stimulated peripheral blood from cattle infected withMycobacterium bovisacross an experimental time course
Authors: Correia Carolina N. , McHugo Gillian P. , Browne John A. , McLoughlin Kirsten E. , Nalpas Nicolas C. , Magee David A. , Whelan Adam O. , Villarreal-Ramos Bernardo , Vordermeier H. Martin , Gormley Eamonn , Gordon Stephen V. , MacHugh David E. 
Published: April 2022

AbstractObjectivesImproved bovine tuberculosis (bTB) diagnostics with higher sensitivity and specificity are urgently required. A better understanding of the peripheral blood transcriptional response ofMycobacterium bovis-infected animals after bovine purified protein derivative (PPD-b) stimulation of whole blood—an important component of current bTB diagnostics—will provide new information for development of better diagnostics.MethodsRNA sequencing (RNA-seq) was used to study the peripheral blood transcriptome after stimulation with PPD-b across four time points (-1 wk pre-infection, and +1 wk, +2 wk, and +10 wk post-infection) from a 14-weekM. bovisinfection time course experiment with ten age-matched Holstein-Friesian cattle.ResultsIn vitro PPD-b stimulation of peripheral blood fromM. bovis-infected and non-infected cattle elicited a strong transcriptional response. Comparison of PPD-b stimulated, and unstimulated samples revealed higher expression of genes encoding cytokine receptors, transcription factors, and interferon-inducible proteins. Lower expression was seen for genes encoding proteins involved in antimicrobial activity, C-type lectin receptors, inhibition of signal transduction, and genes encoding metal ion transporters.ConclusionsA transcriptional signature associated with the peripheral blood response to PPD-b stimulation consisting of 170 genes was identified exclusively in the post-infection time points. Therefore, this represents a panel of potential biomarkers ofM. bovisinfection.
mTORC1 activity is essential for disease progression in chronic lymphocytic leukemia
Authors: Malik Natasha , Hay Jodie , Dunn Karen M. , Nakagawa Rinako , Sansom Owen J. , Michie Alison M. 
Published: April 2022

AbstractThe precise role of mechanistic target of rapamycin complex 1 (mTORC1) during chronic lymphocytic leukemia (CLL) pathogenesis remains to be elucidated. Targeted deletion of mTORC1 componentRaptorin adult mice reveals that mTORC1 function is essential for initiation and maintenance of CLL.Raptor-deficient bone marrow-derived PKCα-KR transduced haemopoietic progenitors failed to generate a CLL-like diseasein vitro, due to an inability to overcome the mTORC1-mediated block in B cell lineage commitment. Induction ofRaptor-deficiency in NSG mice transplanted withMx1-RaptorBM-derived PKCα-KR transduced cells after disease was established, revealed a reduced CLL-like disease load and a significant increase in survival in the mice. Interestingly in mice transplanted with an aggressive CLL-like disease, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive leukemic disease. Rapamycin efficiently targeted the translation elongation axis eEF2/eEF2K downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56phosphorylation. Rapamycin treatment of primary CLL cells halted proliferation, modulated eEF2K/eEF2 phosphorylation and inhibited MCL1 expression. Our studies demonstrate that mTORC1 plays an essential role in leukemia progressionin vitroandin vivoin our CLL mouse model, with evidence for increased rapamycin sensitivity in aggressive secondary CLL transplants. Furthermore, the suppression of translation elongation through inactivation of eEF2 may offer a novel therapeutic target for blocking CLL progression.
Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer
Authors: Agarwal Supreet , Fang Lei , McGowen Kerry , Yin JuanJuan , Bowman Joel , Ku Anson T. , Alilin Aian Neil , Corey Eva , Roudier Martine , True Lawrence , Dumpit Ruthy , Coleman Ilsa , Lee John , Nelson Peter S. , Capaldo Brian J. , Mariani Aida , Hoover Clare , Senatorov Ilya S. , Beshiri Michael , Sowalsky Adam G. , Hurt Elaine M , Kelly Kathleen 
Published: April 2022

AbstractAntibody-drug conjugates (ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, conferred sensitivity and were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive(ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 wild-type ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 non-expressors governed response. Significantly, wild-type TP53 predicted non-responsiveness (7/8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.
NIPBL and WAPL balance cohesin activity to regulate chromatin folding and gene expression
Authors: Luppino Jennifer M. , Field Andrew , Nguyen Son C. , Park Daniel S. , Shah Parisha P. , Lan Yemin , Yunker Rebecca , Jain Rajan , Adelman Karen , Joyce Eric F. 
Published: April 2022

AbstractThe relationship between cohesin-mediated chromatin looping and gene expression remains unclear. We investigated the roles of NIPBL and WAPL, two regulators of cohesin activity, in chromatin folding and transcription in human cells. Consistent with their opposing roles in cohesin regulation, depletion of these factors showed opposite effects on levels of chromatin-bound cohesin and spatial insulation of neighboring domains. We find that NIPBL or WAPL depletion each alter the expression of ~2,000 genes, most of which are uniquely sensitive to either regulator. We find that each set of differentially expressed genes are enriched at chromatin loop anchors and clustered within the genome, suggesting there are genomic regions sensitive to either more or less cohesin. Remarkably, co-depletion of both regulators rescued chromatin misfolding and gene misexpression compared to either single knockdown. Taken together, we present a model in which the relative, rather than absolute, levels of NIPBL and WAPL are required to balance cohesin activity in chromatin folding to regulate transcription.
The mitogen-activated protein kinase kinase kinase, ILK5, regulates plant purinergic receptor-mediated, innate immunity
Authors: Kim Daewon , Chen Dongqin , Ahsan Nagib , Thelen Jay J. , Stacey Gary 
Published: April 2022

AbstractMitogen-activated protein (MAP) kinase signaling cascades play important roles in the regulation of eukaryotic defense against various pathogens. Activation of the extracellular ATP (eATP) receptor P2K1 triggers MAP kinase 3 and 6 (MPK3/6) phosphorylation, which leads to elevated defense responses in Arabidopsis. However, the mechanism by which P2K1 activates the MAPK cascade is unclear. In this study, we identified Raf-like MAPKKK ILK5 as a downstream substrate of the P2K1 kinase. P2K1 phosphorylates ILK5 on serine 192. The interaction between P2K1 and ILK5 was confirmed both in vitro and in planta and their interaction was enhanced by ATP treatment. Similar to P2K1 expression, ILK5 expression levels were highly induced by treatment with ATP, flg22, Pseudomonas syringae pv. tomato DC3000, and various abiotic stresses, such as wounding. ILK5 interacts with both MKK4 and MKK5, but only MKK5 is phosphorylated by ILK5. Moreover, phosphorylation of MPK3/6 was significantly reduced upon ATP treatment in ilk5 mutant plants, relative to wild-type. The ilk5 mutant plants showed higher susceptibility to P. syringae pathogen infection relative to wild-type plants. Plants expressing only the mutant ILK5S192A protein, lacking kinase activity, did not activate the MAPK cascade upon ATP addition. Taken together, the results suggest that eATP activation of P2K1 results in transphosphorylation of the Raf-like MAPKKK ILK5, which subsequently triggers the MAPK cascade, culminating in activation of MAPK3 and 6 associated with an elevated innate immunity response.Significance statementPathogens invasion and subsequent wound stress activates extracellular ATP-mediated purinergic signaling cascades, a danger associated molecular pattern (DAMP) signal, which induces phosphorylation of MAPKs. Previous studies revealed that the P2K1 purinergic receptor increases MPK3/6 phosphorylation in response to eATP signaling cascades in Arabidopsis. However, the specific mechanism by which this occurs remains unknown. Here, we describe the isolation and characterization of Raf-like MAPKKK ILK5 (Integrin-linked Kinase 5) as a downstream substrate of P2K1 kinase activity. Initiation of an eATP-dependent signaling pathway by phosphorylation of ILK5 with subsequent activation of MKK5, leading to activation of MPK3/6 and downstream events is crucial to the plant innate immunity response.
T cell Aryl Hydrocarbon Receptor Activity Tunes the Gut Microenvironment to Sustain Autoimmunity and Neuroinflammation
Authors: Merchak Andrea R. , Cahill Hannah J. , Brown Lucille C. , Brown Ryan M. , Rivet-Noor Courtney , Beiter Rebecca M. , Slogar Erica R. , Olgun Deniz G. , Gaultier Alban 
Published: April 2022

AbstractMultiple sclerosis (MS) is a T cell driven autoimmune disease that attacks the myelin of the central nervous system and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to non-pathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR’s precise function in T lymphocytes, the orchestrators of MS, has not been described. Here we show that in a mouse model of MS, T cell specificAhrknockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.
Disruption of anterior temporal lobe reduces distortions in memory from category knowledge
Authors: Tompary Alexa , Xia Alice , Coslett H. Branch , Thompson-Schill Sharon L. 
Published: April 2022

ABSTRACTMemory retrieval does not provide a perfect recapitulation of past events, but instead an imperfect reconstruction of event-specific details and general knowledge. However, it remains unclear whether this reconstruction relies on mixtures of signals from different memory systems, including one supporting general knowledge. Here, we investigate whether the anterior temporal lobe (ATL) distorts new memories due to prior category knowledge. In this experiment (N=36), participants encoded and retrieved image-location associations. Most images’ locations were clustered according to their category, but some were in random locations. With this protocol, we previously demonstrated that randomly located images were retrieved closer to their category cluster relative to their encoded locations, suggesting an influence of category knowledge. We combined this procedure with transcranial magnetic stimulation (TMS) delivered to the left ATL before retrieval. We separately examined event-specific details (error) and category knowledge (bias) to identify distinct signals attributable to different memory systems. We found that TMS to ATL attenuated bias in location memory, but only for atypical category members. The magnitude of error was not impacted, suggesting that a memory’s fidelity can be decoupled from its distortion by category knowledge. This raises the intriguing possibility that retrieval is jointly supported by separable memory systems.
Sorting of secretory proteins at the trans-Golgi network by human TGN46
Authors: Lujan Pablo , Garcia-Cabau Carla , Wakana Yuichi , Lillo Javier Vera , Rodilla-Ramírez Carmen , Sugiura Hideaki , Malhotra Vivek , Salvatella Xavier , Garcia-Parajo Maria F. , Campelo Felix 
Published: April 2022

ABSTRACTSecretory proteins are sorted at the trans-Golgi network (TGN) for export into specific transport carriers. However, the molecular players involved in this fundamental process remain largely elusive. Here, we identified the human transmembrane protein TGN46 as a receptor for the export of secretory cargo protein PAUF in CARTS – a class of protein kinase D-dependent TGN-to-plasma membrane carriers. We show that TGN46 is necessary for cargo sorting and loading into nascent carriers at the TGN. By combining quantitative fluorescence microscopy and mutagenesis approaches, we further discovered that the lumenal domain of TGN46 encodes for its cargo sorting function. In summary, our results define a cellular function of TGN46 in sorting secretory proteins for export from the TGN.
Predicting the trends and cost impact of COVID-19 OSHA citations on US construction contractors using machine learning and simulation
Authors: Sadeh Hooman , Mirarchi Claudio , Shahbodaghlou Farzad , Pavan Alberto 
Published: April 2022

PurposeOccupational Safety and Health Administration (OSHA) of the U.S. government ensures that all health and safety regulations, protecting the workers, are enforced. OSHA officers conduct inspections and assess fines for non-compliance and regulatory violations. Literature discussion on the economic impact of OSHA inspections with COVID-19 related citations for the construction sector is lacking. This study aims to investigate the relationships between the number of COVID-19 cases, construction employment and OSHA citations and it further evaluates the total and monthly predicted cost impact of OSHA citations associated with COVID-19 violations.Design/methodology/approachAn application of multiple regression analysis, a supervised machine learning linear regression model, based on K-fold cross validation sampling and a probabilistic risk-based cost estimate Monte Carlo simulation were utilized to evaluate the data. The data were collected from numerous websites including OSHA, Centers for Disease Control and the World Health Organization.FindingsThe results show that as the monthly construction employment increased, there was a decrease in OSHA citations. Conversely, the cost impact of OSHA citations had a positive relationship with the number of COVID-19 cases. In addition, the monthly cost impact of OSHA COVID-19 related citations along with the total cost impact of citations were predicted and analyzed.Originality/valueThe application of the two models on cost analysis provides a thorough comparison of predicted and overall cost impact, which can assist the contractors to better understand the possible cost ramifications. Based on the findings, it is suggested that the contractors include contingency fees within their contracts, hire safety managers to implement specific safety protocols related to COVID-19 and request a safety action plan when qualifying their subcontractors to avoid potential fines and citations.