bluuebunny/crossref_metadata_2025 huggingface dataset:
Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis
Authors: Teng Yong‐Sheng , Zhao Yong‐Liang , Li Mao‐Shi , Liu Yu‐Gang , Cheng Ping , Lv Yi‐Pin , Mao Fang‐Yuan , Chen Weisan , Yang Shi‐Ming , Hao Chuan‐Jie , Peng Liu‐Sheng , Zhang Jin‐Yu , Zhang Wei‐Jun , Zou Quan‐Ming , Zhuang Yuan
Published: November 2019

BHLHE40, a member of the basic helix‐loop‐helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)‐associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori‐infected GECs express BHLHE40 via cagA‐ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein‐activated p‐STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA‐BHLHE40‐CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.
Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease
Authors: Canet Geoffrey , Pineau Fanny , Zussy Charleine , Hernandez Célia , Hunt Hazel , Chevallier Nathalie , Perrier Véronique , Torrent Joan , Belanoff Joseph K. , Meijer Onno C. , Desrumaux Catherine , Givalois Laurent
Published: November 2019

Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid‐β oligomers (oAβ), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAβ impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAβ potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed‐forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aβ and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.
PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer
Authors: Wang Chao , Feng Yaping , Zhang Chengyue , Cheng David , Wu Renyi , Yang Yuqing , Sargsyan Davit , Kumar Dibyendu , Kong Ah‐Ng
Published: November 2019

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is a tumor suppressor gene and one of the most frequently mutated/deleted genes in human prostate cancer (PCa). However, how PTEN deletion would impact the epigenome and transcriptome alterations remain unknown. This hypothesis was tested in a prostate‐specific PTEN−/− (KO) mouse prostatic adenocarcinoma model through DNA methyl‐Seq and RNA‐Seq analyses. Examination of cancer genomic datasets revealed that PTEN is expressed at lower levels in PTEN‐deleted tumor samples than in normal solid tissue samples. Methylome and transcriptome profiling identified several inflammatory responses and immune response signaling pathways, including NF‐kB signaling, IL‐6 signaling, LPS/IL‐1‐mediated inhibition of RXR Function, PI3K in B lymphocytes, iCOS‐iCOSL in T helper cells, and the role of NFAT in regulating the immune response, were affected by PTEN deletion. Importantly, a small subset of genes that showed DNA hypermethylation or hypomethylation was correlated with decreased or increased gene expression including CXCL1. quantitative polymerase chain reaction analyses of representative genes validated the RNA‐Seq results. Histopathological examinations showed that the severity of prostatic intraepithelial neoplasia and inflammation development gradually increased as PTEN null mice aged. Collectively, these findings suggest that loss of PTEN drives global changes in DNA CpG methylation and transcriptomic gene expression and highly associated with several inflammatory and immune molecular pathways during PCa development. These biomarkers could be valuable molecular targets for cancer drug discovery and development against PCa.
Fasciola helminth defense molecule‐1 protects against experimental arthritis by inhibiting osteoclast formation and function without modulating the systemic immune response
Authors: Khan Yasir Akhtar , Maurya Shailendra Kumar , Kulkarni Chirag , Tiwari Mahesh Chandra , Nagar Geet Kumar , Chattopadhyay Naibedya
Published: November 2019

An inverse correlation between helminth infection and the autoimmune disease appears to be contributed by the anti‐inflammatory factors produced by these organisms. Suppressing osteoclast function without affecting the systemic immunological response is an emerging therapeutic strategy for rheumatoid arthritis (RA). We observed that a synthetic peptide corresponding to 34 amino acids of C‐terminal sequence of Fasciola helminth defense molecule‐1 (C‐FhHDM‐1) inhibited RANKL‐induced osteoclast formation and lysosomal acidification with an attendant upregulation of sequestome1/p62, a negative regulator of NF‐κB expression. C‐FhHDM‐1 also suppressed RANKL production from osteoblasts. Macrophages are the major inflammatory cells in the joints of RA and C‐FhHDM‐1 suppressed ICAM‐1 (an inflammatory surrogate) expression in these cells. In a murine model of collagen II‐induced arthritis (CIA), C‐FhHDM‐1 improved clinical score, protected against cartilage destruction, and maintained bone mass and bone architecture of joints compared with the CIA group. C‐FhHDM‐1 suppressed the CIA‐induced expression of TNF, IL‐17, and IFN‐γ in joints but not their serum levels. The peptide also had no effect on the CIA‐induced suppression of T regulatory response. We conclude that C‐FhHDM‐1 has a joint‐specific protective effect in experimental arthritis without mitigating systemic inflammation, and thus could become an adjuvant anti‐arthritis therapy to prevent RA‐induced osteopenia.
Structure and kinetic properties of human d‐aspartate oxidase, the enzyme‐controlling d‐aspartate levels in brain
Authors: Molla Gianluca , Chaves‐Sanjuan Antonio , Savinelli Antonio , Nardini Marco , Pollegioni Loredano
Published: November 2019

d‐Amino acids are the “wrong” enantiomers of amino acids as they are not used in proteins synthesis but evolved in selected functions. On this side, d‐aspartate (d‐Asp) plays several significant roles in mammals, especially as an agonist of N‐methyl‐d‐aspartate receptors (NMDAR), and is involved in relevant diseases, such as schizophrenia and Alzheimer's disease. In vivo modulation of d‐Asp levels represents an intriguing task to cope with such pathological states. As little is known about d‐Asp synthesis, the only option for modulating the levels is via degradation, which is due to the flavoenzyme d‐aspartate oxidase (DASPO). Here we present the first three‐dimensional structure of a DASPO enzyme (from human) which belongs to the d‐amino acid oxidase family. Notably, human DASPO differs from human d‐amino acid oxidase (attributed to d‐serine degradation, the main coagonist of NMDAR) showing peculiar structural features (a specific active site charge distribution), oligomeric state and kinetic mechanism, and a higher FAD affinity and activity. These results provide useful insights into the structure‐function relationships of human DASPO: modulating its activity represents now a feasible novel therapeutic target.
DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2‐DMR0 as a DNA methylation‐dependent, P0 promoter‐specific enhancer
Authors: Watanabe Hidetaka , Higashimoto Ken , Miyake Noriko , Morita Sumiyo , Horii Takuro , Kimura Mika , Suzuki Takayuki , Maeda Toshiyuki , Hidaka Hidenori , Aoki Saori , Yatsuki Hitomi , Okamoto Nobuhiko , Uemura Tetsuji , Hatada Izuho , Matsumoto Naomichi , Soejima Hidenobu
Published: November 2019

Haploinsufficiency of NSD1, which dimethylates histone H3 lysine 36 (H3K36), causes Sotos syndrome (SoS), an overgrowth syndrome. DNMT3A and DNMT3B recognizes H3K36 trimethylation (H3K36me3) through PWWP domain to exert de novo DNA methyltransferase activity and establish imprinted differentially methylated regions (DMRs). Since decrease of H3K36me3 and genome‐wide DNA hypomethylation in SoS were observed, hypomethylation of imprinted DMRs in SoS was suggested. We explored DNA methylation status of 28 imprinted DMRs in 31 SoS patients with NSD1 defect and found that hypomethylation of IGF2‐DMR0 and IG‐DMR in a substantial proportion of SoS patients. Luciferase assay revealed that IGF2‐DMR0 enhanced transcription from the IGF2 P0 promoter but not the P3 and P4 promoters. Chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) revealed active enhancer histone modifications at IGF2‐DMR0, with high enrichment of H3K4me1 and H3 lysine 27 acetylation (H3K27ac). CRISPR‐Cas9 epigenome editing revealed that specifically induced hypomethylation at IGF2‐DMR0 increased transcription from the P0 promoter but not the P3 and P4 promoters. NSD1 knockdown suggested that NSD1 targeted IGF2‐DMR0; however, IGF2‐DMR0 DNA methylation and IGF2 expression were unaltered. This study could elucidate the function of IGF2‐DMR0 as a DNA methylation dependent, P0 promoter‐specific enhancer. NSD1 may play a role in the establishment or maintenance of IGF2‐DMR0 methylation during the postimplantation period.
Phellinus linteus polysaccharide extract improves insulin resistance by regulating gut microbiota composition
Authors: Liu Yangyang , Wang Chaorui , Li Jinshan , Li Tiantian , Zhang Yong , Liang Yunxiang , Mei Yuxia
Published: November 2019

The hypoglycemic effect of Phellinus linteus polysaccharide extract (PLPE) has been documented in several previous studies, but the functional interactions among PLPE, gut microbiota, and the hypoglycemic effect remain unclear. We examined the regulatory effect of PLPE on gut microbiota, and the molecular mechanism underlying improvement of insulin resistance, using a type 2 diabetic rat model. Here, 24 male Sprague‐Dawley rats were randomly divided into four groups that were subjected to intervention of saline (normal and model control group), metformin (120 mg/kg.bw), and PLPE (600 mg/kg.bw) by oral administration. After 8 weeks of treatment, PLPE increased levels of short‐chain fatty acids (SCFAs) by enhancing abundance of SCFA‐producing bacteria. SCFAs maintained intestinal barrier function and reduced lipopolysaccharides content in blood, thereby helping to reduce systemic inflammation and reverse insulin resistance. Our findings suggest that PLPE (in which polysaccharides are the major component) has potential application as a prebiotic for regulating gut microbiota composition in diabetic patients.
Nucleolar control by a non‐apoptotic p53‐caspases‐deubiquitinylase axis promotes resistance to bacterial infection
Authors: Chen Po‐Hsiang , Chen Yi‐Tung , Chu Tai‐Ying , Ma Tian‐Hsiang , Wu Mei‐Hsuan , Lin Hsi‐Hsien , Chang Yu‐Sun , Tan Bertrand Chin‐Ming , Lo Szecheng J.
Published: November 2019

The nucleolus is best known for its cellular role in regulating ribosome production and growth. More recently, an unanticipated role for the nucleolus in innate immunity has recently emerged whereby downregulation of fibrillarin and nucleolar contraction confers pathogen resistance across taxa. The mechanism of this downregulation, however, remains obscure. Here we report that rather than fibrillarin itself being the proximal factor in this pathway, the key player is a fibrillarin‐stabilizing deubiquitinylase USP‐33. This was discovered by a candidate‐gene search of Caenorhabditis elegans in which CED‐3 caspase was revealed to execute targeted cleavage of USP‐33, thus destabilizing fibrillarin. We also showed that cep‐1 and ced‐3 mutant worms altered nucleolar size and decreased antimicrobial peptide gene, spp‐1, expression rendering susceptibility to bacterial infection. These phenotypes were reversed by usp‐33 knockdown, thus linking the CEP‐1‐CED‐3‐USP‐33 pathway with nucleolar control and resistance to bacterial infection in worms. Parallel experiments with the human analogs of caspases and USP36 revealed similar roles in coordinating these two processes. In summary, our work outlined a conserved cascade that connects cell death signaling to nucleolar control and innate immune response.
Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling
Authors: Bhedi Chinmayee D. , Nasirova Sabina , Toksoz Deniz , Warburton Rod R. , Morine Kevin J. , Kapur Navin K. , Galper Jonas B. , Preston Ioana R. , Hill Nicholas S. , Fanburg Barry L. , Penumatsa Krishna C.
Published: November 2019

The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose‐induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose‐induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis‐mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia.
A new workflow combining R packages for statistical analysis of metabolites
Authors: Ferrario Paola G.
Published: November 2019

In metabolomics, the investigation of an association between many metabolites and one trait (such as age in humans or cultivar in foods) is a central research question. On this topic, we present a complete statistical analysis, combining selected R packages in a new workflow, which we are sharing completely, according to modern standards and research reproducibility requirements. We demonstrate the workflow using a large-scale study with public data, available on repositories. Hence, the workflow can directly be re-used on quite different metabolomics data, when searching for association with one covariate of interest.
Gamma coherence mediates interhemispheric integration during multiple object tracking
Authors: Bland Nicholas S. , Mattingley Jason B. , Sale Martin V.
Published: November 2019

Our ability to track the paths of multiple visual objects moving between the hemifields requires effective integration of information between the two cerebral hemispheres. Coherent neural oscillations in the gamma band (35–70 Hz) are hypothesised to drive this information transfer. Here we manipulated the need for interhemispheric integration using a novel multiple object tracking (MOT) task in which stimuli either moved between the two visual hemifields—requiring interhemispheric integration—or moved within separate visual hemifields. We used electroencephalography (EEG) to measure interhemispheric coherence during the task. Human observers (21 female; 20 male) were poorer at tracking objects between-versus within-hemifields, reflecting a cost of interhemispheric integration. Critically, gamma coherence was greater in trials requiring interhemispheric integration, particularly between sensors over parieto-occipital areas. In approximately half of the participants, the observed cost of integration was associated with a failure of the cerebral hemispheres to become coherent in the gamma band. Moreover, individual differences in this integration cost correlated with endogenous gamma coherence at these same sensors, though with generally opposing relationships for the real and imaginary part of coherence. The real part (capturing synchronisation with a near-zero phase-lag) benefited between-hemifield tracking; imaginary coherence was detrimental. Finally, instantaneous phase-coherence over the tracking period uniquely predicted between-hemifield tracking performance, suggesting that effective integration benefits from sustained interhemispheric synchronisation. Our results show that gamma coherence mediates interhemispheric integration during MOT, and add to a growing body of work demonstrating that coherence drives communication across cortically distributed neural networks.
Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
Authors: Lucey Maria , Pickford Philip , Minnion James , Ungewiss Jan , Schoeneberg Katja , Rutter Guy A , Bloom Stephen R , Tomas Alejandra , Jones Ben
Published: November 2019

Objective

To determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy and appetite suppression.

Methods

In vitro signalling responses were measured using biochemical and biosensor assays. GLP-1 receptor trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects and appetite suppression were measured in acute, sub-chronic and chronic settings in mice.

Results

A C-terminally acylated ligand, exendin-phe1-C16, was identified with undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator exendin-asp-3-C16 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.

Conclusions

C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
Mushroom Body Homology and Divergence across Pancrustacea
Authors: Strausfeld Nicholas J. , Wolff Gabriella H. , Sayre Marcel E.
Published: November 2019

Descriptions of crustacean brains have mainly focused on three highly derived lineages: the reptantian infraorders represented by spiny lobsters, lobsters, and crayfish. Those descriptions advocate the view that dome- or cap-like neuropils, referred to as “hemiellipsoid bodies,” are the ground pattern organization of centers that are comparable to insect mushroom bodies in processing olfactory information. Here we challenge the doctrine that hemiellipsoid bodies are a derived trait of crustaceans, whereas mushroom bodies are a derived trait of hexapods. We demonstrate that mushroom bodies typify lineages that arose before Reptantia and exist in Reptantia. We show that evolved variations of the mushroom body ground pattern are, in some lineages, defined by extreme diminution or loss and, in others, by the incorporation of mushroom body circuits into lobeless centers. Such transformations are ascribed to modifications of the columnar organization of mushroom body lobes that, as shown inDrosophilaand other hexapods, contain networks essential for learning and memory. We propose that lobed mushroom bodies distinguish crustaceans that negotiate the multidimensionality of complex ecologies, where continuous updating of multistimulus valence and memory is paramount.
Extensive ethnolinguistic diversity in Vietnam reflects multiple sources of genetic diversity
Authors: Liu Dang , Duong Nguyen Thuy , Ton Nguyen Dang , Van Phong Nguyen , Pakendorf Brigitte , Hai Nong Van , Stoneking Mark
Published: November 2019

Vietnam features extensive ethnolinguistic diversity and occupies a key position in Mainland Southeast Asia (MSEA). Yet, the genetic diversity of Vietnam remains relatively unexplored, especially with genome-wide data, because previous studies have focused mainly on the majority Kinh group. Here we analyze newly-generated genome-wide SNP data for the Kinh and 21 additional ethnic groups in Vietnam, encompassing all five major language families in MSEA. In addition to analyzing the allele and haplotype sharing within the Vietnamese groups, we incorporate published data from both nearby modern populations and ancient samples for comparison. We find that the Vietnamese ethnolinguistic groups harbor multiple sources of genetic diversity that are associated with heterogeneous ancestry sharing profiles in each language family. However, linguistic diversity does not completely match genetic diversity; there have been extensive interactions between the Hmong-Mien and Tai-Kadai groups, and a likely case of cultural diffusion in which some Austro-Asiatic groups shifted to Austronesian languages. Overall, our results highlight the importance of genome-wide data from dense sampling of ethnolinguistic groups in providing new insights into the genetic diversity and history of an ethnolinguistically-diverse region, such as Vietnam.
Spontaneous generation of innate number sense in untrained deep neural networks
Authors: Kim Gwangsu , Jang Jaeson , Baek Seungdae , Song Min , Paik Se-Bum
Published: November 2019

Number-selective neurons are observed in numerically naïve animals, but it was not understood how this innate function emerges in the brain. Here, we show that neurons tuned to numbers can arise in random feedforward networks, even in the complete absence of learning. Using a biologically inspired deep neural network, we found that number tuning arises in three cases of networks: one trained to non-numerical natural images, one randomized after trained, and one never trained. Number-tuned neurons showed characteristics that were observed in the brain following the Weber-Fechner law. These neurons suddenly vanished when the feedforward weight variation decreased to a certain level. These results suggest that number tuning can develop from the statistical variation of bottom-up projections in the visual pathway, initializing innate number sense.
Island species-area relationships in the Andaman islands emerge because rarer species are disproportionately favored on larger islands
Authors: Gooriah Leana D. , Davidar Priya , Chase Jonathan M.
Published: November 2019

The Island Species-Area relationship (ISAR) describes how the number of species increases with increasing size of an island (or island-like habitat), and is of fundamental importance in island biogeography and conservation. Here, we use a framework based on individual-based rarefactions to infer whether ISARs result from random sampling, or whether some process are acting beyond sampling (e.g., disproportionate effects and/or habitat heterogeneity). Using data on total and relative abundances of four taxa (birds, butterflies, amphibians and reptiles) across the Andamans and Nicobar archipelago, we examine how different metrics of biodiversity (total species richness, rarefied species richness, and abundance-weighted effective numbers of species emphasizing common species) vary with island area. Total species richness increased for all taxa, as did rarefied species richness for a given sampling effort. This indicates that the ISAR did not result because of random sampling, but that instead, species were disproportionately favored on larger islands. This disproportionate effect was primarily due to changes in the abundance of rarer species, because there was no effect on the abundance-weighted diversity measure for all taxa except butterflies. Furthermore, for the two taxa for which we had plot-level data (lizards and frogs), within-island β -diversity did not increase with island size, suggesting that heterogeneity effects were unlikely to be driving these ISARS. Overall, our results indicate that the ISAR of these taxa is most likely because rarer species are more likely to survive and persist beyond that which would have been expected by random sampling alone, and emphasizes the role of these larger islands in the preservation and conservation of species.
VIP interneurons selectively enhance weak but behaviorally-relevant stimuli
Authors: Millman Daniel J. , Ocker Gabriel Koch , Caldejon Shiella , Kato India , Larkin Josh D. , Lee Eric Kenji , Luviano Jennifer , Nayan Chelsea , Nguyen Thuyanh V. , North Kat , Seid Sam , White Cassandra , Lecoq Jerome A. , Reid R. Clay , Buice Michael A. , de Vries Saskia E.J.
Published: November 2019

Vasoactive intestinal peptide-expressing (VIP) interneurons in cortex regulate feedback inhibition of pyramidal neurons through suppression of somatostatin-expressing (SST) interneurons and, reciprocally, SST neurons inhibit VIP neurons. Here, we show that VIP neurons in mouse primary visual cortex have complementary contrast tuning to SST neurons and respond synergistically to front-to-back visual motion and locomotion. Network modeling indicates that this VIP-SST mutual antagonism regulates the gain of cortex to achieve both sensitivity to behaviorally-relevant stimuli and network stability.
Herpes Simplex Virus Glycoprotein C Regulates Low pH Entry
Authors: Sari Tri Komala , Gianopulos Katrina A. , Weed Darin J. , Schneider Seth M. , Pritchard Suzanne M. , Nicola Anthony V.
Published: November 2019

Herpes simplex viruses (HSVs) cause significant morbidity and mortality in humans worldwide. Herpesviruses mediate entry by a multi-component, virus-encoded machinery. Herpesviruses enter cells by endosomal low pH and pH-neutral mechanisms in a cell-specific manner. HSV mediates cell entry via envelope glycoproteins gB, gD, and the heterodimer gH/gL regardless of pH or endocytosis requirements. HSV envelope proteins that function selectively in a given entry pathway have been elusive. Here we demonstrate that gC regulates cell entry and infection by a low pH pathway. Conformational changes in the core herpesviral fusogen gB are critical for membrane fusion. The presence of gC conferred a higher pH threshold to acid-induced antigenic changes in gB. Thus, gC may selectively facilitate low pH entry by regulating conformational changes in the fusion protein gB. We propose that gC modulates the HSV fusion machinery during entry into pathophysiologically relevant cells, such as human epidermal keratinocytes.

Importance

Herpesviruses are ubiquitous pathogens that cause lifelong latent infections and are characterized by multiple entry pathways. We propose that herpes simplex virus (HSV) gC plays a selective role in modulating HSV entry by a low pH pathway, such as into epithelial cells. gC facilitates conformational change of the main fusogen gB, a class III fusion protein. We propose a model whereby gC functions with gB, gD, and gH/gL to allow low pH entry. In the absence of gC, HSV entry occurs at a lower pH, coincident with trafficking to a lower pH compartment where gB changes occur at more acidic pHs. This study identifies a new function for gC and provides novel insight into the complex mechanism of HSV entry and fusion.
A physicochemical roadmap of yeast replicative aging
Authors: Mouton Sara N. , Thaller David J. , Crane Matthew M. , Rempel Irina L. , Steen Anton , Kaeberlein Matt , Lusk C. Patrick , Boersma Arnold J. , Veenhoff Liesbeth M.
Published: November 2019

Cellular aging is a multifactorial process that is characterized by a decline in homeostatic capacity, best described at the molecular level. Physicochemical properties such as pH and macromolecular crowding, are essential to all molecular processes in cells and require maintenance. Whether a drift in physicochemical properties contributes to the overall decline of homeostasis in aging is not known. Here we show that the cytosol of yeast cells acidifies modestly in early aging and sharply after senescence. Using a macromolecular crowding sensor optimized for long-term FRET measurements, we show the macromolecular crowding changes less in longer-lived cells in contrast to shorter-lived cells. While the average pH and crowding levels change only modestly with aging, we observe drastic changes in organellar volume, leading to crowding on the µm scale, which we term organellar crowding. Our measurements provide an initial framework of physicochemical parameters of replicatively-aged yeast cells.
E2F-dependent genetic oscillators control endoreplication
Authors: Kim Minhee , Moon Nam-Sung
Published: November 2019

Polyploidy is an integral part of development and is associated with cellular stress, aging and pathological conditions. The endoreplication cycle, comprised of successive alternations of G and S phases without cell division, is widely employed to produce polyploid cells. The endocycle is driven by continuous oscillations of Cyclin E/Cdk2 activity, which is governed by E2F transcription factors. In this study, we provide mechanistic insight on how E2F-dependent Cdk oscillations during endocycles are maintained in Drosophila salivary glands. Genetic experiments revealed that an alternative splicing isoform of E2F1, E2F1b, regulates the circuitry of timely S phase entry and exit by activating a subset of E2F target genes. E2F1b regulates the Drosophila ortholog of p27CIP/KIP-like Cdk inhibitor Dacapo to precisely time S phase entry by controlling the CycE/Cdk2 activity threshold. Upon entry to S phase, E2F1b-dependent PCNA expression establishes a negative feedback loop through the PIP box-mediated degradation of E2F1. Overall, our study uncovers a network of E2F-dependent genetic oscillators that are critical for the periodic transition between G and S phases during endoreplication.
The SWI/SNF subunits BRG1 affects alternative splicing by changing RNA binding factor interactions with RNA
Authors: Zapater Antoni Gañez , Mackowiak Sebastian D. , Guo Yuan , Jordan-Pla Antonio , Friedländer Marc R. , Visa Neus , Farrants Ann-Kristin Östlund
Published: November 2019

BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes. The function of the SWI/SNF complexes in transcriptional initiation has been well studied, while a function in alternative splicing has only been studied for a few cases for BRM-containing SWI/SNF complexes. Here, we have expressed BRG1 in C33A cells, a BRG1 and BRM-deficient cell line, and we have analysed the effects on the transcriptome by RNA sequencing. We have shown that BRG1 expression affects the splicing of a subset of genes. For some, BRG1 expression favours exon inclusion and for others, exon skipping. Some of the changes in alternative splicing induced by BRG1 expression do not require the ATPase activity of BRG1. Among the exons regulated through an ATPase-independent mechanism, the included exons had signatures of high GC-content and lacked a positioned nucleosome at the exon. By investigating three genes in which the expression of either wild-type BRG1 or a BRG1-ATPase-deficient variant favoured exon inclusion, we showed that expression of the ATPases promotes the local recruitment of RNA binding factors to chromatin and RNA in a differential manner. The hnRNPL, hnRNPU and SAM68 proteins associated to chromatin in C33A cells expressing BRG1 or BRM, but their association with RNA varied. We propose that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and altering their binding to the nascent pre-mRNA, which changes RNP structure.

Author summary

Splicing, in particular alternative splicing, is a combinatorial process which involves splicing factor complexes and many RNA binding splicing regulatory proteins in different constellations. Most splicing events occur during transcription, which also makes the DNA sequence, the chromatin state and the transcription rate at the exons important components that influence the splicing outcome. We show here that the ATP-dependent chromatin remodelling complex SWI/SNF influences the interactions of splicing regulatory factors with RNA during transcription on certain exons that have a high GC-content. The splicing on this type of exon rely on the ATPase BRG1 and favour inclusion of alternative exons in an ATP-independent manner. SWI/SNF complexes are known to alter the chromatin structure at promoters in transcription initiation, and have been previously shown to alter the transcription rate or nucleosome position in splicing. Our results suggests a further mechanism for chromatin remodelling proteins in splicing: to change the interaction patterns of RNA binding splicing regulatory factors at alternative exons to alter the splicing outcome.
Effects of a novel three-dimensional grid intrauterine device on the uterus, steroid receptor and PAX2 of rhesus macaques
Authors: Zhang Mei-Hua , Zhai Li-Ping , Yu Ling , Song Xia , Yu Jian-Chun , Qiu Yi
Published: November 2019

Intrauterine devices (IUDs) is the most effective methods of the reversible and long-acting contraception. 1) To develop a novel three-dimensional grid intrauterine device (3-DGIUD) with nickel-titanium (Ni-Ti) and silicone rubber. 2) To observe the effect of the 3-DGIUD on contraceptive efficacy and the change of uterus, endometrial sex steroid receptor, PAX2 in rhesus macaques (Macaca mulatta). The materials of the 3-DGIUD were the nitinol wire and the silicone rubber. The frame of the 3-DGIUD was three-dimensional and grid-like. Twenty adult female rhesus macaques were divided into the 3-DGIUD group (placing the 3-DGIUD, n=9), the sham operation group (no placing the 3-DGIUD, n=9) and the control group (n=2). On the 10th-day after surgery, the 3-DGIUD group and the sham operation group macaques were caged together with male macaques (female: male = 1:1). The uterus, 3-DGIUD and pregnancy of 18 female rhesus monkeys were examined by abdominal ultrasound every month. The endometrium pathological examination was carried out and the expression of PAX2 and hormone receptor (ER, PR) was detected by immunohistochemical staining. After 3-DGIUD was placed in case group for 3 and 12 months, only 1 of female macaque was pregnant in 9. The contraceptive effective rate was 88.9% (8/9). The 3-DGIUD in the uterus of macaques was observed by ultrasound. In the sham operation group, 9 macaques were pregnant (9/9). There was significant difference in uterine size of the 3-DGIUD group between pre-placement and after surgery for 3 and 12 months (P<0.05). The endometrial epithelium was intact, just a small number of glands vacuoles and a few neutrophils infiltration around the 3-DGIUD. The expression of endometrial ER, PR and PAX2 in 3-DGIUD group on 12 months after surgery was similar to those in control macaque. The 3-DGIUD has a good contraceptive effect on female macaques, and has no significant affection on the expression of endometrial steroid receptor and PAX2 in rhesus monkeys.
Physiological response to slalom water skiing: A case study of a sit-skier with paraplegia
Authors: Suárez-Iglesias David , Pérez Carlos Ayán , Rodríguez-Marroyo José Antonio , Villa-Vicente José Gerardo
Published: November 2019

Recreational and competitive slalom waterskiing is popular among those with spinal cord injuries. People with paraplegia can practice on the slalom course using a sit-ski. A slalom run consists of a boat towing the sit-skier through a set of buoys and normally begins with a deep-water start. Despite its popularity, very little is known about the physiological aspects of the sit-skier's preparation. We examined the internal training load (TL) experienced by a sit-skier with paraplegia while learning and improving the slalom deep-water starts, executed with both the traditional technique and an alternative method. The TL was determined by means of heart rate (HR) and session rating of perceived exertion (sRPE) methods. The percentage of maximal heart rate values ranged from from 63.2% to 81.3% during deep-water starts. Training sessions were performed most of the time below the ventilatory threshold and tended to be qualitatively described as hard. A moderate but non-significant correlation existed between HR and sRPE-based methods. We also found a significant decrement in handgrip strength after practice. These findings indicate that the intensity of training experienced by our sit-skier was moderate in terms of physiological internal load during an adaptive slalom waterskiing training program.
Clinically significant acute pain disturbs motor cortex intracortical inhibition and facilitation in orthopedic trauma patients: A TMS study
Authors: Jodoin Marianne , Rouleau Dominique M. , Bellemare Audrey , Provost Catherine , Larson-Dupuis Camille , Sandman Émilie , Laflamme G-Yves , Benoit Benoit , Leduc Stéphane , Levesque Martine , Gosselin Nadia , De Beaumont Louis
Published: November 2019

Objective

Primary motor (M1) cortical excitability alterations are involved in the development and maintenance of chronic pain. Less is known about M1-cortical excitability implications in the acute phase of an orthopedic trauma. This study aims to assess acute M1-cortical excitability in patients with an isolated upper limb fracture (IULF) in relation to pain intensity.

Methods

Eighty-four (56 IULF patients <14 days post-trauma and 28 healthy controls) performed a single transcranial magnetic stimulation (TMS) session over M1 (resting motor threshold (rMT); short-intracortical inhibition (SICI); intracortical facilitation (ICF); long-interval cortical inhibition (LICI)). IULF patients were divided into two subgroups according to pain intensity (mild versus moderate to severe pain).

Results

Reduced SICI and ICF were found in IULF patients with moderate to severe pain, whereas mild pain was not associated with M1 alterations. Age, sex, and time since the accident had no influence on TMS measures.

Discussion

These findings show altered M1 in the context of acute moderate to severe pain, suggesting early signs of altered GABAergic inhibitory and glutamatergic facilitatory activities.
Cestode larvae excite host neuronal circuits via glutamatergic signaling
Authors: de Lange Anja , Tomes Hayley , Selfe Joshua S , Prodjinotho Ulrich Fabien , Verhoog Matthijs B , Mahanty Siddhartha , Smith Katherine , Horsnell William , Sikasunge Chummy , da Costa Clarissa Prazeres , Raimondo Joseph V
Published: November 2019

Neurocysticercosis (NCC) is caused by infection of the brain by larvae of the parasitic cestodeTaenia solium. It is the most prevalent parasitic infection of the central nervous system and one of the leading causes of adult-acquired epilepsy worldwide. However, little is known about how cestode larvae affect neurons directly. To address this, we used whole-cell patch-clamp electrophysiology and calcium imaging in rodent and human brain slices to identify direct effects of cestode larval products on neuronal activity. We found that both whole cyst homogenate and excretory/secretory products of cestode larvae have an acute excitatory effect on neurons, which can trigger seizure-like eventsin vitro. Underlying this effect was cestode-induced neuronal depolarization, which was mediated by glutamate receptor activation but not by nicotinic acetylcholine receptors, acid-sensing ion channels nor Substance P. Glutamate-sensing fluorescent reporters (iGluSnFR) and amino acid assays revealed that the larval homogenate of the cestodesTaenia crassicepsandTaenia soliumcontained high concentrations of the amino acids glutamate and aspartate. Furthermore, we found that larvae of both species consistently produce and release these excitatory amino acids into their immediate environment. Our findings suggest that perturbations in glutamatergic signaling may play a role in seizure generation in NCC.
Hierarchical modeling of mechano-chemical dynamics of epithelial sheets across cells and tissue
Authors: Asakura Yoshifumi , Kondo Yohei , Aoki Kazuhiro , Naoki Honda
Published: November 2019

Collective cell migration is a macroscopic population-level phenomenon that has emerged across hierarchy from mi-croscopic interactions between cells; however, the underlying mechanism remains unclear. Here, we targeted epithe-lial collective cell migration, driven by the mechanical force regulated by chemical signals of traveling ERK activation waves, observed in wound healing. We propose a hierarchical mathematical framework for understanding how cells are orchestrated through mechanochemical cell-cell interaction. We mathematically transformed a particle-based model at the cellular level into a continuum model at the tissue level. The continuum model described relationships between cell migration and mechanochemical variables, namely, ERK activity gradients, cell density, and velocity field, which could be compared with live-cell imaging data. The continuum model recapitulated the ERK wave-induced collective cell migration in wound healing. We also numerically confirmed a consistency between the two models. This framework allows us to connect hierarchical causality from the single-cell level to the tissue level.
Crystal structures and Hirshfeld surface analyses of (E)-N′-benzylidene-2-oxo-2H-chromene-3-carbohydrazide and the disordered hemi-DMSO solvate of (E)-2-oxo-N′-(3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide: lattice energy and intermolecular interaction energy calculations for the former. Corrigendum
Authors: Gomes Ligia R. , Low John Nicolson , Wardell James L. , Capelini Camila , Figueroa Villar José Daniel , Câmara Vitoria R.F. , da Silva Edson F. , Carvalho Samir A.
Published: November 2019

In the paper by Gomes et al. [Acta Cryst. (2019), E75, 1403–1410], there was an error and omission in the author and affiliation list.
Crystal structure, Hirshfeld surface analysis and DFT studies of 2-[5-(4-methylbenzyl)-6-oxo-3-phenyl-1,6-dihydropyridazin-1-yl]acetic acid
Authors: Daoui Said , Baydere Cemile , El Kalai Fouad , Mahi Lhassane , Dege Necmi , Karrouchi Khalid , Benchat Noureddine
Published: November 2019

The title pyridazinone derivative, C20H18N2O3, is not planar. The phenyl ring and the pyridazine ring are inclined to each other by 10.55 (12)°, whereas the 4-methylbenzyl ring is nearly orthogonal to the pyridazine ring, with a dihedral angle of 72.97 (10)°. In the crystal, molecules are linked by pairs of O—H...O hydrogen bonds, forming inversion dimers with an R
2
2(14) ring motif. The dimers are linked by C—H...O hydrogen bonds, generating ribbons propagating along the c-axis direction. The intermolecular interactions were additionally investigated using Hirshfeld surface analysis and two-dimensional fingerprint plots. They revealed that the most significant contributions to the crystal packing are from H...H (48.4%), H...O/O...H (21.8%) and H...C/C...H (20.4%) contacts. Molecular orbital calculations providing electron-density plots of HOMO and LUMO molecular orbitals and molecular electrostatic potentials (MEP) were also computed, both with the DFT/B3LYP/6–311 G++(d,p) basis set.
Crystal structure, computational study and Hirshfeld surface analysis of ethyl (2S,3R)-3-(3-amino-1H-1,2,4-triazol-1-yl)-2-hydroxy-3-phenylpropanoate
Authors: Ben Ali Abdelkader , El Bakri Youness , Lai Chin-Hung , Sebhaoui Jihad , El Ghayati Lhoussaine , Essassi El Mokhtar , Mague Joel T.
Published: November 2019

In the title molecule, C13H16N4O3, the mean planes of the phenyl and triazole rings are nearly perpendicular to one another as a result of the intramolecular C—H...O and C—H...π(ring) interactions. In the crystal, layers parallel to (101) are generated by O—H...N, N—H...O and N—H...N hydrogen bonds. The layers are connected by inversion-related pairs of C—H...O hydrogen bonds. The experimental molecular structure is close to the gas-phase geometry-optimized structure calculated by DFT methods. Hirshfeld surface analysis indicates that the most important interaction involving hydrogen in the title compound is the H...H contact. The contribution of the H...O, H...N, and H...H contacts are 13.6, 16.1, and 54.6%, respectively.
The crystal structure of the triclinic polymorph of 1,4-bis([2,2′:6′,2′′-terpyridin]-4′-yl)benzene
Authors: Sedykh Alexander E. , Kurth Dirk G. , Müller-Buschbaum Klaus
Published: November 2019

The title triclinic polymorph (Form I) of 1,4-bis([2,2′:6′,2′′-terpyridin]-4′-yl)benzene, C36H24N6, was formed in the presence of the Lewis acid yttrium trichloride in an attempt to obtain a coordination compound. The crystal structure of the orthorhombic polymorph (Form II), has been described previously [Fernandes et al. (2010). Acta Cryst. E66, o3241–o3242]. The asymmetric unit of Form I consists of half a molecule, the whole molecule being generated by inversion symmetry with the central benzene ring being located about a crystallographic centre of symmetry. The side pyridine rings of the 2,2′:6′,2′′-terpyridine (terpy) unit are rotated slightly with respect to the central pyridine ring, with dihedral angles of 8.91 (8) and 10.41 (8)°. Opposite central pyridine rings are coplanar by symmetry, and the angle between them and the central benzene ring is 49.98 (8)°. The N atoms of the pyridine rings inside the terpy entities, N...N...N, lie in trans–trans positions. In the crystal, molecules are linked by C—H...π and offset π–π interactions [intercentroid distances are 3.6421 (16) and 3.7813 (16) Å], forming a three-dimensional structure.
Rubidium tetrafluoridobromate(III): redetermination of the crystal structure from single-crystal X-ray diffraction data
Authors: Malin Artem V. , Ivlev Sergei I. , Ostvald Roman V. , Kraus Florian
Published: November 2019

Single crystals of rubidium tetrafluoridobromate(III), RbBrF4, were grown by melting and recrystallizing RbBrF4 from its melt. This is the first determination of the crystal structure of RbBrF4 using single-crystal X-ray diffraction data. We confirmed that the structure contains square-planar [BrF4]− anions and rubidium cations that are coordinated by F atoms in a square-antiprismatic manner. The compound crystallizes in the KBrF4 structure type. Atomic coordinates and bond lengths and angles were determined with higher precision than in a previous report based on powder X-ray diffraction data [Ivlev et al. (2015). Z. Anorg. Allg. Chem.
641, 2593–2598].