bluuebunny/crossref_metadata_2025 huggingface dataset:
Aggregated gene co-expression networks for predicting transcription factor regulatory landscapes in a non-model plant species
Authors: Orduña-Rubio Luis , Santiago Antonio , Navarro-Payá David , Zhang Chen , Wong Darren C. J. , Matus J. Tomás
Published: April 2023

Gene co-expression networks (GCNs) have not been extensively studied in non-model plants. However, the rapid accumulation of transcriptome datasets in these species represents an opportunity to explore underutilized network aggregation approaches that highlight robust co-expression interactions and improve functional connectivity. We applied and evaluated two different aggregation methods on public grapevine RNA- Seq datasets belonging to three different tissue conditions (leaf, berry and ‘all organs’). Our results show that co-occurrence-based aggregation generally yielded the best-performing networks. We applied GCNs to study several TF gene families, showing its capacity of detecting both already-described and novel regulatory relationships between R2R3-MYBs, bHLH/MYC and multiple secondary metabolism pathway reactions. Specifically, TF gene-and pathway-centered network analyses successfully ascertained the previously established role ofVviMYBPA1in controlling the accumulation of proanthocyanidins while providing insights into its novel role as a regulator ofp-coumaroyl-CoA biosynthesis as well as the shikimate and aromatic amino-acid pathways. This network was validated using DNA Affinity Purification Sequencing data, demonstrating that co-expression networks of transcriptional activators can serve as a proxy of gene regulatory networks. This study presents an open repository to reproduce networks and a GCN application within the Vitviz platform, a user-friendly tool for exploring co-expression relationships.
Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding
Authors: Wiedemann C. , Whittaker J.J. , Pérez Carrillo V.H. , Goretzki B. , Dajka M. , Tebbe F. , Harder J.-M. , Krajczy P. , Joseph B. , Hausch F. , Guskov A. , Hellmich U.A.
Published: April 2023

Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens includingLegionella pneumophila, the causative agent of Legionnaires’ disease and protozoans such asTrypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans- isomerase domain that hence presents an attractive drug target. Some MIPs such as theLegionella pneumophilaprotein (LpMIP) have additional appendage domains of mostly unknown function. In full- length, homodimericLpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures ofLpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors toL. pneumophilaandT. cruziMIP was greatly improved. The resulting X-ray inhibitor-complex structures ofLpMIP andTcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.
Autophagic activity acts as a rheostat in the control of nitrogen transfer from Arabidopsis rosette leaves to the seeds according to a principle of communicating vessels
Authors: James Maxence , Trouverie Jacques , Marmagne Anne , Chardon Fabien , Etienne Philippe , Masclaux-Daubresse Céline
Published: April 2023

Macroautophagy is known for long as essential for the degradation and the recycling of different macromolecules in eukaryotes. However how important is autophagy for nitrogen management at the whole plant level and for plant biomass and yield productivity in unstressed and well feed plants needed further investigation. In this study, we used both autophagy knock-out mutants and autophagy over-expressors that constitutively produce numerous autophagosomes. These mutants and over-expressors were cultivated using hydroponic system to observe and compare their phenotypes under sufficient nitrate supply, and when submitted after a while to strict nitrate starvation. The shift from nitrate sufficient condition to nitrate starvation allowed us to determine how autophagy defective or stimulated lines can use their own nitrogen resources to complete their cycle. Unexpectedly we observed that irrespective of the nitrate conditions, both mutants and over-expressors exhibited early leaf senescence phenotypes relative to wild type. While autophagy mutants exhibited strong defect for N remobilisation and seed production irrespective of nitrate condition, the better performance of autophagy-over expressors for N remobilisation and seeds production was only significant under sufficient nitrate supply, i.e. when autophagy was not naturally stimulated by nitrate limitation. Interestingly, comparisons of genotypes showed that the nitrogen pool used for seed filling originated from rosette leaves, as if rosette and seeds were used as communicating vessels independently of the stem and pod connecting organs. Altogether, results show that autophagy is a master player in nitrogen management at the whole plant level that controls yield production and leaf senescence.
Exercise improved P2Y12-regulated microglial dynamics during stroke via endocannabinoid signaling
Authors: He Xiao-fei , Zhao Yun , Li Ge , Luo Jing , Xu Jing-hui , Zheng Hai-qing , Zhang Li-ying , Hu Xi-quan
Published: April 2023

Microglia are vigilant housekeepers in the adult brain, they continually extend and retract their processes to survey their microenvironment. In a dependent manner involving P2Y12 receptors, microglia undergo morphological and functional changes to form microglia-neuron contacts to protect neurons from damage. By usingin vivotwo-photon imaging, we found that physical exercise (PE) upregulated microglial P2Y12 expression, increased microglial dynamics, and promoted the microglia contacting with neurons in a mouse model of transit middle cerebral artery occlusion (tMCAO). As a result, microglial processes inhibited neuronal calcium overloads, protected against damage of the neuronal mitochondria and synaptic structure. Inhibition of P2Y12 by PSB0739 abolished the protection induced by PE. Mechanistically, we found PE increased the cannabinoid receptor 2 (CBR2) in microglia, and administration of AM630, a CBR2 antagonist, decreased P2Y12R expression and abolished PE-mediated effects. These findings identified endocannabinoid signaling may as the critical regulator of the PE-induced P2Y12-mediated effect whereby PE increased the endocannabinoid system to regulate purinergic signaling, further inducing microglial processes at microglia-neuron contacts to monitor and protect neuronal functioning.
Comparison of different genotyping techniques to distinguish recrudescence from new infection in studies assessing the efficacy of antimalarial drugs againstPlasmodium falciparum
Authors: Schnoz Annina , Beuret Carla , Concu Maura , Hosch Salome , Rutaihwa Liliana K. , Golumbeanu Monica , Nsanzabana Christian
Published: April 2023

Distinguishing recrudescence from new infections is crucial for the assessment of antimalarial drug efficacy againstPlasmodium falciparum (P. falciparum). Different genotyping methods are used and may impede the comparison of drug efficacy estimates in space and time, particularly in patients from high transmission settings with polyclonal infections.

We compared five different genotyping methods currently used to assess their sensitivity in detecting minority clones in polyclonal infections, their robustness, and the genetic diversity of the markers used. Our study utilized four well-characterizedP. falciparumlaboratory strains mixed in varying ratios, and 20 paired patient samples collected from a clinical trial.

We found that high-resolution capillary electrophoresis (H-CE) using length-polymorphic markers, as well as targeted amplicon deep sequencing (TADS) using single nucleotide polymorphism (SNP)-rich markers, revealed the highest sensitivity in detecting minority clones, while also exhibiting robustness, and high genetic diversity in the used markers. Moreover, markers used by TADS gave more consistent results. We observed that microsatellites had a lower genetic diversity compared to markers such as msp1,msp2, glurpand SNP-rich markers, with some genotypes having allelic frequencies of > 30 %.

The replacement ofglurpby microsatellites did not result in a change in the genotyping outcome, probably due to the lower genetic diversity of microsatellites used in comparison toglurp. More studies with large sample sizes are necessary to identify the most suitable microsatellites that could replaceglurpas per the latest recommendations from the World Health Organization (WHO) on genotyping to distinguish recrudescence from new infections in high transmission settings. Our study indicates that TADS should be considered the gold standard for genotyping to differentiate recrudescence from new infection and should be used to validate other techniques.
Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect
Authors: Becattini Barbara , Molinaro Angela , Henricsson Marcus , Borén Jan , Solinas Giovanni
Published: April 2023

Insulin secretion is governed by insulin-PI3K signaling. Resolving the mechanism of this feedback is necessary to understand how insulin operates. Mice lacking the insulin receptor, or AKT1 and AKT2 in adipocytes, are severely lipoatrophic. Thus, the role of adipocyte insulin-PI3K signaling in the control of insulin secretion remains unknown. Using adipocyte- specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we have found that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors had no effect on adipocyte AKT phosphorylation in control mice but blunted AKT phosphorylation specifically in adipocytes of PI3KαAdQmice, demonstrating adipocyte-selective inhibition of PI3K signaling. Adipocyte-selective PI3K inhibition increased serum FFA and potently induced insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect was dissociated from blood glucose and blood glucose counterregulatory response. The contribution of lipolysis, lipid, and amino acid metabolism, and selected adipokines to the adipoincretin effect has been investigated. We conclude that basal insulin secretion is chiefly controlled by adipocyte PI3K signaling through the adipoincretin effect. This phenomenon reveals an essential role for adipocyte insulin-PI3K signaling in linking the rates of adipose tissue lipolysis with baseline insulin secretion during fasting.
PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease
Authors: Upadhyay Vaibhav , Yoon Young me , Vazquez Sara E. , Velez Tania E. , Jones Kirk D. , Lee Cathryn T. , Law Christopher S. , Wolters Paul J. , Lee Seoyeon , Yang Monica M. , Farrand Erica , Noth Imre , Strek Mary E. , Anderson Mark , DeRisi Joseph , Sperling Anne I. , Shum Anthony K.
Published: April 2023

Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.
mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations
Authors: Gasparski Alexander N. , Moissoglu Konstadinos , Pallikkuth Sandeep , Meydan Sezen , Guydosh Nicholas R. , Mili Stavroula
Published: April 2023

Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that protein targeting can additionally be determined by mRNA location and translation rate, through modulating protein binding to specific interacting partners. Peripheral localization of theNET1mRNA and fast translation lead to higher cytosolic retention of the NET1 protein, through promoting its binding to the membrane-associated scaffold protein CASK. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting, through promoting binding to importins. This mRNA location-dependent mechanism is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. These results reveal that the location of protein synthesis and the rate of translation elongation act in coordination as a ‘partner-selection’ mechanism that robustly influences protein distribution and function.
Structurally-informed human interactome reveals proteome-wide perturbations by disease mutations
Authors: Xiong Dapeng , Qiu Yunguang , Zhao Junfei , Zhou Yadi , Lee Dongjin , Gupta Shobhita , Torres Mateo , Lu Weiqiang , Liang Siqi , Kang Jin Joo , Eng Charis , Loscalzo Joseph , Cheng Feixiong , Yu Haiyuan
Published: April 2023

Human genome sequencing studies have identified numerous loci associated with complex diseases. However, translating human genetic and genomic findings to disease pathobiology and therapeutic discovery remains a major challenge at multiscale interactome network levels. Here, we present a deep-learning-based ensemble framework, termed PIONEER (Protein-proteinInteractiOn iNtErfacEpRediction), that accurately predicts protein binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms, generating comprehensive structurally-informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods. We further systematically validated PIONEER predictions experimentally through generating 2,395 mutations and testing their impact on 6,754 mutation-interaction pairs, confirming the high quality and validity of PIONEER predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces after mapping mutations from ∼60,000 germline exomes and ∼36,000 somatic genomes. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from pan-cancer analysis of ∼11,000 tumor whole-exomes across 33 cancer types. We show that PIONEER-predicted oncoPPIs are significantly associated with patient survival and drug responses from both cancer cell lines and patient-derived xenograft mouse models. We identify a landscape of PPI-perturbing tumor alleles upon ubiquitination by E3 ligases, and we experimentally validate the tumorigenic KEAP1-NRF2 interface mutation p.Thr80Lys in non-small cell lung cancer. We show that PIONEER-predicted PPI-perturbing alleles alter protein abundance and correlates with drug responses and patient survival in colon and uterine cancers as demonstrated by proteogenomic data from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels.
Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus
Authors: A.B. Leithead , A. Godino , M. Barbier , H. Harony-Nicolas
Published: April 2023

Background

The posterior intralaminar (PIL) complex of the thalamus is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed.

Methods

We used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real-time during social and non-social interactions. Finally, we used inhibitory DREADDs in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation.

Results

We observed significantly morec-fos-positive cells in the PIL of mice exposed to social versus object or no stimuli. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time it took female mice to form social habituation.

Conclusions

Together these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.
Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome
Authors: Scott Isaac L. , Dominguez Matthew J. , Snow Adam , Harsini Faraz M. , Williams Justin , Fuson Kerry L. , Thapa Roshan , Bhattacharjee Pushpak , Cornwall Gail A. , Keyel Peter A. , Sutton R. Bryan
Published: April 2023

Limb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in thedysferlingene (DYSF). This disease has two known pathogenic missense mutations that occur within dysferlin’s C2A domain, namely C2AW52Rand C2AV67D. Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlin’s ability to repair cells. The failure of C2AW52Rand C2AV67Dto initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes β-strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1β. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving C2AW52Rand C2AV67D, as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.
Discovery of microsized RNA-derived RNAs and proteins in human cells
Authors: Huang Xiaoqiang , Wu Haidong , Zhong Weilong , Li Wenbo , Liu Zhiyong , Zhao Min , Xi Xiaonan , Cao Bo , Pu Yong , Kong Xiangxu , Zhao Huan , Zhang Ronghua , Lai Keguan , Lv Xinze , Lv Yue , Bao Jingyu , Wang Meimei , Xiong Yanan , Dong Lijie , Zhang Jifeng , Zhang Guangling , Hu Yuanjing , Xu Jie , Chen Y. Eugene , Chen Shuang
Published: April 2023

MicroRNAs (miRNAs) are a class of short noncoding RNAs that can regulate gene expression through the binding of their 5’-end to mRNA. However, the biological effects of miRNA’s 3’-end binding to mRNA remain unclear. Here we discover that the exact reverse pairing of the 3’-ends of miRNAs or miRNA-like RNAs, collectively referred to as microsized RNAs (msRNAs), with template RNAs could initiate the production of msRNA-derived RNAs (msdRs), which consequently translate into msRNA-derived proteins (msdPs). Starting with 2,632 human miRNAs or miRNA-like msRNAs taken from the miRBase database, we predicted 11,121 and 1,239 unique msdRs and msdPs respectively using a 15-nt pairing threshold. We verified the authentic presence of example msdRs and msdPs in human cells. Of clinical relevance, we demonstrated that msdP0188 is highly expressed in human lung and breast cancer tissues and cells, and its corresponding msdRs represent novel anti-cancer targets. Intriguingly, inhibiting the human telomerase reverse transcriptase, a putative RNA-dependent RNA polymerase suggested by bioinformatic screening, led to reduced levels of msdP0188 in human cells. Our findings propose a novel “msRNA → msdR → msdP” axis that not only represents an augmentation to the central dogma of molecular biology but also predicts thousands of previously unknown RNAs and proteins that may have significant biological and pathological roles in human cells as well as in other biological systems.

One-Sentence Summary

This work reports the discovery of msRNA-derived RNAs and proteins that may have significant roles in biology and medicine.
Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein Kinase 1
Authors: Harold Rachel L. , Tulsian Nikhil K. , Narasimamurthy Rajesh , Yaitanes Noelle , Ayala Hernandez Maria G. , Lee Hsiau-Wei , Crosby Priya , Tripathi Sarvind M. , Virshup David M. , Partch Carrie L.
Published: April 2023

Casein kinase 1 δ (CK1δ) controls essential biological processes including circadian rhythms and Wnt signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C-termini (XCT), but with marked changes in potential phosphorylation sites. Here we test if the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and HDX-MS, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity bothin vitroand in cells and leads to changes in circadian period, similar to what is reportedin vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase.

Significance

Subtle control of kinase activity is critical to physiologic modulation of multiple physiological processes including circadian rhythms. CK1δ and the closely related CK1ε regulate circadian rhythms by phosphorylation of PER2, but how kinase activity itself is controlled is not clear. Building on the prior observation that two splice isoforms of CK1δ regulate the clock differently, we show that the difference maps to three phosphorylation sites in the variably spliced region (XCT) that cause feedback inhibition of the kinase domain. More broadly, the data suggest a general model where CK1 activity on diverse substrates can be controlled by signaling pathways that alter tail phosphorylation. These inhibitory phosphorylation sites could also be targets for new therapeutic interventions.
Differences in AD-related pathology profiles across APOE groups
Authors: Morrison Cassandra , Dadar Mahsa , Kamal Farooq , Collins D. Louis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2023

BACKGROUND

The apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer’s disease (AD), while the e2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype and results are inconsistent for those with an e2 allele.

METHODS

We analyzed Alzheimer’s Disease Neuroimaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load, ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV-45), and phosphorylated tau (pTau). Participants were divided into one of four APOE allele profiles (E4=e4e4 or e3e4; E2=e2e2 or e2e3; E3=e3e3; or E24=e2e4, Fig.1). Linear mixed models examined the relationship between APOE profiles and each pathology (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures). while controlling for age, sex, education, and diagnostic status at baseline and over time.

RESULTS

APOE ε4 is associated with increased pathology while ε2 positivity is associated with reduced baseline and lower accumulation of pathologies and rates of neurodegeneration. APOE ε2ε4 is similar to ε4 (increased neurodegeneration) but with a slower rate of change.

CONCLUSIONS

The strong associations observed between APOE and pathology in this study show the importance of how genetic factors influence structural brain changes. These findings suggest that ε2ε4 genotype is related to increased declines associated with the ε4 as opposed to the protective effects of the ε2. These findings have important implications for initiating treatments and interventions. Given that people who have the ε2ε4 genotype can expect to have increased atrophy, they must be included (alongside those with an ε4 profile) in targeted interventions to reduce brain changes that occur with AD.
TRANS-AORTIC VALVULAR FLOW DYNAMICS AND LEFT VENTRICULAR EJECTION FRACTION FOR MONITORING RECOVERY OF PATIENTS WITH LEFT VENTRICULAR SYSTOLIC HEART FAILURE
Authors: Vasudevan Viswajith S. , Rajagopal Keshava , Rame Jesus E. , Antaki James F.
Published: April 2023

Abstract

Durable mechanical circulatory support in the form of left ventricular (LV) assist device (LVAD) therapy is increasingly considered in the context of the recovery of native cardiac function. Progressive improvement in LV function may facilitate LVAD explantation and a resultant reduction in device-related risk. However, ascertaining LV recovery remains a challenge. In this study, we investigated the use of trans-aortic valvular flow rate and trans-LVAD flow rate to assess native LV systolic function using a well-established lumped parameter model of the mechanically assisted LV with pre-existing systolic dysfunction. Trans Aortic Valvular Ejection Fraction (TAVEF) was specifically found to characterize the preload-independent contractility of the LV. It demonstrated excellent sensitivity to simulated pharmacodynamic stress tests and volume infusion tests. TAVEF may prove to be useful in the ascertainment of LV recovery in LVAD-supported LVs with pre-existing LV systolic dysfunction.
VODKA2: A fast and accurate method to detect non-standard viral genomes from large RNA-seq datasets
Authors: Achouri Emna , Felt Sébastien A. , Hackbart Matthew , Rivera-Espinal Nicole S. , López Carolina B.
Published: April 2023

During viral replication, viruses carrying an RNA genome produce non-standard viral genomes (nsVGs), including copy-back viral genomes (cbVGs) and deletion viral genomes (delVGs), that play a crucial role in regulating viral replication and pathogenesis. Because of their critical roles in determining the outcome of RNA virus infections, the study of nsVGs has flourished in recent years exposing a need for bioinformatic tools that can accurately identify them within Next-Generation Sequencing data obtained from infected samples. Here, we present our data analysis pipeline, Viral Opensource DVG Key Algorithm2 (VODKA2), that is optimized to run on a High Performance Computing (HPC) environment for fast and accurate detection of nsVGs from large data sets.

Availability and implementation

VODKA2 is freely available at GitHub (https://github.com/lopezlab-washu/VODKA2)
Synaptopodin is necessary forShigella flexneriintercellular spread
Authors: Vickery Jenna M. , Toperzer Jody D. , Raab Julie E. , Lenz Laurel L. , Colgan Sean P. , Russo Brian C.
Published: April 2023

For many intracellular pathogens, their virulence depends on an ability to spread between cells of an epithelial layer. For intercellular spread to occur, these pathogens deform the plasma membrane into a protrusion structure that is engulfed by the neighboring cell. Although the polymerization of actin is essential for spread, how these pathogens manipulate the actin cytoskeleton in a manner that enables protrusion formation is still incompletely understood. Here, we identify the mammalian actin binding protein synaptopodin as required for efficient intercellular spread. Using a model cytosolic pathogen,Shigella flexneri, we show that synaptopodin contributes to organization of actin around bacteria and increases the length of the actin tail at the posterior pole of the bacteria. We show that synaptopodin presence enables protrusions to form and to resolve at a greater rate, indicating that greater stability of the actin tail enables the bacteria to push against the membrane with greater force. We demonstrate that synaptopodin recruitment around bacteria requires the bacterial protein IcsA, and we show that this recruitment is further enhanced in a type 3 secretion system dependent manner. These data establish synaptopodin as required for intracellular bacteria to reprogram the actin cytoskeleton in a manner that enables efficient protrusion formation and enhance our understanding of the cellular function of synaptopodin.

Authors Summary

Intercellular spread is essential for many cytosolic dwelling pathogens during their infectious life cycle. Despite knowing the steps required for intercellular spread, relatively little is known about the host-pathogen interactions that enable these steps to occur. Here, we identify a requirement for the actin binding protein synaptopodin during intercellular spread by cytosolic bacteria. We show synaptopodin is necessary for the stability and recruitment of polymerized actin around bacteria. We also demonstrate synaptopodin is necessary to form plasma membrane structures known as protrusions that are necessary for the movement of these bacteria between cells. Thus, these findings implicate synaptopodin as an important actin-binding protein for the virulence of intracellular pathogens that require the actin cytoskeleton for their spread between cells.
Members of an array of zinc finger proteins specify distinctHoxchromatin boundaries
Authors: Ortabozkoyun Havva , Huang Pin-Yao , Gonzalez-Buendia Edgar , Cho Hyein , Kim Sang Y. , Tsirigos Aristotelis , Mazzoni Esteban O. , Reinberg Danny
Published: April 2023

Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type specific gene expression patterns. While this partitioning is reconstructed during differentiation, the chromatin occupancy of the key insulator, CTCF, is unchanged at the developmentally importantHoxclusters. Thus, dynamic changes in chromatin boundaries must entail other activities. Given its requirement for chromatin loop formation, we examined cohesin-based chromatin occupancy without known insulators, CTCF and MAZ, and identified a family of zinc finger proteins (ZNFs), some of which exhibit tissue-specific expression. Two such ZNFs foster chromatin boundaries at theHoxclusters that are distinct from each other and from MAZ. PATZ1 was critical to the thoracolumbar boundary in differentiating motor neurons and mouse skeleton, while ZNF263 contributed to cervicothoracic boundaries. We propose that these insulating activities act with cohesin, alone or combinatorially, with or without CTCF, to implement precise positional identity and cell fate during development.
Environmental RNA as a non-invasive tool for assessing toxic effects in fish: a proof-of-concept study using Japanese medaka exposed to pyrene
Authors: Hiki Kyoshiro , Yamagishi Takahiro , Yamamoto Hiroshi
Published: April 2023

Although environmental RNA (eRNA) is emerging as a non-invasive tool to assess the health status of aquatic macro-organisms, the potential of eRNA remains largely untested. In this study, we investigated the ability of eRNA to detect changes in gene expression in Japanese medaka fish (Oryzias latipes) in response to sub-lethal pyrene exposure, as a model toxic chemical. We performed standardized acute toxicity tests and collected eRNA from tank water and RNA from fish tissue after 96 h of exposure. Our results showed that over 1000 genes were detected in eRNA and the sequenced read counts of these genes correlated with those in fish tissue (r= 0.50). Moreover, eRNA detected 86 differentially expressed genes in response to pyrene, some of which were shared by fish RNA, including suppression of collagen fiber genes. These results suggest that eRNA has the potential to detect changes in gene expression in fish in response to environmental stressors without the need for sacrificing or causing pain to fish. However, we also found that the majority of sequenced reads of eRNA (> 99%) were not mapped to the reference medaka genome and they originated from bacteria and fungi, resulting in low sequencing-depth. In addition, eRNA, in particular nuclear genes, was highly degraded with a median transcript integrity number (TIN) of < 20. These limitations highlight the need for future studies to improve the analytical methods of eRNA application.

TOC Art
Human Attention during Goal-directed Reading Comprehension Relies on Task Optimization
Authors: Zou Jiajie , Zhang Yuran , Li Jialu , Tian Xing , Ding Nai
Published: April 2023

The computational principles underlying attention allocation in complex goal-directed tasks remain elusive. Goal-directed reading, i.e., reading a passage to answer a question in mind, is a common real-world task that strongly engages attention. Here, we investigate what computational models can explain attention distribution in this complex task. We show that the reading time on each word is predicted by the attention weights in transformer-based deep neural networks (DNNs) optimized to perform the same reading task. Eye-tracking further reveals that readers separately attend to basic text features and question-relevant information during first-pass reading and rereading, respectively. Similarly, text features and question relevance separately modulate attention weights in shallow and deep DNN layers. Furthermore, when readers scan a passage without a question in mind, their reading time is predicted by DNNs optimized for a word prediction task. Therefore, we offer a computational account of how task optimization modulates attention distribution during real-world reading.
A systematic review of the prevalence of persistent gastrointestinal symptoms and incidence of new gastrointestinal illness after acute SARS-CoV-2 infection
Authors: Hawkings Michael J. , Vaselli N. Marcella , Charalampopoulos Dimitrios , Brierley Liam , Elliot Alex J. , Buchan Iain , Hungerford Daniel
Published: April 2023

It is known that SARS-CoV-2 infection can result in gastrointestinal symptoms. For some, these symptoms may persist beyond acute infection, in what is known as ‘post-COVID syndrome’. We conducted a systematic review to examine the prevalence of persistent gastrointestinal symptoms and the incidence of new gastrointestinal illness following acute SARS-CoV-2 infection. We searched scientific literature using MedLine, SCOPUS, Embase, Europe PubMed Central, medRxiv and Google Scholar from December 2019 to October 2022. Two reviewers independently identified 28 eligible articles which followed participants for various gastrointestinal outcomes after acute SARS-CoV-2 infection. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools. The weighted pooled prevalence for persistent gastrointestinal symptom of any nature and duration was 10.7%, compared to 4.9% in healthy controls. For six studies at a low risk of methodological bias, the symptom prevalence ranged from 0.2% to 24.1% with a median follow-up time of 13 weeks. We also identified the presence of functional gastrointestinal disorders in historically SARS-CoV-2 exposed individuals. Our review has shown that, from a limited pool of mostly low-quality studies, previous SARS-CoV-2 exposure may be associated with ongoing gastrointestinal symptoms and the development of functional gastrointestinal illness. Furthermore, we show the need for high-quality research to better understand the SARS-CoV-2 association with gastrointestinal symptoms, particularly as population exposure to enteric infections returns to pre-COVID-19-restriction levels.

Highlights

Acute SARS-CoV-2 infection can result in gastrointestinal symptoms

The burden of gastrointestinal illness after acute SARS-CoV-2 infection is not known

This systematic review evaluates the evidence across 28 observational studies

Most studies identified are at high risk of bias and of low quality

SARS-CoV-2 exposure may be associated with new post-infection gastrointestinal illness
Brain network flexibility as a predictor of skilled musical performance
Authors: Uehara Kazumasa , Yasuhara Masaki , Koguchi Junya , Oku Takanori , Shiotani Sachiko , Morise Masanori , Furuya Shinichi
Published: April 2023

Interactions between the body and the environment are dynamically modulated by upcoming sensory information and motor execution. To adapt to this behavioral state-shift, brain activity must also be flexible and possess a large repertoire of brain networks so as to switch them flexibly. Recently, flexible internal brain communications, i.e., brain network flexibility, have come to be recognized as playing a vital role in integrating various sensorimotor information. Therefore, brain network flexibility may be one of the key factors that define sensorimotor skill. However, little is known about how flexible communications within a brain characterizes inter-individual variation of sensorimotor skill and trial-by-trial variability within individuals. To address this, we recruited highly skilled musical performers (i.e. brass instrumentalists) and used a novel approach that combined multichannel-scalp electroencephalography (EEG) recordings, behavioral measurements of musical performance, and mathematical approaches to extract brain network flexibility.

We found that brain network flexibility immediately before initiating the performance predicted inter-individual differences in the precision of tone timbre (as represented by spectral centroid of the sound), but not trial-by-trial variability at the individual level. Furthermore, brain network flexibility in broader cortical regions, rather than specific local cortical regions, predicted skilled musical performance, indicating that whole-cortical fluctuations determine individual skill. Our results provide novel evidence that brain network flexibility during movement preparation plays an important role in skilled sensorimotor performance and our findings have potentials for designing a new approach to predict an individual’s skill from neural dynamics and a new intervention tool to facilitate physical education.
Synchronized LFP rhythmicity in the social brain reflects the context of social encounters
Authors: Mohapatra Alok Nath , Peles David , Netser Shai , Wagner Shlomo
Published: April 2023

Mammalian social behavior is highly context-sensitive. Yet, little is known about the mechanisms that modulate social behavior according to its context. Recent studies have revealed a network of mostly limbic brain regions, here termed the “social brain”, which regulates social behavior. We hypothesized that coherent theta and gamma rhythms reflect the organization of the social brain regions into functional networks in a context-dependent manner. To test this concept, we simultaneously recorded extracellular activity from multiple social brain regions in mice performing three social discrimination tasks. Local field potential (LFP) rhythmicity across all tasks was dominated by a general internal state. However, during stimulus investigation LFP rhythmicity was sensitive to stimulus characteristics. Specifically, the pattern of LFP coherence between the various regions reflected mainly the social context. Moreover, we found the ventral dentate gyrus to play a pivotal role in coordinating the context-specific rhythmic activity in the network.
Authentic corporate social responsibility: antecedents and effects on consumer purchase intention
Authors: Mäncher Lars , Zerres Christopher , Breyer-Mayländer Thomas
Published: April 2023

Purpose

The aim of the research is to identify the factors that create an authentic company's corporate social responsibility (CSR) engagement and to investigate whether an authentic CSR engagement influences the purchase intention. In addition, the study attempts to provide insights into the mediation role of attitude toward the company and frequency of purchase on purchase intention.

Design/methodology/approach

In this study, a theoretical framework is developed in which major antecedents of authentic CSR are identified. A specific example of a brand and its corporate social responsibility activities was used for the study. An online questionnaire was used to collect the data. To verify the hypothesis, structural equation modeling with the partial least squares method was used. A total of 240 people participated in the study.

Findings

The results of the study confirmed that CSR authenticity positively influences consumer purchase intention. Furthermore, the hypothesized impact of CSR authenticity on attitudes toward the company and frequency of purchase could be verified.

Originality/value

Although there is research on the antecedents influencing the consumer's perceived authenticity of CSR, it has not addressed differences in impact and has not presented a full picture of influencing antecedents. In addition, CSR proof as a new antecedent is investigated in the study. Moreover, research on outcomes of perceived CSR authenticity still lacks depth. The study therefore addresses this research gap by providing an extensive research framework including antecedents influencing CSR authenticity and outcomes of CSR authenticity.
Small concept luxury department stores: psychographic characteristics affecting patronage intentions
Authors: Slaton Kelcie , Testa Danielle Sponder
Published: April 2023

Purpose

The aim of this study is to investigate the psychographic factors of shopping enjoyment, market mavenism and consumer innovativeness and their influence on hedonic and utilitarian values, attitudes and patronage intentions of the small concept luxury department (SCLD) store.

Design/methodology/approach

The researchers utilized a quantitative method. An online survey was created and distributed over a three-week period to a representative sample of US luxury consumers. Structural equation modeling (SEM) was used to test the hypothesized relationships among variables.

Findings

The theory of reasoned action (TRA) theoretical framework provided an effective model to investigate the perspectives and behaviors of luxury consumers within the SCLD. The findings of this study suggest the SCLD is an effective store format for consumers who are characterized as market mavens, are considered innovative and enjoy shopping.

Practical implications

The findings from this research are beneficial to luxury department store retailers looking to invest resources into a new experiential format to appeal to their consumer base.

Originality/value

The research extends the literature in a rapidly evolving area of retail formats and consumer perception by exploring psychographic factors, including shopping enjoyment, market mavenism and consumer innovativeness, and their impact on the beliefs regarding retail formats' hedonic and utilitarian value.
Pragmatic approaches to control inbound sex tourism and prostitution in Thailand and Cambodia: the examination of relevant policy gaps and suggestion of multifaceted policy development
Authors: Hung Jason
Published: April 2023

Purpose

The essay aims to suggest policies that can help strategically deconstruct and dereproduce the establishment of (child) sexual exploitation in Thailand and Cambodia in phases, for the purpose of upholding child and human rights and rebranding the global image of these two regional commercial sex hubs in the long term.

Design/methodology/approach

This essay is constructed based on the theoretical framework of the social control and general strain theories. Supported by the theories, the essay examines what are the socioeconomic determinants driving the prevalence of the (child) commercial sex industry in Thailand and Cambodia. Here the essay highlights and summarises how the (child) commercial sex industry has been constructed and reproduced. Next, the essay presents the existing policy gaps in relation to (child) sex tourism and sex exploitation. Last, and more importantly, the essay delivers perspectives on how Thai and Cambodian lawmakers and policymakers should respond to the severe societal problems of (child) sex trafficking and prostitution in relation to the prevailing sex tourism.

Findings

At the national level, Bangkok and Phnom Penh have an urgent need to rebrand their countries, despite partially allowing commercial sex activities. Moreover, to promote gender equality, Bangkok and Phnom Penh should redistribute their education and occupational opportunities, enabling more school-aged girls or work-aged women to obtain a fairer share of life chances for self-empowerment. At the regional level, Bangkok and Phnom Penh have to tighten regulations against (child) sex exploitation. At the community level, the promotion of community policing can be conducive to minimising any prostitution activities. At the family level, more positive socialisation should be exercised. When more children, including girls, are subsidised to enter school, and are positively parented, there are more educational opportunities for school-aged cohorts.

Originality/value

This essay contains scholarly originality and significance in the presentation of the socioeconomic construction of (child) sexual exploitation, and its relationship to sex tourism and (child) prostitution in Thai and Cambodian contexts, grounded in up-to-date, relevant sociological arguments. A major area that identifies the originality of this essay is the examination of existing, relevant policy gaps in a timely fashion, and correspondingly, the suggestion of policy development that helps deconstruct and deproduce (child) sexual exploitation at the national, regional, community and family levels.