bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison and evaluation of data-driven protein stability prediction models
Authors: Csicsery-Ronay Jennifer A. , Zaitzeff Alexander , Singer Jedediah M.
Published: March 2022

Predicting protein stability is important to protein engineering yet poses unsolved challenges. Computational costs associated with physics-based models, and the limited amount of data available to support data-driven models, have left stability prediction behind the prediction of structure. New data and advancements in modeling approaches now afford greater opportunities to solve this challenge. We evaluate a set of data-driven prediction models using a large, newly published dataset of various synthetic proteins and their experimental stability data. We test the models in two separate tasks, exercising extrapolation to new protein classes and prediction of the effects on stability of small mutations. Small convolutional neural networks trained from scratch on stability data and large protein embedding models passed through simple downstream models trained on stability data are both able to predict stability comparably well. The largest of the embedding models yields the best performance in all tasks and metrics. We also explored the marginal performance gains seen with two ensemble models.
A novel method accounting for predictor uncertainty and model transferability of invasive species distribution models
Authors: Hill Matt , Caley Peter , Camac James , Elith Jane , Barry Simon
Published: March 2022

Predicting novel ranges of non-native species is a critical component to understanding the biosecurity threat posed by pests and diseases on economic, environmental and social assets. Species distribution models (SDMs) are often employed to predict the potential ranges of exotic pests and diseases in novel environments and geographic space. To date, researchers have focused on model complexity, data available for model fitting, the size of the geographic area to be considered and how the choice of model impacts results. These investigations are coupled with considerable examination of how model evaluation methods and test scores are influenced by these choices. An area that remains under-discussed is how to account for uncertainty in predictor selection while also selecting variables that increase a model’s ability to predict to novel environments (model transferability).

Here we propose a novel method to finesse this problem by using multiple simple (bivariate) models to search for the candidate sets of predictor variables that are likely to produce transferable models. Once identified, each set is then used to construct 2-dimensional niche envelopes of pest presence/absence. This process ultimately results in a number of possible models that can be used to predict pest potential distributions, however, rather than relying on a single model, we ensemble these models in an attempt to account for predictor uncertainty. We apply this method to both virtual species and real species data, and find that it generally performs well against conventional approaches for statistically fitting numerous variables in a single model. While our methods only consider simple ecological relationships of species to environmental predictors, they allow for increased model transferability because they reduce the likelihood of over-fitting and collinearity issues. Simple models are also likely to be more conservative (over-predict potential distributions) relative to complex models containing many covariates – making them more appropriate for risk-averse applications such as biosecurity. The approach we have explored transforms a model selection problem, for which there is no true correct answer amongst the typically distal covariates on offer, to one of model uncertainty. We argue that increased model transferability at the expense of model interpretation is perhaps more important for effective rapid predictions and management of non-native species and biological invasions.
High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors
Authors: Mazzarella Luca , Falvo Paolo , Adinolfi Marta , Tini Giulia , Gatti Elena , Piccioni Rossana , Bonetti Emanuele , Dorronzoro Elena Gavilan , Bodini Margherita , Gallo Barbara , Orecchioni Stefania , Duso Bruno Achutti , Ronchini Chiara , Sanarico Anna Giulia , Pallavi Rani , Roerink Sophie , Bertolini Francesco , Alcalay Myriam , Dellino Gaetano Ivan , Pelicci Pier Giuseppe
Published: March 2022

Obesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RARα oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA α in the hematopoietic system (PML-RARα KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RARα KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RARα this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RARα HPCs by activating the peroxisome proliferator-activated receptor delta (PPARδ), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity.

Key points

high fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humans

although HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPARδ
Prediction of m6A and m5C at single-molecule resolution reveals a cooccurrence of RNA modifications across the transcriptome
Authors: Acera Mateos P. , Sethi A.J. , Ravindran A. , Srivastava A. , Woodward K. , Mahmud S. , Kanchi M. , Guarnacci M. , Xu J. , Yuen Z.W.S. , Zhou Y. , Sneddon A. , Hamilton W. , Gao J. , Starrs L.M. , Hayashi R. , Wickramasinghe V. , Zarnack K. , Preiss T. , Burgio G. , Dehorter N. , Shirokikh N. , Eyras E.
Published: March 2022

The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI’s capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis
Authors: Steiner Alex , Owen Benjamin M. , Bauer James P. , Seanez Leann , Kwon Sam , Biddinger Jessica E. , Huffman Ragan , Ayala Julio E. , Nobis William P. , Lewis Alan S.
Published: March 2022

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. What is not well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through selective expression of its receptor, GLP-1R. RNA-seq demonstrated that most Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study identifies a potential neurohormonal mechanism linking a critically important satiety signal with activity of MCs in the ventral DG that might have functional effects on learning and memory during distinct states.
Tetrasulfide Bridge (TTSB) Formation: an Extraordinary Intermediate Structure in the Architecture and Dynamics of the HIV-1’s gp120 molecule
Authors: Crevecoeur Harry F.
Published: March 2022

Gp120, one of the molecules that execute HIV viral entry in CD4+ cells has a number of allosteric disulfide bridges. In this study we explore the dynamics of these potential disulfide (disulphide) bridges in the 3-D configuration (based on crystallography) and UNSW DBA analyses of various gp120 crystals. The data reveal the existence of a tetrasulfide (tetrasulphide) bridge (TTSB) which, together with a disulfide bridge, keeps two perpendicular beta sheets (namely V3 and V4) approximated in the architecture of the gp120 while allowing safe transfer of energy between the allosteric bonds. Analyses of multiple gp120 crystals reveal the existence of the TTSB to be more as an intermediate as opposed to a constant landmark, which implies more complex functions than just structural attributes. This TTSB, which is observed in various crystals of gp120, in various strains and clades of HIV-1, is demonstrated by various rendering software and some are also detected, reported and characterized by the UNSW Disulfide Bond Analysis (DBA) engine. This tetrasulfide bridge connects the allosteric bond Cys296–Cys331 to Cys385-Cys418, sometimes as CYS331:SG – CYS385:SG, and sometimes as CYS331:SG – CYS418:SG. Moreover in crystals 3TIH, 4LSR and 4R4N, we also observed an intermediate state of the TTSB where it presents a triangular formation in which the sulfur atom CYS331:SG binds to both CYS385:SG and CYS418:SG simultaneously, which represents an important intermediate in the functional dynamics of the gp120 molecule. The presence of this extraordinary structure (TTSB) does point to some intriguing insights in the multifunctional design and mechanics as well as some complex fragilities of the gp120 molecule, exposing a new target for antiviral therapy.
AHR agonist ITE boosted PD1 antibody’s effects by inhibiting myeloid-derived cells suppressive cells in an orthotopic mouse glioma model
Authors: Zhao Lijiao , Ma Yunlong , Shu Qiuting , Sun Hui , Lu Jing , Gong Pei , Meng Fanhua , Wan Fang
Published: March 2022

Glioblastoma is a “cold“ tumor lacking T cell infiltration and tryptophan metabolites such as kynurenine function as an immune suppressor by binding to aryl hydrocarbon receptor(AHR). Hence AHR antagonists have been developed and some shown to activate the immune response in IDO over-expressing cancer models. Paradoxically, AHR has been reported to block glioma cell invasion like a tumor suppressor, and how to target AHR in cancer remains an open question. We previously discovered that an AHR agonist ITE can effectively inhibit glioma invasion. Here we report that ITE combined with PD1 antibody significantly increased the infiltration of CD8+ T cells while reducing that of the myeloid-derived suppressive cells (MDSCs), extending mouse survival. To identify factors that possibly mediated ITE’s effects, we analyzed RNA-seq data and discovered that ITE significantly down-regulated IL11, a known MDSC regulator. In contrast, kynurenine upregulated IL11, further supporting IL11 as an AHR target. Moreover, ITE inhibited IL11’s induction of MDSC from mouse PBMC in vitro, supporting that IL11 might mediate ITE’s MDSC regulation effects. The discovery of ITE’s immune-activating effects highlighted the complexity of AHR’s signaling in cancers. The unexpected increase in STAT3, downstream of IL11 provided clues for combination therapy development.
Little skate genome exposes the gene regulatory mechanisms underlying the evolution of vertebrate locomotion
Authors: Yoo DongAhn , Lee Chul , Park JunHee , Lee Young Ho , Heguy Adriana , Dasen Jeremy S. , Kim Heebal , Baek Myungin
Published: March 2022

The little skateLeucoraja erinacea, a cartilaginous fish, displays pelvic fin driven walking-like behaviors using genetic programs and neuronal subtypes similar to those of land vertebrates. However, mechanistic studies on little skate motor circuit development have been limited, due to a lack of high-quality reference genome. Here, we generated an assembly of the little skate genome, containing precise gene annotation and structures, which allowed post-genome analysis of spinal motor neurons (MNs) essential for locomotion. Through interspecies comparison of mouse, skate and chicken MN transcriptomes, shared and divergent MN expression profiles were identified. Conserved MN genes were enriched for early-stage nervous system development. Comparison of accessible chromatin regions between mouse and skate MNs revealed conservation of the potential regulators with divergent transcription factor (TF) networks through which expression of MN genes is differentially regulated. TF networks in little skate MNs are much simpler than those in mouse MNs, suggesting a more fine-grained control of gene expression operates in mouse MNs. These findings suggest conserved and divergent mechanisms controlling MN development system of vertebrates during evolution and the contribution of intricate gene regulatory networks in the emergence of sophisticated motor system in tetrapods.
Direct detection of natural selection in Bronze Age Britain
Authors: Mathieson Iain , Terhorst Jonathan
Published: March 2022

We developed a novel method for efficiently estimating time-varying selection coefficients from genome-wide ancient DNA data. In simulations, our method accurately recovers selective trajectories, and is robust to mis-specification of population size. We applied it to a large dataset of ancient and present-day human genomes from Britain, and identified seven loci with genome-wide significant evidence of selection in the past 4500 years. Almost all of them are related to increased vitamin D or calcium levels, and we conclude that lack of vitamin D and consequent low calcium was consistently the most important selective pressure in Britain since the Bronze Age. However, the strength of selection on individual loci varied substantially over time, suggesting that cultural or environmental factors moderated the genetic response to this pressure. Of 28 complex anthropometric and metabolic traits, skin pigmentation was the only one with significant evidence of polygenic selection, further underscoring the importance of phenotypes related to vitamin D. Our approach illustrates the power of ancient DNA to characterize selection in human populations and illuminates the recent evolutionary history of Britain.
Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies
Authors: O’Neill Matthew J. , Wada Yuko , Hall Lynn D. , Mitchell Devyn W. , Glazer Andrew M. , Roden Dan M.
Published: March 2022

Background

Rare protein-altering variants in SCN5A, KCNQ1, and KCNH2 are major causes of Brugada Syndrome (BrS) and the congenital Long QT Syndrome (LQTS). While splice-altering variants lying outside 2-bp canonical splice sites can cause these diseases, their role remains poorly described.

Objective

We implemented two functional assays to assess 12 recently reported putative splice-altering variants of uncertain significance (VUS) and 1 likely pathogenic (LP) variant without functional data observed in BrS and LQTS probands.

Methods

We deployed minigene assays to assess the splicing consequences of 10 variants. Three variants incompatible with the minigene approach were introduced into control induced pluripotent stem cells (iPSCs) by CRISPR genome editing. We differentiated cells into iPSC-derived cardiomyocytes (iPSC-CMs) and studied splicing outcomes by reverse transcription-polymerase chain reaction (RT-PCR). We used the American College of Medical Genetics and Genomics functional assay criteria (PS3/BS3) to reclassify variants.

Results

We identified aberrant splicing, with presumed disruption of protein sequence, in 8/10 variants studied using the minigene assay and 1/3 studied in iPSC-CMs. We reclassified 9 VUS to LP, 1 VUS to Likely Benign, and 1 LP variant to pathogenic.

Conclusions

Functional assays reclassified splice-altering variants outside canonical splice sites in BrS- and LQTS-associated genes.
Spontaneous myocarditis in mice predisposed to autoimmune disease: Including Vaccination-induced onset
Authors: Hayashi Takuma , Ichikawa Motoki , Konishi Ikuo
Published: March 2022

Non-obese diabetic (NOD)/ShiLtJ mice, like biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. Previously, in non-obese diabetic (NOD)/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of LMP2/β1i, an immunoproteasome β subunit, and associated decreased expression of NF-κB1 (also called as p50) in the development of type 1 diabetes was argued between our research team and other research groups. In response to these arguments, we created NOD mice in which NF-κB1 expression is not consistently observed. Unexpectedly, most NOD Nfκb1 homozygote mice were found to die by the 8th week of age due to the development of severe myocarditis. Furthermore, in all NOD Nfκb1 heterozygote mice, the onset of Insulitis was observed from 4 months of age. In addition, in NOD Nfκb1 heterozygote mice, an increase in cTnT due to vaccination with influenza or HBV vaccine was observed without gender difference. Now, we found a direct involvement of decreased expression of NF-κB1 in the development of autoimmune diseases in NOD/ShiLtJ mice. Therefore, we would like to introduce new research results on autoimmune diseases, including findings on important risk factors for the development of myocarditis observed after vaccination with mRNA-based COVID-19 vaccine.
Conditions of Confinement in U.S. Carceral Facilities during COVID-19: Individuals Speak: Incarcerated during the COVID-19 Epidemic (INSIDE)
Authors: Cassarino Nicole , Dabbara Harika , Monteiro Carla B. , Bembury Arthur , Credle Leslie , Grandhi Uma , White Samantha , Jiménez Monik C.
Published: March 2022

Objectives

We aimed to describe conditions of confinement among people incarcerated in the United States during the coronavirus disease 2019 (COVID-19) pandemic and assess the feasibility of a community-science data collection approach.

Methods

We developed a web-based survey with community partners to collect information on confinement conditions (COVID-19 safety, basic needs, support). Formerly incarcerated adults released after March 1, 2020, or non-incarcerated adults in communication with an incarcerated person (proxy) were recruited through social media from July 25, 2020, through March 27, 2021. Descriptive statistics were estimated in aggregate and separately by proxy or formerly incarcerated status. Additionally, we compared responses between proxy and formerly incarcerated respondents using chi-square or Fisher’s exact tests as appropriate based on alpha=0.05.

Results

Of 378 responses, 94% were by proxy, and 76% reflected state prison conditions. Participants reported inability to physically distance (≥6ft at all times) (92%), inadequate access to soap (89%), water (46%), toilet paper (49%) and showers (68%). Among people who received mental healthcare before the pandemic, 75% reported reduced care. We found that responses were consistent between formerly incarcerated people and proxy-respondents.

Conclusions

Our findings suggest that a community-science approach to data collection is feasible. Based on these findings, COVID-19 safety and basic needs were not sufficiently addressed within some carceral settings. Thus, we recommend the lived experiences of incarcerated individuals should be included to make informed and equitable policy decisions.
UniFuncNet: a flexible network annotation framework
Authors: Queirós Pedro , Hickl Oskar , Arbas Susana Martínez , Wilmes Paul , May Patrick
Published: March 2022

Functional annotation is an integral part in the analysis of organisms, as well as of multi-species communities. A common way to integrate such information is using biological networks. However, current data integration network tools are heavily dependent on a single source of information, which might strongly limit the amount of relevant data contained within the network. Here we present UniFuncNet, a network annotation framework that dynamically integrates data from multiple biological databases, thereby enabling data collection from various sources based on user preference. This results in a flexible and comprehensive data retrieval framework for network based analyses of omics data. Importantly, UniFuncNet’s data integration methodology allows for the output of a non-redundant composite network and associated metadata. In addition, a workflow exporting UniFuncNet’s output to the graph database management system Neo4j was implemented, which allows for efficient querying and analysis.

Availability

Source code is available at https://github.com/PedroMTQ/UniFuncNet.
Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models
Authors: Dickson Elna , Dwijesha Amoolya Sai , Andersson Natalie , Lundh Sofia , Björkqvist Maria , Petersén Åsa , Soylu-Kucharz Rana
Published: March 2022

Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.
Zika virus NS4A hijacks host ANKLE2 to promote viral replication
Authors: Fishburn Adam T , Kenaston Matthew W , Lopez Nicholas J , Hoang Vivian , Shiu Traci N , Haggard Arcé Sophia T , Khan Shahabal S , Shah Priya S
Published: March 2022

Zika virus (ZIKV) is infamous among flaviviruses for its unique association with congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV NS4A and host ANKLE2, which itself has established ties to congenital microcephaly. In fruit flies, NS4A induces microcephaly phenotypes in an ANKLE2-dependent manner. This suggests that NS4A interacts with ANKLE2 to dysregulate cell behavior and contributes to abnormal host neurodevelopment. Here, we explore the role of ANKLE2 in ZIKV replication to understand the biological significance of the interaction from the viral perspective. We show that knockdown of ANKLE2 reduces replication of two ZIKV strains, across multiple MOIs and timepoints. We observe that localization of ANKLE2 is drastically shifted to sites of NS4A accumulation during infection. We investigate which domains of ANKLE2 mediate this behavior and the interaction with NS4A. Using co-immunoprecipitation, we show that deletion of either the transmembrane or LEM domain has little impact on the interaction, but deletion of both significantly reduces interaction with NS4A. We show that the C-terminal transmembrane domains of NS4A stabilize the interaction with ANKLE2. Finally, we explore this interaction in other flaviviruses and observe ANKLE2 interacts with NS4A across four additional mosquito-borne flaviviruses. Together, these results suggest NS4A interacts with ANKLE2 through a combination of its transmembrane and LEM domains, bringing it to sites of ZIKV replication to promote replication through an unknown mechanism. Taken together with our previous results, our findings indicate that, in the process of hijacking ANKLE2 for replication, ZIKV disrupts its physiological function to cause disease.

Importance

The ZIKV epidemic led to the astonishing revelation that congenital ZIKV infection is associated with devastating birth defects, including microcephaly. Microcephaly is the condition in which head and brain size are severely reduced, and is often accompanied by intellectual disability. The molecular mechanisms by which ZIKV replicates and causes microcephaly are still incompletely understood. We previously identified the protein interaction between ZIKV NS4A and host ANKLE2, which is associated with congenital microcephaly. In flies, NS4A induces microcephaly in an ANKLE2-dependent manner, suggesting this interaction is crucial for ZIKV pathogenesis. Here, we explore the relevance of this physical interaction for virus replication. We find that ANKLE2 promotes ZIKV replication, concentrates at sites of NS4A accumulation during infection, and interacts with NS4A via its N-terminal domain. Thus, this represents a rare example of a ZIKV-host protein interaction that impacts both disease and virus replication.
Molecular Dynamics simulation of TDP-43 RRM in the presence and absence of RNA
Authors: Scott David Donald , Mowrey David , Nagarajan Karthi , François-Moutal Liberty , Nair Anil , Khanna May
Published: March 2022

Structural characterization of the prion prone TAR DNA Binding protein (TDP)-43 has been challenging since its intrinsically disordered regions represents 15-30% of the total protein. TDP-43 is a nucleic acid binding protein with an N-terminal domain, two RNA Recognition Motifs (RRM1 and RRM2) and the C-terminal domain. In this study, we seek to define possible new targetable sites on the apo structure of TDP-43 RRM domains. To do so, we used molecular dynamic (MD) simulations on the NMR solved TDP-43RRM1-2 structure bound to RNA to predict the apo structure. Contact analysis of TDP-43 showed that while the integrity of the individual domains was maintained upon RNA removal, a decrease in interdomain contacts was observed. Moreover, we compared apo TDP-43 structures obtained from MD to AlphaFold 2 (AF2) predicted TDP-43 structures and found differences in loop regions. A Sitemap analysis identified five druggable sites for the RNA bound structure solved by NMR, while fewer sites were identified following MD simulations and AF2 predicted apo structures.
Chlamydia trachomatis suppresses host cell store-operated Ca2+ entry and inhibits NFAT/calcineurin signaling
Authors: Chamberlain Nicholas B. , Hackstadt Ted
Published: March 2022

The obligate intracellular bacterium, Chlamydia trachomatis, replicates within a parasitophorous vacuole termed an inclusion. During development, host proteins critical for regulating intracellular calcium (Ca2+) homeostasis interact with the inclusion membrane. The inclusion membrane protein, MrcA, interacts with the inositol-trisphosphate receptor (IP3R), an ER cationic channel that conducts Ca2+. Stromal interaction molecule 1 (STIM1), an ER transmembrane protein important for regulating store-operated Ca2+ entry (SOCE), localizes to the inclusion membrane via an uncharacterized interaction. We therefore examined Ca2+ mobilization in C. trachomatis infected cells. Utilizing a variety of Ca2+ indicators to assess changes in cytosolic Ca2+ concentration, we demonstrate that C. trachomatis impairs host cell SOCE. Ca2+ regulates many cellular signaling pathways. We find that the SOCE-dependent NFAT/calcineurin signaling pathway is impaired in C. trachomatis L2 infected HeLa cells and likely has major implications on host cell physiology as it relates to C. trachomatis pathogenesis.
A novel conserved protein in Streptococcus agalactiae, BvaP, is important for vaginal colonization and biofilm formation
Authors: Thomas Lamar S. , Cook Laura C.
Published: March 2022

Streptococcus agalactiae (Group B Strep, GBS) infections in neonates are often fatal and strongly associated with maternal GBS vaginal colonization. Here, we investigated the role of a previously uncharacterized protein, BvaP, in GBS vaginal colonization. BvaP was previously identified as the most highly upregulated gene in the GBS A909 transcriptome when comparing vaginal colonization to growth in liquid culture. We found that expression of BvaP affects GBS adherence to extracellular matrix components and human vaginal epithelial cells and a ΔbvaP mutant was significantly decreased in its ability to colonize the murine vaginal tract. Cellular morphological alterations such as changes in cell shape, chain length, and clumping were also observed in a knockout mutant strain. Given its high expression in vivo, high degree of conservation among GBS strains, and role in vaginal colonization, BvaP may be an eligible target for GBS vaccination and/or drug therapy.

IMPORTANCE

Neonatal GBS disease is a major cause of morbidity and mortality and maternal vaginal colonization is the leading risk factor for disease. Colonization prevention would greatly impact rates of disease transmission, but vaccine development has stalled as capsular polysaccharide vaccines have low immunogenicity in vivo. While these vaccines are still in development, addition of a protein conjugate may prove fruitful in increasing immunogenicity and strain coverage across GBS serotypes. Previous research identified sak_1753 as a gene very highly upregulated gene during murine vaginal colonization. This study reveals that Sak_1753 is required to maintain proper GBS cellular morphology and colonization phenotypes and is required for in vivo vaginal colonization in a murine model. We have renamed Sak_1753 Group B Strep vaginal adherence protein (BvaP). The findings of this study indicate that BvaP is important in GBS colonization of the vaginal tract and may be a candidate for vaccine development.
Plasma MIA, CRP, and albumin predict cognitive decline in Parkinson’s Disease
Authors: Shen Junchao , Amari Noor , Zack Rebecca , Skrinak R. Tyler , Unger Travis L. , Posavi Marijan , Tropea Thomas F. , Xie Sharon X. , Van Deerlin Vivianna M. , Dewey Richard B. , Weintraub Daniel , Trojanowski John Q. , Chen-Plotkin Alice S.
Published: March 2022

Objective

Using a multi-cohort, Discovery-Replication-Validation design, we sought new plasma biomarkers that predict which PD individuals will experience cognitive decline.

Methods

In 108 Discovery Cohort PD individuals and 83 Replication Cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associating with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which PD patients showed fast (>=1 point drop/year on Montreal Cognitive Assessment (MoCA)) vs. slow (<1 point drop/year on MoCA) cognitive decline in the Discovery Cohort, testing it in the Replication Cohort. We developed alternate assays for the top three proteins and confirmed their ability to predict cognitive decline – defined by change in MoCA or development of incident Mild Cognitive Impairment (MCI) or dementia – in a Validation Cohort of 118 PD individuals. We investigated the top plasma biomarker for causal influence by Mendelian randomization.

Results

A model with only three proteins (Melanoma Inhibitory Activity Protein (MIA), C-Reactive Protein (CRP), albumin) separated Fast vs. Slow cognitive decline subgroups with an AUC of 0.80 in the Validation Cohort. Validation Cohort PD individuals in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes atMIASNP rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA’s causal influence.

Conclusions

An easily-obtained plasma-based predictor identifies PD individuals at risk for cognitive decline. MIA may participate causally in development of cognitive decline.
Longitudinal assessment of lung function in Swiss childhood cancer survivors
Authors: Kasteler Rahel , Otth Maria , Halbeisen Florian S , Mader Luzius , Singer Florian , Rössler Jochen , von der Weid Nicolas X , Ansari Marc , Kuehni Claudia E
Published: March 2022

Rationale

Childhood cancer survivors (CCSs) are at increased risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapies, radiotherapy, and surgery. Longitudinal data on lung function, with information on how outcomes change over time, in CCSs are scarce.

Objectives

To investigate lung function trajectories in childhood cancer survivors over time and investigate the association with lung-toxic treatment.

Methods

This retrospective, multi-center cohort study included CCSs, who were diagnosed between 1990 and 2013 in Switzerland and had been exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs) were obtained from hospital charts. We assessed quality of PFTs systematically and calculated z-scores and percentage predicted of forced expiratory volume in first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC) and diffusion capacity for carbon-monoxide (DLCO) based on recommended reference equations. We described lung function over time and determined risk factors for change in FEV1 and FVC using multivariable linear regression.

Results

We included 790 PFTs from 183 CCSs, with a median age of 12 years (IQR 7 – 14) at diagnosis. Common diagnoses were lymphoma (55%), leukemia (11%) and CNS tumors (12%). Median follow-up time was 5.5 years. Half (49%) of CCSs had at least one abnormal pulmonary function parameter, with restrictive impairment being common (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. CCSs treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (−2.02 to -0.15) and an FVC of -1.42 z-scores (−2.27 to -0.57) compared to those without surgery. In CCS exposed to lung-toxic chemotherapeutics FEV1 z-scores increased slightly over time (0.12 per year; 95%CI 0.02 - 0.21).

Conclusion

The large proportion of CCSs with reduced lung function identified in this study underlines the need for more research and long-term surveillance of this vulnerable population.
In depth exploration of the alternative proteome of Drosophila melanogaster
Authors: Fabre Bertrand , Choteau Sebastien A , Duboé Carine , Pichereaux Carole , Montigny Audrey , Korona Dagmara , Deery Michael J. , Camus Mylène , Brun Christine , Burlet-Schiltz Odile , Russell Steven , Combier Jean-Philippe , Lilley Kathryn S , Plaza Serge
Published: March 2022

Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.
A general calculus of fitness landscapes finds genes under selection in cancers
Authors: Hsu Teng-Kuei , Asmussen Jennifer , Koire Amanda , Choi Byung-Kwon , Gadhikar Mayur A. , Huh Eunna , Lin Chih-Hsu , Konecki Daniel M. , Kim Young Won , Pickering Curtis R. , Kimmel Marek , Donehower Lawrence A. , Frederick Mitchell J. , Myers Jeffrey N. , Katsonis Panagiotis , Lichtarge Olivier
Published: March 2022

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype–phenotype relationship and discover genes associated with complex traits and diseases.
Assessing the moderating role of organizational culture in the relationship between organizational leadership and organizational efficiency in the banking sector
Authors: Omama Koranteng Francisca , Iddris Faisal , Dwomoh Gabriel , Kofi Dogbe Courage Simon
Published: March 2022

Purpose

This study explored the moderating role of organizational culture in the relationship between organizational leadership and organizational culture in the banking sector.

Design/methodology/approach

The sample comprised of 331 full-time bank employees in the Ashanti region of Ghana. The reliability and validity of the data was tested using confirmatory factor analysis, with structural equation modeling as the main means of analysis, run using Amos (V23) in the data analysis.

Findings

The study concluded that all four leadership styles (transformational, transactional, servant and sustainable leadership styles) had a positive effect on banks' efficiency. Organizational culture also had a direct positive effect on banks' efficiency in Ghana. The study concludes that organizational culture positively moderated the relationship between organizational leadership and organizational efficiency in the banking industry. This implies organizational culture strengthens the relationship between organizational leadership and organizational efficiency in the banking industry.

Research limitations/implications

– A limitation of this study was to consider organizational culture as a composite variable, instead of considering the effects of the individual dimensions (clan culture, adhocracy culture, hierarchy culture and market culture). Although using the composite variable was not theoretically wrong, each of the four dimensions had unique characteristics and may influence organizational outcomes differently, and should have been considered.

Practical implications

To achieve strategic organizational outcomes, leaders are to comprehend the various leaderships styles and how they could be transformed to influence organizational outcomes.

Originality/value

Past studies have paid limited attention to the interaction between organizational leadership and organizational culture, and how this affects organizational efficiency.
Risk events recognition using smartphone and machine learning in construction workers' material handling tasks
Authors: Duan Pinsheng , Zhou Jianliang , Tao Shiwei
Published: March 2022

Purpose

The outbreak of the pandemic makes it more difficult to manage the safety or health of construction workers in infrastructure construction. Risk events in construction workers' material handling tasks are highly relevant to workers' work-related musculoskeletal disorders. However, there are still many problems to be resolved in recognizing risk events accurately. The purpose of this research is to propose an automatic and non-invasive recognition method for construction workers in material handling tasks during the pandemic based on smartphone and machine learning.

Design/methodology/approach

This research proposes a method to recognize and classify four different risk events by collecting specific acceleration and angular velocity patterns through built-in sensors of smartphones. The events were simulated with anterior handling and shoulder handling methods in the laboratory. After data segmentation and feature extraction, five different machine learning methods are used to recognize risk events and the classification performances are compared.

Findings

The classification result of the shoulder handling method was slightly better than the anterior handling method. By comparing the accuracy of five different classifiers, cross-validation results showed that the classification accuracy of the random forest algorithm was the highest (76.71% in anterior handling method and 80.13% in shoulder handling method) when the window size was 0.64 s.

Originality/value

Less attention has been paid to the risk events in workers' material handling tasks in previous studies, and most events are recorded by manual observation methods. This study provided a simple and objective way to judge the risk events in manual material handling tasks of construction workers based on smartphones, which can be used as a non-invasive way for managers to improve health and labor productivity during the pandemic.
Examining the role of China's outward direct investment in realizing carbon neutrality: empirical evidence from Belt and Road countries
Authors: Jiang Qingyan , Yang Cuihong , Wu Jie , Xia Yan
Published: March 2022

Purpose

Known as the major capital providers in Belt and Road countries and the largest carbon emitter in the world, what role China's outward direct investment (ODI) plays in carbon neutralization has become a matter of concern. This study aims to measure the impact of China's ODI on the carbon emissions of Belt and Road countries.

Design/methodology/approach

Based on an econometric model and an inter-regional input–output model, a new model measuring the carbon emission effects of ODI is developed.

Findings

The empirical results show that (1) in general, China's ODI generates an emission-reduction effect in Belt and Road countries; (2) The relationship between the emission-reduction effect and income level of host countries shows an approximate inverted U-shaped trend; and (3) China's ODI generates stronger emission-reduction effects on capital-intensive industries.

Originality/value

This study quantitatively measures the scale of carbon emission-increase and reduction effect, which is relatively lacking in previous studies. This study explores the heterogeneity from the perspectives of regions, countries and industries. The authors have compiled an inter-regional input–output table for the Belt and Road countries for 2014 to provide a broad basis for the study of related issues.
Synthesis and temperature-sensitive lubrication behavior of PNIPAM microgels for titanium alloy
Authors: Xu Yufu , Sun Kequn , Zheng Quan , Yao Lulu , Dong Yinghui , Song Ruhong
Published: March 2022

Purpose

This paper aims to offeri novel nano-additives polymer microgels to precisely improve the lubrication properties of titanium alloy under different temperatures.

Design/methodology/approach

The surfactant-free emulsion polymerization method was used to prepare Poly(N-isoprolylacrylamide) (PNIPAM) microgels. A ball-on-disk tribometer was applied to investigated the temperature-sensitive lubrication behavior of PNIPAM microgels.

Findings

The results show that the as-prepared microgels are ball-like nanoparticles with the size of 50–900 nm. In addition, potassium persulfate as initiator, complete mixing technic and high sodium dodecyl sulfate (SDS) concentration contribute to the formation of microgels with small size. The tribosystem shows a lower friction coefficient with the lubrication of PNIPAM microgels as aqueous solution additives when the temperature exceeding the critical temperature.

Originality/value

This work reports the temperature-sensitive lubrication of PNIPAM microgels. The critical temperature of PNIPAM microgels could be regulated by the addition of SDS in the solutions. This offers an effective and facile strategy for regulation of the critical temperature of smart microgels, which is helpful for the smart lubrication in the future.