bluuebunny/crossref_metadata_2025 huggingface dataset:
Exome-wide analysis reveals role ofLRP1and additional novel loci in cognition
Authors: Chakraborty Shreya , Kahali Bratati
Published: October 2022

Cognitive functioning is heritable, with metabolic risk factors known to accelerate ageassociated cognitive decline. Identifying genetic underpinnings of cognition is thus crucial.

Here, we undertake single-variant and gene-based association analyses upon six neurocognitive phenotypes across six cognition domains in whole-exome sequencing data from 157,160 individuals in the UK Biobank to expound the genetic architecture of human cognition. We further identify genetic variants interacting withAPOE, a significant genetic risk factor for cognitive decline, while controlling for lipid and glycemic risks, towards influencing cognition. Additionally, considering lipid and glycemic traits, we conduct bivariate analysis to underscore pleiotropic effects and also highlight suggestive mediation effects of metabolic risks on cognition.

We report 18 independent novel loci associated with five cognitive domains while controlling forAPOEisoform-carrier status and metabolic risk factors. Our novel variants are mostly in genes which could also impact cognition via their functions on synaptic plasticity and connectivity, oxidative stress, neuroinflammation. Variants in or near these identified loci show genetic links to cognitive functioning in association withAPOE, Alzheimer’s disease and related dementia phenotypes and brain morphology phenotypes, and are also eQTLs significantly controlling expression of their corresponding genes in various regions of the brain. We further report four novel pairwise interactions between exome-wide significant loci andAPOEvariants influencing episodic memory, and simple processing speed while accounting for serum lipid and serum glycemic traits. We obtain bothAPOC1andLRP1as significantly associated with complex processing speed and visual attention in our gene-based analysis. They also exhibit significant interaction effect withAPOEvariants in influencing visual attention. We find that variants inAPOC1andLRP1act as significant eQTLs for regulating their expression in basal ganglia and cerebellar hemispheres, crucial to visual attention. Taken together, our findings suggest thatAPOC1andLRP1have plausible roles along pathways of amyloid-β, lipid and/or glucose metabolism in affecting visual attention and complex processing speed. Interestingly, variants inMTFR1L, PPFIA1, PCDHB16, ATP2A1show evidence of pleiotropy and mediation effects through serum glucose/HDL levels affecting four different cognition domains.

This is the first report from large-scale exome-wide study with evidence underscoring the effect ofLRP1on cognition. Our research highlights a novel set of loci that augments our understanding of the genetic underpinnings of cognition during ageing, considering cooccurring metabolic conditions that can confer genetic risk to cognitive decline in addition toAPOE, which can aid in finding causal determinants of cognitive decline.
Resting-state functional connectivity predictors of subjective visual Gestalt experience
Authors: Wilding Marilena , Ischebeck Anja , Zaretskaya Natalia
Published: October 2022

Subjective perceptual experience is influenced not only by bottom-up sensory information and experience-based top-down processes, but also by an individual’s current brain state. Specifically, a previous study found increased prestimulus insula and intraparietal sulcus (IPS) activity before participants perceived an illusory Gestalt (global) compared to the non-illusory (local) interpretation in a bistable stimulus. This study provided only a snapshot of the prestimulus brain state that favors an illusory interpretation. In the current study, we tested the hypothesis that the neural machinery that biases perception towards the illusory interpretation immediately before the stimulus onset, is also predictive of an individual’s general tendency to perceive it, which remains stable over time. We examined individual differences in task-free functional connectivity of insula and IPS and related it to differences in the individuals’ duration of the two interpretations. We found stronger connectivity of the IPS with areas of the default mode and visual networks to predict shorter local perceptual phases, i.e., a faster switch to an illusory percept, but no equivalent results for the insula. Our findings suggest a crucial role of an IPS interaction with nodes of key intrinsic networks in forming a perceptual tendency towards illusory Gestalt perception.
Stability of SARS-CoV-2 spike antigens against mutations
Authors: De la Fuente Ildefonso M. , Malaina Iker , Fedetz Maria , Chruszcz Maksymilian , Grandes Gontzal , Targoni Oleg , Lozano-Pérez Antonio A. , Shteyer Eyal , Ya’acov Ami Ben , de la Cámara Agustín Gómez , Borobia Alberto M. , Carrasco-Pujante Jose , Pijoan Jose Ignacio , Bringas Carlos , Pérez-Yarza Gorka , Ouro Alberto , Crawford Michael J. , Shoshan-Barmatz Varda , Zhurov Vladimir , López José I. , Knafo Shira , Tary-Lehmann Magdalena , Gabaldón Toni , Grbic Miodrag
Published: October 2022

Modern health care needs preventive vaccines and therapeutic treatments with stability against pathogen mutations to cope with current and future viral infections. At the beginning of the COVID-19 pandemic, our analytic and predictive tool identified a set of eight short SARS-CoV-2 S-spike protein epitopes that had the potential to persistently avoid mutation. Here a combination of genetic, Systems Biology and protein structure analyses confirm the stability of our identified epitopes against viral mutations. Remarkably, this research spans the whole period of the pandemic, during which 93.9% of the eight peptides remained invariable in the globally predominant 43 circulating variants, including Omicron. Likewise, the selected epitopes are conserved in 97% of all 1,514 known SARS-CoV-2 lineages. Finally, experimental analyses performed with these short peptides showed their specific immunoreactivity. This work opens a new perspective on the design of next-generation vaccines and antibody therapies that will remain reliable against future pathogen mutations.

Highlights

Our novel method predicts SARS-CoV-2 epitopes that are stable against future mutations

Genetic analyses (performed 2 years after epitopes were identified) validate the stability of the identified peptides

These epitopes remained invariable in 97% of all 1,514 known SARS-CoV-2 lineages

93.9% of such peptides were conserved in the 43 variants of most interest, including Omicron

Graphical Abstract
ACSM1 and ACSM3 regulate prostate cancer fatty acid metabolism to promote tumour growth and constrain ferroptosis
Authors: Shrestha Raj , Nassar Zeyad D. , Hanson Adrienne R. , Iggo Richard , Townley Scott L. , Dehairs Jonas , Mah Chui Yan , Helm Madison , Ghodsi Mohammadreza , Pickering Marie , Watt Matthew J. , Quek Lake-Ee , Hoy Andrew J. , Tilley Wayne D. , Swinnen Johannes V. , Butler Lisa M. , Selth Luke A.
Published: October 2022

Prostate tumours are highly reliant on lipids for energy, growth and survival. Activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes in prostate cancer, although the molecular underpinnings of this relationship remain to be fully elucidated. Here, we identified Acyl-CoA Synthetase Medium Chain Family Members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 are upregulated in prostate tumours compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected PCa cells from deathin vitro, while silencing ACSM3 led to reduced tumour growth in an orthotopic xenograft model. We show that ACSM1 and ACSM3 are major regulators of the PCa lipidome and enhance energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, over-expression of ACSM1/3 enabled PCa cells to survive toxic doses of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, these studies uncover a new link between AR and lipid metabolism and position ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.
A Leaky Human Colon Model Reveals Uncoupled Apical/Basal Cytotoxicity in EarlyClostridioides difficileToxin Exposure
Authors: Ok Meryem T. , Liu Jintong , Bliton R. Jarrett , Hinesley Caroline M. , San Pedro Ekaterina Ellyce T. , Breau Keith A. , Gomez-Martinez Ismael , Burclaff Joseph , Magness Scott T.
Published: October 2022

Background & Aims

Clostridioides difficile(C. difficile) toxins A (TcdA) and B (TcdB) cause antibiotic-associated colitis and increase morbidity and mortality. Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop pre-clinical models for new therapies. Properties of cancer cell lines and 3D organoids inherently limit these efforts. Here, we develop adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigate the impact of toxin application to apical/basal aspects of monolayers, and evaluate whether a leaky epithelial barrier enhances toxicity.

Methods

Single-cell RNA-sequencing (scRNAseq) mappedC. difficile-relevant genes to cell lineages across the human gut. Transcriptomics informed timing of stem cell differentiation to achieve in vitro colonocyte maturation like that observed in vivo. Transepithelial electrical resistance (TEER) and fluorescent dextran permeability assays measured cytotoxicity as barrier loss post-toxin exposure. Leaky epithelial barriers were induced with diclofenac.

Results

scRNAseq demonstrated broad and variable toxin receptor expression across the human gut lineages. Absorptive colonocytes displayed generally enhanced toxin receptor, Rho GTPase, and cell junction expression. 21-day differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes. hCE monolayers exhibited high barrier function after 1-day differentiation. Basal TcdA/B application to monolayers caused more toxicity and apoptosis than apical exposure. Diclofenac induced leaky hCE monolayers and enhanced toxicity of apical TcdB exposure.

Conclusions

Apical/basal toxicities are uncoupled with more rapid onset and increased magnitude of basal toxicity. Leaky paracellular junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive culture system to evaluate the impact of microbial toxins on gut epithelium.
Candida albicanspromotes neutrophil extracellular trap formation and leukotoxic hypercitrullination via the peptide toxin candidalysin
Authors: Unger Lucas , Backman Emelie , Amulic Borko , Ponce-Garcia Fernando M. , Yellagunda Sujan , Krüger Renate , von Bernuth Horst , Bylund Johan , Hube Bernhard , Naglik Julian R. , Urban Constantin F.
Published: October 2022

The cytolytic peptide toxin candidalysin is secreted by the invasive, hyphal form of the human fungal pathogen,Candida albicans. Candidalysin is essential for inducing host cell damage during mucosal and systemicC. albicansinfections, resulting in neutrophil recruitment. Neutrophil influx toC. albicans-infected tissue is critical for limiting fungal growth and preventing the fungal dissemination. Here, we demonstrate that candidalysin secreted by hyphae promotes the stimulation of neutrophil extracellular traps (NETs), while synthetic candidalysin triggers a distinct mechanism for NET-like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leukotoxic hypercitrullination, which is governed by protein arginine deaminase 4 activation via calcium influx and initiation of intracellular signalling events. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin-dependent kinases that are crucial for NET release. Interestingly, exposure to candidalysin does not immediately restrict the capability of neutrophils to produce reactive oxygen species (ROS), nor to phagocytose particles. Instead, candidalysin triggers ROS production, calcium influx and subsequent activation of downstream signalling that drive morphological alteration and the formation of NLS in a dose- and time-dependent manner. Notably, candidalysin-triggered NLS demonstrate anti-Candidaactivity, which is resistant to nuclease treatment and dependent on the deprivation of Zn2+. This study reveals thatC. albicanshyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entanglesC. albicanshyphae and inhibits their growth. Importantly, this explains discrepancies of previous studies demonstrating that neutrophil-derived extracellular chromatin structures triggered byC. albicanscan be both dependent and independent of ROS. Our data also demonstrate that while candidalysin hampers neutrophil function, the toxin also increases the capability of neutrophils to entangle hyphae and to restrict their growth, reflecting the importance of human neutrophils in controlling the dissemination ofC. albicans.
The potentiative cytotoxic effect of IGF1R and EGFR inhibition on the Head and Neck Cancer Proteome
Authors: Hall Sarah , Lehman Christine E. , Wulfkuhle Julia , Petricoin Emanuel F. , Bekiranov Stefan , Dolatshahi Sepideh , Jameson Mark J. , Gioeli Daniel
Published: October 2022

Head and neck cancers are the sixth most common cancer worldwide. Combinatorial targeted therapy has the potential to reduce drug resistance and increase cytotoxicity to head and neck squamous cell carcinoma (HNSCC). Using drug combinations is especially important when targeting the epidermal growth factor receptor (EGFR) since we previously demonstrated that activation of the insulin-like growth factor 1 receptor (IGF1R) is a mechanism for resistance against EGFR inhibition and that a combination of an IGF1R inhibitor, BMS754807, and an EGFR inhibitor, BMS599626, robustly inhibited the growth of HNSCC cell linesin vitro. To examine the mechanism of cytotoxicity, we performed protein pathway activation mapping via reverse phase protein array (RPPA) analysis of 145 proteins and phosphoproteins in five HNSCC cell lines to map key proteins and phosphoproteins important in tumorigenesis. By performing principal component analysis, calculating log fold changes, and constructing protein networks, we were able to provide evidence to support the hypothesis that the combination of IGF1R and EGFR inhibitors has a potentiative effect on inhibiting receptor tyrosine kinase signaling. The effects of the individual drugs are amplified, demonstrating that the combination more robustly inhibits the pathways of both receptors.
Phylogenomic analysis of the understudiedNeisseriaceaespecies reveals a poly- and paraphyleticKingellagenus
Authors: Morreale Daniel P. , St Geme Joseph W. , Planet Paul J.
Published: October 2022

Taxonomic classification and phylogenetic analysis of theNeisseriaceaefamily has focused on the pathogensNeisseria meningitidisandNeisseria gonorrhoeae. Less is known about the relationships of commensalNeisseriaspecies and otherNeisseriaceaegenera, raising the possibility that the phylogeny of this family may not agree with taxonomy. In this study we used available nucleotide sequences and a phylogenetic approach to assess theKingellagenus and its relatives. We found that this genus is both paraphyletic and polyphyletic.Kingella potusis more closely related toNeisseria bacilliformisthan otherKingellaspecies. TheAlysiellaandSimonsiellagenera form a distinct clade within theKingellagenus that is closely related to the pathogensK. kingaeandK. negevensis. We find a phylogenetic relationship betweenConchiformibius,Alysiella,Simonsiella, andKingella, which we name the CASK clade. Finally, we define the gene sets that differentiate each genus of the CASK clade from one another and from the rest of theNeisseriaceaefamily.

Importance

Understanding the evolutionary relationships between the species in theNeisseriaceaehas been a persistent challenge in bacterial systematics due to high recombination rates in these species. Previous studies of this family have focused onN. meningitidisandN. gonorrhoeae. However, previously understudiedNeisseriaceaespecies are gaining new attention, withK. kingaenow recognized as a common human pathogen and withAlysiellaandSimonsiellabeing unique in the bacterial world as multicellular organisms. A better understanding of the genomic evolution of theNeisseriaceaecan lead to identification of the specific genes and traits that characterize the remarkable diversity of this family.
TCID50 Measurements of anti-viral efficacy on metal printed masks and plastic surfaces
Authors: Bilynsky Colette S.M. , Taylor Kishana , Anand Megha , Wayne Elizabeth
Published: October 2022

The SARS-CoV-2 pandemic has created a need for effective personal protective equipment (PPE) to prevent viral spread. PPE like face masks contain the spread of virus-filled droplets and thus reduce infection rates, has been a critical tool in stopping the spread of SARS-CoV-2. PET plastic barriers have also been used in public settings to reduce face to face viral transmission. However, in some cases, they have provided additional contact with the virus due to contamination. In order study, we evaluated the effectiveness of face masks and PET plastics coated in different metals in reducing viral load. We compared PPE printed with silver, copper, or zinc for their ability to inactivate live human coronavirus HCoV 229E. Our results show that silver and copper have significant anti-viral efficacy when printed on nonwoven fabric compared to the controls. The metal-printed PET showed around 70% anti-viral efficacy with any formulations, with copper performing the best. This work builds more data to support the development of metal printed materials for enhanced protection against coronaviruses.
Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron
Authors: Chen Da-Yuan , Kenney Devin , Chin Chue Vin , Tavares Alexander H. , Khan Nazimuddin , Conway Hasahn L. , Liu GuanQun , Choudhary Manish C. , Gertje Hans P. , O’Connell Aoife K. , Kotton Darrell N. , Herrmann Alexandra , Ensser Armin , Connor John H. , Bosmann Markus , Li Jonathan Z. , Gack Michaela U. , Baker Susan C. , Kirchdoerfer Robert N. , Kataria Yachana , Crossland Nicholas A. , Douam Florian , Saeed Mohsan
Published: October 2022

The recently identified, globally predominant SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals, and causes attenuated disease compared with other major viral variants recognized to date1–7. The Omicron spike (S) protein, with an unusually large number of mutations, is considered the major driver of these phenotypes3,8. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.
Vector diversity and malaria prevalence: global trends and local determinants
Authors: Hoi Amber Gigi , Gilbert Benjamin , Mideo Nicole
Published: October 2022

Identifying determinants of global infectious disease burden is a central goal of disease ecology. While it is widely accepted that host diversity structures parasite diversity and prevalence across large spatial scales, the influence of vector diversity on disease risk has rarely been examined despite the role of vectors as obligatory intermediate hosts for many parasites. Malaria, for instance, can be transmitted by over 70 species of mosquitoes, but the impact of this diversity on malaria risk remains unclear. Further, such relationships are likely dependent on the context in which disease transmission occurs, as arthropod life history and behavior are highly sensitive to environmental factors such as temperature. We studied the relationship between vector diversity, malaria prevalence, and environmental attributes using a unique dataset we curated by integrating several open-access sources. Globally, the association between vector species richness and malaria prevalence differed by latitude, indicating that this relationship is strongly dependent on underlying environmental conditions. Structural equation models further revealed different processes by which the environment impacts vector community assemblage and function, and subsequently disease prevalence, in different regions. In Africa, the environment exerted a top-down influence on disease through its role in shaping vector communities, whereas in Southeast Asia, disease prevalence is influenced by more complex interactions between the physical and socioeconomic environment (i.e., rainfall and GDP) and vector diversity across sites. This work highlights the key role of vector diversity in structuring disease distribution at large spatial scales and offers crucial insights to vector management and disease control.

Significance statement

The global health threat from persistent and emerging vector-borne diseases continues to increase and is exacerbated by rapid environmental and societal change. Predicting how disease burden will shift in response to these changes necessitates a clear understanding of existing determinants of disease risk. We focused on an underappreciated potential source of variation in disease burden – vector diversity – and its role in structuring global malaria distribution. Our work revealed that vector diversity influences malaria prevalence and that the strength and nature of this association strongly depend on local environmental context. Extending disease transmission theory, surveillance, and control to embrace heterogeneity in vector community structure and function across space and time is an asset in the fight against vector-borne diseases.
ULTRAFAST STRUCTURAL CHANGES DIRECT THE FIRST MOLECULAR EVENTS OF VISION
Authors: Gruhl Thomas , Weinert Tobias , Rodrigues Matthew , Milne Christopher J , Ortolani Giorgia , Nass Karol , Nango Eriko , Sen Saumik , Johnson Philip J M , Cirelli Claudio , Furrer Antonia , Mous Sandra , Skopintsev Petr , James Daniel , Dworkowski Florian , Båth Petra , Kekilli Demet , Ozerov Dmitry , Tanaka Rie , Glover Hannah , Bacellar Camila , Brünle Steffen , Casadei Cecilia M , Diethelm Azeglio D , Gashi Dardan , Gotthard Guillaume , Guixà-González Ramon , Joti Yasumasa , Kabanova Victoria , Knopp Gregor , Lesca Elena , Ma Pikyee , Martiel Isabelle , Mühle Jonas , Owada Shigeki , Pamula Filip , Sarabi Daniel , Tejero Oliver , Tsai Ching-Ju , Varma Niranjan , Wach Anna , Boutet Sébastien , Tono Kensuke , Nogly Przemyslaw , Deupi Xavier , Iwata So , Neutze Richard , Standfuss Jörg , Schertler Gebhard FX , Panneels Valerie
Published: October 2022

Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon is absorbed by the 11-cisretinal chromophore of rhodopsin which isomerises within 200 femtoseconds to the all-transconformation, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains elusive. In this work, we use ultrafast time-resolved crystallography at room temperature to determine how an isomerised twistedall-transretinal stores the photon energy required to initiate protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at 1 ps time-delay of photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Strikingly, the very early structural motions in the protein side chains of rhodopsin appear in regions involved in later stages of the conserved Class A GPCR activation mechanism. Our work sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.
Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in neurogenesis of the offspring
Authors: Srinivas Vilasagaram , Varma Saikanth , Kona Suryam Reddy , Ibrahim Ahamed , Duttaroy Asim K , Basak Sanjay
Published: October 2022

Maternal n-3 PUFA (omega-3) deficiency can affect brain developmentin uteroand postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal brain remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, expression of fatty acid desaturases, elongases, signalling receptors of free fatty acids, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 folds), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus (p<0.05). Increasing dietary LA to ALA (50:1) elevated ARA to DHA ratio by ∼8 folds in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient brain exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression (p<0.05). Maternal n-3 PUFA deficiency affects the expression of key neurogenesis genes in the offspring with concomitant expression of desaturases and elongases genes suggesting the importance of dietary n-3 PUFA for neurodevelopment.
Identification and functional validation of human islet microRNAs associated with donor trait
Authors: Wong Wilson K.M. , El-Azzi Isabelle , Nachanekar Aditya , Alvandi Ehsan , Pham Ho Trong Nhan , Sara Mya , Cheng Feifei , Jiang Guozhi , Sørensen Anja E. , Chew Yi Vee , Loudovaris Thomas , Thomas Helen E. , Ma Ronald C.W. , Hawthorne Wayne J. , Dalgaard Louise T. , Joglekar Mugdha V. , Hardikar Anandwardhan A.
Published: October 2022

Objectives

Human islets are widely researched to understand pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing insulin secretion. Islet function is also regulated by an intricate network of microRNAs.

Methods

Here, we profiled 754 microRNAs and 58,190 potential targets in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. We further performed mechanistical studies to observe the causal role of the age-associated key microRNAs on relative telomere length in human islets.

Results

MicroRNA discovery analyses identified miR-199a-5p and miR-214-3p associated with sex, age and BMI; miR-147b with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. There were 959 mRNA transcripts associated with sex (excluding those from sex-chromosomes), 940 with age and 418 with BMI. MicroRNA-199a-5p and miR-214-3p levels inversely associate with transcripts critical in islet function, metabolic regulation, and senescence. Our functional studies verified that inhibition of these two microRNAs (miR-199a-5p/-214-3p) slowed down telomere length shortening in human islet cells maintained in vitro and demonstrating cellular senescence.

Conclusions

Our analyses identify human islet cell microRNAs influenced by donor traits.

Graphical abstract
The first archaeal PET-degrading enzyme belongs to the feruloyl-esterase family
Authors: Perez-Garcia Pablo , Chow Jennifer , Costanzi Elisa , Gurschke Marno F. , Dittrich Jonas , Dierkes Robert F. , Applegate Violetta , Feuerriegel Golo , Tete Prince , Danso Dominik , Schumacher Julia , Pfleger Christopher , Gohlke Holger , Smits Sander H. J. , Schmitz Ruth A. , Streit Wolfgang R.
Published: October 2022

Polyethylene terephthalate (PET) is a commodity polymer known to globally contaminate marine and terrestrial environments. Today, around 40 bacterial and fungal PET-active enzymes (PETases) are known, originating from four bacterial and two fungal phyla. In contrast, no archaeal enzyme has been identified to degrade PET. Here we report on the structural and biochemical characterization of PET46, an archaeal promiscuous feruloyl esterase exhibiting degradation activitiy on PET, bis-, and mono-(2-hydroxyethyl) terephthalate (BHET and MHET). The enzyme, found by a sequence-based metagenome search, was derived from a non-cultivated, deep-sea Candidatus Bathyarchaeota archaeon. Biochemical characterization demonstrated that PET46 is a promiscuous, heat-adapted hydrolase. Its crystal structure was solved at a resolution of 1.71 Å. It shares the core alpha/beta-hydrolase fold with bacterial PETases, but contains a unique lid common in feruloyl esterases, which is involved in substrate binding. Thus, our study significantly widens the currently known diversity of PET-hydrolyzing enzymes, by demonstrating PET depolymerization by a lignin-degrading esterase.
Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells
Authors: Francis Meenal , Sheshadri Preethi , Prasanna Jyothi , Kumar Anujith
Published: October 2022

Diabetes is a metabolic disease caused majorly due to loss of insulin secreting β-cells. Along with apoptosis, recent reports revealed dedifferentiation to be the added reason for the reduced β-cell mass. The Ubiquitin Proteasome system comprising of E3 ligase and deubiquitinases (DUBs) control several key aspects of pancreatic β-cell functions. The role of deubiquitinases in orchestrating the dedifferentiation process in several cancers have been well deciphered, but its role in dedifferentiation of pancreatic β-cells remains elusive. In this study, screening for key DUBs that regulate dedifferentiation, identified USP1 to be specifically involved in the process. Inhibition of USP1 either by genetic intervention or small molecule inhibitor ML323 restored epithelial phenotype of β-cells, but not with inhibition of other DUBs. Conversely overexpression of USP1 was sufficient to dedifferentiate β-cells, even in absence of dedifferentiation inducing cues. Mechanistic insight showed USP1 to probably mediate its effect via modulating the expression of Inhibitor of Differentiation (ID) 2. Further, in anin vivostreptozotocin (STZ) induced dedifferentiation mouse model system, treatment with ML323 rescued the hyperglycaemic state. Overall, this study assigns a novel role to USP1 in dedifferentiation of β-cells and its inhibition may have a therapeutic application of reducing the β-cell loss during diabetes.
Probing the conserved roles of Cut in the development and function of optically different insect compound eyes
Authors: Rathore Shubham , Meece Michael , Charlton-Perkins Mark , Cook Tiffany A. , Buschbeck Elke K
Published: October 2022

Astonishing functional diversity exists among arthropod eyes, yet eye development relies on deeply conserved genes. This phenomenon is best understood for early events, whereas fewer investigations have focused on the influence of later transcriptional regulators on diverse eye organizations and the contribution of critical support cells, such as Semper cells (SCs). As SCs inDrosophila melanogastersecrete the lens and function as glia, they are critical components of ommatidia. Here, we perform RNAi-based knockdowns of the transcription factorcut(CUX in vertebrates), a marker of SCs, the function of which has remained untested in these cell types. To probe for the conserved roles ofcut, we investigate two optically different compound eyes: the apposition optics ofD. melanogasterand the superposition optics of the diving beetleThermonectus marmoratus. In both cases, we find that multiple aspects of ocular formation are disrupted, including lens facet organization and optics as well as photoreceptor morphogenesis. Together, our findings highlight a generalized role for SCs in arthropod eye form and function and define Cut as a central player in mediating these functions.
Removal ofpomt1in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes
Authors: Karas Brittany F. , Terez Kristin R. , Mowla Shorbon , Battula Namarata , Flannery Kyle P. , Gural Brian M. , Aboussleman Grace , Mubin Numa , Manzini M. Chiara
Published: October 2022

Biallelic mutations inProtein O-mannosyltransferase 1(POMT1) are among the most common causes of a severe group of congenital muscular dystrophies (CMDs) known as dystroglycanopathies. POMT1 is a glycosyltransferase responsible for the attachment of a functional glycan mediating interactions between the transmembrane glycoprotein dystroglycan and its binding partners in the extracellular matrix (ECM). Disruptions in these cell-ECM interactions lead to multiple developmental defects causing brain and eye malformations in addition to CMD. RemovingPomt1in the mouse leads to early embryonic death due to the essential role of dystroglycan during placental formation in rodents. Here, we characterized and validated a model ofpomt1loss of function in the zebrafish showing that developmental defects found in individuals affected by dystroglycanopathies can be recapitulated in the fish. We also discovered thatpomt1mRNA provided by the mother in the oocyte supports dystroglycan glycosylation during the first few weeks of development. Muscle disease, retinal synapse formation deficits, and axon guidance defects can only be uncovered during the first week post fertilization by generating knock-out embryos from knock-out mothers. Conversely, maternalpomt1from heterozygous mothers was sufficient to sustain muscle, eye, and brain development only leading to loss of photoreceptor synapses at 30 days post fertilization. Our findings show that it is important to define the contribution of maternal mRNA while developing zebrafish models of dystroglycanopathies and that offspring generated from heterozygous and knock-out mothers can be used to differentiate the role of dystroglycan glycosylation in tissue formation and maintenance.
Extreme quantile connectedness and spillovers between oil and Vietnamese stock markets: a sectoral analysis
Authors: Mensi Walid , Ziadat Salem Adel , Vo Xuan Vinh , Kang Sang Hoon
Published: October 2022

Purpose

This study examines the extreme quantile connectedness and spillovers between West Texas Intermediate (WTI) crude oil futures and ten Vietnamese stock market sectors. Knowledge of such links is important to both investors and policymakers in understanding the transmission of shocks across markets.

Design/methodology/approach

The authors employ the extreme quantile connectedness methodology of Ando et al. (2022).

Findings

Initial results show that the size of spillovers is higher during bearish markets than bullish markets and under major financial, political, energy and pandemic events. The oil market is a net receiver of spillovers during downward markets and net contributors during upward markets. The banking sector is a net contributor of spillovers, whereas consumer discretionary and consumer staples are net receivers for different quantiles. The role of the remaining sectors as net receivers/contributors is sensitive to the quantiles. Oil has a large spillover effect on the electricity sector for all quantiles. Comparing all crises, oil offers the best hedging effectiveness to the Vietnamese sector during the coronavirus disease 2019 (COVID-19) crisis. Moreover, oil was a cheap hedge asset during oil crises. Finally, oil provides the highest hedging effectiveness for healthcare during the global financial crisis (GFC) and consumer staples during the European debt crisis (EDC), oil crisis and COVID-19.

Originality/value

Acknowledging the presence of heterogeneity in the relation between oil and economic sectors under different market conditions, this study is the first to examine the extreme quantile connectedness between oil and Vietnamese sectors.
Nonlinear relationship between financial inclusion and inclusive economic development in developed economies: evidence from panel smooth transition regression model
Authors: Timer Sehrish , Raza Syed Ali
Published: October 2022

Purpose

The purpose of this study is to investigate the nonlinear association between financial inclusion and inclusive economic growth (IEG) in developed economies. A Block of G7 countries (Germany, Japan, Canada, France, Italy, the UK and the US) are considered in this study.

Design/methodology/approach

For analysis, the authors have employed the “Panel Smooth Transition Regression model.” Annual data consists of the period from 1995 to 2019.

Findings

This research makes a unique contribution to literature with reference to G7 countries, being a pioneering attempt to apply the panel threshold regression model to analyze the relationship between financial inclusion and IEG by applying more rigorous and advanced econometric techniques.

Originality/value

The results indicate that total labor force available in a country, gross fixed capital formation and financial inclusion are positive and significant in lower regimes, but as it moves toward the higher regime, the labor force available in a country becomes less impactful. However, an increase has been observed in financial inclusion in the higher regime. The complete sample generally exhibits a positive yet significant relationship between financial inclusion and inclusive economic development.
Distinguishing signatures of scalar leptoquarks at hadron and muon colliders
Authors: Bandyopadhyay Priyotosh , Karan Anirban , Mandal Rusa , Parashar Snehashis
Published: October 2022

While the hunt for new states beyond the standard model (SM) goes on for various well motivated theories, the leptoquarks are among the most appealing scenarios at recent times due to a series of tensions observed in B-meson decays. We consider SU(2) singlet and triplet scalar leptoquarks separately, which contribute to charged and neutral current B-meson decays. Focusing on the single production of these two scalar leptoquarks, we perform a PYTHIA-based simulation considering all the dominant SM backgrounds at the current and future setups of the Large Hadron Collider (LHC). The mono-b-jet + $$\not \!\!{p_T}$$

⧸

p
T

finalstate gives the strongest signal for the singlet leptoquark at the 30 TeV LHC or Future Circular Collider (FCC), with a possibility of $$5\sigma $$

5
σ

signal significance with $$\gtrsim 1000$$

≳
1000

fb$$^{-1}$$

-
1

of integrated luminosity, for the chosen benchmark scenarios. The finalstate consisting of a c-jet and two $$\tau $$
τ
-jets provides highest reach for the singlet leptoquark, probing an $${\mathcal {O}}(10^{-1})$$

O
(

10

-
1

)

value of the Yukawa-type couplings for up to 3.0 TeV leptoquark mass. For the triplet leptoquark, "Equation missing" topology is the most optimistic signature at the LHC, probing leptoquark couplings to fermions at $${\mathcal {O}}(10^{-1})$$

O
(

10

-
1

)

value for the leptoquark mass range up to 4.0 TeV. The invariant mass edge distribution is found to be instrumental in determination of the leptoquark mass scale at the LHC. We also perform the analysis at the proposed multi-TeV muon collider, where an $${\mathcal {O}}(10^{-1})$$

O
(

10

-
1

)

leptoquark Yukawa coupling can be probed for a 5.0 TeV leptoquark mass.
Doubly-polarized WZ hadronic cross sections at NLO QCD + EW accuracy
Authors: Le Duc Ninh , Baglio Julien
Published: October 2022

We present new results for next-to-leading order (NLO) electroweak (EW) corrections to double polarization signals in the WZ production channel at the LHC using the $$e^+\nu _e \mu ^+ \mu ^-$$

e
+

ν
e

μ
+

μ
-

final state. It is found that the EW corrections are most sizable in the transverse momentum distributions of the doubly longitudinal polarization, being around $$-\,10$$

-

10

% compared to the NLO QCD prediction at $$p_{T,e}\approx 200$$

p

T
,
e

≈
200

 GeV, which is in the accessible energy range of the current LHC data.
Recent Progress, Advancements, and Efficiency Improvement Techniques of Natural Plant Pigment‐Based Photosensitizers for Dye‐Sensitized Solar Cells
Authors: Bekele Eneyew Tilahun , Sintayehu Yilkal Dessie
Published: October 2022

Production of green energy by using environment friendly and cost‐effective components is attracting the attention of the research world and is found to be a promising approach to replace nonrenewable energy sources. Among the green energy sources, dye‐sensitized solar cells (DSSCs) are found to be the most alternative way to reduce the energy demand crises in current situation. The efficiency of DSSCs is dependent on numerous factors such as the solvent used for dye extraction, anode and cathode electrodes, and the thickness of the film, electrolyte, dye, and nature of FTO/ITO glasses. The efficiency of synthetic dye‐based DSSCs is enhanced as compared to their counterparts. However, it has been found that many of the synthetic sensitizers used in DSSCs are toxic, and some of them are found to cause carcinogenicity in nature by forming a complex agent. Instead, using various parts of green plants such as leaves, roots, steam, peel waste, flowers, various spices, and mixtures of them would be a highly environmentally friendly and good efficient. The present review focuses on and summarizes the efficiency affecting factors, the various categories of natural sensitizers, and solvent effects. Furthermore, the review work assesses the experimentally and computationally obtained values and their progress in development.
The Efficacy of Rosuvastatin, Amlodipine, and Aspirin in the Treatment of Hypertension with Coronary Heart Disease and Its Effect on Platelet Aggregation
Authors: Fu Jianli , Wang Ting , Li Botao , Zhao Na
Published: October 2022

Objective. This study was to study the efficacy of rosuvastatin, amlodipine, and aspirin in the treatment of hypertension with coronary heart disease and its effect on platelet aggregation. Methods. The participants included 60 patients with hypertension and coronary heart disease who were treated at our hospital between January 2020 and May 2021 and were randomly assigned to receive either rosuvastatin, amlodipine, and Ziyin Huoxue Recipe (observation group) or rosuvastatin, amlodipine, Ziyin Huoxue Recipe, and aspirin (experimental group), with 30 patients in each. Outcome measures included clinical effectiveness, blood pressure indicators, blood lipid indices, plasma viscosity, platelet aggregation, cardiac function, and adverse responses. Results. The clinical efficacy in the experimental group was significantly higher than that in the observation group (P<0.05). The differences were found in blood pressure indices and blood lipid indices between the two groups before treatment (P>0.05). However, after treatment, the blood pressure indices in the experimental group were significantly lower than those in the observation group (P<0.05). After treatment, the blood lipid indices, plasma viscosity, and platelet aggregation in the experimental group were significantly lower than those in the observation group (P<0.05). The left ventricular ejection fraction (LVEF) of patients in the experimental group after treatment was significantly higher than that of patients in the observation group (P<0.05). There was no significant difference in the incidence of adverse reactions among patients in the two groups (P>0.05). Conclusion. The clinical efficacy of rosuvastatin, amlodipine, and aspirin markedly reduces the blood pressure indices, blood lipid indices, plasma viscosity, and platelet aggregation of patients with hypertension and coronary heart disease, improves LVEF, and has a good safety profile.
Code Vulnerability Detection Based on Deep Sequence and Graph Models: A Survey
Authors: Wu Bolun , Zou Futai
Published: October 2022

With the flourishing of the open-source software community, the problem of software vulnerabilities is becoming more and more serious. Hence, it is urgent to come up with an effective and efficient code vulnerability detection method. Source code vulnerability detection techniques used in practice today like symbolic execution and fuzz testing suffer from high false positives and low code coverage, respectively. Traditional machine-learning-based solutions fail to cope with the diversity of vulnerabilities. To overcome these drawbacks, a large number of deep-learning-based code vulnerability detection works have emerged, aiming at building powerful neural network models to fully learn code semantics and vulnerability patterns. In this survey, we mainly focus on code vulnerability detection approaches based on deep sequence modeling and graph modeling technologies. Our goal is to investigate how these two methods are applied to facilitate code vulnerability detection. We also go over current prevailing datasets that are used to evaluate detection models. At last, we identify the current challenges in this field and share our views on future work.
Targeted Perioperative Nursing Combined with Propofol and Fentanyl for Gynecological Laparoscopic Surgery
Authors: Yun Xue-Yu , Chen Shu-Juan , Zheng Qiu-Wu
Published: October 2022

Objective. The aim of this study is to investigate the clinical effects of targeted perioperative nursing combined with propofol and fentanyl in gynecological laparoscopic surgery. Methods. Patients who were admitted to our hospital for gynecological laparoscopic surgeries from October 1, 2019 to November 30, 2021 were included in this retrospective study. Patients in group A received routine propofol and fentanyl. Patients in group B received targeted perioperative nursing on the basis of interventions in group A. The anesthetic effects, clinical indicators, mental health status, and adverse reactions were compared between the two groups. Results. A total of 84 qualified patients were retrieved. The total effective anesthesia rate, extubation time, operation time, consciousness recovery time, intraoperative blood loss, hospital stay, SAS score, SDS score, health status indicators, and adverse events in group B were all significantly better than those in group A (

P
<
0.05

for all comparisons). Conclusion. Combined intervention (propofol + fentanyl + targeted perioperative care) for gynecological laparoscopic surgery patients has a significant anesthesia effect, which can effectively improve the patient's clinical indicators and mental health status and can also reduce the occurrence of adverse events. It has good safety and can be widely used in clinical practice.