bluuebunny/crossref_metadata_2025 huggingface dataset:
Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors
Authors: Rathinaswamy Manoj K , Gaieb Zied , Fleming Kaelin D , Borsari Chiara , Harris Noah J , Moeller Brandon E , Wymann Matthias P , Amaro Rommie E , Burke John E
Published: December 2020

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the p110γ subunit playing a key role in immune signalling. PI3Kγ is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the c-terminus can inactivate or activate enzyme activity. Screening of small molecule inhibitors using HDX-MS revealed that activation loop binding inhibitors induce allosteric conformational changes that mimic those seen for the R1021C mutant. Structural analysis of clinically advanced PI3K inhibitors revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insight into the regulatory mechanisms that control PI3Kγ kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.
Single cell profiling reveals novel tumor and myeloid subpopulations in small cell lung cancer
Authors: Chan Joseph M , Quintanal-Villalonga Álvaro , Gao Vianne , Xie Yubin , Allaj Viola , Chaudhary Ojasvi , Masilionis Ignas , Egger Jacklynn , Chow Andrew , Walle Thomas , Mattar Marissa , Yarlagadda Dig VK , Wang James L. , Uddin Fathema , Offin Michael , Ciampricotti Metamia , Bhanot Umesh K , Lai W Victoria , Bott Matthew J , Jones David R , Ruiz Arvin , Hollmann Travis , Poirier John T , Nawy Tal , Mazutis Linas , Sen Triparna , Pe’er Dana , Rudin Charles M
Published: December 2020

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression ofASCL1,NEUROD1, andPOU2F3(SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 54,523 cellular transcriptomes from 21 human biospecimens. Our single-cell SCLC atlas reveals tumor diversity exceeding lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discovered aPLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival, and manipulation ofPLCG2expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent,PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis.
Glycan-Protein Interactions Determine Kinetics ofN-Glycan Remodeling
Authors: Mathew Corina , Weiß R. Gregor , Giese Christoph , Lin Chia-wei , Losfeld Marie-Estelle , Glockshuber Rudi , Riniker Sereina , Aebi Markus
Published: December 2020

A hallmark ofN-linked glycosylation in the secretory compartments of eukaryotic cells is the sequential remodeling of an initially uniform oligosaccharide to a site-specific, heterogeneous ensemble of glycostructures on mature proteins. To understand site-specific processing, we used protein disulfide isomerase (PDI), a model protein with five glycosylation sites, for molecular dynamics (MD) simulations and compared the result to a biochemicalin vitroanalysis with four different glycan processing enzymes. As predicted by an analysis of the accessibility of theN-glycans for their processing enzymes derived from the MD simulations,N-glycans at different glycosylation sites showed different kinetic properties for the processing enzymes. In addition, altering the tertiary structure context ofN-glycan substrates affectedN-glycan remodeling in a site-specific way. We propose that differential, tertiary structure context dependentN-glycan reactivities lead to different glycan structures in the same protein through kinetically controlled processing pathways.
Rac guanine nucleotide exchange factors promoting Lgl1 phosphorylation in glioblastoma
Authors: Lavictoire Sylvie J , Jomaa Danny , Gont Alexander , Jardine Karen , Cook David P , Lorimer Ian AJ
Published: December 2020

The protein Lgl1 has key roles in the regulation of cell polarity. We have shown that Lgl1 is inactivated by hyperphosphorylation in glioblastoma as a consequence ofPTENloss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell differentiation. Lgl1 is phosphorylated by atypical protein kinase C in a complex with Par6 and activated Rac. Here we have investigated the role of specific Rac guanine nucleotide exchange factors in Lgl1 hyperphosphorylation in glioblastoma. We used CRISPR/Cas9 to knockout PREX1, a PI 3-kinase pathway-responsive Rac guanine nucleotide exchange factor, in patient-derived glioblastoma cells. Knockout cells had reduced Lgl1 phosphorylation which could be reversed by re-expressing PREX1. PREX1 knockout cells showed reduced motility and an altered phenotype suggestive of partial neuronal differentiation; consistent with this, RNA-seq analyses identified sets of PREX1-regulated genes associated with changes in cell motility and neuronal differentiation. PREX1 knockout in glioblastoma cells from a second patient did not affect Lgl1 phosphorylation. These cells overexpressed a short isoform of the Rac guanine nucleotide exchange factor TIAM1; knockdown of TIAM1 in PREX1-knockout cells from this patient reduced Lgl1 phosphorylation. These data show that PREX1 links aberrant PI 3-kinase signaling to Lgl1 phosphorylation in glioblastoma, but that TIAM1 can also promote Lgl phosphorylation in a subset of patients. While this shows redundant mechanisms for Lgl1 phosphorylation, PREX1 appears to have a non-redundant role in glioblastoma cell motility, as this was impaired in PREX1 knockout cells from both patients.
Mechanisms of antibody binding revealed by asymmetric Fab-virus complexes
Authors: Goetschius Daniel J. , Hartmann Samantha R. , Organtini Lindsey J. , Callaway Heather , Huang Kai , Bator Carol M. , Ashley Robert E. , Makhov Alexander M. , Conway James F. , Parrish Colin R. , Hafenstein Susan
Published: December 2020

Overlap on the surface of parvovirus capsids between the antigenic epitope and the receptor binding site contributes to species jumping. Mab 14 strongly binds and neutralizes canine, but not feline parvovirus. The high resolution map of the canine parvovirus capsid complexed with Fab 14 was used to solve local structures of the Fab-bound and -unbound antigenic sites extracted from the same complex. The subsequent analysis includes a new method for using cryo EM to investigate complementarity of antibody binding.
A hydro-osmotic coarsening theory of biological cavity formation
Authors: Le Verge-Serandour Mathieu , Turlier Hervé
Published: December 2020

Fluid-filled biological cavities are ubiquitous, but their collective dynamics has remained largely unexplored from a physical perspective. Based on experimental observations in early embryos, we propose a model where a cavity forms through the coarsening of myriad of pressurized micrometric lumens, that interact by ion and fluid exchanges through the intercellular space. Performing extensive numerical simulations, we find that hydraulic fluxes lead to a self-similar coarsening of lumens in time, characterized by a robust dynamic scaling exponent. The collective dynamics is primarily controlled by hydraulic fluxes, which stem from lumen pressures differences and are dampened by water permeation through the membrane. Passive osmotic heterogeneities play, on the contrary, a minor role on cavity formation but active ion pumping can largely modify the coarsening dynamics: it prevents the lumen network from a collective collapse and gives rise to a novel coalescence-dominated regime exhibiting a distinct scaling law. Interestingly, we prove numerically that spatially biasing ion pumping may be sufficient to position the cavity, suggesting a novel mode of symmetry breaking to control tissue patterning. Providing generic testable predictions, our model forms a comprehensive theoretical basis for hydro-osmotic interaction between biological cavities, that shall find wide applications in embryo and tissue morphogenesis.

Author summary

The formation of a single biological cavity, or lumen, in tissues and embryos has been widely studied experimentally but the collective dynamics of multiple lumens has received much less attention. Here, we focus on a particular type of lumens, which are located at the adhesive side of cells and can therefore interact directly through the intercellular space, as recently observed in the very first stages of embryogenesis. We propose a generic model to describe the hydraulic and osmotic exchanges between lumens themselves, and with the surrounding cellular medium. Lumens are pressurized by a surface tension, which leads naturally to their coarsening into a single final cavity through hydraulic exchanges. With extensive numerical simulations and mean-field theory we predict that such coarsening dynamics follows a robust scaling law, that barely depends on concentration heterogeneities between lumens. On the contrary, active osmotic pumping largely influences the collective dynamics by favoring lumen coalescence and by biasing the position of the final cavity. Our theoretical work highlights the essential role of hydraulic and osmotic flows in morphogenesis.
Assembly principles and stoichiometry of a complete human kinetochore module
Authors: Walstein Kai , Petrovic Arsen , Pan Dongqing , Hagemeier Birte , Vogt Dorothee , Vetter Ingrid , Musacchio Andrea
Published: December 2020

Centromeres are epigenetically determined chromosomal loci that seed kinetochore assembly to promote chromosome segregation during cell division. CENP-A, a centromere-specific histone H3 variant, establishes the foundations for centromere epigenetic memory and kinetochore assembly. It recruits the constitutive centromere-associated network (CCAN), which in turn assembles the microtubule-binding interface. How the specific organization of centromeric chromatin relates to kinetochore assembly and to centromere identity through cell division remains conjectural. Here, we break new ground by reconstituting a functional full-length version of CENP-C, the largest human CCAN subunit and a blueprint of kinetochore assembly. We show that full-length CENP-C, a dimer, binds stably to two nucleosomes, and permits further assembly of all other kinetochore subunitsin vitrowith relative ratios that closely match those of endogenous human kinetochores. Our results imply that human kinetochores emerge from clustering multiple copies of a fundamental module, and may have important implications for trans-generational inheritance of centromeric chromatin.
Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19
Authors: Yu Chen , Littleton Sejiro , Giroux Nicholas , Mathew Rose , Ding Shengli , Kalnitsky Joan , Petzold Elizabeth W. , Chung Hong , Palomino Grecia Rivera , Rotstein Tomer , Xi Rui , Ko Emily R. , Tsalik Ephraim L. , Sempowski Gregory D. , Denny Thomas N. , Burke Thomas W. , McClain Micah T. , Woods Christopher W. , Shen Xiling , Saban Daniel R.
Published: December 2020

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.
A Genetic Screen for Temperature-sensitive Morphogenesis-defectiveCaenorhabditis elegansMutants
Authors: Jud Molly Christine , Lowry Josh , Padilla Thalia , Clifford Erin , Yang Yuqi , Fennell Francesca , Miller Alexander , Hamill Danielle , Harvey Austin , Avila-Zavala Martha , Shao Hong , NguyenTran Nhah , Bao Zhirong , Bowerman Bruce
Published: December 2020

Morphogenesis involves coordinated cell migrations and cell shape changes that generate tissues and organs, and organize the body plan. Cell adhesion and the cytoskeleton are important for executing morphogenesis, but their regulation remains poorly understood. As genes required for embryonic morphogenesis may have earlier roles in development, temperature-sensitive embryonic-lethal mutations are useful tools for investigating this process. From a collection of ∼200 suchCaenorhabditis elegansmutants, we have identified 17 that have highly penetrant embryonic morphogenesis defects after upshifts from the permissive to the restrictive temperature, just prior to the cell shape changes that mediate elongation of the ovoid embryo into a vermiform larva. Using whole genome sequencing, we identified the causal mutations in seven affected genes. These include three genes that have roles in producing the extracellular matrix, which is known to affect the morphogenesis of epithelial tissues in multicellular organisms. Therib-1andrib-2genes encode glycosyltransferases, and theemb-9gene encodes a collagen subunit. We also used live imaging to characterize epidermal cell shape dynamics in one mutant,or1219ts, and observed cell elongation defects during dorsal intercalation and ventral enclosure that may be responsible for the body elongation defects. These results indicate that our screen has identified factors that influence morphogenesis and provides a platform for advancing our understanding of this fundamental biological process.

We performed a systematic, forward genetics screen for temperature-sensitive embryonic-lethal (TS-EL)Caenorhabditis elegansmutants that are specifically defective in embryonic morphogenesis. By taking advantage of temperature-upshifts, we identified several essential genes influencing morphogenesis. We also demonstrated that one mutant has defects in epidermal cell shape changes that likely account for the failure in morphogenesis. The TS-EL mutants we identified will be useful tools for advancing our understanding of the gene networks controlling cell shape changes and movements during morphogenesis.
“Set yourself free!” Exploring help-seeking motives in at-risk gamblers
Authors: De Vos Svetlana , Ilicic Jasmina , Quester Pascale G. , Crouch Roberta Carolyn
Published: December 2020

Purpose

With limited research on help-seeking in the social marketing domain, this research takes a unique perspective through the lens of McGuire’s psychological framework examining the intrinsic and extrinsic motivations (or perceived help-seeking benefits) influencing help-seeking attitudes and behaviour in at-risk gamblers. This paper aims to examine the role that response efficacy has on the relationship between perceived help-seeking benefits and help-seeking behavioural intentions.

Design/methodology/approach

Study 1 used focus groups to explore the positive influence of help-seeking in at-risk gamblers. Studies 2 and 3 used online surveys to further test the direct and indirect impacts of perceived help-seeking benefits on attitudes and behavioural intentions. Structural equation modelling with multi-group analysis (low/high response efficacy) tested the hypotheses.

Findings

Both cognitive and affective psychological motives manifest as distinct intrinsic (well-being, self-esteem and self-control) and extrinsic motivators (social influence) that influence at-risk gamblers’ help-seeking attitudes and intentions to seek professional services. These perceived benefits influence help-seeking intentions directly (for those high in response efficacy) and indirectly via serial attitudinal mediators.

Practical implications

The results provide a guide for practitioners to enhance the promotion of professional help. Practitioners should develop marketing communication messages centred on the specific psychological needs of at-risk gamblers to encourage help-seeking behaviour including an emphasis on assertion, affiliation, independence, utilitarian, tension reduction, ego defence and consistency.

Originality/value

This research is the first, to the knowledge, to examine the psychological motivations that encourage help-seeking in at-risk gamblers, demonstrating that both preservation and growth motives influence help-seeking attitudes and the decision to act.
Has tourism the resources and answers to a more inclusive society?
Authors: Costa Jorge
Published: December 2020

Purpose

The purpose of this paper is to introduce the various papers in this issue and explain the pertinence of the strategic question.

Design/methodology/approach

A brief context for the strategic question is provided, as well as the issue alignment and a content analysis of the papers selected.

Findings

From the analysis of the papers selected for this theme issue, it becomes clear that destinations should reflect and work in a new model of tourism – more sustainable, innovative, responsible and supportive – adding value to the tourism ecosystem.

Originality/value

From various angles of analysis, the papers selected for this issue shed light on a relevant problem: the importance of tourist destinations in adopting a more inclusive approach. All tourist agents need to maintain their commitment to work together to promote universal accessibility and inclusiveness.
Tree phylogenetic diversity structures multitrophic communities
Authors: Staab Michael , Liu Xiaojuan , Assmann Thorsten , Bruelheide Helge , Buscot François , Durka Walter , Erfmeier Alexandra , Klein Alexandra‐Maria , Ma Keping , Michalski Stefan , Wubet Tesfaye , Schmid Bernhard , Schuldt Andreas
Published: December 2020

Plant diversity begets diversity at other trophic levels. While species richness is the most commonly used measure for plant diversity, the number of evolutionary lineages (i.e. phylogenetic diversity) could theoretically have a stronger influence on the community structure of co‐occurring organisms. However, this prediction has only rarely been tested in complex real‐world ecosystems.

Using a comprehensive multitrophic dataset of arthropods and fungi from a species‐rich subtropical forest, we tested whether tree species richness or tree phylogenetic diversity relates to the diversity and composition of organisms.

We show that tree phylogenetic diversity but not tree species richness determines arthropod and fungi community composition across trophic levels and increases the diversity of predatory arthropods but decreases herbivorous arthropod diversity. The effect of tree phylogenetic diversity was not mediated by changed abundances of associated organisms, indicating that evolutionarily more diverse plant communities increase niche opportunities (resource diversity) but not necessarily niche amplitudes (resource amount).

Our findings suggest that plant evolutionary relatedness structures multitrophic communities in the studied species‐rich forests and possibly other ecosystems at large. As global change non‐randomly threatens phylogenetically distinct plant species, far‐reaching consequences on associated communities are expected.

A free Plain Language Summary can be found within the Supporting Information of this article.
Drivers of assemblage‐wide calling activity in tropical anurans and the role of temporal resolution
Authors: Sugai Larissa S. M. , Silva Thiago S. F. , Llusia Diego , Siqueira Tadeu
Published: December 2020

Temporal scale in animal communities is often associated with seasonality, despite the large variation in species activity during a diel cycle. A gap thus remains in understanding the dynamics of short‐term activity in animal communities.

Here we assessed calling activity of tropical anurans and addressed how species composition varied during night activity in assemblages along gradients of local and landscape environmental heterogeneity.

We investigated 39 anuran assemblages in the Pantanal wetlands (Brazil) with passive acoustic monitoring during the peak of one breeding season, and first determined changes in species composition between night periods (early, mid and late) using two temporal resolutions (1‐ and 3‐hr intervals). Then, we addressed the role of habitat structure (local and landscape heterogeneity variables from field‐based and remote sensing metrics) and ecological context (species richness and phylogenetic relatedness) in determining changes in species composition (a) between night periods and (b) across days.

Nocturnal calling activity of anuran assemblages varied more within the 1‐hr resolution than the 3‐hr resolution. Differences in species composition between early‐ and late‐night periods were related to local habitat structure and phylogenetic relatedness, while a low variation in compositional changes across days was associated with low‐heterogeneous landscapes. None of these relationships were observed using the coarser temporal resolution (3 hr).

Our findings on the variation of calling activity in tropical anuran assemblages suggest potential trade‐offs mediated by fine‐temporal partitioning. Local and landscape heterogeneity may provide conditions for spatial partitioning, while the relatedness among co‐signalling species provides cues on the ecological overlap of species with similar requirements. These relationships suggest a role of niche dimensional complementarity on the structuring of these anuran assemblages over fine‐temporal scales. We argue that fine‐temporal differences between species in breeding activity can influence the outcome of species interaction and thus, addressing temporal scaling issues can improve our understanding of the dynamics of animal communities.
Omega‐3 fatty acid‐fortified butter: Preparation and characterisation of textural, sensory, thermal and physico‐chemical properties
Authors: Pandule Vishal S , Sharma Monika , HC Devaraja , B Surendra Nath
Published: December 2020

The influence of adding flaxseed oil (2.9–5.1%) and flaxseed–whey protein concentrate (WPC) emulsion (4.8–8.6%) to cream as an omega‐3 fatty acid source was evaluated on the thermal, sensory and physico‐chemical properties of the developed butter. Pulsed nuclear magnetic resonance analysis revealed lower saturated fat content in the fortified butter than control butter. Differential scanning calorimetry exotherms and endotherms also corroborated these findings. Fortified butter prepared with 6.8% flaxseed oil–WPC emulsion had 3.7 times more alpha‐linolenic acid content than control and provided nearly 25% of the recommended dietary allowance in one serving. The developed butter exhibited improved spreadability.
Primum Non Nocere (First, do no Harm)
Authors: Ibrahim Maria
Published: December 2020

Maria Ibrahim, a kidney doctor in training, explains the vital role of statistics and statistical analysis in transplant medicine: from matching donor organs to patients, to helping doctors and patients discuss the risks and benefits of a life-changing operation
Environmental reservoirs of Vibrio cholerae serogroups in the flowing freshwater environs from the tribal areas of Odisha, Eastern India
Authors: Pal Bibhuti Bhusan , Nayak Smruti Ranjan , Biswal Bhagyalaxmi , Das Basanta Kumar
Published: December 2020

The environmental reservoirs of different serogroups of Vibrio cholerae causing cholera in the flowing freshwater bodies of the tribal areas of Odisha are not known. So the present study was conducted from June 2017 to March 2020 to find out the environmental reservoirs of V. cholerae serogroups in the water and plankton samples collected from the river, nala, stream and chua from Rayagada district. Similarly, rectal swabs were collected from diarrhoea patients and correlation was established among the V. cholerae strains isolated from diarrhoea patients and environmental V. cholerae isolates through routine culture, different multiplex PCR assays and pulse field gel electrophoresis (PFGE) analysis using standard techniques. The multiplex PCR assays on biotypes and different toxic genes exhibited similar correlation between the clinical and water isolates, which was further strengthened by PFGE analysis. The planktonic DNA was positive for ctxA gene which established that the environmental water bodies were the reservoirs for virulence genes of V. cholerae serogroups. The detection of environmental reservoirs of V. cholerae serogroups in temporarily stagnant condition of water; partially encircled by stones, and near the bank of the river, nala and stream were the reservoirs which is a rare report from Odisha, India and Globe.
Guideline for the management of hip fractures 2020
Authors: Griffiths R. , Babu S. , Dixon P. , Freeman N. , Hurford D. , Kelleher E. , Moppett I. , Ray D. , Sahota O. , Shields M. , White S.
Published: December 2020

We convened a multidisciplinary Working Party on behalf of the Association of Anaesthetists to update the 2011 guidance on the peri‐operative management of people with hip fracture. Importantly, these guidelines describe the core aims and principles of peri‐operative management, recommending greater standardisation of anaesthetic practice as a component of multidisciplinary care. Although much of the 2011 guidance remains applicable to contemporary practice, new evidence and consensus inform the additional recommendations made in this document. Specific changes to the 2011 guidance relate to analgesia, medicolegal practice, risk assessment, bone cement implantation syndrome and regional review networks. Areas of controversy remain, and we discuss these in further detail, relating to the mode of anaesthesia, surgical delay, blood management and transfusion thresholds, echocardiography, anticoagulant and antiplatelet management and postoperative discharge destination. Finally, these guidelines provide links to supplemental online material that can be used at readers' institutions, key references and UK national guidance about the peri‐operative care of people with hip and periprosthetic fractures during the COVID‐19 pandemic.
Kcnh2 mediates FAK/AKT‐FOXO3A pathway to attenuate sepsis‐induced cardiac dysfunction
Authors: Li Zhigang , Meng Yilei , Liu Chang , Liu Huan , Cao Wenze , Tong Chang , Lu Min , Li Li , Peng Luying
Published: December 2020

Objectives

Myocardial dysfunction is a significant manifestation in sepsis, which results in high mortality. Even Kcnh2 has been hinted to associate with the pathological process, its involved signalling is still elusive.

Materials and methods

The caecal ligation puncture (CLP) surgery or lipopolysaccharide (LPS) injection was performed to induce septic cardiac dysfunction. Western blotting was used to determine KCNH2 expression. Cardiac function was examined by echocardiography 6 hours after CLP and LPS injection in Kcnh2 knockout (Kcnh2+/‐) and NS1643 injection rats (n ≥ 6/group). Survival was monitored following CLP‐induced sepsis (n ≥ 8/group).

Results

Sepsis could downregulate KCNH2 level in the rat heart, as well as in LPS‐stimulated cardiomyocytes but not cardiac fibroblast. Defect of Kcnh2 (Kcnh2+/‐) significantly aggravated septic cardiac dysfunction, exacerbated tissue damage and increased apoptosis under LPS challenge. Fractional shortening and ejection fraction values were significantly decreased in Kcnh2+/‐ group than Kcnh2+/+ group. Survival outcome in Kcnh2+/‐ septic rats was markedly deteriorated, compared with Kcnh2+/+ rats. Activated Kcnh2 with NS1643, however, resulted in opposite effects. Lack of Kcnh2 caused inhibition of FAK/AKT signalling, reflecting in an upregulation for FOXO3A and its downstream targets, which eventually induced cardiomyocyte apoptosis and heart tissue damage. Either activation of AKT by activator or knockdown of FOXO3A with si‐RNA remarkably attenuated the pathological manifestations that Kcnh2 defect mediated.

Conclusion

Kcnh2 plays a protection role in sepsis‐induced cardiac dysfunction (SCID) via regulating FAK/AKT‐FOXO3A to block LPS‐induced myocardium apoptosis, indicating a potential effect of the potassium channels in pathophysiology of SCID.
Efficacy and safety of adding sotagliflozin, a dual sodium‐glucose co‐transporter (SGLT)1 and SGLT2 inhibitor, to optimized insulin therapy in adults with type 1 diabetes and baseline body mass index ≥ 27 kg/m2
Authors: Danne Thomas , Edelman Steven , Frias Juan Pablo , Ampudia‐Blasco Francisco Javier , Banks Philip , Jiang Wenjun , Davies Michael J. , Sawhney Sangeeta
Published: December 2020

Sotagliflozin, a dual sodium‐glucose co‐transporter (SGLT)1/SGLT2 inhibitor, is currently approved in Europe as an adjunct to optimal insulin therapy in adults with type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m2. In this post hoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 clinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m2. Sotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin level and increased time in range assessed by continuous glucose monitoring versus placebo and also reduced body weight and systolic blood pressure. Differences in efficacy endpoints between sotagliflozin and placebo tended to be greater among patients with BMI ≥ 27 kg/m2 compared to those with baseline BMI < 27 kg/m2. Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo in patients with BMI ≥ 27 kg/m2. Sotagliflozin as an adjunct to optimized insulin therapy in overweight/obese patients with T1D addressed some unmet needs and may help achieve optimal glycaemic control, mitigating weight gain without increasing hypoglycaemia risk in this high‐risk population.
Commentary: ‘Camouflaging’ in autistic people – reflection on Fombonne (2020)
Authors: Lai Meng‐Chuan , Hull Laura , Mandy William , Chakrabarti Bhismadev , Nordahl Christine Wu , Lombardo Michael V. , Ameis Stephanie H. , Szatmari Peter , Baron‐Cohen Simon , Happé Francesca , Livingston Lucy Anne
Published: December 2020

Fombonne’s (2020) editorial is a thought‐provoking appraisal of the literature on ‘camouflaging’, whereby some autistic people mask or compensate for their autistic characteristics as an attempt to fit in and to cope with disabilities under neurotypical social norms. Fombonne (2020) highlights three issues of contention: (a) construct validity and measurement of camouflaging; (b) camouflaging as a reason for late autism diagnosis in adolescence/adulthood; and (c) camouflaging as a feature of the ‘female autism phenotype’. Here, we argue that (a) establishing construct validity and measurement of different aspects of camouflaging is warranted; (b) subjective experiences are important for the differential diagnosis of autism in adolescence/adulthood; and (c) camouflaging is not necessarily a feature of autism in female individuals – nevertheless, taking into account sex and gender influences in development is crucial to understand behavioural manifestations of autism. Future research and clinical directions should involve clarification of associated constructs and measurements, demography, mechanisms, impact (including harms and benefits) and tailored support.
Coordinated regulation of energy and glucose homeostasis by insulin and the NPY system
Authors: Lee Nicola J. , Herzog Herbert
Published: December 2020

Insulin is a major contributor to many important physiological processes. Although its function in the periphery has been studied in detail, the contributions that it makes to functions in the brain are far less understood. The neuropeptide Y (NPY) neurones comprise a major target of insulin in the brain and are inhibited by its action. In particular, NPY neurones in the arcuate nucleus of the hypothalamus are critical control centres for insulin’s central action on control energy homeostasis, as well as glucose homeostasis regulation. However, the colocalisation of insulin receptors with NPY neurones is also found in many other brain areas, although very little is known about their interactions and control functions. In this review, we explore the recent advances that have been made to further the understanding of the hypothalamic insulin receptor‐NPY network, as well as provide insights from other lesser explored areas, such as the amygdala and hippocampus. We will also look at the peripheral interaction of the NPY system with insulin release, thereby closing the loop between these two energy and glucose homeostasis controlling systems and highlighting the critical interaction points that may be dysregulated in conditions of obesity and diabetes.
Type 2 diabetes and remission: practical management guided by pathophysiology
Authors: Taylor Roy
Published: December 2020

The twin cycle hypothesis postulated that type 2 diabetes was a result of excess liver fat causing excess supply of fat to the pancreas with resulting dysfunction of both organs. If this was so, the condition should be able to be returned to normal by calorie restriction. The Counterpoint study tested this prediction in short‐duration type 2 diabetes and showed that liver glucose handling returned to normal within 7 days and that beta‐cell function returned close to normal over 8 weeks. Subsequent studies have demonstrated the durability of remission from type 2 diabetes. Remarkably, during the first 12 months of remission, the maximum functional beta‐cell mass returns completely to normal and remains so for at least 24 months, consistent with regain of insulin secretory function of beta cells which had dedifferentiated in the face of chronic nutrient oversupply. The likelihood of achieving remission after 15% weight loss has been shown to be mainly determined by the duration of diabetes, with responders having better beta‐cell function at baseline. Remission is independent of BMI, underscoring the personal fat threshold concept that type 2 diabetes develops when an individual acquires more fat than can be individually tolerated even at a BMI which in the nonobese range. Observations on people of South Asian or Afro‐American ethnicity confirm that substantial weight loss achieves remission in the same way as in the largely White Europeans studied in detail. Diagnosis of type 2 diabetes can now be regarded as an urgent signal that weight loss must be achieved to avoid a progressive decline of health.
Whole‐exome sequencing reveals novel vacuolar ATPase genes’ variants and variants in genes involved in lysosomal biology and autophagosomal formation in oral granular cell tumors
Authors: França Josiane Alves , Gayden Tenzin , Bareke Eric , Santos Jean Nunes , de Sousa Sílvia Ferreira , Bastos‐Rodrigues Luciana , Majewski Jacek , Jabado Nada , Gomez Ricardo Santiago , Gomes Carolina Cavalieri
Published: December 2020

Background

Granular cell tumors (GCTs) are rare neuroectodermal soft tissue neoplasms that mainly affect the skin of the upper limbs and trunks and the oral cavity. GCTs are derived from Schwann cells and, ultrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation.

Methods

In this study, a convenience set of 22 formalin‐fixed, paraffin‐embedded samples of oral GCTs, all but one sample located at the tongue, was screened for mutations by whole‐exome (WES) or targeted sequencing.

Results

WES revealed two novel variants in genes of the vacuolar ATPase (V‐ATPase) complex: ATP6AP1 frameshift c.746_749del, leading to p.P249Hfs*4, and ATP6V1A non‐synonymous c.G868A, leading to p.D290N. Each of these mutations occurred in one case. With regard to the samples that were wild type for these V‐ATPase variants, at least two samples presented variants in genes that are part of endosomal/lysosomal/autophagosomal networks including ABCA8, ABCC6, AGAP3, ATG9A, CTSB, DNAJC13, GALC, NPC1, SLC15A3, SLC31A2, and TMEM104.

Conclusion

Although the mechanisms involved in oral GCT initiation and progression remain unclear, our results suggest that oral GCTs have V‐ATPase variants similarly to GCTs from other tissues/organs, and additionally show variants in lysosomes/endosomes/autophagosomal genes.
Use of diaries as a research strategy on sensory perception and consumer behavior of Canastra cheese
Authors: Rodrigues Jessica Ferreira , Siman Ingrid Brandemburg , de Oliveira Lorena Eduarda Aparecida , de Fátima Barcelos Alessandra , Oliveira Rhaí André Arriel , Silva Ramon , da Cruz Adriano Gomes
Published: December 2020

The diary method has been used in some areas of knowledge, being uncommon in the area of sensory analysis of food. In addition, given the expanding market and the added value of Canastra artisanal Minas cheese, it is important to study consumer behavior, as well as understand the consumption habits of the product. Thus, the objective of this study was to use the diary method to collect sensory data, in addition to investigating the behavior and perceptions of consumers of artisanal Minas cheese. Potentials and weaknesses of the application of the method were discussed. The results of this study will contribute to sensory science, focusing on the assessment of real and continued food consumption. Moreover, they provide a better understanding of consumer behavior and consumption habits of artisanal Minas cheese from Canastra, directing planning production, marketing and commercialization strategies.

Practical Application

The findings of this study are useful for Brazilian artisanal cheese producers as it enables understanding the consumer behavior and consumption habits of artisanal cheese to plan production, marketing, and commercialization strategies. In addition, it shows practical utility for consumer‐based methodologies, focusing on the assessment of real and continued food consumption.
The clinical value of holmium laser enucleation of the prostate in octogenarians
Authors: Tamalunas Alexander , Westhofen Thilo , Schott Melanie , Keller Patrick , Atzler Michael , Stief Christian G. , Magistro Giuseppe
Published: December 2020

Objectives

With holmium laser enucleation of the prostate (HoLEP) a size‐independent method for surgical treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO) has been introduced. HoLEP offers durable long‐term results with reduced perioperative morbidity. As the risk of disease progression increases with age, the main goals, when offering surgery to an elderly population, are reducing perioperative morbidity and preserving quality of life (QoL). We therefore analyzed the impact of age on outcomes and perioperative morbidity in patients undergoing HoLEP for LUTS at our tertiary referral center.

Methods

We retrospectively collected data of 487 patients who underwent HoLEP for LUTS secondary to BPO between 2018 and 2019. Patients were divided into group 1 (<70 years), group 2 (70‐79 years), and group 3 (≥80 years). Perioperative parameters, safety, and short‐term functional outcomes were assessed and analyzed.

Results

Perioperative Clavien‐Dindo grade ≥II complications were seen in 4.1% of patients (20/487). There was no difference in perioperative complications between all age groups (P = .176). Functional outcome was assessed 30 days post surgery. There was significant improvement in median International Prostate Symptom Score of 14, 10, and 8 points for groups 1, 2, and 3 (P < .001), respectively, with constant improvement of median QoL of 3 points for all groups. Median maximum flow rate (Qmax) showed significant improvement of 14.5, 10.5, and 13 mL/s for groups 1 to 3 (P = .467), respectively.

Conclusion

HoLEP offers acceptable perioperative complication rates even in the oldest patient cohort (≥80 years). Therefore, HoLEP is a safe and efficient option even in oldest patients.
Brain potentials reveal differential processing of masculine and feminine grammatical gender in native Spanish speakers
Authors: Beatty‐Martínez Anne L. , Bruni Michelle R. , Bajo María Teresa , Dussias Paola E.
Published: December 2020

Studies of Spanish grammatical gender have shown that native speakers exploit gender cues in determiners to facilitate speech processing and are sensitive to gender mismatches. However, past research has not considered attested distributional asymmetries between masculine and feminine gender, collapsing performance on trials with one or the other gender into a single analysis. We use event‐related potentials to investigate whether masculine and feminine grammatical gender elicit qualitatively different brain responses. Forty monolingual Spanish speakers read sentences that were well‐formed or contained determiner‐noun gender violations. Half of the nouns were masculine and the other half were feminine. Consistent with previous research, brain responses varied along a continuum between LAN‐ and P600‐dominant effects for both gender categories. However, results showed that individuals’ ERP response dominance (LAN/P600) systematically differed across the two genders: participants who showed a LAN‐dominant response to masculine‐noun violations were more likely to show a P600 effect in response to feminine‐noun violations. Correlations with individual difference measures further revealed that responses to masculine‐noun violations were modulated by performance on the AX‐CPT, a measure of cognitive control, whereas responses to feminine‐noun violations were modulated by lexical knowledge, as indexed by verbal fluency. Together, the results demonstrate that even when processing features of language that belong to the same “natural class,” native speakers can exhibit patterns of brain activity attuned to distributional patterns of language use. The inherent variability in native speaker processing is, therefore, an important factor when explaining purported deviations from the “native norm” reported in other types of populations.
Upregulated microRNA‐132 in T helper 17 cells activates hepatic stellate cells to promote hepatocellular carcinoma cell migration in vitro
Authors: Feng Rui , Cui Zilin , Liu Zirong , Zhang Yamin
Published: December 2020

MicroRNAs play an important role in the modulation of the immune system. T helper 17 (Th17) cells are involved in the modulation of the tumour microenvironment. However, the function of miRNA in Th17 cells in the tumour microenvironment is unclear. In this study, we analysed miR‐132 expression in Th17 cells and assessed the function of miR‐132 on Th17 cell differentiation. In addition, the effect of miR‐132 on Th17 cells in the tumour microenvironment, especially hepatic stellate cells (HSCs), was confirmed. CD4+ IL‐17 ∓ cells were isolated from hepatocellular carcinoma (HCC) tumour tissues. The expression of miR‐132 was higher in CD4+ IL‐17 + cells than in CD4+ IL‐17‐ cells. Human primary CD4+ T cells were used for Th17 cell differentiation. Compared with primary CD4+ T cells, Th17 cells expressed high levels of miR‐132. During Th17 cell differentiation, a miR‐132 mimic and inhibition were applied. After treatment with the miR‐132 mimic, the differentiation of Th17 cells accelerated, showing a a higher percentage of Th17 cells and the expression and secretion of IL‐17 and IL‐22. Smad nuclear interacting protein 1 (SNIP1), as one of the targets of miR‐132, decreased during Th17 cell differentiation–related Th17 differentiation and IL‐17 expression. The conditioned medium of miR‐132–overexpressing Th17 cells could increase the activation of the HSCs, which strongly promoted HCC cell migration and epithelial‐mesenchymal transition (EMT). In summary, miR‐132 positively regulates Th17 cell differentiation and improves the function of Th17 on HSCs for their tumour‐promoting effects.
Stench and sensibilities: On living with waste, animals and microbes in India
Authors: Doron Assa
Published: December 2020

Stench is often the most immediate mark of something dirty, decaying and diseased. In India, stench and the smell of acrid smoke commonly indicate the proximity of an open dump or landfill. Frequently a slum is located in the vicinity too, housing waste‐pickers who forage in these sprawling dumps for salvageable waste. These spaces are also host to vermin, birds, stray dogs, pigs, cows and, more recently, dangerous bacteria resistant to even top‐end antibiotics, popularly known as ‘superbugs’. In this paper I examine the socio‐ecological context of neighbourhood, community open garbage dumps and larger landfills in an effort to understand these as part of a dynamic ecosystem of ‘more‐than‐human’ relations. Perceptual variations of smell as experienced in and around waste (in its solid, liquid and gas states) are intrinsically linked to symbolic and material practices across species. Additionally, I suggest that one productive way to think about the emergence of disease and pathogenicity is by considering the information stimulated by smell, which is mediated by cultural interpretations, biological capacities and wider political economies.
The PalWRKY77 transcription factor negatively regulates salt tolerance and abscisic acid signaling in Populus
Authors: Jiang Yuanzhong , Tong Shaofei , Chen Ningning , Liu Bao , Bai Qiuxian , Chen Yang , Bi Hao , Zhang Zhiyang , Lou Shangling , Tang Hu , Liu Jianquan , Ma Tao , Liu Huanhuan
Published: December 2020

High salinity, one of the most widespread abiotic stresses, inhibits photosynthesis, reduces vegetation growth, blocks respiration and disrupts metabolism in plants. In order to survive their long‐term lifecycle, trees, such as Populus species, recruit the abscisic acid (ABA) signaling pathway to adapt to a saline environment. However, the molecular mechanism behind the ABA‐mediated salt stress response in woody plants remains elusive. We have isolated a WRKY transcription factor gene, PalWRKY77, from Populus alba var. pyramidalis (poplar), the expression of which is repressed by salt stress. PalWRKY77 decreases salt tolerance in poplar. Furthermore, PalWRKY77 negatively regulated ABA‐responsive genes and relieved ABA‐mediated growth inhibition, indicating that PalWRKY77 is a repressor of the ABA response. In vivo and in vitro assays revealed that PalWRKY77 targets the ABA‐ and salt‐induced PalNAC002 and PalRD26 genes by binding to the W‐boxes in their promoters. In addition, overexpression of both PalNAC002 and PalRD26 could elevate salt tolerance in transgenic poplars. These findings reveal a novel negative regulation mechanism for the ABA signaling pathway mediated by PalWRKY77 that results in more sensitivity to salt stress in poplar. This deepens our understanding of the complex responses of woody species to salt stress.