bluuebunny/crossref_metadata_2025 huggingface dataset:
A megaprotein-based molecular bridge critical for lipid trafficking and cold resilience
Authors: Wang Changnan , Wang Bingying , Pandey Taruna , Long Yong , Zhang Jianxiu , Oh Fiona , Sima Jessica , Guo Ruyin , Liu Yun , Zhang Chao , Mukherjee Shaeri , Bassik Michael , Lin Weichun , Deng Huichao , Vale Goncalo , McDonald Jeffrey , Shen Kang , Ma Dengke K.
Published: August 2022

Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through homeostatic mechanisms conserved in nearly all forms of life. As most eukaryotic enzymes for lipid synthesis and desaturation localize on endoplasmic reticulum (ER) membranes, it remains unknown how ER-resident lipids rapidly distribute to plasma membranes (PM). Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that plays critical roles in lipid trafficking and cold resilience. We identified lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7, and found that the 452 kDa megaprotein LPD-3 bridges ER and PM, consisting of a structurally predicted hydrophobic tunnel for lipid trafficking. Loss of LPD-3 caused abnormal cellular distribution of phospholipids, diminished FAT-7 abundance, and organismic vulnerability to cold. These phenotypic defects of lpd-3 mutants were rescued by Lecithin comprising unsaturated phospholipids. Importantly, we found that deficient lpd-3 homologues in Zebrafish and mammalian cells led to defects similar to those observed in C. elegans. As mutations in KIAA1109/BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, we propose that the LPD-3 family proteins may serve as evolutionarily conserved “highway bridges” critical for ER-associated non-vesicular trafficking of lipids and resilience to cold stress in eukaryotic cells.
Genetic Association of CSN2 Variant 6:85451298C>A with A1/A2 Milk Phenotype in Pakistani Cows
Authors: Ullah Sibghat , Ahmed Zubair , Karim Asma , Saif Rashid
Published: August 2022

The cow is a very important mammal from the bovine family renowned for providing milk, meat and hide around the globe. β-casein is one of the principal proteins found in cow’s milk encoded by the CSN2 gene with 12-13 reported genetic variants present on Chr.6 in the cow’s genome. The current study investigated A1/A2 associated variant g.6:85451298C>A (rs43703011) in exon 7th according to the GenBank ID: M55158.1 position 8101C>A (c.245C>A), which is responsible to change the 67th amino acid of the β-casein polypeptide from proline (CCT, A2) to histidine (CAT, A1). The milk containing A2 protein variant is good while A1 milk has some negative effects on human health due to the production of β-casmomorphin-7. Genetic screening of the subject variant was conducted using ARMS-PCR on 48 native and exotic cows from Pakistan. Our initial results showed that 37.5% of the population is homozygous wild-type (C/C), 56.25% is heterozygous (C/A) and the remaining 6.25% is homozygous mutant-type (A/A). Additionally, the Chi-square association test was applied using the PLINK data analysis toolset which presented a significant p-value of 2.811×10−3 and OR of 3.8 with an alternative allele frequency of 0.2 and 0.5 in native and exotic populations respectively. Hence, there is significant variability in A1/A2 genotype which may be addressed by adopting selective breeding programs in Pakistan.
Systematic analysis of IL-1 cytokine signaling by high-risk HPV oncoproteins
Authors: Castagnino Paola , Kim Hee Won , Lam Long Kwan Metthew , Basu Devraj , White Elizabeth A.
Published: August 2022

Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1β. Models of early-stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1β treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1β-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.

IMPORTANCE

Human papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by pro-inflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1β in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
Mortality Improvements in Adult Patients Hospitalised with Community Acquired COVID-19 in Wales From March 2020 to December 2021
Authors: Barry Simon M , Davies Gareth R , Davies Chris R , Lewis Keir E
Published: August 2022

Background

A COVID-19 hospital guideline was implemented across all acute hospitals in Wales in March 2020, and data was collected across the first 3 Waves of the pandemic. We aimed to observe trends in mortality with a focus on ward-based outcomes.

Methods

Retrospective case-note review of data for adults admitted to hospital with community acquired COVID-19 between March 2020 and December 2021

Results

5887 cases were analysed. Overall mortality from COVID-19 fell from 31.5% in Wave 1 to 22.6% in Wave 2 to 18.8% in Wave 3 (p<0.01). Ward mortality for patients on oxygen fell from 34.6% in Wave 1 to 19.5% in Wave 2 (p<0.01) to 14.3% in Wave 3 (p=0.03). For those managed with CPAP/HFNO on wards, the mortality reduced from 58.9% in Wave 1 to 45.6% in Wave 2 (p=0.05) and further to 42.6% in Wave 3 (p=0.03). The mortality for patients managed with CPAP/HFNO on ICU reduced from 43.8% in Wave 1 to 24.7% in Wave 2 (p=0.12) and further to 20.4% in Wave 3 (p=0.03). Patients receiving CPAP/HFNO on the wards were on average 11 years older and more co-morbid than those on ICU. In Wave 3, 77% of hospital admissions with COVID-19 were unvaccinated with mortality rates of 20.5% compared to 4.8% mortality in those who had received three vaccines (p<0.01).

Conclusions

There were successive reductions in mortality in inpatients over the 3 Waves reflecting new treatments and better management of complications. The impact of vaccines on outcomes of hospitalised patients was notable in Wave 3.

Key Messages

What is the key question?

What are the outcomes from COVID-19 pneumonitis managed on respiratory wards and how have they changed over successive waves of the pandemic?

What is the bottom line?

Significant improvements in mortality over time were noted in patients requiring oxygen, CPAP or HFNO. Patients managed with these modalities in ICU had lower mortality rates than those on wards, but they were younger and less co-morbid. In wave 3 patients were largely unvaccinated with higher mortality rates than those who were fully vaccinated.

Why read on?

This is a national study including all acute hospitals in Wales over three waves of the pandemic from March 2020 to December 2021. It is the first paper to demonstrate at a national level the outcomes of ward management of COVID pneumonitis over successive waves.
Development and Clinical Validation of a Miniaturized Finger Probe for Bedside Hemodynamic Monitoring
Authors: Panula Tuukka , Sirkiä Jukka-Pekka , Koivisto Tero , Pänkäälä Mikko , Niiranen Teemu , Kantola Ilkka , Kaisti Matti
Published: August 2022

Background

Hypertension, or elevated blood pressure (BP), is a marker for many cardiovascular diseases and can lead to life-threatening conditions such as heart failure, coronary artery disease, and stroke. BP monitoring using a traditional arm cuff device is often inconvenient and possibly painful in long-term use, i.e. during sleep.

Methods

We present a miniature cuffless tonometric finger probe system, that uses the oscillometric method to measure blood pressure (BP). Our approach uses a motorized press that is used to apply pressure to the finger tip to measure BP.

Results

We verified the functionality of the device in a clinical trial (n=43) resulting in systolic (SBP) and diastolic (DBP) pressures ((mean±SD) mmHg) of (−3.5 ± 8.4) mmHg and (−4.0 ± 4.4) mmHg, respectively. Comparison was made with manual auscultation (n=26) and automated cuff oscillometry (n=18). In addition to BP, we demonstrated the ability of the device to assess arterial stiffness (n=18) and detect atrial fibrillation (n=6).

Conclusions

We were able to introduce a sufficiently small device that could be used for convenient ambulatory measurements and worn during sleep with minimal discomfort. Lastly, we evaluate methods to further develop the concept and discuss future directions.

Plain language summary

Traditional cuff-based automated BP instruments are mainly suitable for individual measurements and are often inconvenient to use. Patients in a hospital ward are typically monitored with many systems and devices. Our aim is to develop a blood pressure measurement technology that could be integrated into a finger-worn pulse oximeter. This way the need for a bulky and inconvenient arm cuff could be eliminated and the number of needed monitoring devices could be reduced. The proposed technology is especially suitable for pseudo-continuous BP measurement, that is, taking automated measurements periodically, enabling BP trend tracking and analysis. In this study, we clinically validate our technology for blood pressure monitoring and further demonstrate its potential to measure arterial stiffness and detect atrial fibrillation.
Cytokine and chemokine gene expression in patients with clinically suspect arthralgia; a longitudinal study during progression to inflammatory arthritis or non-progression
Authors: Heutz J.W. , Rogier C. , Niemantsverdriet E. , van den Eeden S.J.F. , de Jong P.H.P. , Lubberts E. , Geluk A. , van der Helm-van Mil A.H.M.
Published: August 2022

Background

Autoantibody-responses rise years before onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels can also rise years before IA-onset, but the course after CSA-onset is unknown. To better understand the processes in this symptomatic at-risk phase, we studied the course of cytokine, chemokine and related receptors gene expression in CSA-patients during progression to IA, and in CSA-patients who ultimately did not develop IA. Differential expressed genes between ACPA-positive and ACPA-negative CSA-patients who developed IA were also explored.

Methods

Whole blood RNA expression of 37 inflammatory cytokines/chemokines/related receptors was determined by dual-color reverse-transcription multiplex ligation-dependent probe amplification, in paired samples of CSA-patients at CSA-onset and either at IA-development or after 24-months without IA-development. ACPA-positive and ACPA-negative CSA-patients developing IA were compared at CSA-onset and during progression to IA. GEE-models tested changes over time. A false discovery rate approach was applied to correct for multiple testing.

Results

None of the cytokines/chemokine genes significantly changed in expression between CSA-onset and IA-development. In CSA-patients without IA development, G-CSF expression decreased (p=0.001), whereas CCR6 and TNIP expression increased (p<0.001 and p=0.002, respectively) over a 2-year period. Expression levels in ACPA-positive and ACPA-negative CSA-patients who developed IA were similar.

Conclusion

Whole blood gene expression of cytokines, chemokines and related receptors did not change significantly from CSA to IA-development. This suggests that changes in expression of these molecules occurred preceding CSA-onset and may not relate to the final hit of developing chronic arthritis. Observed changes in CSA-patients not developing IA can provide clues for processes related to resolution.
Potential health and economic impact of paediatric vaccination using next generation influenza vaccines in Kenya: a modelling study
Authors: Waterlow Naomi R , Radhakrishnan Sreejith , Dawa Jeanette , van Leeuwen Edwin , Lambach Philipp , Bresee Joseph , Mazur Marie , Eggo Rosalind M , Jit Mark
Published: August 2022

Background

Influenza is a major year-round cause of respiratory illness in Kenya, particularly in children under 5. Current influenza vaccines result in short-term, strain-specific immunity and were found in a previous study not to be cost-effective in Kenya. However, next generation vaccines are in development that may have a greater impact and cost-effectiveness profile.

Methods

We expanded a model previously used to evaluate cost-effectiveness of seasonal influenza vaccines in Kenya to include next generation vaccines by allowing for enhanced vaccine characteristics and multi-annual immunity. We specifically examined vaccinating children under 5 years of age with improved vaccines, evaluating vaccines with combinations of increased vaccine effectiveness, cross protection between strains (breadth) and duration of immunity. We evaluated cost-effectiveness using incremental cost-effectiveness ratios (ICERs) and incremental net monetary benefits (INMBs) for a range of values for the willingness-to-pay (WTP) per DALY averted. Finally, we estimated threshold per-dose vaccine prices at which vaccination becomes cost-effective.

Results

Next generation vaccines can be cost-effective, dependent on the vaccine characteristics and assumed WTP thresholds. Universal vaccines (assumed to provide long-term and broad immunity) are most cost-effective in Kenya across three of four WTP thresholds evaluated, with the lowest median value of ICER per DALY averted ($263, 95% Credible Interval (CrI): $-1698, $1061) and the highest median INMBs. At a WTP of $623, universal vaccines are cost-effective at or below a median price of $5.16 per dose (95% CrI: $0.94, $18.57). We also show that the assumed mechanism underlying infection-derived immunity strongly impacts vaccine outcomes.

Conclusion

This evaluation provides evidence for country-level decision makers about future next generation vaccine introduction, as well as global research funders about the potential market for these vaccines. Next generation vaccines may offer a cost-effective intervention to reduce influenza burden in low-income countries with year-round seasonality like Kenya.
Longitudinal health survey of women from Venezuela in Colombia (ELSA-VENCOL): first report
Authors: Acosta-Reyes Jorge , Bonilla-Tinoco Laura Juliana , Aguirre Melissa , Rojas-Botero Maylen , Anillo Luis Ángel , Rodríguez David Alejandro , Cifuentes Lida Yoana , Jiménez Iván , León Luisa Fernanda , Bojorquez-Chapela Ietza , Fernández-Niño Julián Alfredo
Published: August 2022

Background

Colombia is currently the world’s main recipient country for Venezuelan migrants, and women represent a high proportion of them. This article presents the first report of a cohort of Venezuelan migrant women entering Colombia through Cúcuta and its metropolitan area (the main land entry point to this country). The study aimed to describe the health status and access to healthcare services among Venezuelan migrant women in Colombia with irregular migration status, and to analyze changes in those conditions at a one-month follow-up.

Methods

A longitudinal cohort study of Venezuelan migrant women, 18 to 45 years, who entered Colombia with an irregular migration status, was carried out in 2021. Study participants were recruited in temporary shelters, transit points, and migrant settlements in Cúcuta and the metropolitan area. At baseline, we administered a structured questionnaire including sociodemographic characteristics, migration history, health history, access to health services, sexual and reproductive health, practice of early detection of cervical cancer and breast cancer, food insecurity, and depressive symptoms. The women were again contacted by phone one month later, between March and July 2021, and a second questionnaire was applied.

Results

A total of 2,298 women were included in the baseline measurement and 56.4% could be contacted again at the one-month follow-up. A significant increase was found in the percentage of women who had a health problem during the past month (from 23.1% to 31.4%; p<0.01); as well as in the share who reported moderate, severe, or extreme difficulty working or performing daily chores (from 5.5% to 11.0%; p= 0.03) and who rated their health as fair (from 13.0% to 31.2%; p<0.01). Meanwhile, the percentage of women with depressive symptoms decreased from 80.5% to 71.2% (p<0.01).

Conclusion

This report is a starting point for the longitudinal follow-up of the cohort, which will allow us to better understand how the health status of Venezuelan women changes during the migration flow in Colombia.
A network of mixed actin polarity in the leading edge of spreading cells
Authors: Chung Wen-Lu , Eibauer Matthias , Li Wenhong , Boujemaa-Paterski Rajaa , Geiger Benjamin , Medalia Ohad
Published: August 2022

Physical interactions of cells with the underlying extracellular matrix (ECM) play key roles in multiple cellular processes, such as tissue morphogenesis, cell motility, wound healing, cancer invasion and metastasis. The actin cytoskeletal network is a central driver and regulator of cellular dynamics, that produces membrane protrusions such as lamellipodia and filopodia. In this study, we examined actin organization in the expanding lamellipodia during the early stages of cell spreading. To gain insight into the 3D actin organization, at a molecular resolution, we plated cultured fibroblasts on galectin-8 coated EM grids, an ECM protein presents in disease states. We then combined cryo-electron tomography (cryo-ET) with advanced image processing tools for reconstructing the structure of F-actin in the lamellipodia. This approach enabled us to resolve the polarity and orientation of the filaments, and the structure of the Arp2/3 complexes associated with F-actin branches. We show here that F-actin in lamellipodial protrusions forms a dense network with three distinct sub-domains. One consists primarily of radial filaments, with their barbed ends pointing towards the membrane, the other is enriched with parallel filaments that run between the radial fibers, in addition to an intermediate sub-domain. Surprisingly, a minor, yet significant (∼10%) population of actin filaments, are oriented with their barbed ends towards the cell center. Our results provide novel structural insights into F-actin assembly and dynamic reorganization in the leading edge of spreading cells.
Effect of reduced genomic representation on using runs of homozygosity for inbreeding characterization
Authors: Lavanchy Eléonore , Goudet Jérôme
Published: August 2022

Runs of homozygosity (ROHs) are proxy for genomic Identical-by-Descent segments and are increasingly used to measure individual inbreeding. ROHs analyses are mostly carried out on SNPs-arrays and whole-genome-sequencing data. Softwares recurrently used for their detection usually assume that genomic positions which have not been genotyped are non-variant. This might be true for whole-genome-sequencing data, but not for reduced genomic representations and can lead to spurious ROHs detection. We simulated the outputs of whole-genome-sequencing, two SNP-arrays and RAD-sequencing for three populations with different sizes. We compare the results of ROHs calling with two softwares: PLINK and RZooRoH. We demonstrate that to obtain meaningful estimates of inbreeding coefficients, RZooRoH requires fraction of genome seven times smaller compared to PLINK. When the SNP density is above 20 SNPs/Mb for PLINK and 3 SNPs/Mb for RZooRoH, ranks of ROHs-based inbreeding coefficients are conserved among individuals. With reduced genomic representations, ROHs distributions are consistently biased towards an underestimation of the total numbers of small and an overestimation of the total numbers of large ROHs, except for RZooRoH and high-density SNPs-arrays. We conclude that both ROHs-based inbreeding coefficients and ROHs distributions exact quantification are highly dependent on the fraction of genome sequenced and should thus be treated with caution. However, relative inbreeding estimates, such as comparison between individuals or populations, are reliable with reduced genomic representations providing that the fraction of genome sequenced is large enough. Consequently, we advise researchers working with reduced genomic data to use SNPs-independent measures or model-based ROHs calling methods for inbreeding estimations.
Unraveling the Potential Role of Tecomella undulatain Experimental NASH
Authors: Srinivas Akshatha N. , Suresh Diwakar , Suvarna Deepak , Pathak Pankaj , Giri Suresh , Suman  , Satish Suchitha , Chidambaram Saravana Babu , Kumar Divya P.
Published: August 2022

Background and Aim

The pathophysiology of NASH is complex owing to its diverse pathological drivers, and until recently, there were no approved drugs for this disease.Tecomella undulatais a popular herbal medicine used to treat hepatosplenomegaly, hepatitis, and obesity. However, the potential role ofTecomella undulatain NASH has not yet been scientifically investigated.

Experimental Procedure

Mice fed with chow diet and normal water (CDNW) or western diet and sugar water (WDSW) for 12 weeks were randomized to receive vehicle control, Saroglitazar, orTecomella undulatafor an additional 12 weeks. Insulin resistance, lipid profiles, histological analysis, and liver enzymes were assessed. The oxidative stress, ER and inflammatory markers were determined by quantitative RT-PCR (qRT-PCR) and western blot analysis.

Results and Conclusion

The administration ofTecomella undulatavia oral gavage lowered body weight, insulin resistance, alanine transaminase (ALT), aspartate transaminase (AST), triglycerides, and total cholesterol in WDSW mice but had no effect on CDNW mice.Tecomella undulataimproved steatosis, lobular inflammation, and hepatocyte ballooning and resolved NASH in WDSW mice. Furthermore,Tecomella undulataalso alleviated the WDSW-induced ER stress and oxidative stress, enhanced antioxidant status, and thus reduced inflammation in the treated mice. Of note, these effects were on par with Saroglitazar, the approved drug used to treat human NASH and positive control used in the study.

Thus, our findings indicate the potential ofTecomella undulatato ameliorate WDSW-induced steatohepatitis, and these preclinical data provide a strong rationale for assessingTecomella undulatafor the treatment of NASH in humans.
The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions
Authors: van Beest Enny H. , Abdelwahab Mohammed A.O. , Cazemier J. Leonie , Baltira Chrysiida , Maes M. Cassandra , Peri Brandon D. , Self Matthew W. , Willuhn Ingo , Roelfsema Pieter R.
Published: August 2022

The striatum, input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect pathways with antagonistic effects on the output of the basal ganglia. We optogenetically stimulated the direct and indirect pathways in mice and measured their influence on perceptual decisions and neuronal activity in the cortex. In a task in which mice had to detect a visual stimulus, unilateral direct-pathway stimulation increased the probability of lick responses to the non-stimulated side and increased cortical activity globally. In contrast, indirect-pathway stimulation increased the probability of licks to the stimulated side and decreased activity in visual cortical areas. To probe the possible role of the two pathways in working memory, we trained the mice to report the location of a stimulus with licking one of two spouts, after a memory delay. Direct-pathway stimulation prior to and during the memory delay enhanced both the neural representation of a contralateral visual stimulus and the number of contraversive choices, whereas indirect-pathway stimulation had the opposite effects, in accordance with an antagonistic influence of the direct and indirect pathways on licking direction. Our results demonstrate how these two pathways influence perceptual decisions and working memories, and modify activity in the cerebral cortex.

One sentence summary

Visuomotor transformations are influenced antagonistically by the direct and indirect pathways of the basal ganglia during visual detection and working memory tasks
Introgression between highly divergent fungal sister species
Authors: Kinneberg Vilde Bruhn , Lü Dabao Sun , Peris David , Ravinet Mark , Skrede Inger
Published: August 2022

To understand how species evolve and adapt to changing environments, it is important to study gene flow and introgression due to their influence on speciation and radiation events. Here, we apply a novel experimental system for investigating these mechanisms using natural populations. The system is based on two fungal sister species with morphological and ecological similarities occurring in overlapping habitats. We examined introgression between these species by conducting whole genome sequencing of individuals from populations in North America and Europe. We assessed genome wide nucleotide divergence and performed crossing experiments to study reproductive barriers. We further used ABBA-BABA statistics together with a network analysis to investigate introgression, and conducted demographic modelling to gain insight into divergence times and introgression events. The results revealed that the species are highly divergent and incompatible in vitro. Despite this, small regions of introgression were scattered throughout the genomes and one introgression event likely involves a ghost population (extant or extinct). This study demonstrates that introgression can be found among divergent species and that population histories can be studied without collections of all the populations involved. Moreover, the experimental system is shown to be a useful tool for research on reproductive isolation in natural populations.
Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation
Authors: Luda Katarzyna M. , Kitchen-Goosen Susan M. , Ma Eric H. , Watson McLane J. , Duimstra Lauren R. , Oswald Brandon M. , Longo Joseph , Fu Zhen , Madaj Zachary , Kupai Ariana , Dickson Bradley M. , Kaymak Irem , Lau Kin H. , Compton Shelby , DeCamp Lisa M. , Kelly Daniel P. , Puchalska Patrycja , Williams Kelsey S. , Krawczyk Connie M. , Lévesque Dominique , Boisvert François-Michel , Sheldon Ryan D. , Rothbart Scott B. , Crawford Peter A. , Jones Russell G.
Published: August 2022

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. However, the metabolic pathways critical for optimal T cell responses remain poorly understood. Here, we identify ketone bodies (KBs) – including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc) – as essential fuels supporting CD8+ T cell metabolism and effector function. Ketolysis is an intrinsic feature of highly functional CD8+ T effector (Teff) cells and βOHB directly increases CD8+ Teff cell IFN-γ production and cytolytic activity. Using metabolic tracers, we establish that CD8+ Teff cells preferentially use KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boost the respiratory capacity of CD8+ T cells and TCA cycle-dependent metabolic pathways that fuel T cell growth. Mechanistically, we find that βOHB is a major substrate for acetyl-CoA production in CD8+ T cells and regulates effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

One Sentence summary

Ketone bodies promote CD8+ T cell metabolism and effector function through regulation of epigenetic programming
Mutation in the TRKB cholesterol recognition site that blocks antidepressant binding does not influence the basal or BDNF-stimulated activation of TRKB
Authors: Biojone Caroline , Cannarozzo Cecilia , Seiffert Nina , Diniz Cassiano RAF , Brunello Cecilia A , Castrén Eero , Casarotto Plinio
Published: August 2022

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol-recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressants drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Y433F). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Y433F mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Y433F mutant mice (hTRKB.Y433F) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Y433F mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Y433F mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Y433F mutants, making them an interesting mouse model for antidepressant research.
Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population
Authors: Keele Gregory R.
Published: August 2022

Multiparental populations (MPPs) encompass greater genetic diversity than traditional experimental crosses of two inbred strains, enabling broader surveys of genetic variation underlying complex traits. Two such mouse MPPs are the Collaborative Cross (CC) inbred panel and the Diversity Outbred (DO) population, which are descended from the same eight inbred strains. Additionally, the F1 intercrosses of CC strains (CC-RIX) have been used and enable study designs with replicate outbred mice. Genetic analyses commonly used by researchers to investigate complex traits in these populations include characterizing how heritable a trait is,i.e., its heritability, and mapping its underlying genetic loci,i.e., its quantitative trait loci (QTLs). Here we evaluate the relative merits of these populations for these tasks through simulation, as well as provide recommendations for performing the quantitative genetic analyses. We find that sample populations that include replicate animals, as possible with the CC and CC-RIX, provide more efficient and precise estimates of heritability. We report QTL mapping power curves for the CC, CC-RIX, and DO across a range of QTL effect sizes and polygenic backgrounds for samples of 174 and 500 mice. The utility of replicate animals in the CC and CC-RIX for mapping QTLs rapidly decreased as traits became more polygenic. Only large sample populations of 500 DO mice were well-powered to detect smaller effect loci (7.5-10%) for highly complex traits (80% polygenic background). All results were generated with our R package musppr, which we developed to simulate data from these MPPs and evaluate genetic analyses from user-provided genotypes.
Modelling Sex Differences in Circadian Regulation of Kidney Function of the Mouse
Authors: Layton Anita T. , Gumz Michelle L.
Published: August 2022

Kidney function is regulated by the circadian clock. Not only do glomerular filtration rate (GFR) and urinary excretion oscillate during the day, the expressions of several renal transporter proteins also exhibit circadian rhythms. Interestingly, the circadian regulation of these transporters may be sexually dimorphic. Thus, the goal of this study is to investigate the mechanisms by which kidney function of the mouse is modulated by sex and time of day. To accomplish this, we have developed the first computational models of epithelial water and solute transport along the mouse nephrons that represent the effects of sex and circadian clock on renal hemodynamics and transporter activity. We conduct simulations to study how the circadian control of renal transport genes affects overall kidney function, and how that process differs between male and female mice. Simulation results predict that tubular transport differs substantially among segments, with relative variations in water and Na+ reabsorption along the proximal tubules and thick ascending limb tracking that of GFR. In contrast, relative variations in distal segment transport are much larger, with Na+ reabsorption almost doubling during the active phase. Oscillations in Na+ transport drive K+ transport variations in the opposite direction. Model simulations of BMAL1 knockout mice predict a significant reduction in net Na+ reabsorption along the distal segments in both sexes, but more so in males than females. This can be attributed to the reduction of mean ENaC activity in males only, a sex-specific effect that may lead to a reduction in blood pressure in males.
Molecular phenotyping of single pancreatic islet leader beta cells by “Flash-Seq”
Authors: Chabosseau Pauline , Yong Fiona , Delgadillo-Silva Luis F. , Lee Eun Young , Li Shiying , Gandhi Nidhi , Wastin Jules , Noriega Livia Lopez , Leclerc Isabelle , Ali Yusuf , Hughes Jing W. , Sladek Robert , Martinez-Sanchez Aida , Rutter Guy A.
Published: August 2022

Aims

Spatially-organised increases in cytosolic Ca2+within pancreatic beta cells in the pancreatic islet underlie the stimulation of insulin secretion by high glucose. Recent data have revealed the existence of subpopulations of beta cells including “leaders” which initiate Ca2+waves. Whether leader cells possess unique molecular features, or localisation, is unknown.

Main methods

High speed confocal Ca2+imaging was used to identify leader cells and connectivity analysis, running under MATLAB and Python, to identify highly connected “hub” cells. To explore transcriptomic differences between beta cell sub-groups, individual leaders or followers were labelled by photo-activation of the cryptic fluorescent protein PA-mCherry and subjected to single cell RNA sequencing (“Flash-Seq”).

Key findings

Distinct Ca2+wave types were identified in individual islets, with leader cells present in 73 % (28 of 38 islets imaged). Scale-free, power law-adherent behaviour was also observed in 29% of islets, though “hub” cells in these islets did not overlap with leaders. Transcripts differentially expressed (295; padj<0.05) between leader and follower cells included genes involved in cilium biogenesis and transcriptional regulation. Functionally validating these findings, cilia number and length tended to be lower in leadervsfollower cells. Leader cells were also located significantly closer to delta cells in Euclidian space than were follower cells.

Significance

The existence of both a discrete transcriptome and unique localisation implies a role for these features in defining the specialized function of leaders. Specifically, these data raise the possibility of altered signalling from delta cells towards somatostatin receptors present on leader cell cilia.
A method for chronic and semi-chronic microelectrode array implantation in deep brain structures using image guided neuronavigation
Authors: Mahmoudian Borna , Dalal Hitarth , Lau Jonathan , Corrigan Benjamin , Barker Kevin , Rankin Adam , Chen Elvis C.S. , Peters Terry , Martinez-Trujillo Julio C.
Published: August 2022

Precise targeting of deep brain structures in humans and large animal models has been a challenge for neuroscientists. Conventional protocols used in animal models typically require large access chambers which are prone to infection and involve assembly and implantation of complex microdrives for semi-chronic applications. Here we present a methodology for improving targeting of subcortical structures in large animals such as macaque monkeys, using image guided neuronavigation. Design of custom cranial caps allowed for incorporation of stable fiducial markers, required for increased targeting accuracy in neuronavigation procedures, resulting in an average targeting error of 1.6 mm over three implantations. Incorporation of anchor bolt chambers, commonly used in human neurosurgery, provided a minimally invasive entrance to the brain parenchyma, allowing for chronic recordings. By leveraging existing 3D printing technology, we fabricated an anchor bolt-mounted microdrive for semi-chronic applications. Our protocol leverages commercially available tools for implantation, decreases the risk of infection and complications of open craniotomies, and improves the accuracy and precision of chronic electrode implantations targeting deep brain structures in large animal models.
Design, synthesis and spectroscopic and structural characterization of novelN-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology
Authors: Çakmak Şükriye , Aycan Tuğba , Öztürk Filiz , Veyisoğlu Aysel
Published: August 2022

The novel compoundN-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide, C16H17NO4,I, was prepared by a two-step reaction and then characterized by elemental analysis and X-ray diffraction (XRD) methods. Moreover, its spectroscopic properties were investigated by FT–IR and1H and13C NMR. CompoundIcrystallized in the monoclinic space groupP21/cand the molecular geometry is not planar, being divided into three planar regions. Supramolecular structures are formed by connecting unitsviahydrogen bonds. The ground-state molecular structure ofIwas optimized by the DFT-B3LYP/6-31G(d,p) method and the theoretical structure was compared with that obtained by X-ray diffraction. Intermolecular interactions in the crystal network were studied by two-dimensional (2D) and three-dimensional (3D) Hirshfeld analyses. The calculated electronic transition results were examined and the molecular electrostatic potentials (MEPs) were also determined. Thein vitroantimicrobial activities ofIagainst three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined. The compound was compared with several control drugs and showed better activity than the amoxicillin standard against Gram-positive bacteriaB. subtilis,S. aureusandE. faecalis, and Gram-negative bacteriaE. coli,K. pneumoniaeandP. aeruginosa. The density functional theory (DFT)-optimized structure of the small molecule was used to perform molecular docking studies with proteins from experimentally studied bacterial and fungal organisms usingAutoDockto determine the most preferred binding mode of the ligand within the protein cavity. A druglikeness assay and ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out and predict a good drug-like character.
When working from home might come at a cost: the relationship between family boundary permeability, overwork climate and exhaustion
Authors: Lazauskaite-Zabielske Jurgita , Ziedelis Arunas , Urbanaviciute Ieva
Published: August 2022

Purpose

Drawing on boundary theory, this study aims to analyse whether the intensity of working from home will be related to higher exhaustion through family boundary permeability, with this relationship being more robust when overwork climate is high.

Design/methodology/approach

In this paper eight hundred eighty-three white-collar employees working from home during the COVID-19 pandemic in Lithuania were surveyed online.

Findings

The results confirmed the hypotheses, demonstrating that family boundary permeability may explain the relationship between telework intensity and exhaustion. Furthermore, the mediating relationship between the intensity of working from home, family boundary permeability and exhaustion were moderated by overwork climate. Employees who felt the pressure to overwork were more likely to have a more permeable family boundary when working from home and appeared to experience a much higher psychological cost in terms of emotional exhaustion.

Originality/value

The study provides an insight into the relationships between the intensity of working from home, boundary permeability and exhaustion and their boundary conditions when working from home during the COVID-19 pandemic.
Flashover of insulation materials induced by electrostatic electromagnetic pulse
Authors: Zhang Yan , Ge Xianghu , Zhao Xin , Yang Xiaorui , Liu Shanghe , Xuan Jingjing
Published: August 2022

Purpose

The purpose of this paper is to research the induced flashover laws of different insulation materials under electrostatic electromagnetic pulse, and the induced flashover characteristics of different electrode structures are further explored.

Design/methodology/approach

According to standard IEC 61000–4-2, an experimental system of electrostatic electromagnetic pulse flashover for insulation materials is established. The induction flashover laws of polytetrafluoroethylene, epoxy resin and polymethyl methacrylate surface-mounted finger electrodes under the different intensity of electrostatic electromagnetic pulse are researched. The influence of the finger electrode, needle–needle electrode and needle–plate electrode on insulation flashover was compared. Secondary electron emission avalanche (SEEA) and field superposition theory are used to analyze the experimental results of electrostatic electromagnetic pulse induced flashover.

Findings

The larger the dielectric strength of insulation materials, the more difficult flashover occurs on the surface. The field superposition enhances collision ionization between electrons and gas molecules, which leads to the insulation materials surface induced flashover easily by electrostatic electromagnetic pulse. The sharper the electrode shapes on the insulation materials surface, the stronger the electric field intensity at the cathode triple junction, more initial electrons are excited to form the discharge channel, which easily leads to flashover on the surface of the insulating material.

Originality/value

The proposed field superposition combined with the SEEA method provides a new study perspective and enables a more rational, comprehensive analysis of electrostatic electromagnetic pulse induced flashover of insulation materials. The work of this paper can provide a reference for the safety protection of spacecraft in orbit under a strong electromagnetic field environment, increase the service life of spacecraft and improve the reliability of spacecraft’s safe operation in orbit. It provides a basis for the selection of insulation materials for equipment under the different intensities of the external electromagnetic environment.
Role transitions at the prosumer level: spillover effects in the collaborative economy from an interactive marketing perspective
Authors: Ertz Myriam , Boily Émilie , Sun Shouheng , Sarigöllü Emine
Published: August 2022

Purpose

The purpose of this study is to examine the process underlying how consumers shift roles from users to suppliers of goods or services in the collaborative economy (CE). It examines quantatively the impact of a series of explanatory variables underlying that switchover process.

Design/methodology/approach

This study identifies and tests the key factors that motivate the user-provider transition by introducing the spillover effect from the proenvironmental literature into collaborative practices and using four experimental designs. Considering behavioral characteristics, context, intrinsic variables and socialization, this study provides an in-depth understanding of the process of transition from user to supplier in the CE.

Findings

The results suggest the interactive nature of the spillover as peer influence boosts changes in individual motivations, preferences and behaviors. Furthermore, promoting solidarity between members of the CE platform facilitates the transition of participants from users to providers. In addition, the users’ perception of socialization, satisfaction and sense of indebtedness may also play a significant role in the transition.

Research limitations/implications

The study highlights the process underlying the switchover from user to provider at the prosumer level. More specifically, this study identifies key variables influencing the intention to switchover in the CE by drawing on the spillover effect from pro-environmental behavior and considering the spillover as an interactive process.

Practical implications

Managers who wish to develop collaborative systems must attract a critical mass of providers to ensure the viability of their systems. Instead of recruiting new providers, managers may convert existing users into providers. This study identifies the key variables to modulate to this end.

Originality/value

The findings offer important managerial implications and shed new light on the CE literature.
A stakeholder perspective on risk and safety planning in a major sporting event
Authors: Børve Hege Eggen , Thøring Thor Atle
Published: August 2022

Purpose

This study analyses the impact of institutional logics on the outcomes of a sporting event's risk process.

Design/methodology/approach

The research design is an exploratory case study of the 2017 Road World Cycling Championship using a qualitative approach. By drawing on multiple sources, documents and experiences of six key stakeholders the richness of the qualitative data were utilised to provide a deeper understanding of the impact of institutional logics on the process.

Findings

Stakeholders relied on different organisational and professional logics in arguments for certain risk preferences and strategies. Further, the logics behind stakeholder attention varied between stakeholder groups and within a stakeholder group. This led to a tension-filled relationship amongst stakeholders working in the same organisation and between those in different organisations. Finally, new professional practices emerged; however, there were also unintended consequences, such as a large financial deficit, with a significant part of the cost overrun being the risk assessment work.

Research limitations/implications

The study includes a case study of a major sporting event that was arranged some years ago. Events are usually organised as temporary projects in collaboration with public sector organisations and must be arranged in accordance with the logics of efficiency as well as meeting the particular needs of citizens. Assuming similar risk planning processes may occur in other contexts is reasonable.

Originality/value

The study contributes to knowledge about the impact of logics on the outcome of risk planning and improves scholars' understanding of risk management and the outcomes of planning mega-sporting events. Moreover, insights into these micro-level processes reveal the importance of dealing with the logics that lie beneath stakeholders' perceptions of risk in order to collaborate, achieve common goals, and prevent cost overruns.