bluuebunny/crossref_metadata_2025 huggingface dataset:
Finnish Diabetes Risk Score FINDRISC and HbA1c test as a screening test for the metabolic syndrome in people who lives in high-altitude, La Paz – Bolivia (3600 m.a.s.l.)
Authors: Philco-Lima Patricia , Ramírez-Laura Aydeé Cristina , Suxo-Tejada Marlene Isabel , Alanes-Fernandez Ángela María Clara , Choque-Churqui Aida Virginia , Paye-Huanca Omar Erick , Farah-Bravo Luz Jaqueline , Ascaso-Terren Carlos
Published: March 2021

BACKGROUND

The identification of the metabolic syndrome is essential for a timely diagnosis and to avoid type 2 diabetes, the objective was to determine the validity of the FINDRISC test and glycated hemoglobin for risk screening for diabetes mellitus in a high-altitude resident population (3600 m.a.s.l.) city of La Paz - Bolivia 2018.

METHODS

Analytical study of diagnostic tests, the gold test was the definition of metabolic syndrome according to the criteria of the Harmonization Consensus, compared with the FINDRISC test and glycated hemoglobin. People with an age greater than or equal to 18, who agreed to participate, were included. Pregnant women, people with cancer or thyroid disease were excluded.

RESULTS

400 people were included. There were 358 women (89.5%) and 42 men (10.5%) with age of 48.38±14.1 years old. The prevalence of metabolic syndrome was 46.75%. The area under the curve, sensitivity, specificity, positive predictive value and positive likelihood ratio of FINDRISC with cut-off point 10 were 0.7073(CI95% 0.66-0.75), 74.33%(CI95% 67.34-80.30), 67.14%(CI95% 60.33-73.31), 66.51%(CI95% 59.62-72.78) and 2.26(CI95% 1.83-2.79) respectively. With FINDRISC’s (cut-off point 10) and HbA1c (cut-off point 5.7%) together, were 0.8025 (CI95% 0.74-0.84), 88.1%(CI95% 80.82-92.96), 72.41%(CI95% 63.21-80.11), 77.62%(CI95% 69.74-83.98) and 3.19 (CI95% 2.36-4.32) respectively.

CONCLUSIONS

The FINDRISC test is a good metabolic syndrome screening test, with a cut point of 10, this is synergized with 5.7% for HbA1c in a high-altitude resident population (3600 m.a.s.l.).

Summary Box

What is already known on this subject?

To exist evidence that FINDRISC test is useful with HbA1c together. It to predict diabetes risk. But there are different cutoff points in both. In high altitude population as La Paz to 3600 m.a.s.l., it doesn’t know.

What are the new findings?

The FINDRISC test is a good metabolic syndrome screening test, with a cut point of 10, this is synergized with 5.7% for HbA1c in high altitude population as La Paz to 3600 m.a.s.l.

How might these results change the focus of research or clinical practice?

The FINDRISC test is easy to apply in primary care, plus the determination of glycosylated hemoglobin, enhances its diagnostic capacity to predict metabolic syndrome, in high altitude resident population, where insulin sensitivity is different.
Engaging the complexity of diet and healthy aging in humans
Authors: Senior Alistair M. , Legault Véronique , Lavoie Francis B. , Presse Nancy , Gaudreau Pierrette , Turcot Valérie , Raubenheimer David , Le Couteur David G. , Simpson Stephen J. , Cohen Alan A.
Published: March 2021

Little is known about how normal variation in dietary patterns in humans affects the aging process, largely because both nutrition and the physiology of aging are highly complex and multidimensional. Here, we apply the nutritional geometry framework to data from 1560 older adults followed over four years to assess how nutrient intake patterns affect the aging process. Aging was quantified via blood biomarkers integrated to measure loss of homeostasis. Additionally, we extend nutritional geometry to 19 micronutrients. Salient results include benefits of intermediate protein and vitamin E intake. Broadly, we show that there are few simple answers of “good” or “bad” nutrients – optimal levels are generally intermediate, but dependent on other nutrients. Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results, and our approach presents a roadmap for future studies to explore the full complexity of the nutrition-aging landscape.

Impact Statement

Multidimensional nutritional analyses reveal how the association between diet and healthy aging is hard to untangle, as most nutrients have non-linear and interactive effects in humans.
Idéfix: identifying accidental sample mix-ups in biobanks using polygenic scores
Authors: Warmerdam Robert , Lanting Pauline ,   LifeLines Cohort Study, Deelen Patrick , Franke Lude
Published: March 2021

Structured abstract

Identifying sample mix-ups in biobanks is essential to allow the repurposing of genetic data for clinical pharmacogenetics. Pharmacogenetic advice based on the genetic information of another individual is potentially harmful. Existing methods for identifying mix-ups are limited to datasets in which additional omics data (e.g. gene expression) is available. Cohorts lacking such data can only use sex, which can reveal only half of the mix-ups. Here, we describe Idéfix, a method for the identification of accidental sample mix-ups in biobanks using polygenic scores. In the Lifelines population-based biobank we calculated polygenic scores (PGSs) for 25 traits for 32,786 participants. Idéfix then compares the actual phenotypes to PGSs and uses the relative discordance that is expected for mix-ups, compared to correct samples.

In a simulation, using induced mix-ups, Idéfix reaches an AUC of 0.90 using 25 polygenic scores and sex. This is a substantial improvement over using only sex, which has an AUC of 0.75. Idéfix therefore is not yet able to identify every sample mix-up. However, this will likely improve soon, with highly powered GWAS summary statistics that will likely become available for more commonly measured traits.

Nevertheless, Idéfix can already be used to identify a high-quality set of participants for whom it is very unlikely that they reflect sample mix-ups, and therefore could be offered a pharmacogenetic passport. For instance, when selecting the 10% of participants for whom predicted phenotypes adhere best to the actually measured phenotypes, we estimate that the proportion of sample mix-ups is reduced 250-fold.

Availability and implementation

Idéfixis freely available athttps://github.com/molgenis/systemsgenetics/wiki/Idefix

Contact

l.h.franke@umcg.nl
Integrative Analysis ofSorghum BicolorGreen Prop Roots Under Elevated CO2and Water Deficit Conditions
Authors: de Souza Rodrigues Tamires , Arge Luis Willian Pacheco , de Freitas Guedes Fernanda Alves , Travassos-Lins João , de Souza Amanda Pereira , Cocuron Jean-Christophe , Buckeridge Marcos Silveira , Grossi-de-Sá Maria Fátima , Alves-Ferreira Márcio
Published: March 2021

Elevated CO2(E[CO2]) improves the biomass and yield when combined with water-stress in C4 plants. Although several studies described the molecular response of the C4 plantSorghum bicolorduring drought exposure, none reported its combinatorial effect with E[CO2] in the roots. We decided to perform a molecular analysis using green prop roots, the portion of the radicular system photosynthetically active and more sensible to drought. Whole-transcriptome analysis identified 394 up- and 1,471 down-regulated genes. Among the E[CO2] induced pathways, photosynthesis stood out. Carbon fixation, phenylpropanoid, phenolic compounds, and fatty acid biosynthesis-related pathways were repressed. Protein family analysis showed induction of chlorophylla-bbinding protein family, and repression of glutathione-related enzymes. Protein-protein interaction networks exhibited well-defined clusters, including genes related to cell organization and biogenesis, oxi-reduction process, and photosynthesis being induced. The findings suggest that the E[CO2] mitigates the water deficit by antioxidant and osmoregulation activity, as well as by accumulation of sugar-alcohols in the green prop roots, which may be responsible by the increase in biomass together with the cell proliferation. The higher carbon uptake explains the increase in photosynthetic and primary metabolism activities. Our data revealed that green prop roots present an intriguing metabolism under water deficit and E[CO2], showing its crucial role in the drought tolerance acquisition in a predicted future global atmosphere.
Optimized structure of monoubiquitinated FANCD2 (human) at Lys 561: a theoretical approach
Authors: Mondal Sudipa , Reddy Subba , Mukhopadhyay Sudit S.
Published: March 2021

Fanconi anaemia pathway repairs inter-strand cross linking damage (ICL) of the DNA. Monoubiquitination of FANCD2 and FANCI is very crucial for ICL repairing. In this work we have tried to understand the monoubiquitinated FANCD2 structure, which facilitates the FANCD2 for binding the damage part of the chromatin. Crystal structure of the monoubiquitinated FANCD2 alone is not available, therefore we have developed the optimized structure of the human monoubiquitinated (Lys 561) FANCD2. As there is no suitable software or web server we have developed a method for building up monoubiquitinated product and validated on simplest monoubiquitinated protein, diubiquitin. We have predicted the structure of human monoubiquitinated FANCD2 by using our method and studied the interaction with DNA by docking studies. Molecular Dynamics (MD) simulation was used to understand the stability of the structure. Large structural differences have been observed between FANCD2 and monoubiquitinated FANCD2. DNA docking studies suggest that the binding site varies for the FANCD2 and monoubiquitinated FANCD2.
Sub-spreading events limit the reliable elimination of heterogeneous epidemics
Authors: Parag Kris V
Published: March 2021

We show that sub-spreading events i.e., transmission events in which an infection propagates to few or no individuals, can be surprisingly important for defining the lifetime of an infectious disease epidemic and hence its waiting time to elimination or fade-out, measured from the time-point of its last observed case. While limiting super-spreading promotes more effective control when cases are growing, we find that when incidence is waning, curbing sub-spreading is more important for achieving reliable elimination of the epidemic. Controlling super-spreading in this low-transmissibility phase offers diminishing returns over non-selective, population-wide measures. By restricting sub-spreading we efficiently dampen remaining variations among the reproduction numbers of infectious events, which minimises the risk of premature and late end-of-epidemic declarations. Because case-ascertainment or reporting rates can be modelled in exactly the same way as control policies, we concurrently show that the under-reporting of sub-spreading events during waning phases will engender overconfident assessments of epidemic elimination. While controlling sub-spreading may not be easily realised, the likely neglecting of these events by surveillance systems could result in unexpectedly risky end-of-epidemic declarations. Super-spreading controls the size of the epidemic peak but sub-spreading mediates the variability of its tail.
Ageing and Dementia: Age-Period-Cohort Effects of Policy Intervention in England, 2006-2016
Authors: Kolpashnikova Kamila
Published: March 2021

Background

Dementia is one of the most important challenges of our time. According to the Dementia Statistics Hub, only about 66% of all UK residents with dementia were diagnosed in 2017-2018. Yet, there are reservations about the early diagnosis of dementia-related diseases. As a result, the UK National Screening Committee does not recommend systematic population screening of dementia.

Methods

This study added additional evidence of the effectiveness of the National Dementia Strategy and increased numbers of diagnosis of dementia on the younger cohorts of the elderly, using the intrinsic estimator age-period-cohort models and the English Longitudinal Study of Ageing data.

Results

Age effects show that screening and diagnosis increases in volume only among those aged 75 and above, suggesting that many of the younger elderly were not diagnosed. Period effects show that although there was an initial increase due to new policy implementation, the trend stalled in later years, indicating that the increase might not have been even across the period when controlled for age and cohort. The study also shows that cohort effects indicate lower prevalence in younger cohorts controlled for age and period.

Conclusions

Although more research in diverse contexts is warranted, this study cautions against the abandonment of timely diagnosis and increased screening and shows some effectiveness of prevention strategies on the national level.
Is there a serum proteome signature to predict mortality in severe COVID-19 patients?
Authors: Völlmy Franziska , van den Toorn Henk , Chiozzi Riccardo Zenezini , Zucchetti Ottavio , Papi Alberto , Volta Carlo Alberto , Marracino Luisa , Vieceli Dalla Sega Francesco , Fortini Francesca , Campo Gianluca , Contoli Marco , Spadaro Savino , Rizzo Paola , Heck Albert J.R.
Published: March 2021

Here we recorded serum proteome profiles of 33 COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later timepoints. We focused on serum proteins different in abundance between the group of survivors and non-survivors and observed that a rather small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, HRG and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3 and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also did show opposite trends in protein abundance during disease progression. This panel of eight proteins, complemented with a few more, may represent a panel for mortality risk assessment and eventually even for treatment, by administration of exogenous proteins possibly aiding survival. Such administration is not unprecedented, as administration of exogenous inter-α-trypsin inhibitors is already used in the treatment of patients with severe sepsis and Kawasaki disease. The mortality risk panel defined here is in excellent agreement with findings in two recent COVID-19 serum proteomics studies on independent cohorts, supporting our findings. This panel may not be unique for COVID-19, as some of the proteins here annotated as mortality risk factors have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.
Development of a pest threshold decision support system for minimising damage to winter wheat from wheat bulb fly,Delia coarctata
Authors: Leybourne Daniel J , Storer Kate E , Berry Pete , Ellis Steve
Published: March 2021

Graphical Abstract

In this article we describe two predictive models that can be used for the integrated management of wheat bulb fly. Our first model is a pest level prediction model and our second model predicts the number of shoots a winter wheat crop will achieve by the terminal spikelet developmental stage. We revise and update current wheat bulb fly damage thresholds and combine this with our two models to devise a tolerance-based decision support system that can be used to minimise the risk of crop damage by wheat bulb fly.

Wheat bulb fly,Delia coarctata,is an important pest of winter wheat in the UK, causing significant damage of up to 4 t ha-1. Accepted population thresholds forD. coarctataare 250 eggs m-2for crops sown up to the end of October and 100 eggs m-2for crops sown from November. Fields with populations ofD. coarctatathat exceed the thresholds are at higher risk of experiencing economically damaging pest infestations. In the UK, recent withdrawal of insecticides means that only a seed treatment is available for chemical control ofD. coarctata,however this is only effective for late-sown crops (November onwards) and accurate estimations of annual population levels are required to ensure a seed treatment is applied if needed. As a result of the lack of post-drilling control strategies, the management ofD. coarctatais becoming increasingly reliant on non-chemical methods of control. Control strategies that are effective in managing similar stem-boring pests of wheat include sowing earlier and using higher seed rates to produce crops with more shoots and greater tolerance to shoot damage.

In this study we develop two predictive models that can be used for integratedD. coarctatamanagement. The first is an updated pest level prediction model that predictsD. coarctatapopulations from meteorological parameters with a predictive accuracy of 70%, which represents a significant improvement on the previousD. coarctatapopulation prediction model. Our second model predicts the maximum number of shoots for a winter wheat crop that would be expected at the terminal spikelet development stage. This shoot number model uses information about the thermal time from plant emergence to terminal spikelet, leaf phyllochron length, plant population, and sowing date to predict the degree of tolerance a crop will have againstD. coarctata.The shoot number model was calibrated against data collected from five field experiments and tested against data from four experiments. Model testing demonstrated that the shoot number model has a predictive accuracy of 70%. A decision support system using these two models for the sustainable management ofD. coarcatarisk is described.
The impact of policy timing on the spread of COVID-19
Authors: Elitzur Moshe , Kaplan Scott , Ivezić Željko , Zilberman David
Published: March 2021

We model COVID-19 data for 89 nations and US states with a recently developed formalism that describes mathematically any pattern of growth with the minimum number of parameters. The results show that the disease has a typical duration of 18 days, with a significant increase in fatality when it lasts longer than about 4 months. Searching for correlations between “flattening of the curve” and preventive public policies, we find strong statistical evidence for the impact of the first implemented policy on decreasing the pandemic growth rate; a delay of one week in implementation nearly triples the size of the infected population, on average. Without any government action, the initial outburst still slows down after 36 days, possibly thanks to changes in public behavior in response to the pandemic toll. Stay-at-home (lockdown) was not the first policy of any sample member and we do not find statistically meaningful evidence for its added impact, similar to a recent study that employed an entirely different approach. However, lockdown was mostly imposed only shortly before the exponential rise was arrested. The possibility remains that lockdown might have shortened significantly the initial exponential rise had it been employed as first, rather than last resort.
SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2
Authors: Weekley Claire M. , Purcell Damian F. J. , Parker Michael W.
Published: March 2021

Since SARS-CoV-2 emerged in 2019, genomic sequencing has identified mutations in the viral RNA including in the receptor-binding domain of the Spike protein. Structural characterisation of the Spike carrying point mutations aids in our understanding of how these mutations impact binding of the protein to its human receptor, ACE2, and to therapeutic antibodies. The Spike G485R mutation has been observed in multiple isolates of the virus and mutation of the adjacent residue E484 to lysine is known to contribute to antigenic escape. Here, we have crystallised the SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. The crystal structure shows that while the G485 residue does not have a direct interaction with ACE2, its mutation to arginine affects the structure of the loop made by residues 480-488 in the receptor-binding motif, disrupting the interactions of neighbouring residues with ACE2 and with potential implications for antigenic escape from vaccines, antibodies and other biologics directed against SARS-CoV-2 Spike.
Yeast surface display-based identification of ACE2 mutations that modulate SARS-CoV-2 spike binding across multiple mammalian species
Authors: Heinzelman Pete , Greenhalgh Jonathan C. , Romero Philip A.
Published: March 2021

Understanding how SARS-CoV-2 interacts with different mammalian angiotensin-converting enzyme II (ACE2) cell entry receptors elucidates determinants of virus transmission and facilitates development of vaccines for humans and animals. Yeast display-based directed evolution identified conserved ACE2 mutations that increase spike binding across multiple species. Gln42Leu increased ACE2-spike binding for human and four of four other mammalian ACE2s; Leu79Ile had a effect for human and three of three mammalian ACE2s. These residues are highly represented, 83% for Gln42 and 56% for Leu79, among mammalian ACE2s. The above findings can be important in protecting humans and animals from existing and future SARS-CoV-2 variants.
HIV-1 Vpu promotes phagocytosis of infected CD4+T cells by macrophages through downregulation of CD47
Authors: Cong Lijun , Sugden Scott M. , Leclair Pascal , Lim Chinten James , Pham Tram NQ. , Cohen Éric A.
Published: March 2021

Human immunodeficiency virus (HIV) remodels the cell surface of infected cells to facilitate viral dissemination and promote immune evasion. The membrane-associated Vpu accessory protein encoded by HIV-1 plays a key role in this process by altering cell surface levels of multiple host proteins. Using an unbiased quantitative plasma membrane profiling approach, we previously identified CD47 as a putative host target downregulated by Vpu. CD47 is a ubiquitously-expressed cell surface protein that interacts with the myeloid cell inhibitory receptor SIRPα to deliver a “don’t-eat-me” signal, thus protecting cells from phagocytosis. In this study, we investigate whether CD47 modulation by HIV-1 Vpu might promote the susceptibility of macrophages to viral infection via phagocytosis of infected CD4+T cells. Indeed, we find that Vpu downregulates CD47 expression on infected CD4+T cells leading to an enhanced capture and phagocytosis by macrophages. Interestingly, it is through this process that a CCR5-tropic transmitted/founder (T/F) virus, which otherwise poorly infects macrophages in its cell-free form, becomes infectious in macrophages. Importantly, we show that HIV-1-infected cells expressing a Vpu-resistant CD47 mutant are less prone to infect macrophages through phagocytosis. Mechanistically, Vpu forms a physical complex with CD47 through its transmembrane domain and targets the latter for lysosomal degradation. These results reveal a novel role of Vpu in modulating macrophage infection, which has important implications for HIV-1 transmission in early stages of infection and the establishment of viral reservoir.

IMPORTANCE

Macrophages play critical roles in HIV transmission, viral spread early in infection, and as a reservoir of virus. Selective capture and engulfment of HIV-1 infected T cells was shown to drive efficient macrophage infection suggesting that this mechanism represents an important mode of infection notably for weakly macrophage-tropic T/F viruses. In this study, we provide insight into the signals that regulate this process. We show that the HIV-1 accessory protein Vpu downregulates cell surface levels of CD47, a host protein that interacts with the inhibitory receptor SIRPα to deliver a “don’t-eat-me” signal to macrophages. This allows for enhanced capture and phagocytosis of infected T cells by macrophages, ultimately leading to their productive infection even with T/F virus. These findings provide new insights into the mechanisms governing the intercellular transmission of HIV-1 to macrophages with implications for the establishment of the macrophage reservoir and early HIV-1 disseminationin vivo.
Longitudinal characterization of humoral and cellular immunity in hospitalized COVID-19 patients reveal immune persistence up to 9 months after infection
Authors: Sandberg John Tyler , Varnaitė Renata , Christ Wanda , Chen Puran , Muvva Jagadeeswara R. , Maleki Kimia T. , García Marina , Dzidic Majda , Folkesson Elin , Skagerberg Magdalena , Ahlén Gustaf , Frelin Lars , Sällberg Matti ,   The Karolinska COVID-19 Study Group, Eriksson Lars I. , Rooyackers Olav , Sönnerborg Anders , Buggert Marcus , Björkström Niklas K. , Aleman Soo , Strålin Kristoffer , Klingström Jonas , Ljunggren Hans-Gustaf , Blom Kim , Gredmark-Russ Sara
Published: March 2021

Background

Insights into early, specific humoral and cellular responses to infection with SARS-CoV-2, as well as the persistence and magnitude of resulting immune memory is important amidst the ongoing pandemic. The combination of humoral and cellular immunity will most likely contribute to protection from reinfection or severe disease.

Methods

Here, we conducted a longitudinal study on hospitalized moderate and severe COVID-19 patients from the acute phase of disease into convalescence at five- and nine-months post symptom onset. Utilizing flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune memory during and after human SARS-CoV-2 infection.

Findings

During acute COVID-19, we observed an increase in germinal center activity, a substantial expansion of antibodysecreting cells, and the generation of SARS-CoV-2-neutralizing antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralizing antibody titers as well as robust specific memory B cell responses and polyfunctional T cell responses at five- and nine-months after symptom onset in both moderate and severe COVID-19 patients. Long-term SARS-CoV-2 specific responses were marked by preferential targeting of spike over nucleocapsid protein.

Conclusions

Our findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2 specific immunological memory in hospitalized COVID-19 patients long after recovery, likely contributing towards protection against reinfection.
3’-Sulfated Lewis A is a Biomarker for Metaplastic and Oncogenic Transformation of Several Gastrointestinal Epithelia
Authors: Brown Jeffrey W. , Das Koushik K. , Kalas Vasilios , Das Kiron M. , Mills Jason C.
Published: March 2021

Introduction

Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) specifically recognizes metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett’s esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive.

Methods

In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA.

Results

The epitope recognized by mAb Das-1 is 3’-Sulfo-Lewis A (3’-Sulfo-LeA). 3’-Sulfo-LeAis broadly reexpressed across numerous GI epithelia and elsewhere only after metaplastic and carcinomatous transformation.

Discussion

3’-Sulfo-LeAis a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.
RABL6A promotes pancreatic neuroendocrine tumor angiogenesis and progressionin vivo
Authors: Maharjan Chandra K. , Kaemmer Courtney A. , Muniz Viviane P. , Bauchle Casey , Mott Sarah L. , Zamba K.D. , Breheny Patrick , Leidinger Mariah R. , Darbro Benjamin W. , Stephens Samuel B. , Meyerholz David K. , Quelle Dawn E.
Published: March 2021

Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survivalin vitro. Here, we investigated the role of RABL6A in pNET progressionin vivousing a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenicc-Mycin RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and developmentin vivo.
Histone sample preparation for bottom-up mass spectrometry: a roadmap to informed decisions
Authors: Daled Simon , Willems Sander , Van Puyvelde Bart , Corveleyn Laura , Verhelst Sigrid , De Clerck Laura , Deforce Dieter , Dhaenens Maarten
Published: March 2021

Histone-based chromatin organization enabled eukaryotic genome complexity. This epigenetic control mechanism allowed for the differentiation of stable gene-expression and thus the very existence of multicellular organisms. This existential role in biology makes histones one of the most complexly modified molecules in the biotic world, which makes these key regulators notoriously hard to analyze. We here provide a roadmap to enable fast and informed selection of a bottom-up mass spectrometry sample preparation protocol that matches a specific research question. We therefore propose a two-step assessment procedure: (i) visualization of the coverage that is attained for a given workflow and (ii) direct alignment-between-runs to assess potential pitfalls at the ion level. To illustrate the applicability, we compare four different sample preparation protocols, while adding a new enzyme to the toolbox, i.e., RgpB (GingisREX®, Genovis), an endoproteinase that selectively and efficiently cleaves at the c-terminal end of arginine residues.

Raw data is available via ProteomeXchange with identifier PXD024423.
A distinct assembly pathway of the human 39S late pre-mitoribosome
Authors: Cheng Jingdong , Berninghausen Otto , Beckmann Roland
Published: March 2021

Assembly of the mitoribosome is largely enigmatic and involves numerous assembly factors. However, little is known about their function and the architectural transitions of the pre-ribosomal intermediates. Here, we solved cryo-EM structures of the human 39S large subunit pre-ribosomes, representing four distinct late state intermediates. Besides the MALSU1 complex, we identified several assembly factors, including the DDX28 helicase, MRM3, GTPBP10 and the NSUN4-mTERF4 complex, all of which keep the 16S rRNA in immature conformations. The late transitions mainly involved rRNA domains IV and V, which form the central protuberance, the intersubunit side and the peptidyltransferase center of the 39S subunit. Unexpectedly, we found deacylated tRNA in the ribosomal E-site, suggesting a role in 39S assembly. Taken together, our study provides an architectural inventory of the distinct late assembly phase of the human 39S mitoribosome.
Single-stranded nucleic acid sensing and coacervation by linker histone H1
Authors: Leicher Rachel , Osunsade Adewola , Latham Andrew P. , Chua Gabriella N. L. , Watters John W. , Christodoulou-Rubalcava Sophia , Zhang Bin , David Yael , Liu Shixin
Published: March 2021

The linker histone H1 is the most abundant group of eukaryotic chromatin-binding proteins. The mechanism underlying the diverse physiological functions of H1 remains unclear. Here we used single-molecule fluorescence and force microscopy to observe the behavior of H1 on DNA under different tensions. Unexpectedly, we found that H1 coalesces around nascent ssDNA. Molecular dynamics simulations revealed that multivalent and transient interactions between H1 and ssDNA mediate their phase separation. We further showed that longer and unpaired nucleic acids result in more viscous, gel-like H1 droplets. Finally, we imaged H1 puncta in cells under normal and stressed conditions and observed that RPA and H1 occupy separate nuclear regions. Overall, our results provide a new perspective to understanding the role of H1 in genome organization and maintenance.
Identification of guanylyltransferase activity in the SARS-CoV-2 RNA polymerase
Authors: Walker Alexander P , Fan Haitian , Keown Jeremy R , Grimes Jonathan M , Fodor Ervin
Published: March 2021

SARS-CoV-2 is a positive-sense RNA virus that is responsible for the ongoing Coronavirus Disease 2019 (COVID-19) pandemic, which continues to cause significant morbidity, mortality and economic strain. SARS-CoV-2 can cause severe respiratory disease and death in humans, highlighting the need for effective antiviral therapies. The RNA synthesis machinery of SARS-CoV-2 is an ideal drug target and consists of non-structural protein 12 (nsp12), which is directly responsible for RNA synthesis, and numerous co-factors that are involved in RNA proofreading and 5’ capping of viral mRNAs. The formation of the 5’ cap-1 structure is known to require a guanylyltransferase (GTase) as well as 5’ triphosphatase and methyltransferase activities. However, the mechanism of SARS-CoV-2 mRNA capping remains poorly understood. Here we show that the SARS-CoV-2 RNA polymerase nsp12 functions as a GTase. We characterise this GTase activity and find that the nsp12 NiRAN (nidovirus RdRP-associated nucleotidyltransferase) domain is responsible for carrying out the addition of a GTP nucleotide to the 5’ end of viral RNA via a 5’ to 5’ triphosphate linkage. We also show that remdesivir triphosphate, the active form of the antiviral drug remdesivir, inhibits the SARS-CoV-2 GTase reaction as efficiently as RNA polymerase activity. These data improve understanding of coronavirus mRNA cap synthesis and highlight a new target for novel or repurposed antiviral drugs against SARS-CoV-2.

Importance

SARS-CoV-2 is a respiratory RNA virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. Coronaviruses encode an RNA polymerase which, in combination with other viral proteins, is responsible for synthesising capped viral mRNA. mRNA cap synthesis requires a guanylyltransferase enzyme; here we show that the SARS-CoV-2 guanylyltransferase is located in the viral RNA polymerase, and we identify the protein domain responsible for guanylyltransferase activity. Furthermore we demonstrate that remdesivir triphosphate, the active metabolite of remdesivir, inhibits both the guanylyltransferase and RNA polymerase functions of the SARS-CoV-2 RNA polymerase. These findings improve understanding of the coronavirus mRNA cap synthesis mechanism, in addition to highlighting a new target for the development of therapeutics to treat SARS-CoV-2 infection.
The ConservedColletotrichumspp. Effector CEC3 Induces Nuclear Expansion and Cell Death in Plants
Authors: Tsushima Ayako , Narusaka Mari , Gan Pamela , Kumakura Naoyoshi , Hiroyama Ryoko , Kato Naoki , Takahashi Shunji , Takano Yoshitaka , Narusaka Yoshihiro , Shirasu Ken
Published: March 2021

Plant pathogens secrete small proteins, known as effectors, that promote infection by manipulating host cells. Members of the phytopathogenic fungal genusColletotrichumcollectively have a broad host range and generally adopt a hemibiotrophic lifestyle that includes an initial biotrophic phase and a later necrotrophic phase. We hypothesized thatColletotrichumfungi use a set of conserved effectors during infection to support the two phases of their hemibiotrophic lifestyle. This study aimed to examine this hypothesis by identifying and characterizing conserved effectors amongColletotrichumfungi. Comparative genomic analyses using genomes of ascomycete fungi with different lifestyles identified seven effector candidates that are conserved across the genusColletotrichum. Transient expression assays showed that one of these conserved effectors, CEC3, induces nuclear expansion and cell death inNicotiana benthamiana, suggesting that CEC3 is involved in promoting host cell death during infection. Nuclear expansion and cell death induction were commonly observed in CEC3 homologs from four differentColletotrichumspecies that vary in host specificity. Thus, CEC3 proteins could represent a novel class of core effectors with functional conservation in the genus Colletotrichum.
The fungal root endophyteSerendipita vermiferadisplays inter-kingdom synergistic beneficial effects with the microbiota inArabidopsis thalianaand barley
Authors: Mahdi Lisa K. , Miyauchi Shingo , Uhlmann Charles , Garrido-Oter Ruben , Langen Gregor , Wawra Stephan , Niu Yulong , Robertson-Albertyn Senga , Bulgarelli Davide , Parker Jane E. , Zuccaro Alga
Published: March 2021

Plant root-associated bacteria can confer protection against pathogen infection. By contrast, the beneficial effects of root endophytic fungi and their synergistic interactions with bacteria remain poorly defined. We demonstrate that the combined action of a fungal root endophyte from a widespread taxon with core bacterial microbiota members provides synergistic protection against an aggressive soil-borne pathogen inArabidopsis thalianaand barley. We additionally show early inter-kingdom growth promotion benefits which are host and microbiota composition dependent.

Highlights

The root endophytic fungusSerendipita vermiferacan functionally replace core bacterial microbiota members in mitigating pathogen infection and disease symptoms.

S. vermiferaadditionally stabilizes and potentiates the protective activities of root-associated bacteria and mitigates the negative effects of a non-native bacterial community inA. thaliana.

Inter-kingdom synergistic beneficial effects do not require extensive host transcriptional reprogramming nor high levels ofS. vermiferacolonisation.

Inter-kingdom protective benefits are largely independent of the host while synergism leading to early inter-kingdom growth promotion is driven by host species and microbiota composition.
C-Jun N-terminal kinase post-translational regulation of pain-related Acid-Sensing Ion Channels 1b and 3
Authors: Verkest Clément , Diochot Sylvie , Lingueglia Eric , Baron Anne
Published: March 2021

Neuronal proton-gated Acid-Sensing Ion Channels (ASICs) participate in the detection of tissue acidosis, a phenomenon often encountered in painful pathological diseases. Such conditions often involve in parallel the activation of various signaling pathways such as the Mitogen Activated Protein Kinases (MAPKs) that ultimately leads to phenotype modifications of sensory neurons. Here, we identify one member of the MAPKs, c-Jun N-terminal Kinase (JNK), as a new post-translational positive regulator of ASIC channels in rodent sensory neurons. Recombinant H+-induced ASIC currents in HEK293 cells are potently inhibited within minutes by the JNK inhibitor SP600125 in a subunit and species dependent manner, targeting both rat and human ASIC1b and ASIC3 subunits but only mouse ASIC1b subunit. The regulation by JNK of recombinant ASIC1b- and ASIC3-containing channels (homomers and heteromers) is lost upon mutation of a putative phosphorylation site within the intracellular N- and the C-terminal domain of the ASIC1b and ASIC3 subunit, respectively. Moreover, short-term JNK activation regulates the activity of native ASIC1b- and ASIC3-containing channels in rodent sensory neurons and is involved in the rapid potentiation of ASIC activity by the proinflammatory cytokine TNFα. Local JNK activationin vivoin mice induces a short-term potentiation of the acid-induced cutaneous pain in inflammatory conditions that is partially blocked by the ASIC1-specific inhibitor mambalgin-1. Collectively, our data identify pain-related channels as novel physiological JNK substrates in nociceptive neurons, and propose JNK-dependent phosphorylation as a fast post-translational mechanism of regulation of sensory neuron-expressed ASIC1b- and ASIC3-containing channels that may contribute to peripheral sensitization and pain hypersensitivity.
Comprehensive mouse gut metagenome catalog reveals major difference to the human counterpart
Authors: Kieser Silas , Zdobnov Evgeny M. , Trajkovski Mirko
Published: March 2021

Mouse is the most used model for studying the impact of microbiota on its host, but the repertoire of species from the mouse gut microbiome remains largely unknown. Here, we construct a Comprehensive Mouse Gut Metagenome (CMGM) catalog by assembling all currently available mouse gut metagenomes and combining them with published reference and metagenome-assembled genomes. The 50’011 genomes cluster into 1’699 species, of which 78.1% are uncultured, and we discovered 226 new genera, 7 new families, and 1 new order. Rarefaction analysis indicates comprehensive sampling of the species from the mouse gut. CMGM enables an unprecedented coverage of the mouse gut microbiome exceeding 90%. Comparing CMGM to the human gut microbiota shows an overlap 64% at the genus, but only 16% at the species level, demonstrating that human and mouse gut microbiota are largely distinct.
Geographic Confounding in Genome-Wide Association Studies
Authors: Abdellaoui Abdel , Verweij Karin J.H. , Nivard Michel G.
Published: March 2021

Gene-environment correlations can bias associations between genetic variants and complex traits in genome-wide association studies (GWASs). Here, we control for geographic sources of gene-environment correlation in GWASs on 56 complex traits (N=69,772–271,457). Controlling for geographic region significantly decreases heritability signals for SES-related traits, most strongly for educational attainment and income, indicating that socio-economic differences between regions induce gene-environment correlations that become part of the polygenic signal. For most other complex traits investigated, genetic correlations with educational attainment and income are significantly reduced, most significantly for traits related to BMI, sedentary behavior, and substance use. Controlling for current address has greater impact on the polygenic signal than birth place, suggesting both active and passive sources of gene-environment correlations. Our results show that societal sources of social stratification that extend beyond families introduce regional-level gene-environment correlations that affect GWAS results.
Mixed emotional appeal enhances advertising effectiveness of pro-environmental luxury brands: the mediating role of cognitive flexibility
Authors: Nallaperuma Kaushalya , Septianto Felix , Bandyopadhyay Argho
Published: March 2021

Purpose

The concepts of luxury and pro-environment may be viewed as being in contradiction with each other. Consequently, it is unclear how to promote pro-environmental luxury brands. The present research seeks to develop effective advertising strategies for pro-environmental luxury brands by employing mixed emotional appeals.

Design/methodology/approach

Two experimental studies were conducted to test two hypotheses. Study 1 examines the effects of mixed emotions (happiness and sadness vs. happiness alone) on intentions to purchase a pro-environmental luxury product. Study 2 replicates the findings of Study 1 using a different product and extends it by establishing the underlying mechanism.

Findings

The results reveal that an advertisement featuring mixed emotions of happiness and sadness (vs. happiness alone) enhances intentions to purchase a pro-environmental luxury product. Further, the effect is mediated by cognitive flexibility.

Originality/value

The present research tests a novel perspective on how mixed emotional appeals can leverage the advertising effectiveness of pro-environmental luxury brands.
On heat transfer and flow characteristics of jets impinging onto concave surface with varying bleeding arrangements
Authors: Qiu Dandan , Luo Lei , Zhao Zhiqi , Wang Songtao , Wang Zhongqi , Sunden Bengt Ake
Published: March 2021

Purpose

The purpose of this study is to investigate the effects of film holes’ arrangements and jet Reynolds number on flow structure and heat transfer characteristics of jet impingement conjugated with film cooling in a semicylinder double wall channel.

Design/methodology/approach

Numerical simulations are used in this research. Streamlines on different sections, skin-friction lines, velocity, wall shear stress and turbulent kinetic energy contours near the concave target wall and vortices in the double channel are presented. Local Nusselt number contours and surface averaged Nusselt numbers are also obtained. Topology analysis is applied to further understand the fluid flow and is used in analyzing the heat transfer characteristics.

Findings

It is found that the arrangement of side films positioned far from the center jets helps to enhance the flow disturbance and heat transfer behind the film holes. The heat transfer uniformity for the case of 55° films arrangement angle is most improved and the thermal performance is the highest in this study.

Originality/value

The film holes’ arrangements effects on fluid flow and heat transfer in an impingement cooled concave channel are conducted. The flow structures in the channel and flow characteristics near target by topology pictures are first obtained for the confined film cooled impingement cases. The heat transfer distributions are analyzed with the flow characteristics. The highest heat transfer uniformity and thermal performance situation is obtained in present work.
“We have tiny purses in our vaginas!!! #thanksforthat”: absurdity as a feminist method of intervention
Authors: Sundén Jenny , Paasonen Susanna
Published: March 2021

Purpose

According to thesaurus definitions, the absurd translates as “ridiculously unreasonable, unsound, or incongruous”; “extremely silly; not logical and sensible”. As further indicated in the Latin root absurdus, “out of tune, uncouth, inappropriate, ridiculous,” humor in absurd registers plays with that which is out of harmony with both reason and decency. In this article, the authors make an argument for the absurd as a feminist method for tackling heterosexism.

Design/methodology/approach

By focusing on the Twitter account “Men Write Women” (est. 2019), the rationale of which is to share literary excerpts from male authors describing women's experiences, thoughts and appearances, and which regularly broadens into social theater in the user reactions, the study explores the critical value of absurdity in feminist social media tactics.

Findings

The study proposes the absurd as a means of not merely turning things around, or inside out, but disrupting and eschewing the hegemonic logic on offer. While both absurd humor and feminist activism may begin from a site of reactivity and negative evaluation, it need not remain confined to it. Rather, by turning things preposterous, ludicrous and inappropriate, absurd laughter ends up somewhere different. The feminist value of absurd humor has to do with both its critical edge and with the affective lifts and spaces of ambiguity that it allows for.

Originality/value

Research on digital feminist activism has largely focused on the affective dynamics of anger. As there are multiple affective responses to sexism, our article foregrounds laughter and ambivalence as a means of claiming space differently in online cultures rife with hate, sexism and misogyny.