bluuebunny/crossref_metadata_2025 huggingface dataset:
Strong gene dose dependent protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria
Authors: Awab Ghulam R. , Aaram Fahima , Jamornthanyawat Natsuda , Suwannasin Kanokon , Pagornrat Watcharee , Watson James A , Woodrow Charles J , Dondorp Arjen , Day Nicholas PJ , Imwong Mallika , White Nicholas J.
Published: August 2020

Background

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PDd Med) is common across Europe and Asia. Epidemiological studies investigating the potential protective effect of G6PD deficiency against malaria have yielded conflicting results.

Methods

G6PDd Med genotyping was performed in Pashtun patients in Afghanistan with acute Plasmodium vivax malaria and Pashtun subjects attending the same study centres with unrelated conditions or for routine vaccinations. A Bayesian statistical model assuming Hardy-Weinberg equilibrium was used to estimate the potential protective effects of G6PDd Med on vivax malaria, and was fitted to all available data from this and previous studies.

Findings

In patients with vivax malaria 1.6% (5 of 308) of males were G6PD Med hemizygotes compared with 8.2% (28 of 342) of controls (risk ratio; 95% confidence interval: 0.198 [0.078 to 0.507]), and 6.8% (31 of 458) of female patients were heterozygotes compared with 11.2% (40 of 358) of controls (RR 0.606 [0.387 to 0.948]). From all available data, the estimated allele frequency of G6PDd Med in the Pasthun is 8.8% (95% credible interval, 7.5-10.2). In hemizygous males and homozygous females, G6PDd Med confers a strong protective effect against symptomatic P. vivax malaria reducing the incidence by 73% (95% C.I. 53-87). In heterozygous females the estimated protective effect was 56% (95% C.I. 40-69). The protective effect in heterozygous females is 0.78 (95% CI, 1.09-0.53) of that observed in hemizygous males and homozygous females.

Interpretation

The G6PD Mediterranean genotype confers a very large and gene dose proportional protective effect against vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by epidemiological studies in healthy subjects.
Quality of Life in elderly ICU survivors: A Rapid Systematic Review and Meta-Analysis of Cohort Studies
Authors: Ariyo Kevin , Canestrini Sergio , David Anthony S. , Keene Alex Ruck , Owen Gareth S.
Published: August 2020

BACKGROUND

The influence of age upon intensive care unit (ICU) decision-making is complex and it is unclear if it is based on expected subjective or objective patient outcomes. To address recent concerns over age-based ICU decision-making we explored patient-assessed quality of life (QoL) in ICU survivors.

METHODS

We conducted a rapid database search of cohort studies published between January 2000 to April 2020, of elderly patients admitted to ICUs. We extracted data on self-reported QoL (EQ-5D composite score), study characteristics and demographic and clinical variables. Using a random-effects model, we then compared QoL scores at follow-up to scores either before admission, age-matched population controls or younger ICU survivors. Finally, we conducted follow-up quantitative analyses to explore potential moderators of these effects, and a qualitative synthesis of QoL subscores. A study protocol was registered prospectively on PROSPERO, ID: CRD42020181181.

FINDINGS

Our database search found 2536 studies and from these we reviewed 376 potentially relevant full texts. 21 of these studies met the inclusion criteria for qualitative synthesis and 18 were also included in the meta-analysis (N= 2090 elderly adults). The follow-up periods ranged between 3-100 months. There was no significant difference in the elderly’s QoL scores between one month before ICU and follow-up, or between follow-up and age-matched community controls. QoL in elderly ICU survivors was significantly worse than younger ICU survivors, with a small-to-medium effect size (d= .33 [.10 to .55]). Mortality rates and length of follow up were possible intermediary factors. The qualitative synthesis suggested that any reductions in QoL were primarily due to reductions in physical health, rather than mental health items.

INTERPRETATION

Overall, elderly ICU patients did not experience significantly impaired QoL at follow up, compared to before ICU or their healthy peers. Elderly patients who survive ICU can be expected to have slightly worse QoL compared to younger patients, especially in the longterm. The results suggest that the proportionality of age as a determinant of (population level) ICU resource allocation should be kept under close review and that subjective QoL outcomes (not only objective survival data) should inform person-centred decision making in elderly ICU patients.

DECLARATIONS OF INTEREST

Alex Ruck Keene is an adviser on the Faculty of Intensive Care Medicine’s Legal and Ethical Policy Unit. We report no other competing interests.
Proteomic signatures of perioperative oxygen delivery in skin after major surgery
Authors: Ackland Gareth L. , Bliss Emily , Bahelil Fatima , Cyrus Trinda , Crescente Marilena , Jones Timothy , Iqbal Sadaf , Paredes Laura Gallego , Toner Andrew J. , Arroyo Ana Gutierrez del , Heywood Wendy E. , O’Toole Edel A. , Mills Kevin
Published: August 2020

Objective

Maintaining adequate oxygen delivery after major surgery is associated with minimizing organ dysfunction, although the precise molecular mechanisms remain unclear.

Background

Skin, the largest organ in the body, is vulnerable to reduced oxygen delivery. We hypothesized that the skin proteome, assessed before and after surgery, would reveal molecular differences in patients randomized to receive cardiovascular therapy aimed at maintaining preoperative oxygen delivery (DO2).

Methods

Abdominal punch skin biopsies were snap frozen or fixed in paraformaldehyde immediately before and 48h after elective esophageal or liver resection. Immediately after surgery, patients were randomized to standard of care or therapy to maintain preoperative DO2. On-line two-dimensional liquid chromatography, followed by ultra-high definition label-free mass spectrometry analysis, and/or immunoblots quantified significant proteomic changes. Selected proteins identified by mass spectrometry were confirmed by immunohistochemistry and immunoblot. In a murine hepatic resection model, confirmation of specific proteomic signatures identified in patients was sought by immunoblotting.

Results

Paired biopsies were analyzed from 35 patients (mean age:68±9y; 31% female). We identified 2096 proteins, of which 157 were differentially expressed after surgery. Similar results for selected proteins were found using immunohistochemistry (n=6 patients), immunoblots (n=12 patients) and murine abdominal skin obtained after liver resection (n=14). After surgery, 14 proteins distinguished esophagectomy patients with normal (n=10) versus low (n=7) DO2.values. Failure to maintain preoperative DO2 was associated with upregulation of proteins counteracting oxidative stress and.

Conclusions

Serial skin biopsies afford mechanistic insight into end-organ injury by quantifying proteomic changes associated with impaired oxygen delivery during high-risk surgery.

Trial registration

ISRCTN76894700

Funding

Academy of Medical Sciences/Health Foundation Clinician Scientist Award [GLA]; British Oxygen Company research chair grant in Anesthesia [GLA]; Great Ormond Street Hospital Biomedical Research Centre [EB,WH,KM]; British Heart Foundation:PG/17/40/33028 [MC]; UK NIHR [GLA]; Barts Charity [TJ]

Mini-Abstract

Skin, one of the largest organs in the body, is vulnerable to reduced oxygen delivery. Proteomic analysis of skin biopsies obtained before and after surgery show distinct metabolic and inflammatory changes related to perioperative oxygen delivery. Mirrored by complementary laboratory data in mice, skin proteomics reveal new insights into perioperative organ dysfunction.
Twitter Interaction to Analyze Covid-19 Impact in Ghana, Africa from March to July
Authors: Chire Saire Josimar E. , Panford-Quainoo Kobby
Published: August 2020

Present pandemic generated by Coronavirus Covid-19 has stopped the world, from Tourism, Business, Education and more. Actually, there are reported cases in every continent from America to Europe, from Europe to Australia. Africa is one continent in process of development with a variety of languages, limitations/problems and of course, abundance of culture. The aim of this paper is to analyze the impact in one country located in the middle-west, named Ghana. The data source for the analysis is Twitter(Social Network) and the analysis is using a Text Mining approach. Besides, a composition of graphics are presented considering Google search, daily reported cases. The study is exploratory to know what topics are most frequent in Great Accra Region. The conclusions are: Twitter is useful to get data for the analysis, and the interest of user from Ghana was high at the beginning but it was decreasing from April until July, probably the people is tired or adapting themselves to the actual situation.
SARS-CoV-2 induces inflammasome-dependent pyroptosis and downmodulation of HLA-DR in human monocytes, which can be prevented by atazanavir
Authors: Ferreira André C. , Soares Vinicius Cardoso , de Azevedo-Quintanilha Isaclaudia G. , Dias Suelen da Silva Gomes , Fintelman-Rodrigues Natalia , Sacramento Carolina Q. , Mattos Mayara , de Freitas Caroline S. , Temerozo Jairo R. , Teixeira Lívia , Hottz Eugenio Damaceno , Barreto Ester A , Pão Camila R. R. , Palhinha Lohanna , Miranda Milene , Bou-Habib Dumith Chequer , Bozza Fernando A. , Bozza Patrícia T. , Souza Thiago Moreno L.
Published: August 2020

Infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with leukopenia and uncontrolled inflammatory response in critically ill patients. A better comprehension of SARS-CoV-2-induced monocytes death is essential for the identification of therapies capable to control the hyper-inflammation and reduce viral replication in patients with COVID-19. Here, we show that SARS-CoV-2 induces inflammasome activation and cell death by pyroptosis in human monocytes, experimentally infected and in patients under intensive care. Pyroptosis was dependent on caspase-1 engagement, prior to IL-1ß production and inflammatory cell death. Monocytes exposed to SARS-CoV-2 downregulate HLA-DR, suggesting a potential limitation to orchestrate the immune response. Our results originally describe the mechanism by which monocytes, a central cellular component recruited from peripheral blood to respiratory tract, succumb in patients with severe 2019 coronavirus disease (COVID-19), and emphasize the need for identifying anti-inflammatory and antiviral strategies to prevent SARS-CoV-2-induced pyroptosis.
Racing against stomatal attenuation: rapid CO2response curves more reliably estimate photosynthetic capacity than steady state curves in a low conductance species
Authors: Vincent C , Pierre MO , Stinziano JR
Published: August 2020

A/Cicurves are an important gas-exchange-based approach to understanding the regulation of photosynthesis, describing the response of net CO2assimilation (A) to leaf internal concentration of CO2(Ci). Low stomatal conductance species pose a challenge to the measurement ofA/Cicurves by reducing the signal-to-noise ratio of gas exchange measures. Additionally, the stomatal attenuation effect of elevated ambient CO2leads to further reduction of conductance and may lead to erroneous interpretation of highCiresponses ofA. RapidA/Ciresponse (RACiR) curves offer a potential practice to developA/Cicurves faster than the stomatal closure response to elevated CO2. We used the moderately low conductanceCitrusto compare traditional steady state (SS)A/Cicurves with RACiR curves. SS curves failed more often than RACiR curves. Overall parameter estimates were the same between SS and RACiR curves. When low stomatal conductance values were removed, triose-phosphate utilization (TPU) limitation estimates increased. Overall RACiR stomatal conductance values began and remained higher than SS values. Based on the comparable resulting parameter estimates, higher likelihood of success and reduced measurement time, we propose RACiR as a valuable tool to measureA/Ciresponses in low conductance species.
Genetic diversity analysis of Chinese plum (Prunus salicinaL.) based on whole-genome resequencing
Authors: Wei Xiao , Shen Fei , Zhang Qiuping , Liu Ning , Zhang Yuping , Xu Ming , Liu Shuo , Zhang Yujun , Ma Xiaoxue , Liu Weisheng
Published: August 2020

Chinese plum (Prunus salicinaL.), also known as Japanese plum, is gaining importance due to their extensive genetic diversity and nutritional attributes beneficial for human health. Single-nucleotide polymorphisms (SNPs) are the most abundant form of genomic polymorphisms and are widely used in population genetics research. Here, we construed high-density haplotype map by whole-genome resequencing of 67Prunusaccessions with a depth of ~20× to evaluate the genome-level diversity and population structure. The phylogenetic analysis, the principal component analysis, and the population structure profiling, indicated that the 67 plum accessions could be classified into four groups corresponding to their origin location, the southern cultivar group (SCG), the northern cultivar group (NCG), the foreign cultivar group (FG), and the mixed cultivar group (MG). Some cultivars from South China were clustered with the other three groups. The genetic diversity indices including the private allele number, the observed heterozygosity, the expected heterozygosity, and the nucleotide diversity of the SCG were higher than those of the NCG. The gene flow from the SCG to the FG was detected as well. We concluded that the origin center of Chinese plum was at the Yangtze River Basin in South China. This study provided genetic variation features and population structure of Chinese plum cultivars, laying a foundation for breeders to use diverse germplasm and allelic variants for improving Chinese plum varieties.
Natural selection and the advantage of recombination
Authors: Gerrish Philip J , Galeota-Sprung Benjamin , Cordero Fernando , Sniegowski Paul , Colato Alexandre , Hengartner Nicholas , Vejalla Varun , Chevallier Julien , Ycart Bernard
Published: August 2020

The ubiquity of sex and recombination in nature is widely viewed as enigmatic, despite an abundance of limited-scope explanations. Natural selection, it seems, should amplify well-matched combinations of genes. Recombination would break up these well-matched combinations and should thus be suppressed. We show, to the contrary, that on average: 1) natural selection amplifies poorly-matched gene combinations and 2) creates time-averaged negative associations in the process. Recombination breaks up these poorly-matched combinations, neutralizes the negative associations, and should thus be passively and universally favored.
Nutri rich cattle feed (NuCa feed) supplement with improved fiber content free of anti-nutritional factor Phytic acid
Authors: Makam Shivakiran , Kolla Harish Babu , Golla Daya Mouni , Payal Ananya , Somarowthu Meghanath
Published: August 2020

Most of the commercial ruminant feeds comprise Corn meal, Groundnut cake, Maize etc., which contain anti-nutritional factors called Phytates. They have high binding affinity to cationic minerals. This results in decrease in activity of the cattle by making minerals unavailable for absorption in the intestine. Many of the feed industries add Phytase enzyme that degrades the Phytic acid. Addition of Phytase enzyme is very complex method and increases the cost of the feed. If Phytase is not added, Phytic acid enters the ecosystem through the dung and due to microbial degradation, the Phytic acid gets converted into Phosphates. Phosphate abundance in water bodies leads to Eutrophication, which is a serious ecological issue. And also, in many parts of the country, post-harvest Paddy straw is burnt unused. This intentional stubble burning causes air pollution. We combined paddy straw and Azolla along with jaggery to prepare animal feed supplement. The feed pellets were evaluated for their nutritional composition and efficacy. The efficacy of the developed feed was evaluated by feeding it to milch cows and compared with regular feed for a period of 15 days. The Azolla-Hay feed improved the milk yield and also quality of the milk in comparison to the control group. This study revealed that Azolla in combination with paddy straw powder can be low-cost feed alternative especially during the lean period where the availability of feed is scarce.
Full-lengthde novoprotein structure determination from cryo-EM maps using deep learning
Authors: He Jiahua , Huang Sheng-You
Published: August 2020

Advances in microscopy instruments and image processing algorithms have led to an increasing number of cryo-EM maps. However, building accurate models for the EM maps at 3-5 Å resolution remains a challenging and time-consuming process. With the rapid growth of deposited EM maps, there is an increasing gap between the maps and reconstructed/modeled 3-dimensional (3D) structures. Therefore, automatic reconstruction of atomic-accuracy full-atom structures from EM maps is pressingly needed. Here, we present a semi-automaticde novostructure determination method using a deep learning-based framework, named as DeepMM, which builds atomic-accuracy all-atom models from cryo-EM maps at near-atomic resolution. In our method, the main-chain and Cα positions as well as their amino acid and secondary structure types are predicted in the EM map using Densely Connected Convolutional Networks. DeepMM was extensively validated on 40 simulated maps at 5 Å resolution and 30 experimental maps at 2.6-4.8 Å resolution as well as an EMDB-wide data set of 2931 experimental maps at 2.6-4.9 Å resolution, and compared with state-of-the-art algorithms including RosettaES, MAINMAST, and Phenix. Overall, our DeepMM algorithm obtained a significant improvement over existing methods in terms of both accuracy and coverage in building full-length protein structures on all test sets, demonstrating the efficacy and general applicability of DeepMM.

Availability

https://github.com/JiahuaHe/DeepMM

Supplementary information

Supplementary data are available.
Dissection of PRC1 and PRC2 recruitment in Arabidopsis connects EAR repressome to PRC2 anchoring
Authors: Baile Fernando , Merini Wiam , Hidalgo Inés , Calonje Myriam
Published: August 2020

PcG complexes ensure that every cell in an organism expresses the genes needed at a particular stage, time or condition. However, it is still not fully understood how PRC1 and PRC2 are recruited to target genes in plants. Recent results in Arabidopsis support that PRC2 recruitment is mediated by different TFs. However, it is unclear how all these TFs interact with PRC2 and whether they can also recruit PRC1 activity. Here, by using a system toin vivobind selected factors to a synthetic promoter lacking the complexity of PcG target promoters, we show that while VAL1 binding recapitulates PRC1 and PRC2 marking, the binding of other TFs only render PRC2 marking. Interestingly, all these TFs contain an EAR domain that acts as docking point for PRC2 and HDACs, connecting two different repressive mechanisms. Furthermore, we show that different TFs act synergistically in PRC2 anchoring to maintain a long-term repression.
Rest is Required to Learn an Appetitively-Reinforced Operant Task inDrosophila
Authors: Wiggin Timothy D. , Hsiao Yung-Yi , Liu Jeffrey B. , Huber Robert , Griffith Leslie C.
Published: August 2020

Maladaptive operant conditioning contributes to development of neuropsychiatric disorders. Candidate genes have been identified that contribute to this maladaptive plasticity, but the neural basis of operant conditioning in genetic model organisms remains poorly understood. The fruit flyDrosophila melanogasteris a versatile genetic model organism that readily forms operant associations with punishment stimuli. However, operant conditioning with a food reward has not been demonstrated in flies, limiting the types of neural circuits that can be studied. Here we present the first sucrose-reinforced operant conditioning paradigm for flies. In the paradigm, flies walk along a Y-shaped track with reward locations at the terminus of each hallway. When flies turn in the reinforced direction at the center of the track, sucrose is presented at the end of the hallway. Only flies that rest early in training learn the reward contingency normally. Flies rewarded independently of their behavior do not form a learned association but have the same amount of rest as trained flies, showing that rest is not driven by learning. Optogenetically-induced sleep does not promote learning, indicating that sleep itself is not sufficient for learning the operant task. We validated the sensitivity of this assay to detect the effect of genetic manipulations by testing the classic learning mutantdunce.Dunceflies are learning impaired in the Y-Track task, indicating a likely role for cAMP in the operant coincidence detector. This novel training paradigm will provide valuable insight into the molecular mechanisms of disease and the link between sleep and learning.
CyAnno: A semi-automated approach for cell type annotation of mass cytometry datasets
Authors: Kaushik Abhinav , Dunham Diane , He Ziyuan , Manohar Monali , Desai Manisha , Nadeau Kari C , Andorf Sandra
Published: August 2020

For immune system monitoring in large-scale studies at the single-cell resolution using CyTOF, (semi-)automated computational methods are applied for annotating live cells of mixed cell types. Here, we show that the live cell pool can be highly enriched with undefined heterogeneous cells, i.e. ‘ungated’ cells, and that current (semi-)automated approaches ignore their modeling resulting in misclassified annotations. Therefore, we introduce ‘CyAnno’, a novel semi-automated approach for deconvoluting the unlabeled cytometry dataset based on a machine learning framework utilizing manually gated training data that allows the integrative modeling of ‘gated’ cell types and the ‘ungated’ cells. By applying this framework on several CyTOF datasets, we demonstrated that including the ‘ungated’ cells can lead to a significant increase in the prediction accuracy of the ‘gated’ cell types. CyAnno can be used to identify even a single cell type, including rare cells, with higher efficacy than current state-of-the-art semi-automated approaches.
RNA-Seq analysis of genes affected by Cyclophilin A/DIAGEOTROPICA (DGT) in tomato root development
Authors: Ivanchenko Maria G. , Ozguc Olivia R. , Bollmann Stephanie R. , Fraser Valerie N. , Megraw Molly
Published: August 2020

Cyclophilin A/DIAGEOTROPICA (DGT) has been linked to auxin-regulated development in tomato and appears to affect multiple developmental pathways. Loss of DGT function results in a pleiotropic phenotype that is strongest in the roots, including shortened roots with no lateral branching. Here, we present an RNA-Seq dataset comparing the gene expression profiles of wildtype (‘Ailsa Craig’) anddgttissues from three spatially separated developmental stages of the tomato root tip, with three replicates for each tissue and genotype. We also identify differentially expressed genes, provide an initial comparison of genes affected in each genotype and tissue, and provide the pipeline used to analyze the data. Further analysis of this dataset can be used to gain insight into the effects of DGT on various root developmental pathways in tomato.
Deep learning and alignment of spatially-resolved whole transcriptomes of single cells in the mouse brain with Tangram
Authors: Biancalani Tommaso , Scalia Gabriele , Buffoni Lorenzo , Avasthi Raghav , Lu Ziqing , Sanger Aman , Tokcan Neriman , Vanderburg Charles R. , Segerstolpe Asa , Zhang Meng , Avraham-Davidi Inbal , Vickovic Sanja , Nitzan Mor , Ma Sai , Buenrostro Jason , Brown Nik Bear , Fanelli Duccio , Zhuang Xiaowei , Macosko Evan Z. , Regev Aviv
Published: August 2020

Charting a biological atlas of an organ, such as the brain, requires us to spatially-resolve whole transcriptomes of single cells, and to relate such cellular features to the histological and anatomical scales. Single-cell and single-nucleus RNA-Seq (sc/snRNA-seq) can map cells comprehensively5,6, but relating those to their histological and anatomical positions in the context of an organ’s common coordinate framework remains a major challenge and barrier to the construction of a cell atlas7–10. Conversely, Spatial Transcriptomics allows forin-situmeasurements11–13at the histological level, but at lower spatial resolution and with limited sensitivity. Targetedin situtechnologies1–3solve both issues, but are limited in gene throughput which impedes profiling of the entire transcriptome. Finally, as samples are collected for profiling, their registration to anatomical atlases often require human supervision, which is a major obstacle to build pipelines at scale. Here, we demonstrate spatial mapping of cells, histology, and anatomy in the somatomotor area and the visual area of the healthy adult mouse brain. We devise Tangram, a method that aligns snRNA-seq data to various forms of spatial data collected from the same brain region, including MERFISH1, STARmap2, smFISH3, and Spatial Transcriptomics4(Visium), as well as histological images and public atlases. Tangram can map any type of sc/snRNA-seq data, including multi-modal data such as SHARE-seq data5, which we used to reveal spatial patterns of chromatin accessibility. We equipped Tangram with a deep learning computer vision pipeline, which allows for automatic identification of anatomical annotations on histological images of mouse brain. By doing so, Tangram reconstructs a genome-wide, anatomically-integrated, spatial map of the visual and somatomotor area with ∼30,000 genes at single-cell resolution, revealing spatial gene expression and chromatin accessibility patterning beyond current limitation ofin-situtechnologies.
Glucose restriction drives spatial re-organization of mevalonate metabolism and liquid-crystalline lipid droplet biogenesis
Authors: Rogers Sean , Hariri Hanaa , Gui Long , Wood N. Ezgi , Speer Natalie , Nicastro Daniela , Henne W. Mike
Published: August 2020

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. AGR-induced HMGCR compartmentalization enhances mevalonate metabolism and sterol-ester biosynthesis that generates lipid droplets (LDs) with liquid-crystalline sub-architecture. Loss of NVJ-dependent HMGCR partitioning affects yeast growth, but can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting HMGCR inter-enzyme associations. We propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes, and reveal that AGR creates LDs with remarkable phase transition properties.

One Sentence Summary

Spatial compartmentalization of HMG-CoA Reductases at ER-lysosome contacts modulates mevalonate pathway flux
Microtubule-independent movement of the fission yeast nucleus
Authors: Ashraf Sanju , Kelly David A. , Sawin Kenneth E.
Published: August 2020

Movement of the cell nucleus typically involves the cytoskeleton and either polymerization-based pushing forces or motor-based pulling forces. In fission yeastSchizosaccharomyces pombe, nuclear movement and positioning are thought to depend on microtubule polymerization-based pushing forces. Here we describe a novel, microtubule-independent, form of nuclear movement in fission yeast. Microtubule-independent nuclear movement is directed towards growing cell tips, and it is strongest when the nucleus is close to a growing cell tip, and weakest when the nucleus is far from that tip. Microtubule-independent nuclear movement requires actin cables but does not depend on actin polymerization-based pushing or myosin V-based pulling forces. Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) Scs2 and Scs22, which are critical for endoplasmic reticulum-plasma membrane contact sites in fission yeast, are also required for microtubule-independent nuclear movement. We also find that in cells in which microtubule-based pushing forces are present, disruption of actin cables leads to increased fluctuations in interphase nuclear positioning and subsequent altered septation. Our results suggest two non-exclusive mechanisms for microtubule-independent nuclear movement, which may help illuminate aspects of nuclear positioning in other cells.
Imaging transmembrane dynamics of biomolecules at live cell plasma membranes using quenchers in extracellular environment
Authors: Hou Wenqing , Ma Dongfei , He Xiaolong , Han Weijing , Ma Jianbing , Xu Chunhua , Xie Ruipei , Fan Qi-hui , Ye Fangfu , Hu Shuxin , Lu Ying , Li Ming
Published: August 2020

It is a big challenge to measure position changes of biomolecules in the direction normal to the plasma membranes of living cells. We developed a one donor-multiple quenchers Fӧrster resonance energy transfer method by using non-fluorescent quenchers in the extracellular environment. It senses subnanometer position changes of a fluorophore-labeled biomolecule in the plasma membrane. The method was validated by monitoring flip-flops of individual lipid molecules incorporated in plasma membranes. We studies membrane perforation by a host defense peptide from the extracellular side and found that the pore-forming peptide is dynamic, switching among different insertion depths. The method is especially useful in studying interactions of membrane proteins with the inner surfaces of plasma membranes. Our method will find wide applications in systematic analysis of fundamental cellular processes at plasma membranes.
Estimating the impact of differential adherence on the comparative effectiveness of stool-based colorectal cancer screening using the CRC-AIM microsimulation model
Authors: Piscitello Andrew , Saoud Leila , Fendrick A. Mark , Borah Bijan J. , Lich Kristen Hassmiller , Matney Michael , Ozbay A. Burak , Parton Marcus , Limburg Paul J.
Published: August 2020

Background

Real-world adherence to colorectal cancer (CRC) screening strategies is imperfect. The CRC-AIM microsimulation model was used to estimate the impact of imperfect adherence on the relative benefits and burdens of guideline-endorsed, stool-based screening strategies.

Methods

Predicted outcomes of multi-target stool DNA (mt-sDNA), fecal immunochemical tests (FIT), and high-sensitivity guaiac-based fecal occult blood tests (HSgFOBT) were simulated for 40-year-olds free of diagnosed CRC. For robustness, imperfect adherence was incorporated in multiple ways and with extensive sensitivity analysis. Analysis 1 assumed adherence from 0%-100%, in 10% increments. Analysis 2 longitudinally applied real-world first-round differential adherence rates (base-case imperfect rates=40% annual FIT vs 34% annual HSgFOBT vs 70% triennial mt-sDNA). Analysis 3 randomly assigned individuals to receive 1, 5, or 9 lifetime (9=100% adherence) mt-sDNA tests and 1, 5, or 9 to 26 (26=100% adherence) FIT tests. Outcomes are reported per 1000 individuals compared with no screening.

Results

Each screening strategy decreased CRC incidence and mortality versus no screening. In individuals screened between ages 50-75 and adherence ranging from 10%-100%, the life-years gained (LYG) for triennial mt-sDNA ranged from 133.1-300.0, for annual FIT from 96.3-318.1, and for annual HSgFOBT from 99.8-320.6. At base-case imperfect adherence rates, mt-sDNA resulted in 19.1% more LYG versus FIT, 25.4% more LYG versus HSgFOBT, and generally had preferable efficiency ratios while offering the most LYG. Completion of at least 21 FIT tests is needed to reach approximately the same LYG achieved with 9 mt-sDNA tests.

Conclusions

Adherence assumptions affect the conclusions of CRC screening microsimulations that are used to inform CRC screening guidelines. LYG from FIT and HSgFOBT are more sensitive to changes in adherence assumptions than mt-sDNA because they require more tests be completed for equivalent benefit. At imperfect adherence rates, mt-sDNA provides more LYG than FIT or HSgFOBT at an acceptable tradeoff in screening burden.
The global landscape of SARS-CoV-2 genomes, variants, and haplotypes in 2019nCoVR
Authors: Song Shuhui , Ma Lina , Zou Dong , Tian Dongmei , Li Cuiping , Zhu Junwei , Chen Meili , Wang Anke , Ma Yingke , Li Mengwei , Teng Xufei , Cui Ying , Duan Guangya , Zhang Mochen , Jin Tong , Shi Chengmin , Du Zhenglin , Zhang Yadong , Liu Chuandong , Li Rujiao , Zeng Jingyao , Hao Lili , Jiang Shuai , Chen Hua , Han Dali , Xiao Jingfa , Zhang Zhang , Zhao Wenming , Xue Yongbiao , Bao Yiming
Published: August 2020

On 22 January 2020, the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), created the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access SARS-CoV-2 information resource. 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by our in-house automated pipeline. Of particular note, 2019nCoVR performs systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. It also generates visualization of the spatiotemporal change for each variant and yields historical viral haplotype network maps for the course of the outbreak from all complete and high-quality genomes. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on COVID-19 (Coronavirus Disease 2019), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB-NGDC, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with National Center for Biotechnology Information. Collectively, all SARS-CoV-2 genome sequences, variants, haplotypes and literature are updated daily to provide timely information, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible athttps://bigd.big.ac.cn/ncov/.
Formation and synaptic control of active transient working memory representations
Authors: Becker Sophia , Nold Andreas , Tchumatchenko Tatjana
Published: August 2020

Neural representations of working memory maintain information temporarily and make it accessible for processing. This is most feasible in active, spiking representations. State-of-the-art modeling frameworks, however, reproduce working memory representations that are either transient but non-active or active but non-transient. Here, we analyze a biologically motivated working memory model which shows that synaptic short-term plasticity and noise emerging from spiking networks can jointly produce a working memory representation that is both active and transient. We investigate the effect of a synaptic signaling mechanism whose dysregulation is related to schizophrenia and show how it controls transient working memory duration through presynaptic, astrocytic and postsynaptic elements. Our findings shed light on the computational capabilities of healthy working memory function and offer a possible mechanistic explanation for how molecular alterations observed in psychiatric diseases such as schizophrenia can lead to working memory impairments.
Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization
Authors: Chen Dongning , Smith Lucas R. , Khandekar Gauri , Patel Pavan , Yu Christopher K. , Zhang Kehan , Chen Christopher S. , Han Lin , Wells Rebecca G.
Published: August 2020

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.

Highlights

Small leucine rich proteoglycans (SLRPs) and large chondroitin sulfate (CS) proteoglycans (PGs) have distinct effects on collagen fibrous network behavior.

Unlike other matrix proteoglycans, versican promotes collagen fibrillogenesis in anin vitrospectrophotometric (turbidity) assay.

The versican core protein has a larger impact on collagen behavior in a fibrillogenesis assay than its glycosaminoglycan chains do.

Versican increases the diameter of collagen fibers and the porosity of collagen fibrous networks, unlike aggrecan and SLRPs.

The addition of versican to collagen does not alter fibroblast contractility but leads to enhanced cell-mediated collagen reorganization and contraction.
Representational Dynamics Preceding Conscious Access
Authors: Alilović Josipa , van Moorselaar Dirk , Graetz Marcel , van Gaal Simon , Slagter Heleen A.
Published: August 2020

Our senses are continuously bombarded with more information than our brain can process up to the level of awareness. The present study aimed to enhance understanding on how attentional selection shapes conscious access under conditions of rapidly changing input. Using an attention task, EEG, and multivariate decoding of individual target- and distractor-defining features, we specifically examined dynamic changes in the representation of targets and distractors as a function of conscious access and the task-relevance (target or distractor) of the preceding item in the RSVP stream. At the behavioral level, replicating previous work and suggestive of a flexible gating mechanism, we found a significant impairment in conscious access to targets (T2) that were preceded by a target (T1) followed by one or two distractors (i.e., the attentional blink), but striking facilitation of conscious access to targets shown directly after another target (i.e., lag-1 sparing and blink reversal). At the neural level, conscious access to T2 was associated with enhanced early- and late-stage T1 representations and enhanced late-stage D1 representations, and interestingly, could be predicted based on the pattern of EEG activation well before T1 was presented. Yet, across task conditions, we did not find convincing evidence for the notion that conscious access is affected by rapid top-down selection-related modulations of the strength of early sensory representations induced by the preceding visual event. These results cannot easily be explained by existing accounts of how attentional selection shapes conscious access under rapidly changing input conditions, and have important implications for theories of the attentional blink and consciousness more generally.
mRNA translation control by Dhx36 binding to 5’UTR G-quadruplex structures is essential for skeletal muscle stem cell regenerative functions
Authors: Chen Xiaona , Yuan Jie , Xue Guang , Sanz Silvia Campanario , Wang Di , Wang Wen , Mou Xi , Umar Mubarak Ishaq , Isern Joan , Zhao Yu , He Liangqiang , Li Yuying , Mann Christopher J. , Yu Xiaohua , Wang Lei , Perdiguero Eusebio , Chen Wei , Xue Yuanchao , Nagamine Yoshikuni , Kwok Chun-Kit , Sun Hao , Muñoz-Cánoves Pura , Wang Huating
Published: August 2020

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells, also called satellite cells (SCs), that are normally quiescent. When stimulated by damage, SCs activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that Dhx36, a helicase that unwinds RNA quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. We find that Dhx36 (initially named RHAU) is barely expressed at quiescence and is highly induced during SC activation and proliferation. Inducible deletion ofDhx36in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs revealed Dhx36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling showed that Dhx36 promotes mRNA translation via 5’UTR rG4 binding. Furthermore, we demonstrate that Dhx36 specifically regulates the translation ofGnai2mRNA by unwinding its 5’UTR rG4 structures and identify Gnai2 as a downstream effector of Dhx36 for SC expansion. Altogether our findings uncover Dhx36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration through binding and unwinding rG4 structures at 5’UTR of target mRNAs.
Environmental stability of SARS-CoV-2 on different types of surfaces under indoor and seasonal climate conditions
Authors: Kwon Taeyong , Gaudreault Natasha N. , Richt Juergen A.
Published: August 2020

We report the stability of SARS-CoV-2 on various surfaces under indoor, summer and spring/fall conditions. The virus was more stable under the spring/fall condition with virus half-lives ranging from 17.11 to 31.82 hours, whereas under indoor and summer conditions the virus half-lives were 3.5–11.33 and 2.54–5.58 hours, respectively.
Exploring the evolutionary history of kinetic stability in the alpha-lytic protease family
Authors: Nixon Charlotte F. , Lim Shion A. , Sailer Zachary R. , Zheludev Ivan N. , Gee Christine L. , Kelch Brian A. , Harms Michael J. , Marqusee Susan
Published: August 2020

In addition to encoding the final tertiary fold and stability, the primary sequence of a protein encodes the folding trajectory and kinetic barriers that determines the speed of folding. How these kinetic barriers are encoded by the sequence is not well understood. Here, we use evolutionary sequence variation in the alpha-lytic protease (αLP) protein family to probe the relationship between sequence and energy landscape. αLP has an unusual energy landscape: the native state of αLP is not the most thermodynamically favored conformation and, instead, it remains folded due to a large kinetic barrier preventing unfolding. In order to fold, αLP utilizes an N-terminal pro region of similar size to the protease itself that functions as a folding catalyst. Once folded, the pro region is removed, and the native state does not unfold on a biologically relevant timescale. Without the pro region, αLP folds on the order of millennia. A phylogenetic search uncovers αLP homologs with a wide range of pro-region sizes, including some with no pro region at all. In the resulting phylogenetic tree, these homologs cluster by pro-region size. Homologs naturally lacking pro regions are thermodynamically stable, fold much faster than αLP, yet retain the same fold as αLP. Key amino acids thought to contribute to αLP’s extreme kinetic stability are lost in these homologs, further supporting their role in kinetic stability. This study highlights how the entire energy landscape plays an important role in determining the evolutionary pressures on and changes to the protein sequence.
Strategic alignment and its impact on decision effectiveness: a comprehensive model
Authors: Ghonim Mohamed A. , Khashaba Nagi M. , Al-Najaar Hameda M. , Khashan Mohamed A.
Published: August 2020

Purpose

In recent decades, the concept of strategic alignment has been a center of concern for researchers and practitioners. This alignment is associated with the process of strategic planning to achieve high strategic performance and competitiveness. This study aims to investigate the impact of strategic alignment on decision effectiveness.

Design/methodology/approach

Primary data were collected from 383 employees of the Directorate of Health Affairs in the Dakahlia Governorate in Egypt, through a self-administered questionnaire. The PLS-SEM approach was used to analyze the collected data.

Findings

The results revealed that strategic alignment significantly and positively affects decision effectiveness and its dimensions, emphasizing the importance of considering all four dimensions of strategic alignment in an integrated model to achieve the greatest impact on the decision effectiveness.

Research limitations/implications

This study is applied to a developing country, so a comparative study between both developing and developed countries may be needed. Second, the study was restricted to the nonprofit organization, so further research may examine the profit organizations.

Originality/value

Despite the existence of several studies on the relationship between strategic alignment and decision effectiveness in developed countries, studies conducted in the developing countries are still few. This is one of the earliest studies that adopt the multidimensional approach of strategic alignment in the public sector in emerging economies, which could help directors understand the interdependencies and different roles of strategic alignment dimensions in a novel comprehensive model.
Education for sustainable development in Pakistani higher education institutions: an exploratory study of students’ and teachers’ perceptions
Authors: Saqib Zulkaif Ahmed , Zhang Qingyu , Ou Jin , Saqib Khubaib Ahmad , Majeed Salman , Razzaq Amar
Published: August 2020

Purpose

This study aims to determine the current state of implementation and effectiveness of education for sustainable development (ESD) in Pakistani higher education institutions (HEIs) using students’ and teachers’ perceptions of sustainability.

Design/methodology/approach

A survey on teachers and students was conducted in public and private universities in Punjab, Pakistan. Data from 1,915 students and 120 teachers were collected through semi-structured questionnaires implemented during face-to-face interviews. Students were asked to rank social, environmental and economic indicators of sustainability consciousness (SC) on a five-point Likert scale. Structural equation model and regression model are used to analyze the data. The perceptions of students and teachers were assessed from their knowledge of sustainability.

Findings

The occurrence of ESD in Pakistani HEIs is low and teachers have inadequate knowledge of sustainability. The holistic approach to ESD has a more pronounced effect on students’ SC as compared to the pluralistic approach to ESD. Also, there is a correlation between the students’ grades/class and the effectiveness of ESD. There is a need to pay more attention to implement ESD for undergraduate students in Pakistani HEIs.

Originality/value

The study stands out for using cross-sectional data from public and private universities of Pakistan. Furthermore, to the best of the authors’ knowledge, this is the first study in Pakistan which attempts to investigate the effectiveness of ESD in terms of students’ SC.