bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on Hemoglobin A1c
Authors: Westerman Kenneth E. , Miao Jenkai , Chasman Daniel I. , Florez Jose C. , Chen Han , Manning Alisa K. , Cole Joanne B.
Published: December 2020

Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards developing precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large sample size of the UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ∼340,000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (p < 5×10−8): two involved dietary patterns (meat pattern with rs147678157 and a fruit &vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534, and milk type [dairy vs. other] with 4:131148078_TAGAA_T). All of these were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked any genetic main effect that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) were identified as interacting with carbohydrate-containing food groups. Some of these interactions showed nominal replication in non-European ancestry UKB subsets, as well as association using alternative measures of glycemia (fasting glucose and follow-up HbA1c measurements). Our results highlight relevant GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.
Does COVID-19 Testing Create More Cases? An Empirical Evidence on the Importance of Mass Testing During a Pandemic
Authors: Ahmed Ali
Published: December 2020

The importance of testing and surveillance of an infectious disease cannot be underestimated. The testing is the first step to detect an infectious disease, and mass testing can slow or mitigate the spread of an infectious disease. Despite overwhelming evidence and the importance of testing discussed in the literature, there have been claims that “more COVID-19 testing creates more cases”. Therefore, there is a need to study whether massive testing is the reason for detecting more positive COVID-19 cases. In this research, we used a dataset from the U.S. Department of Health & Human Services and empirically showed that by increasing the COVID-19 testing in the U.S., the spread of the COVID-19 decreased significantly. Our results indicate a negative relationship between the number of positive cases and the number of tests performed in the past months. The large-scale testing may have helped identify positive and asymptomatic cases early in the course of illness, which enabled individuals to isolate themselves, thus reducing the chances of spreading the diseases and slowing the spread of the pandemic.
The DNA methylation Profile of Undifferentiated Arthritis Patients Anticipates their Subsequent Differentiation to Rheumatoid Arthritis
Authors: de la Calle-Fabregat Carlos , Niemantsverdriet Ellis , Cañete Juan D. , Li Tianlu , van der Helm-van Mil Annette H. M. , Rodríguez-Ubreva Javier , Ballestar Esteban
Published: December 2020

OBJECTIVE

Undifferentiated arthritis (UA) is the term used to cover all the cases of arthritis that do not fit a specific diagnosis. A significant percentage of UA patients progress to rheumatoid arthritis (RA), others to a different definite rheumatic disease, and the rest undergo spontaneous remission. Therapeutic intervention in patients with UA can delay or halt disease progression and its long-term consequences. It is therefore of inherent interest to identify those UA patients with a high probability of progressing to RA who would benefit from early appropriate therapy. We hypothesised that alterations in the DNA methylation profiles of immune cells may inform on the genetically- or environmentally-determined status of patients and potentially discriminate between disease subtypes.

METHODS

In this study, we performed DNA methylation profiling of a UA patient cohort, in which progression into RA occurs for a significant proportion of the patients.

RESULTS

We find differential DNA methylation in UA patients compared to healthy controls. Most importantly, our analysis identifies a DNA methylation signature characteristic of those UA cases that differentiate to RA. We demonstrate that the methylome of peripheral mononuclear cells can be used to anticipate the evolution of UA to RA, and that this methylome is associated with a number of inflammatory pathways and transcription factors. Finally, we design a machine-learning strategy for DNA methylation-based classification that predicts the differentiation of UA patients towards RA.

CONCLUSION

DNA methylation profiling provides a good predictor of UA-to-RA progression to anticipate targeted treatments and improve clinical management.
Development of an electronic frailty index for predicting mortality in patients undergoing transcatheter aortic valve replacement using machine learning
Authors: Chen Yiyi , Zhou Jiandong , Lee Sharen , Liu Tong , Hothi Sandeep S , Wong Ian Chi Kei , Zhang Qingpeng , Tse Gary , Wang Yan
Published: December 2020

Background

Electronic frailty indices can be useful surrogate measures of frailty. We assessed the role of machine learning to develop an electronic frailty index, incorporating demographics, baseline comorbidities, healthcare utilization characteristics, electrocardiographic measurements, and laboratory examinations, and used this to predict all-cause mortality in patients undergoing transaortic valvular replacement (TAVR).

Methods

This was a multi-centre retrospective observational study of patients undergoing for TAVR. Significant univariate and multivariate predictors of all-cause mortality were identified using Cox regression. Importance ranking of variables was obtained with a gradient boosting survival tree (GBST) model, a supervised sequential ensemble learning algorithm, and used to build the frailty models. Comparisons were made between multivariate Cox, GBST and random survival forest models.

Results

A total of 450 patients (49% females; median age at procedure 82.3 (interquartile range, IQR 79.0-86.0)) were included, of which 22 died during follow-up. A machine learning survival analysis model found that the most important predictors of mortality were APTT, followed by INR, severity of tricuspid regurgitation, cumulative hospital stays, cumulative number of readmissions, creatinine, urate, ALP, and QTc/QT intervals. GBST significantly outperformed random survival forests and multivariate Cox regression (precision: 0.91, recall: 0.89, AUC: 0.93, C-index: 0.96, and KS-index: 0.50) for mortality prediction.

Conclusions

An electronic frailty index incorporating multi-domain data can efficiently predict all-cause mortality in patients undergoing TAVR. A machine learning survival learning model significantly improves the risk prediction performance of the frailty models.
Prediction of Sex and Age from Macular Optical Coherence Tomography Images and Feature Analysis Using Deep Learning
Authors: Chueh Kuan-Ming , Hsieh Yi-Ting , Chen Homer H. , Ma I-Hsin , Huang Sheng-Lung
Published: December 2020

The prevalence of certain macular diseases differs between male and female. However, the actual difference in macular structure between male and female was barely understood. Previous studies reported the mean retinal thickness of macula was thinner for female, but here it was observed that the difference is not statistically large enough for sex distinction. Similarly, the age-related non-pathological change of macular structure was also hardly known. It has been found that the thickness of choroid decreases with age. In this study, deep learning was applied to distinguish sex and age from macular optical coherence tomography (OCT) images of 3134 persons and achieved a sex prediction accuracy of 85.6 ± 2.1% and an age prediction error of 5.78 ± 0.29 years. A thorough analysis of the prediction accuracy and the Grad-CAM showed that 1) the foveal contour leads to a better sex distinction than the macular thickness, 2) B-scan macular OCT images contain more sex-related information than en face fundus images, and 3) the age-related characteristics of the macula are on the whole layers of the retina, not just the choroid. These novel findings reported in this study are useful to ophthalmologists for further investigation in the pathogenesis of sex and age-related macular structural diseases.
Characteristic spatial scales of SARS-CoV-2 pandemics: lessons from mass rapid antigen testing in Slovakia
Authors: Boďová Katarína , Kollár Richard
Published: December 2020

Mass antigen testing in Slovakia conducted in October and November 2020 is a source of important data. We perform its statistical analysis and study epidemic geographical patterns. We observe exponentially distributed test positivity and exponential trends in its geographical distribution, and its approximately 10 km spatial characteristic correlation length. A small correlation between positivity in two consecutive testing rounds appeared on the municipalities level but it significantly increased on the counties level. Recent 7-day PCR tests incidence per capita served as a good proxy for antigen test positivity. Positivity of non-residents was higher than of residents when mass testing was offered only in municipalities with the highest positivity in previous rounds. Reduction in positivity in repeated testing increased with the positivity in the earlier round. Our results contribute to better understanding of pandemic data, and aid an assessment of mass testing efficiency, and planning of mitigation measures.
Global approaches to postmortem genetic testing after sudden cardiac death in the young: A survey among healthcare professionals
Authors: van den Heuvel Lieke M. , Do Judy , Yeates Laura , MacLeod Heather , James Cynthia A. , Duflou Johan , Skinner Jonathan R. , Semsarian Christopher , van Tintelen J. Peter , Ingles Jodie
Published: December 2020

Purpose

Thorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. We explore practices of postmortem genetic testing and attitudes of healthcare professionals worldwide.

Methods

A survey was administered among healthcare professionals recruited through professional associations, social media and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in healthcare professionals’ ability, and attitudes towards postmortem genetic testing practices.

Results

There were 112 respondents, with 93% from North America, Europe and Australia and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case-by-case and not standardised. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48%, p=0.002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members; financial resources varied widely. Half believed practices in their countries perpetuated health inequalities.

Conclusion

Postmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, guided by well-resourced multidisciplinary teams, is critical in ascertaining a cause of death in many cases.
Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis
Authors: Xu Yanhong , Peng Shiqiao , Cao Xinyu , Qian Shengnan , Shen Shuang , Luo Juntao , Zhang Xiaoying , Sun Hongbin , Shen Wei L. , Jia Weiping , Ye Jianping
Published: December 2020

Background and purpose

Sodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. However, the toxic effect of SB remains largely unknown. This issue is addressed in current study.

Experimental approach

SB (0.3 – 2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brain hypothalamus were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect.

Key results

The temperature was reduced by SB (1.2 −2.5 g/kg) in a dose-dependent manner in mice for 2-4 hr. In the brain, the effect was associated with SB elevation and neurotransmitter (Glutamate and GABA) reduction. The mitochondria exhibited a transient volume expansion and crista loss in the hypothalamic neurons. ADP/ATP ratio was increased with accumulation of intermediate metabolites in the glycolysis, TCA cycle and pentose phosphate pathways. The mitochondrial protein, adenine nucleotide transporter (ANT), was activated for proton transportation leading to a transient potential collapse by proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. The temperature drop was attenuated by i.p. injection of norepinephrine. The HDAC inhibitors, such as SAHA and pyruvate, did not exhibit the same effect.

Conclusion and implications

Super-dosed SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial reprogramming in the brain. The mechanism was quick activation of ANT proteins for the proton leak in mitochondria.
Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death
Authors: Szekely Laszlo , Bozoky Bela , Bendek Matyas , Ostad Masih , Lavignasse Pablo , Haag Lars , Wu Jieyu , Jing Xu , Gupta Soham , Saccon Elisa , Sönnerborg Anders , Cao Yihai , Björnstedt Mikael , Szakos Attila
Published: December 2020

Most Covid-19 victims are old and die from unrelated causes. Here we presenttwelve complete autopsies, including two rapid autopsies of young patients where the cause of death was Covid-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163+ macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothel, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced Covid-19 ARDS.
Time series transcriptomics reveals aBBX32-directed control of dynamic acclimation to high light in matureArabidopsisleaves
Authors: Alvarez-Fernandez Ruben , Penfold Christopher A. , Galvez-Valdivieso Gregorio , Exposito-Rodriguez Marino , Stallard Ellie J. , Bowden Laura , Moore Jonathan D. , Mead Andrew , Davey Phillip A. , Matthews Jack S.A. , Beynon Jim , Buchanan-Wollaston Vicky , Wild David L. , Lawson Tracy , Bechtold Ulrike , Denby Katherine , Mullineaux Philip M.
Published: December 2020

The photosynthetic capacity of mature leaves increases after several days’ exposure to constant or intermittent episodes of high light (HL) and is manifested primarily as changes in chloroplast physiology. This is termed dynamic acclimation but how it is initiated and controlled is unknown. From fully expanded Arabidopsis leaves, we determined HL-dependent changes in transcript abundance of 3844 genes in a 0-6h time-series transcriptomics experiment. It was hypothesised that among such genes were those that contribute to the initiation of dynamic acclimation. By focussing on HL differentially expressed transcription (co-)factor (TF) genes and applying dynamic statistical modelling to the temporal transcriptomics data, a gene regulatory network (GRN) of 47 predominantly photoreceptor-regulated (co)-TF genes was inferred. The most connected gene in this network wasB-BOX DOMAIN CONTAINING PROTEIN32(BBX32). Plants over-expressingBBX32were strongly impaired in dynamic acclimation and displayed perturbed expression of genes involved in its initiation. These observations led to demonstrating that as well as regulation of dynamic acclimation byBBX32,CRYPTOCHROME1, LONG HYPOCOTYL5,CONSTITUTIVELY PHOTOMORPHOGENIC1andSUPPRESSOR OF PHYA-105are also important regulators of this process. Additionally, theBBX32-centric GRN provides a view of the transcriptional control of dynamic acclimation distinct from other photoreceptor-regulated processes, such as seedling photomorphogenesis.
Human gutFaecalibacterium prausnitziideploy a highly efficient conserved system to cross-feed on β-mannan-derived oligosaccharides
Authors: Lindstad Lars J. , Lo Galiana , Leivers Shaun , Lu Zijia , Michalak Leszek , Pereira Gabriel V. , Røhr Åsmund K. , Martens Eric C. , McKee Lauren S. , Duncan Sylvia H. , Westereng Bjørge , Pope Phillip B. , La Rosa Sabina Leanti
Published: December 2020

β-Mannans are hemicelluloses that are abundant in modern diets as components in seed endosperms and common additives in processed food. Currently, the collective understanding of β-mannan saccharification in the human colon is limited to a few keystone species, which presumably liberate low-molecular-weight mannooligosaccharide fragments that become directly available to the surrounding microbial community. Here we show that a dominant butyrate-producer in the human gut,Faecalibacterium prausnitzii, is able to acquire and degrade various β-mannooligosaccharides (β-MOS), which are derived by the primary mannanolytic activity of neighboring gut microbiota. Detailed biochemical analyses of selected protein components from their two β-mannooligosaccharides (β-MOS) utilization loci (FpMULs) supported a concerted model whereby the imported β-MOS are stepwise disassembled intracellularly by highly adapted enzymes. Coculturing experiments ofF. prausnitziiwith the primary degraderBacteroides ovatuson polymeric β-mannan resulted in syntrophic growth and production of butyrate, thus confirming the high efficiency of theFpMULs’ uptake system. Genomic comparison with humanF. prausnitziistrains and analyses of 2441 public human metagenomes revealed thatFpMULs are highly conserved and distributed worldwide. Together, our results provide a significant advance in the knowledge of β-mannans metabolism and the degree to which its degradation is mediated by cross-feeding interactions between prominent beneficial microbes in the human gut.

Importance

Commensal butyrate-producing bacteria belonging to the Firmicutes phylum are abundant in the human gut and are crucial for maintaining health. Currently, insight is lacking into how they target otherwise indigestible dietary fibers and into the trophic interactions they establish with other glycan degraders in the competitive gut environment. By combining cultivation, genomic and detailed biochemical analyses this work reveals the mechanism enablingF. prausnitzii, as a model clostridial cluster IV Firmicute, to cross-feed and access β-mannan-derived oligosaccharides released in the gut ecosystem by the action of primary degraders. A comprehensive survey of human gut metagenomes shows thatFpMULs are ubiquitous in human populations globally, highlighting the importance of microbial metabolism of β-mannans/β-MOS as a common dietary component. Our findings provide a mechanistic understanding of the β-MOS utilization capability byF. prausnitziithat may be exploited to select dietary formulations specifically boosting this beneficial symbiont, thus butyrate production, in the gut.
The N501Y and K417N mutations in the spike protein of SARS-CoV-2 alter the interactions with both hACE2 and human derived antibody: A Free energy of perturbation study
Authors: Fratev Filip
Published: December 2020

The N501Y and K417N mutations in spike protein of SARS-CoV-2 and their combination arise questions but the data about their mechanism of action at molecular level is limited. Here, we present Free energy perturbation (FEP) calculations for the interactions of the spike S1 receptor binding domain (RBD) with both the ACE2 receptor and an antibody derived from COVID-19 patients. Our results shown that the S1 RBD-ACE2 interactions were significantly increased whereas those with the STE90-C11 antibody dramatically decreased; about over 100 times. The K417N mutation had much more pronounced effect and in a combination with N501Y fully abolished the antibody effect. This may explain the observed in UK and South Africa more spread of the virus but also raise an important question about the possible human immune response and the success of already available vaccines.
Genetic epidemiology of variants associated with immune escape from global SARS-CoV-2 genomes
Authors: Jolly Bani , Rophina Mercy , Shamnath Afra , Imran Mohamed , Bhoyar Rahul C. , Divakar Mohit Kumar , Rani Pallavali Roja , Ranjan Gyan , Sehgal Paras , Chandrasekhar Pulala , Afsar S. , Lakshmi J. Vijaya , Surekha A. , Sivasubbu Sridhar , Scaria Vinod
Published: December 2020

Many antibody and immune escape variants in SARS-CoV-2 are now documented in literature. The availability of SARS-CoV-2 genome sequences enabled us to investigate the occurrence and genetic epidemiology of the variants globally. Our analysis suggests that a number of genetic variants associated with immune escape have emerged in global populations.
The distribution of waiting distances in ancestral recombination graphs and its applications
Authors: Deng Yun , Song Yun S. , Nielsen Rasmus
Published: December 2020

Theancestral recombination graph(ARG) contains the full genealogical information of the sample, and many population genetic inference problems can be solved using inferred or sampled ARGs. In particular, the waiting distance between tree changes along the genome can be used to make inference about the distribution and evolution of recombination rates. To this end, we here derive an analytic expression for the distribution of waiting distances between tree changes under the sequentially Markovian coalescent model and obtain an accurate approximation to the distribution of waiting distances for topology changes. We use these results to show that some of the recently proposed methods for inferring sequences of trees along the genome provide strongly biased distributions of waiting distances. In addition, we provide a correction to an undercounting problem facing all available ARG inference methods, thereby facilitating the use of ARG inference methods to estimate temporal changes in the recombination rate.
Drs2 regulates TRAPPIII in Atg9 transport: exposing the interplay of P4-ATPases and Multisubunit Tethering Complexes
Authors: Pazos Irene , Puig-Tintó Marta , Cordero Jorge , Jiménez-Menéndez Nereida , Abella Marc , Duran Ana G. , Adachi-Fernández Emi , Belmonte-Mateos Carla , Sabido-Bozo Susana , Hernández Altair C. , Tosi Sébastien , Nezu Akiko , Colombelli Julien , Graham Todd R. , Yoshimori Tamotsu , Muñiz Manuel , Hamasaki Maho , Gallego Oriol
Published: December 2020

Multisubunit Tethering Complexes (MTCs) are a set of conserved protein complexes that tether transported vesicles at the acceptor membrane. Interactions with other components of the trafficking machinery regulate MTCs through mechanisms that are just partially understood. Here we systematically investigate the interactome that regulates the function of MTCs. We found that P4-ATPases, a family of lipid transporters involved in the biogenesis of vesicles, interact with MTCs that participate in the anterograde and retrograde transport at the Golgi, such as TRAPPIII. We used the lipid flippase Drs2 as a model to investigate the mechanism and biological relevance of such interplay during the transport of Atg9 vesicles. Binding to the N-terminal tail of Drs2 stabilizes TRAPPIII on membrane compartments loaded with Atg9 and it is required for the delivery of Atg9 during selective autophagy, a role that is independent of previously reported functions of the P4-ATPase. This mechanism relies on the I(S/R)TTK motif nested in the N-terminal tail cavity of Drs2, a motif that is required for the interaction with MTCs.
Lipooligosaccharide, Vag8, and pertussis toxin ofBordetella pertussiscooperatively cause coughing in mice
Authors: Hiramatsu Yukihiro , Suzuki Koichiro , Nishida Takashi , Onoda Naoki , Satoh Takashi , Akira Shizuo , Ikawa Masahito , Ikeda Hiroko , Kamei Junzo , Derouiche Sandra , Tominaga Makoto , Horiguchi Yasuhiko
Published: December 2020

Whooping cough, a contagious respiratory disease caused byBordetella pertussis, is characterized by paroxysmal coughing; however, the mechanism has not been studied because of the lack of versatile animal models that reproduce the cough. Here, we present a mouse model that reproduces coughing after intranasal inoculation with the bacteria or its components and demonstrate that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause coughing. LOS-induced bradykinin sensitized a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. Vag8 further increased bradykinin levels by inhibiting the C1 esterase inhibitor, the major downregulator of the contact system, which generates bradykinin. PTx inhibits intrinsic negative regulation systems for TRPV1 through inactivation of GiGTPases. Our findings provide a basis for answering long-standing questions on the pathophysiology of the pertussis cough.
MEMS directed evolution of two cytochrome P450 enzymes revealing distinct active-sites for convergent functions
Authors: Ma Li , Li Fengwei , Zhang Xingwang , Chen Hui , Huang Qian , Liu Xiaohui , Sun Tianjian , Fang Bo , Liu Kun , Chen Jingfei , Yao Lishan , Wu Dalei , Zhang Wei , Du Lei , Li Shengying
Published: December 2020

Directed evolution (DE) inspired by natural evolution (NE) has been achieving tremendous successes in protein/enzyme engineering. However, the conventional ‘one-protein-for-one-task’ DE cannot match the ‘multi-proteins-for-multi-tasks’ NE in terms of screening throughput and efficiency, thus often failing to meet the fast-growing demands for biocatalysts with desired properties. In this study, we design a novel ‘multi-enzyme-for-multi-substrate’ (MEMS) DE model and establish the proof-of-concept by running a NE-mimicking and higher-throughput screening on the basis of ‘two-P450s-against-seven-substrates’ (2P×7S) in one pot. With the significantly improved throughput and hit-rate, we witness a series of convergent evolution events of the two archetypal cytochrome P450 enzymes (P450 BM3 and P450cam) in laboratory. Further structural analysis of the two functionally convergent P450 variants provide important insights into how distinct active-sites can reach a common catalytic goal.
ATP-release drives inflammation with lysophosphatidylcholine
Authors: Ismaeel Sana , Qadri Ayub
Published: December 2020

Lysophosphatidylcholine (LPC), a dominant lipid component of oxidized low-density lipoprotein, plays a major role in inflammation associated with atherosclerosis and neurodegenerative disorders. It activates inflammatory responses from macrophages, neuronal cells and endothelial cells. However, the exact mechanism by which LPC promotes inflammation remains incompletely understood. Here, we show that the production of inflammatory cytokines and cytotoxicity with LPC are both critically dependent on its ability to bring about release of ATP from cells. The induction of caspase-1-mediated IL-1β-release with LPC from TLR-primed macrophages and neuronal cells is reduced in presence of ATP-hydrolyzing enzyme, apyrase and the inhibitors of purinergic signaling. ATP released from LPC-treated cells also promotes an IL-12p70hi, low phagocytic and poorly co-stimulatory phenotype in macrophages in a caspase-1 – independent manner. Treatment with apyrase reduces production of inflammatory cytokines with LPCin vivo. These findings reveal a previously unappreciated pathway for generation of inflammatory responses with LPC, and these have significant implications for therapeutic intervention in chronic inflammatory disorders promoted by this lipid.
Novel multicellular prokaryote discovered next to an underground stream
Authors: Mizuno Kouhei , Maree Mais , Nagamura Toshihiko , Koga Akihiro , Hirayama Satoru , Furukawa Soichi , Tanaka Kenji , Morikawa Kazuya
Published: December 2020

The emergence of multicellularity is a key event in the evolution of life and is an attractive challenge among researchers, including those investigating the artificial design of cellular behavior1. Multicellular organisms are widely distributed on Earth, and retracing the specific conditions conducive for the initial transition from unicellularity to multicellularity is difficult. However, by examining organisms that inhabit unique (e.g., isolated) environmental niches, we may be able to get a glimpse into primitive multicellularity in the context of a given environment. Here we report the discovery of a new bacterium that displayed multicellular-like characteristics and behavior. The bacterium, which was isolated adjacent to an underground stream in a limestone cave, is to be namedJeongeupia sacculisp. nov. HS-3. On a solid surface, HS-3 self-organizes its filamentous cells to form an appearance similar to the nematic phase of a liquid crystal2. Mature colonies produce and accommodate clusters of coccobacillus progeny, and release them upon contact with water. HS-3 demonstrated novel, spatiotemporally regulated multicellularity that can resolve the so-called ‘competition-dispersal trade-off’ problem3. This study illustrates a hypothetical missing link on the emergence of multicellularity.
Inborn errors E778K and G908R in NOD2 gene increase risk of nontuberculous mycobacterial infection: a computational study
Authors: Alipoor Shamila D. , Mirsaeidi Mehdi
Published: December 2020

Background

The innate immune system has a critical role in the early detection of pathogens, mainly by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic sensor for recognition of invading molecules and danger signals inside the cells. NOD2’s functions are critical; polymorphisms of its encoding gene are associated with several immune pathological conditions. We recently reported that missense E778K and G908R variants of NOD2 gene are associated with recurrent pulmonary nontuberculous mycobacterial infections

Methods

This is anin-silicoanalysis of NOD2 gene using SNPs functionality analyses, post-translational modification site prediction and network analysis.

Results

Our analysis revealed that these damaging mutations affect the structural properties and function and ligand binding in the mutant receptor.

Conclusion

The consequence of these mutations may also impress downstream processing and receptor crosstalk with other immune molecules and therefore increase susceptibility to infectious disease.
A cancer cell-intrinsic GOT2-PPARδ axis suppresses antitumor immunity
Authors: Sanford-Crane Hannah , Abrego Jaime , Oon Chet , Xiao Xu , Nagarajan Shanthi , Bhattacharyya Sohinee , Tontonoz Peter , Sherman Mara H.
Published: December 2020

Despite significant recent advances in precision medicine1,2, pancreatic ductal adenocarcinoma (PDAC) remains near-uniformly lethal. While the most frequent genomic alterations in PDAC are not presently druggable3and conventional therapies are often ineffective in this disease4, immune-modulatory therapies hold promise to meaningfully improve outcomes for PDAC patients. Development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment, including frequent exclusion of antineoplastic T cells and abundance of immune-suppressive myeloid cells5–9. Here we show that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate-aspartate shuttle10–13and promotes the transcriptional activity of nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ), facilitated by direct fatty acid binding. While GOT2 in PDAC cells is dispensable for cancer cell proliferationin vivo, GOT2 loss results in T cell-dependent suppression of tumor growth, and genetic or pharmacologic activation of PPARδ restores PDAC progression in the GOT2-null context. This cancer cell-intrinsic GOT2-PPARδ axis promotes spatial restriction of both CD4+and CD8+T cells from the tumor microenvironment, and fosters the immune-suppressive phenotype of tumor-infiltrating myeloid cells. Our results demonstrate a non-canonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response.
Distinguish virulent and temperate phage-derived sequences in metavirome data with a deep learning approach
Authors: Wu Shufang , Fang Zhencheng , Tan Jie , Li Mo , Wang Chunhui , Guo Qian , Xu Congmin , Jiang Xiaoqing , Zhu Huaiqiu
Published: December 2020

Background

Prokaryotic viruses referred to as phages can be divided into virulent and temperate phages. Distinguishing virulent and temperate phage-derived sequences in metavirome data is important for their role in interactions with bacterial hosts and regulations of microbial communities. However there is no experimental or computational approach to classify sequences of these two in culture-independent metavirome effectively, we present a new computational method DeePhage, which can directly and rapidly judge each read or contig as a virulent or temperate phage-derived fragment.

Findings

DeePhage utilizes a “one-hot” encoding form to have an overall and detailed representation of DNA sequences. Sequence signatures are detected via a deep learning algorithm, namely a convolutional neural network to extract valuable local features. DeePhage makes better performance than the most related method PHACTS. The accuracy of DeePhage on five-fold validation reach as high as 88%, nearly 30% higher than PHACTS. Evaluation on real metavirome shows DeePhage annotated 54.4% of reliable contigs while PHACTS annotated 44.5%. While running on the same machine, DeePhage reduces computational time than PHACTS by 810 times. Besides, we proposed a new strategy to explore phage transformations in the microbial community by direct detection of the temperate viral fragments from metagenome and metavirome. The detectable transformation of temperate phages provided us a new insight into the potential treatment for human disease.

Conclusions

DeePhage is the first tool that can rapidly and efficiently identify two kinds of phage fragments especially for metagenomics analysis with satisfactory performance. DeePhage is freely available viahttp://cqb.pku.edu.cn/ZhuLab/DeePhageorhttps://github.com/shufangwu/DeePhage.
Interactions between discrete events and continuous dynamics in the regulation of scallops valve opening: insights from a biophysical model
Authors: Guarini Jean-Marc , Coston-Guarini Jennifer , Comeau Luc A.
Published: December 2020

This study constitutes a first attempt to quantify processes that govern valve gape dynamics in bivalves. We elected to focus on the scallop,Pecten maximus, not only because of its economic importance but also because it has a complex behaviour and high sensitivity to stress, which can be inferred from valve gape dynamics. The adductor muscle is the primary organ implicated in valve movements. Scallops, as other bivalves, move their valves sharply to ensure basic physiological functions or to respond to stressing conditions; these sharp events can be perceived as discrete events within a continuous dynamic. A biophysical model, originally designed for human muscles, was first selected to simulate the adductor muscle contraction, countering the passive valve opening by the umbo ligament. However, to maintain the possibility of rapid valve movements, described as typical of bivalves behaviour, it was necessary to modify the model and propose an original formulation. The resulting hybrid modelling simulates how valve opening tends to converge continuously toward a stable steady-state angle, while being interspersed with discrete, sharp closing events, deviating values from this equilibrium. The parameters of the new model were estimated by optimization using Hall-Effect Sensor valvometry data recorded in controlled conditions. Equilibrium of the continuous regime (when fiber activation equals deactivation) was estimated for a gape angle close toca. 15 degrees, which isca. 45% of the maximum opening angle, hence implying a constant effort produced by the adductor muscle. The distribution of time intervals between two successive discrete events did not differ significantly from a random process, but the peak amplitudes deviated from randomness, suggesting they are regulated physiologically. These results suggest that discrete events interact with continuous dynamic regimes, regulating valve opening to minimize physiological efforts and conserve energy. However, because the overall physiological state of the scallop organism conditions the activity of the adductor muscle, a complete understanding of the physiology of bivalves will require linking a more comprehensive model of valve gape dynamics with experimental observations of physiological energy consumption under different conditions.
Negative feedback by NUR77/Nr4a1restrains B cell clonal dominance during early T-dependent immune responses
Authors: Brooks Jeremy F , Tan Corey , Mueller James L. , Hibiya Kenta , Hiwa Ryosuke , Zikherman Julie
Published: December 2020

B cell clones compete for entry into and dominance within germinal centers (GC), where the highest affinity BCRs are selected. However, diverse and low affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesized that a negative feedback loop may operate within B cells to preferentially restrain high affinity clones from monopolizing the early GC niche. Here we report a role for the nuclear receptor NUR77/Nr4a1in this process. We previously showed that NUR77 expression scales with antigen stimulation and restrains B cell expansion when T cell help is limiting. Here we show that, although NUR77 is dispensable for regulating GC size when GC are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. Moreover, this is independent of B cell precursor frequency and reflects, at least in part, a B cell-intrinsic role for NUR77. We propose that this is important to preserve early B cell clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.
Development of novelin vitrohuman alveolar epithelial cell models to study distal lung biology and disease
Authors: Tran Evelyn , Shi Tuo , Li Xiuwen , Chowdhury Adnan Y. , Jiang Du , Liu Yixin , Wang Hongjun , Yan Chunli , Wallace William D. , Lu Rong , Ryan Amy L. , Marconett Crystal N. , Zhou Beiyun , Borok Zea , Offringa Ite A.
Published: December 2020

Many acute and chronic lung diseases affect the distal lung alveoli. Although airway-derived human cell lines exist, alveolar epithelial cell (AEC)-derived lines are needed to better model these diseases. We have generated and characterized novel immortalized cell lines derived from human AECs. They grow as epithelial monolayers expressing lung progenitor markers SOX9 and SOX2, with little to no expression of mature AEC markers. Co-cultured in 3-dimensions (3D) with lung fibroblasts, the cells form NKX2-1+organoids expressing mature AEC markers AQP5 and GPRC5A. Single-cell RNA sequencing of an AEC line in 2Dversus3D revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling, consistent with organoid formation. Activating WNT and FGF pathways resulted in larger organoids. Our approach appears to yield lung progenitor lines that retain a genetic and structural memory of their alveolar cell lineage despite long-term expansion and whose differentiation may be modulated under various 3D conditions. These cell lines provide a valuable new system to model the distal lungin vitro.
Branching of sporogenic aerial hyphae insflAandsflBmutants ofStreptomyces coelicolorcorrelates to ectopic localization of DivIVA and FtsZ in time and space
Authors: Zhang Le , Willemse Joost , Yagüe Paula , de Waal Ellen , Claessen Dennis , van Wezel Gilles P.
Published: December 2020

Bacterial cytokinesis starts with the polymerization of the tubulin-like FtsZ, which forms the cell division scaffold. SepF aligns FtsZ polymers and also acts as a membrane anchor for the Z-ring. While in most bacteria cell division takes place at midcell, during sporulation ofStreptomycesmany septa are laid down almost simultaneously in multinucleoid aerial hyphae. The genomes of streptomycetes encode two additional SepF paralogs, SflA and SflB, which can interact with SepF. Here we show that the sporogenic aerial hyphae ofsflAandsflBmutants ofStreptomyces coelicolorfrequently branch, a phenomenon never seen in the wild-type strain. The branching coincided with ectopic localization of DivIVA along the lateral wall of sporulating aerial hyphae. Constitutive expression of SflA and SflB largely inhibited hyphal growth, further correlating SflAB activity to that of DivIVA. SflAB localized in foci prior to and after the time of sporulation-specific cell division, while SepF co-localized with active septum synthesis. Foci of FtsZ and DivIVA frequently persisted between adjacent spores in spore chains ofsflAandsflBmutants, at sites occupied by SflAB in wild-type cells. This may be caused by the persistance of SepF multimers in the absence of SflAB. Taken together, our data show that SflA and SflB play an important role in the control of growth and cell division duringStreptomycesdevelopment.
Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2
Authors: Neerukonda Sabari Nath , Vassell Russell , Herrup Rachel , Liu Shufeng , Wang Tony , Takeda Kazuyo , Yang Ye , Lin Tsai-Lien , Wang Wei , Weiss Carol D.
Published: December 2020

Pseudoviruses are useful surrogates for highly pathogenic viruses because of their safety, genetic stability, and scalability for screening assays. Many different pseudovirus platforms exist, each with different advantages and limitations. Here we report our efforts to optimize and characterize an HIV-based lentiviral pseudovirus assay for screening neutralizing antibodies for SARS-CoV-2 using a stable 293T cell line expressing human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We assessed different target cells, established conditions that generate readouts over at least a two-log range, and confirmed consistent neutralization titers over a range of pseudovirus input. Using reference sera and plasma panels, we evaluated assay precision and showed that our neutralization titers correlate well with results reported in other assays. Overall, our lentiviral assay is relatively simple, scalable, and suitable for a variety of SARS-CoV-2 entry and neutralization screening assays.
Strategic responses of MNCs in emerging markets: addressing institutional voids associated with informal institutions
Authors: Koch Anne H.
Published: December 2020

Purpose

The purpose of this paper is to address the question how multinational corporations (MNCs) can respond to different domains of formal voids associated with informal institutions in emergent markets.

Design/methodology/approach

The author advances the institution-based view of international business strategy by developing a framework and six propositions. The theoretical distinction of informal institutions as an additional aspect when disrupting formal institutional voids are instrumental in developing a refined understanding of how MNCs can respond to institutional voids.

Findings

By emphasizing the notion of informal institutions that are associated with formal institutional voids, the author moves away from a unidimensional toward a multidimensional view of substituting formal voids. The presented response variety includes a variety of substitutes.

Research limitations/implications

Further research can apply qualitative research to further examine where, when and why social innovations can be used efficiently to address institutional weaknesses or absences. The author suggests further research opportunities in the implication section.

Social implications

Constituting substitutive formal institutions with complementary informal institutions can help strategic managers navigate business activities in emerging markets. Institutional weaknesses can be used as opportunities to create legitimacy and serve social needs. To help facilitate such impacts public policies need to be developed accordingly.

Originality/value

The paper provides a new and critical perspective on how MNCs can use institutional voids as opportunities. The author’s key contribution is to highlight specific substitutive actions from MNCs to institutional voids when different cultural-cognitive and normative circumstances apply in emerging markets.
Variation, replication and selection in evolving industries
Authors: Grandinetti Roberto
Published: December 2020

Purpose

Variation, replication and selection processes are acknowledged as key constructs in studies on how industries evolve, but no theoretical and empirical contributions have applied these key constructs to analyzing industries in specific stages of their history. This paper aims to fill this gap, taking for reference the firm and its strategic action in particular.

Design/methodology/approach

After delineating and discussing the three processes of interest – variation, replication and selection – this paper analyzes three very different evolutionary contexts: “red” industries, that reached maturity maintaining a polypolistic structure, and that continue to evolve in this phase; the oligopolistic transformation undergone by certain industries; and the emergence of new market spaces around new products developed by firms.

Findings

Variations are mainly reactions to the competitive environment in the evolution of red industries or environment-modifying in the case of industries evolving toward an oligopoly, and in the creation of new market spaces. Horizontal replication through employee mobility prevails in red industries, while in the other two contexts firms driving the evolution raise barriers to replication, inhibiting both horizontal and vertical replication. While selection does not come about in a new market space as long as the barriers erected by the first comer remain in place, it occurs in the form of subset selection in the other two settings.

Originality/value

This paper takes an entirely novel approach and proposes a pluralist framing of how industries evolve, interpreting the different evolutionary situations on the strength of the key variables of variation, replication and selection.