bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk interactions of coronavirus infection across age groups after the peak of COVID-19 epidemic
Authors: Yu Xinhua
Published: May 2020

Background

the COVID-19 pandemic has incurred significant disease burden worldwide, particularly on elderly population. This study aims to explore how risks of infection interact across age groups using data from South Korea.

Methods

Daily new COVID-19 cases from March 10 to April 30, 2020 were scraped from online open sources. A multivariate vector autoregressive model for time series count data was used to examine the risk interactions across age groups. Case counts from previous days were included as predictors to dynamically examine the change of risk patterns.

Results

In South Korea, the risk of coronavirus infection among elderly people was significantly affected by other age groups. An increase of virus infection among people aged 20-39 was associated with a double risk of infection among elderly people. Meanwhile, an increase in virus infection among elderly people was also significantly associated with risks of infection among other age groups. The risks of infection among younger people were relatively unaffected by that of other age groups.

Conclusions

Protecting elderly people from coronavirus infection could not only reduce the risk of infection among themselves but also ameliorate the risks of virus infection among other age groups. Such interventions should be effective and for long term.
Host genetic and environmental factors shape the human gut resistome
Authors: Le Roy C.I. , Bowyer R.C. E. , Carr V.R. , Costeira R. , Castillo-Fernandez J.E. , Martin T.C. , Spector T.D. , Steves C.J. , Moyes D. , Forslund S.K. , Bell J.T.
Published: May 2020

Background

Understanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored.

Methods

Using gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure.

Results

We considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals.

Conclusion

Our results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it.
Non-linear randomized Haseman-Elston regression for estimation of gene-environment heritability
Authors: Kerin Matthew , Marchini Jonathan
Published: May 2020

Gene-environment (GxE) interactions are one of the least studied aspects of the genetic architecture of human traits and diseases. The environment of an individual is inherently high dimensional, evolves through time and can be expensive and time consuming to measure. The UK Biobank study, with all 500,000 participants having undergone an extensive baseline questionnaire, represents a unique opportunity to assess GxE heritability for many traits and diseases in a well powered setting. We have developed a non-linear randomized Haseman-Elston (RHE) regression method applicable when many environmental variables have been measured on each individual. The method (GPLEMMA) simultaneously estimates a linear environmental score (ES) and its GxE heritability. We compare the method via simulation to a whole-genome regression approach (LEMMA) for estimating GxE heritability. We show that GPLEMMA is computationally efficient and produces results highly correlated with those from LEMMA when applied to simulated data and real data from the UK Biobank.
Short- and long-read metagenomics of urban and rural South African gut microbiomes reveal a transitional composition and novel taxa
Authors: Tamburini Fiona B. , Maghini Dylan , Oduaran Ovokeraye H. , Brewster Ryan , Hulley Michaella R. , Sahibdeen Venesa , Norris Shane A. , Tollman Stephen , Kahn Kathleen , Wagner Ryan G. , Wade Alisha N. , Wafawanaka Floidy , Xavier Gómez-Olivé F. , Twine Rhian , Lombard Zané , Hazelhurst Scott , Bhatt Ami S.
Published: May 2020

Human gut microbiome research focuses on populations living in high-income countries or on the other end of the spectrum, namely non-urban agriculturalist and hunter-gatherer societies. The scarcity of research between these extremes limits our understanding of how the gut microbiota relates to health and disease in the majority of the world’s population. We present the first study evaluating gut microbiome composition in transitioning South African populations using short- and long-read sequencing. We analyzed stool samples from adult females (age 40 - 72) living in rural Bushbuckridge municipality (n=118) or urban Soweto (n=51) and find that these microbiomes are taxonomically intermediate between those of individuals living in high-income countries and traditional communities. We demonstrate that reference collections are incomplete for characterization of microbiomes of individuals living outside high-income countries, resulting in artificially low species-level beta diversity measurements. To improve reference databases, we generated complete genomes of undescribed taxa, includingTreponema, Lentisphaerae, andSuccinatimonasspecies. Our results suggest that the gut microbiome in South African populations do not exist along a simple “western-nonwestern” axis and that these populations contain microbial diversity that remains to be described.
ITPK1 is an InsP6/ADP phosphotransferase that controls systemic phosphate homeostasis in Arabidopsis
Authors: Riemer Esther , Laha Debabrata , Harmel Robert K. , Gaugler Philipp , Pries Verena , Frei Michael , Hajirezaei Mohammad-Reza , Laha Nargis P. , Krusenbaum Lukas , Schneider Robin , Jessen Henning J. , Saiardi Adolfo , Fiedler Dorothea , Schaaf Gabriel , Giehl Ricardo F.H.
Published: May 2020

In plants, phosphate (Pi) homeostasis is regulated by the interaction of Pistarvation response transcription factors (PHRs) with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates (PP-InsPs). Recently, ITPK1 was shown to generate the PP-InsP InsP7from InsP6in vitro, but the importance of this activity in Pisignaling remained unknown. Here, we show that uncontrolled Piaccumulation in ITPK1-deficient plants is accompanied by impaired Pi-dependent InsP7and InsP8synthesis. Reciprocal grafting demonstrates that Pistarvation responses are mainly controlled by ITPK1 activity in shoots. Nuclear magnetic resonance assays and PAGE analyses with recombinant protein reveal that besides InsP6phosphorylation, ITPK1 is also able to catalyze ATP synthesis using 5-InsP7but not any other InsP7isomer as a P-donor when ATP is low. Additionally, we show that the dynamic changes in InsP7and InsP8to cellular Piare conserved from land plant species to human cells, suggesting that Pi-dependent PP-InsP synthesis is a common component of Pisignaling across kingdoms. Together, our study demonstrates how Pi-dependent changes in nutritional and energetic states modulate ITPK1 activities to fine-tune the synthesis of PP-InsPs.
Spontaneous eye-movements during eyes-open rest reduce resting-state-network modularity by increasing visual-sensorimotor connectivity
Authors: Koba Cemal , Notaro Giuseppe , Tamm Sandra , Nilsonne Gustav , Hasson Uri
Published: May 2020

During wakeful rest, individuals make small eye movements when asked to fixate. We examined how these endogenously-driven oculomotor patterns impact topography and topology of functional brain networks. We used a dataset consisting of eyes-open resting-state (RS) fMRI data with simultaneous eye-tracking (Nilsonne et al., 2016). The eye-tracking data indicated minor movements during rest, on the order of 1.0 degree on average when analyzed over 2sec epochs, which correlated modestly with RS BOLD data. However, the eye-tracking data correlated well with echo-planar imaging (EPI) time series sampled from the area of the Eye-Orbit (EO-EPI), which is a signal previously used to identify eye movements during exogenous saccades and movie viewing. We found that EO-EPI data correlated with activity in an extensive motor and sensory-motor network, but also some components of the dorsal attention network including the frontal and supplementary eye fields. Partialling out variance related to EO-EPI from RS data reduced connectivity, primarily between sensory-motor and visual areas. For three different network sparsity levels, the resulting RS connectivity networks showed higher modularity, lower mean connectivity strength, and lower mean clustering coefficient. Our results highlight new aspects of endogenous eye movement control during wakeful rest. They show that oculomotor-related contributions form an important component of RS network topology, and that those should be considered in interpreting differences in network structure between populations, or as a function of different experimental conditions.
Mud, microbes, and macrofauna: seasonal dynamics of the iron biogeochemical cycle in an intertidal mudflat
Authors: Beam Jacob P. , George Sarabeth , Record Nicholas R. , Countway Peter D. , Johnston David T. , Girguis Peter R. , Emerson David
Published: May 2020

Microorganisms and burrowing animals exert a pronounced impact on the cycling of redox sensitive metals in coastal sediments. Sedimentary metal cycling is likely controlled by seasonal processes including changes in temperature, animal feeding behavior due to food availability, and availability of organic matter in sediments. We hypothesized that the iron biogeochemical cycle and associated sedimentary microbial community will respond to seasonal changes in a bioturbated intertidal mudflat. In this study, we monitored the spatiotemporal dynamics of porewater and highly reactive solid phase iron with the corresponding prokaryotic and eukaryotic sedimentary microbial communities over one annual cycle from November 2015 to November 2016. Continuous and seasonally variable pools of both porewater Fe(II) and highly reactive iron (FeHR) were observed throughout the season with significant increases of Fe(II) and FeHRin response to increased sediment temperature in summer months. Maximum concentrations of Fe(II) and FeHRwere predominantly confined to the upper 5 cm of sediment throughout the season. Iron-oxidizing and -reducing microorganisms were present and stable throughout the season, and exhibited strong depth-dependent stratification likely due to availability of Fe(II) and FeHRpools, respectively. Otherwise, the community was dominated by Deltaproteobacteria, which are involved in sulfur and potentially iron cycling, as well as Gammaproteobacteria and Bacteroidetes. The microbial community was relatively stable throughout the seasonal cycle, but showed strong separation with depth, probably driven by changes in oxygen availability and organic matter. The relative abundance of diatoms revealed a noticeable seasonal signature, which we attribute to spring and fall blooms recorded in the sediments. Macro-, meio, and microfauna were detected throughout the season with some seasonal variations that may influence sedimentary iron transformations by active microbial grazing. The seasonal dynamics of the sedimentary iron cycle are controlled by numerous, interdependent processes, with macrobiota-microbiota relationships and depth stratification comprising primary components. Deciphering these processes in natural ecosystems is essential to understand how they might respond to future environmental perturbations, such as anthropogenic nutrient release to coastal systems.
The minor and major spliceosome interact to regulate alternative splicing around minor introns
Authors: Olthof Anouk M. , White Alisa K. , Lee Madisen F. , Chakroun Almahdi , Abdel Aleem Alice K. , Rousseau Justine , Magnani Cinzia , Campeau Philippe M. , Kanadia Rahul N.
Published: May 2020

Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIGDctn3byin uteroelectroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.
Aligning biological sequences by exploiting residue conservation and coevolution
Authors: Muntoni Anna Paola , Pagnani Andrea , Weigt Martin , Zamponi Francesco
Published: May 2020

Aligning biological sequences belongs to the most important problems in computational sequence analysis; it allows for detecting evolutionary relationships between sequences and for predicting biomolecular structure and function. Typically this is addressed through profile models, which capture position-specificities like conservation in sequences, but assume an independent evolution of different positions. RNA sequences are an exception where the coevolution of paired bases in the secondary structure is taken into account. Over the last years, it has been well established that coevolution is essential also in proteins for maintaining three-dimensional structure and function; modeling approaches based on inverse statistical physics can catch the coevolution signal and are now widely used in predicting protein structure, protein-protein interactions, and mutational landscapes. Here, we present DCAlign, an efficient approach based on an approximate message-passing strategy, which is able to overcome the limitations of profile models, to include general second-order interactions among positions and to be therefore universally applicable to protein- and RNA-sequence alignment. The potential of our algorithm is carefully explored using well-controlled simulated data, as well as real protein and RNA sequences.
Role of Inflammasome-independent Activation of IL-1β by thePseudomonas aeruginosaProtease LasB
Authors: Sun Josh , LaRock Doris L. , Skowronski Elaine A. , Kimmey Jacqueline M. , Olson Joshua , Jiang Zhenze , O’Donoghue Anthony J. , Nizet Victor , LaRock Christopher N.
Published: May 2020

Pulmonary damage byPseudomonas aeruginosaduring cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates management of these deep-seated infections. Therefore, preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Pathological inflammation duringP. aeruginosapneumonia is driven by interleukin-1β (IL-1β). This proinflammatory cytokine is canonically regulated by caspase-family inflammasome proteases, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severeP. aeruginosapulmonary infection. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such that matrix metalloprotease inhibitors blocking LasB limit inflammation and pathology duringP. aeruginosapulmonary infections.

Highlights

IL-1β drives pathology during pulmonary infection byPseudomonas aeruginosa.

ThePseudomonasprotease LasB cleaves and activates IL-1β independent of canonical and noncanonical inflammasomes

Metalloprotease inhibitors active against LasB limit inflammation and bacterial growth

Research in Context

Inflammation is highly damaging during lung infections by the opportunistic pathogenPseudomonas aeruginosa. Sun et al. demonstrate that thePseudomonasLasB protease directly activates IL-1β in an inflammasome-independent manner. Inhibition of IL-1β conversion by LasB protects against neutrophilic inflammation and destruction of the lung. Adjunctive therapeutics that limit pathological inflammation induced by infection would be beneficial for the treatment of pulmonary infections when used with conventional antibiotics.
Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function
Authors: Kliment Corrine R. , Nguyen Jennifer M. K. , Kaltreider Mary Jane , Lu YaWen , Claypool Steven M. , Radder Josiah E. , Sciurba Frank C. , Zhang Yingze , Gregory Alyssa D. , Iglesias Pablo A. , Sidhaye Venkataramana K. , Robinson Douglas N.
Published: May 2020

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4thleading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoebaDictyostelium discoideumas a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS inDictyosteliumand human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT’s presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.
Alterations in resting-state network dynamics along the Alzheimer’s disease continuum: a combined MEG-PET/MR approach
Authors: Puttaert D. , Coquelet N. , Wens V. , Peigneux P. , Fery P. , Rovai A. , Trotta N. , Bier J-C. , Goldman S. , De Tiège X.
Published: May 2020

Human brain activity is intrinsically organized into resting-state networks (RSNs) that transiently activate or deactivate at the sub-second timescale. Few neuroimaging studies have addressed how Alzheimer’s disease (AD) affects these fast temporal brain dynamics, and how they relate to the cognitive, structural and metabolic abnormalities characterizing AD.

We aimed at closing this gap by investigating both brain structure and function using magnetoencephalography (MEG) and hybrid positron emission tomography-magnetic resonance (PET/MR) in 10 healthy elders, 10 patients with Subjective Cognitive Decline (SCD), 10 patients with amnestic Mild Cognitive Impairment (aMCI) and 10 patients with typical Alzheimer’s disease with dementia (AD). The fast activation/deactivation state dynamics of RSNs were assessed using hidden Markov modeling (HMM) of power envelope fluctuations at rest measured with MEG. HMM patterns were related to participants’ cognitive test scores, whole hippocampal grey matter volume and regional brain glucose metabolism.

The posterior default-mode network (DMN) was less often activated and for shorter durations in AD patients than matched healthy elders. No significant difference was found in patients with SCD or aMCI. The time spent by participants in the activated posterior DMN state did not correlate significantly with cognitive scores. However, it correlated positively with the whole hippocampal volume and regional glucose consumption in the right temporo-parietal junctions and dorsolateral prefrontal cortex, and negatively with glucose consumption in the cerebellum.

In AD patients, alterations of posterior DMN power activation dynamics at rest correlate with structural and neurometabolic abnormalities. These findings represent an additional electrophysiological correlate of AD-related synaptic and neural dysfunction.
Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress
Authors: Rosenberg Ayelet , Rausser Shannon , Ren Junting , Mosharov Eugene , Sturm Gabriel , Todd Ogden R , Patel Purvi , Soni Rajesh Kumar , Lacefield Clay , Tobin Desmond J , Paus Ralf , Picard Martin
Published: May 2020

Hair graying is a universal hallmark of aging believed to be linked to psychological stress. Here we develop a novel approach to quantitatively profile natural graying events along individual human hair shafts, resulting in a quantifiable physical timescale of hair pigmentation patterns (HPPs). Using this approach, we quantify rare events of white/gray hairs that naturally regain pigmentation within days to weeks, thereby quantitatively defining the reversibility of graying in healthy, unmedicated individuals. Proteomic analysis shows that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining hair pigmentation profiling and proteomics at the single hair level, we also report hair graying and its reversal occurring in parallel with behavioral and psychological stressors. A computational simulation suggests a threshold-based mechanism for the temporary reversibility of graying. Quantitatively mapping HPPs in humans provides an opportunity to longitudinally examine the influence of life exposures on biological aging.
A rapid, sensitive, scalable method for Precision Run-On sequencing (PRO-seq)
Authors: Judd Julius , Wojenski Luke A. , Wainman Lauren M. , Tippens Nathaniel D. , Rice Edward J. , Dziubek Alexis , Villafano Geno J. , Wissink Erin M. , Versluis Philip , Bagepalli Lina , Shah Sagar R. , Mahat Dig B. , Tome Jacob M. , Danko Charles G. , Lis John T. , Core Leighton J.
Published: May 2020

Tracking active transcription with the nuclear run-on (NRO) assays has been instrumental in uncovering mechanisms of gene regulation. The coupling of NROs with high-throughput sequencing has facilitated the discovery of previously unannotated or undetectable RNA classes genome-wide. Precision run-on sequencing (PRO-seq) is a run-on variant that maps polymerase active sites with nucleotide or near-nucleotide resolution. One main drawback to this and many other nascent RNA detection methods is the somewhat intimidating multi-day workflow associated with creating the libraries suitable for high-throughput sequencing. Here, we present an improved PRO-seq protocol where many of the enzymatic steps are carried out while the biotinylated NRO RNA remains bound to streptavidin-coated magnetic beads. These adaptations reduce time, sample loss and RNA degradation, and we demonstrate that the resulting libraries are of the same quality as libraries generated using the original published protocol. The assay is also more sensitive which permits reproducible, high-quality libraries from 104–105cells instead of 106–107. Altogether, the improved protocol is more tractable allows for nascent RNA profiling from small samples, such as rare samples or FACS sorted cell populations.
Apico-basal cell compression regulates Lamin A/C levels in Epithelial tissues
Authors: Iyer K Venkatesan , Dye Natalie A. , Eaton Suzanne , Jülicher Frank
Published: May 2020

Nuclear lamina bridges mechanical forces from the cytoskeleton to the nucleus, to initiate nuclear mechanotransduction. The concentration of nuclear Lamin proteins, particularly Lamin A/C is crucial for the mechanical properties of the nucleus and nuclear mechanotransduction. Recent studies in mesenchymal tissues show that the concentration of Lamin A/C scales with stiffness and concentration of the underlying extracellular matrix (ECM). But in epithelial tissues, that lack a strong cell-ECM interaction, it is still unclear how Lamin A/C is regulated. Here, we show that concentration of Lamin A/C in epithelial tissues scales with apico-basal compression of cells and is independent of ECM concentration. But, ectopically altering the concentration of Lamin A/C does not influence cell shapes in epithelial tissues. Using genetic perturbations inDrosophilaepithelial tissues, we reveal that apico-basal cell compression regulates the concentration of Lamin A/C by deforming the nucleus. We observe a similar mechanism of Lamin A/C regulation in mammalian Madin Darby Canine Kidney (MDCK) cells suggesting that this mechanism is evolutionarily conserved. Taken together, our results reveal a unidirectional mechanical coupling between cell mechanics and nuclear mechanics via the regulation of Lamin A/C. We anticipate that mechanism of Lamin A/C regulation that we revealed, could form the basis for understanding nuclear mechanotransduction in epithelial tissues.
High-Speed AFM directly visualizes conformational dynamics of the HIV-Vif protein complex
Authors: Pan Yangang , Shlyakhtenko Luda S. , Lyubchenko Yuri L.
Published: May 2020

Viral infectivity factor (Vif) is a protein that is essential for the replication of the HIV-1 virus. The key function of Vif is to disrupt the antiviral activity of APOBEC3 proteins, which mutate viral nucleic acids. Inside the cell, Vif binds to the host cell proteins Elongin-C, Elongin-B, and CBF-β, forming a four-protein complex called VCBC. The structure of VCBC in complex with the Cullin5 (Cul5) protein has been solved by X-ray crystallography, and recently, using molecular dynamic (MD) simulations, the dynamics of VCBC and VCBC-Cul5 complexes were characterized. Here, we applied time-lapse high-speed atomic force microscopy (HS-AFM) to visualize the conformational changes of the VCBC complex. We determined the three most favorable conformations of the VCBC complex, which we identified as triangle, dumbbell, and globular structures. In addition, we characterized the dynamics of each of these structures. While our data show a very dynamic behavior for all these structures, we found the triangle and dumbbell structures to be the most dynamic. These findings provide insight into the structure and dynamics of the VCBC complex and support further research into the improvement of HIV treatment, as Vif is essential for virus survival in the cell.
Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Kidney Disease-Related Genes in Patients with Diabetic Kidney Disease
Authors: Lazaro-Guevara Jose , Morales Julio Fierro , Wright A. Hunter , Gunville River , Frodsham Scott G. , Pezzolesi Melissa H. , Zaffino Courtney A. , Al-Rabadi Laith , Ramkumar Nirupama , Pezzolesi Marcus G.
Published: May 2020

Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their kidney disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. Here, we set out to investigate the genetic basis of disease in non-diabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprised of 345 kidney disease-related genes. Our analysis identified rare diagnostic variants that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes.

Key Messages

What is already known about this subject?

For patients with diabetes and chronic kidney disease, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes; without histopathological confirmation, however, the underlying cause of their kidney disease is unclear.

Next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease.

What are the new findings?

Using targeted NGS and a custom panel comprised of 345 kidney disease-related genes, we found that 22% of diabetic kidney disease patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel.

Genetic variants suggestive of non-diabetic kidney disease were detected in 3% of the diabetic patients included in this study.

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

Our findings suggest that rare variants in kidney disease-related genes in the context of diabetic pathophysiology may play a role in the pathogenesis of kidney disease in patients with diabetes.

Importantly, improved understanding of the underlying disease process in diabetic kidney disease could have major implications in terms of patient care and monitoring as well as for research studies in this field.
ASYMMETRIC EXPRESSION OF ARGONAUTES IN ARABIDOPSIS REPRODUCTIVE TISSUES
Authors: Jullien PE , Bonnet DMV , Pumplin N , Schröder JA , Voinnet O
Published: May 2020

Abstract

During sexual reproduction, development of a totipotent zygote from the fusion of highly differentiated gametes is accompanied by dynamic regulation of gene expression. This notably involves RNA silencing operated by Argonautes (AGO) effector proteins. While AGOs’ roles duringArabidopsissomatic life have been extensively investigated, less is known about their expression during reproduction, which proceeds via double-fertilization of an egg and a central cell, leading respectively to the embryo and a supportive tissue known as endosperm. Using full-locus translational reporters for all tenArabidopsisAGOs, we uncover cell-specific expression patterns and AGO-intrinsic subcellular localizations in reproductive tissues. However, while someArabidopsisAGOs are enriched in both male and female gametes,i.e. sperm and egg cells, they are comparably low-expressed in accessory,i.e. vegetative and central cells. Likewise, following fertilization, several AGOs are expressed in the early embryo, yet below detection in the early endosperm. Thus, there is pre- and post-fertilization asymmetry between the embryo and endosperm lineages. Later during embryo development, AGO9, AGO5 and AGO7 are restricted to the apical embryonic meristem in contrast to AGO1, AGO4, AGO6 and AGO10. Beside shedding light onto potential roles for RNA silencing duringArabidopsisreproduction, the plant material generated here should constitute a valuable asset enabling functional AGOs studies in many tissues beyond those involved in reproduction.

Summary statement

Arabidopsis genome encodes ten Argonautes proteins showing distinct expression pattern as well as intracellular localisation during sexual reproduction.
Early endocytosis as a key to understanding mechanisms of plasmalemma tension regulation in filamentous fungi
Authors: Mazheika Igor , Voronko Oxana , Kamzolkina Olga
Published: May 2020

Two main systems regulate the plasmalemma tension and provide a close connection of the protoplast with the cell wall in fungi: turgor pressure and actin cytoskeleton. These systems work together with the plasmalemma focal adhesion to the cell wall and their contribution to fungal cell organization has been partially studied, but remains controversial in model filamentous ascomycetes and oomycetes, and even less investigated in filamentous basidiomycetes. Early endocytosis, in which F-actin is actively involved, can be used to research of mechanisms regulating the plasmalemma tension, since the latter influences on the primary endocytic vesicles formation. This study examined the effects of actin polymerization inhibitors and hyperosmotic shock on early endocytosis and cell morphology in two filamentous basidiomycetes. The main obtained results: (i) depolymerization of F-actin leads to the fast formation of primary endocytic vesicles but to inhibition of their scission; (ii) moderate hyperosmotic shock does not affect the dynamics of early endocytosis. These and a number of other results allowed offering a curtain model of regulation the plasmalemma tension in basidiomycetes. According to this model, the plasmalemma tension in many nonapical cells of hyphae is more often regulated not by turgor pressure, but by a system of actin driver cables that are associated with the proteins of focal adhesion sites. The change in the plasmalemma tension occurs similar to the movement of the curtain along the curtain rod using the curtain drivers. This model addresses the fundamental properties of the fungal structure and physiology and requires confirmation, including through the yet technically unavailable high quality labeling of the actin cytoskeleton of basidiomycetes.
Seesaw Conformations of Npl4 in the Human p97 Complex and the Inhibitory Mechanism of a Disulfiram Derivative
Authors: Pan Man , Zheng Qingyun , Yu Yuanyuan , Ai Huasong , Xie Yuan , Zeng Xin , Wang Chu , Liu Lei , Zhao Minglei
Published: May 2020

p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis1. Human p97 mutations are associated with several neurodegenerative diseases2,3. Targeting p97 and its cofactors is a strategy for cancer drug development4. Despite significant structural insights into the fungal homolog Cdc485–7, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p978, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that under oxidative conditions, the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) inhibits p97 function by releasing cupric ions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.
Hyperpyrexia leading to death in a patient with severe COVID-19 disease
Authors: Singhal Tanu , Phadtare Sourabh , Pai Sunil , Raodeo Amit
Published: May 2020

We describe here the clinical course of a 42 year old male with severe COVID 19 disease treated at a private hospital in Mumbai, India. This patient with very high inflammatory markers at admission was treated with supportive care, mechanical ventilation, anticoagulation, hydroxychloroquine, corticosteroids, tocilizumab, intravenous insulin, antibiotics, sedation and paralysis. There was sustained improvement in his respiratory status and decline in ventilator settings with decline and normalization of CRP, D dimer and PCT. However high fever persisted that did not respond to paracetamol and NSAIDS. On day 8 of admission his axillary temperature touched 107F followed by rapid clinical deterioration and death within the next 12 hours, Blood cultures were consistently sterile. While death was related to hyperpyrexia, the cause of this hyperpyrexia is uncertain.
Systematic prediction of mortality in trauma patients based on Arterial Blood Gas
Authors: Shayan Zeinab , Sabouri Mohammad , Shayan Milad , Paydar Shahram
Published: May 2020

Context: An effort to predict the final condition of patients is one of the purposes of many studies; since it enables the treatment system to provide the necessary facilities in the best possible time and prevent wasting time and energy as well as increasing patient mortality.

Research purpose: This study was purposed to investigate the correlation between arterial blood gas (ABG) and patient mortality and design a system to predict the final patients' condition.

Method: In this study, a method has been proposed to identify dynamic systems to estimate the final condition of trauma patients and predict their death or survival probability during treatment or being confined in the medical center. The proposed method by using the information of patients' arterial blood gases identifies a linear model indicating the correlation between these gases and the patients' final condition. This method is based on system identification using ARX model simulated in MATLAB and its results are presented.

Results: Data of 2802 patients (365 deaths and 2437 survivors) with an average age of 37.87 years old and GCS average of 9.27 including 470 female and 2332 male patients were studied. The designed structure was tested with 62.57% accuracy to be able to predict patient mortality. Therefore, it can be stated that the proposed method has a good accuracy in predicting the final patients' condition based on dynamic analysis.

Discussion and Conclusion: It is unavoidable mortality due to accidents and severe injuries. Also, it is important to predict the death probability based on data from the early hours of the onset of trauma in patients; since it takes time to collect the data of patient's condition. Therefore, it is very important to find reliable methods to measure the patients' condition and predict the mortality. The study of these methods has always been considered by physicians due to its high importance. This study has almost been able to meet physicians' need by providing a method based on the study of dynamics and dynamic relationships discussing arterial and mortal blood gases.
SARS-CoV-2 seroconversion in health care workers
Authors: Shields Adrian M , Faustini Sian E , Perez-Toledo Marisol , Jossi Sian , Aldera Erin L , Allen Joel D , Al-Taei Saly , Backhouse Claire , Bosworth Andrew , Dunbar Lyndsey , Ebanks Daniel , Emmanuel Beena , Grey Joanne , Kidd I Michael , McGinnell Golaeh , McLoughlin Dee , Morley Gabriella , O'Neill Joanne , Papakonstantinou Danai , Pickles Oliver , Poxon Charlotte , Richter Megan , Walker Eloise , Wanigasooriya Kasun , Watanabe Yasunori , Whalley Celina , Zielinska Agnieszka E , Crispin Max , Wraith David C , Beggs Andrew D , Cunningham Adam F , Drayson Mark T , Richter Alex G
Published: May 2020

Background
The correlates of protection against SARS-CoV-2 and their longevity remain unclear. Studies in severely ill individuals have identified robust cellular and humoral immune responses against the virus. Asymptomatic infection with SARS-CoV-2 has also been described, but it is unknown whether this is sufficient to produce antibody responses.

Methods
We performed a cross-sectional study recruiting 554 health care workers from University Hospitals Birmingham NHS Foundation Trust who were at work and asymptomatic. Participants were tested for current infection with SARS-CoV-2 by nasopharyngeal swab for real-time polymerase chain reaction and for seroconversion by the measurement of anti-SARS-CoV-2 spike glycoprotein antibodies by enzyme linked immunosorbent assay. Results were interpreted in the context of previous, self-reported symptoms of illness consistent with COVID-19.

Results
The point prevalence of infection with SARS-CoV-2, determined by the detection of SARS-CoV-2 RNA on nasopharnygeal swab was 2.39% (n=13/544). Serum was available on 516 participants. The overall rate of seroconversion in the cohort was 24.4% (n=126/516). Individuals who had previously experienced a symptomatic illness consistent with COVID-19 had significantly greater seroconversion rates than those who had remained asymptomatic (37.5% vs 17.1%, χ2 =21.1034, p<0.0001). In the week preceding peak COVID-19-related mortality at UHBFT, seroconversion rates amongst those who were suffering from symptomatic illnesses peaked at 77.8%. Prior symptomatic illness generated quantitatively higher antibody responses than asymptomatic seroconversion. Seroconversion rates were highest amongst those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%) with lower rates observed in participants working in intensive care (14.8%) and emergency medicine (13.3%).

Conclusions
In a large cross-sectional seroprevalence study of health-care workers, we demonstrate that asymptomatic seroconversion occurs, however prior symptomatic illness is associated with quantitatively higher antibody responses. The identification that the potential for seroconversion in health-care workers can associate differentially with certain hospital departments may inform future infection control and occupational health practices.
Improved Reference Genome forCyclotella CrypticaCCMP332, a Model for Cell Wall Morphogenesis, Salinity Adaptation, and Lipid Production in Diatoms (Bacillariophyta)
Authors: Roberts Wade R. , Downey Kala M. , Ruck Elizabeth C. , Traller Jesse C. , Alverson Andrew J.
Published: May 2020

The diatom,Cyclotella cryptica, is a well-established experimental model for physiological studies and, more recently, biotechnology applications of diatoms. To further facilitate its use as a model diatom species, we report an improved reference genome assembly and annotation forC. crypticastrain CCMP332. We used a combination of long- and short-read sequencing to assemble a high-quality and contaminant-free genome. The genome is 171 Mb in size and consists of 662 scaffolds with a scaffold N50 of 494 kb. This represents a 176-fold decrease in scaffold number and 41-fold increase in scaffold N50 compared to the previous assembly. The genome contains 21,250 predicted genes, 75% of which were assigned putative functions. Repetitive DNA comprises 59% of the genome, and an improved classification of repetitive elements indicated that a historically steady accumulation of transposable elements has contributed to the relatively large size of theC. crypticagenome. The high-qualityC. crypticagenome will serve as a valuable reference for ecological, genetic, and biotechnology studies of diatoms.

Data available from

NCBI BioProjects PRJNA628076 and PRJNA589195
Talin Rod Domain Containing Protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation
Authors: Cowell Alana R , Jacquemet Guillaume , Singh Abhimanyu K , Ammon York-Christoph , Brown David G , Akhmanova Anna , Ivaska Johanna , Goult Benjamin T.
Published: May 2020

Talin is a mechanosensitive adapter protein which couples integrins to the cytoskeleton and regulates integrin-mediated adhesion. Talin rod domain-containing protein-1 (TLNRD1) shares 22% homology with the R7R8 domains of talin, and is highly conserved throughout vertebrate evolution, however little is known about its function. Here we show that TLNRD1 is an α-helical protein which shares the same atypical topology as talin R7R8, but forms a novel antiparallel dimer arrangement. Actin co-sedimentation assays and electron microscopy reveal TLNRD1 is an actin-bundling protein that forms tight actin bundles. In addition, TLNRD1 binds to the same LD-motif containing proteins, RIAM and KANK, as talin, and thus may act in competition with talin. Filopodia are cell protrusions supported by tightly bundled actin filaments and TLNRD1 localises to filopodia tips, increases filopodia number and promotes cell migration in 2D. Together our results suggest that TLNRD1 has similar functionality to talin R7R8, serving as a nexus between the actin and microtubule cytoskeletons independent of adhesion complexes.
Agro-morphological and phenotypic variability of sweet basil (Ocimum basilicumL.) genotypes for breeding purposes
Authors: Yaldiz Gulsum , Camlica Mahmut
Published: May 2020

The genus Ocimum is very complicated due to the presence of huge morphological variability along with genetic diversity. Basil (Ocimum basilicum L.) has pharmacological properties like headaches, coughs, diarrhea, constipation, warts, worms, kidney malfunction, and its potential as a therapeutic agent in treating various age-related diseases. The present investigation comprised of sixty-one genotypes of basil was undertaken to characterize the genotypes based on morphological and phenological features, herbs and essential oil yield of genotypes. A wide range of variations for traits like days to first cutting (56.92-101.6), plant height (13.67-71.90 cm), branch number (3.28-19.43 number/plant), fresh herb yields (12.94-274.11 g/plant), and essential oil yield (0.04-1.71%) were observed and can be useful for breeding purposes. PI 652070 and PI 296391 genotypes were found superior in case of the highest herbs yield as compared with other genotypes. Overall, in PI 358469 and Ames 32309 genotypes exhibited the highest essential oil content. The constellation analysis was conducted to investigate the genetic diversity of basil genotypes. According to the constellation plot analysis, leaf shape and color were evaluated in 2017 and most of the basil genotypes located in the same main group. In 2018, moonlight and dino cultivars located in the same cluster 1 (C1) with PI 141198 (US/Maryland) genotype and Georgia genotypes located in the same main group and they also took place in the sub-main group except Ames 32314 genotype depending on UPOV criteria. Each two years, Bolu genotype and midnight were found in the same main group.