bluuebunny/crossref_metadata_2025 huggingface dataset:
Medicago-Sinorhizobium-Ralstonia: A Model System to Investigate Pathogen-Triggered Inhibition of Nodulation
Authors: Benezech Claire , Le Scornet Alexandre , Gourion Benjamin
Published: February 2021

How plants deal with beneficial and pathogenic microorganisms and how they can tolerate beneficial ones and face pathogens at the same time are questions that remain puzzling to plant biologists. Legume plants are good models to explore those issues, as their interactions with nitrogen-fixing bacteria called rhizobia results in a drastic and easy-to-follow phenotype of nodulation. Intriguingly, despite massive and chronic infection, legume defense reactions are essentially suppressed during the whole symbiotic process, raising a question about a potential negative effect of plant immune responses on the establishment of nodulation. In the present study, we used the model legume, Medicago truncatula, coinoculated with mutualistic and phytopathogenic bacteria, Sinorhizobium medicae and Ralstonia solanacearum, respectively. We show that the presence of R. solanacearum drastically inhibits the nodulation process. The type III secretion system of R. solanacearum, which is important for the inhibition of pathogen-associated molecular pattern–triggered immunity (PTI), strongly contributes to inhibit nodulation. Thus, our results question the negative effect of PTI on nodulation. By including a pathogenic bacterium in the interaction system, our study provides a new angle to address the influence of the biotic environment on the nodulation process.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Fatty Acid Desaturases in the Chloroplast and Endoplasmic Reticulum Promote Susceptibility to the Green Peach AphidMyzus persicaeinArabidopsis thaliana
Authors: Li Jiamei , Galla Aravind , Avila Carlos A. , Flattmann Kaitlin , Vaughn Kaleb , Goggin Fiona L.
Published: February 2021

Fatty acid desaturases (FADs) in plants influence levels of susceptibility to multiple stresses, including insect infestations. In this study, populations of the green peach aphid (Myzus persicae) on Arabidopsis thaliana were reduced by mutations in three desaturases: AtFAB2/SSI2, which encodes a chloroplastic stearoyl-[acyl-carrier-protein] 9-desaturase, and AtFAD7 or AtFAD3, which encode ω-3 FADs in the chloroplast and endoplasmic reticulum (ER), respectively. These data indicate that certain FADs promote susceptibility to aphids and that aphids are impacted by desaturases in both the chloroplast and ER. Aphid resistance in ssi2, fad3, and fad7, singly or in combination, might involve altered signaling between these subcellular compartments. C18:1 levels are depleted in ssi2, whereas C18:2 accumulation is enhanced in fad3 and fad7. In contrast, fad8 has higher than normal C18:2 levels but also high C18:1 and low C18:0 and does not impact aphid numbers. Potentially, aphids may be influenced by the balance of multiple fatty acids (FAs) rather than by a single species, with C18:2 promoting aphid resistance and C18:1 promoting susceptibility. Although the fad7 mutant also accumulates higher-than-normal levels of C16:2, this FA does not contribute to aphid resistance because a triple mutant line that lacks detectable levels of C16:2 (fad2fad6fad7) retains comparable levels of aphid resistance as fad7. In addition, aphid numbers are unaffected by the fad5 mutation that inhibits C16:1 synthesis. Together, these results demonstrate that certain FADs are important susceptibility factors in plant-aphid interactions and that aphid resistance is more strongly associated with differences in C18 abundance than C16 abundance.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Flooding by California Rivers Results in Walnut Scion Infections by Species of Phytophthora
Authors: Browne Greg T. , Hasey Janine K. , Ott Natalia J. , Forbes Holly , Arnold Kari , Milliron Luke
Published: February 2021

Many walnut orchards were inundated by flooding from the Feather and Stanislaus Rivers in winter and spring 2017 and developed bleeding cankers in trunk, root, and crown tissues exposed to the water. Orchard surveys and diagnostic isolations associated Phytophthora pini, P. chlamydospora, and P. gonapodyides with the cankers in 2017. Pathogenicity of P. pini was confirmed in seedlings and excised shoots of Juglans regia, but the other species caused negligible amounts of disease. Feather River and associated flood waters were assayed using culture-independent sequencing of rRNA gene amplicons and pear baiting methods; 14 species of Phytophthora were detected, including P. chlamydospora and P. gonapodyides, but not P. pini. Severe and prolonged walnut orchard flooding from rivers, such as occurred in 2017, places diverse mixtures of Phytophthora species from multiple sources into close, infective proximity with susceptible walnut tree scions. Systemic chemical or genetic protection strategies may be valuable for orchards subject to such flooding.
The search for a sustainable alternative to slash-and-burn agriculture in the World's rain forests: the Guama Model and its implementation
Authors: Hands Michael
Published: February 2021

This account describes the context, history and outcomes of a series of studies into the ecology of slash-and-burn (S-B) agriculture in the world's humid tropics. These studies, which began in the mid-1980s, identified promising lines of research and continued to field trials, in Central America, of candidate agricultural systems as possible sustainable alternatives to the practice. The only system to emerge from 7 years' comparative trial with any promise of sustainability, in this context, was the agroforestry technique known as alley-cropping; but only with trees of the genus
Inga
. Inga alley-cropping then underwent field trials with subsistence farming families in northern Honduras. The system was aimed at the twin objectives of achieving food security in basic grains, on minimal inputs, and of providing the means of eliminating further S-B in the region. Since then, Inga alley-cropping has become the heart of a sustainable and integrated rural livelihood model (the Guama Model) which is being implemented successfully in northern Honduras with some 300 families. These families had been attempting to subsist on a few hectares of land degraded by decades or centuries of S-B. The development of Inga alley-cropping, supplemented by rock phosphate and other mineral supplements, as a sustainable subsistence and cash crop alternative means that land previously being held in reserve for subsequent S-B operations can now be planted to permanent forms of agroforestry. Entire landscapes can be re-greened by productive agroforest vegetation. Achieving this at scale will require the investment of huge extension effort and funds. However, the environmental, social and economic returns are also huge; and they are sustainable. In this programme,we are seeing the vitality and goodwill of hundreds of families focussed on the raising, planting and management of trees in ways that feed the living organisms of the soil and, hence, feed themselves. In so cheerfully planting out their own futures, they plant and reshape the future of their own country. Replicating this at scale, as Rattan Lal outlines below, could reshape the future of this planet. In the mid-1980s, progress on sustainable alternatives to S-B, especially in rain forests, was frustrated by a lack of conclusiveness in the literature as to why soil fertility fails so rapidly post-burn; but also by a degree of contradiction on the impacts of the burn on certain plant nutrients. Hands (Hands 1988 The ecology of shifting cultivation. MSc thesis, University of Cambridge) concentrated on the role of soil phosphorus and attempted to resolve these contradictions. The Cambridge Alley-cropping Projects (1988–2002) continued this theme and threw light on the question of sustainable food production in rain forest environments.
Revisiting the classification of squamate adhesive setae: historical, morphological and functional perspectives
Authors: Garner Austin M. , Russell Anthony P.
Published: February 2021

Research on gecko-based adhesion has become a truly interdisciplinary endeavour, encompassing many disciplines within the natural and physical sciences. Gecko adhesion occurs by the induction of van der Waals intermolecular (and possibly other) forces between substrata and integumentary filaments (setae) terminating in at least one spatulate tip. Gecko setae have increasingly been idealized as structures with uniform dimensions and a particular branching pattern. Approaches to developing synthetic simulacra have largely adopted such an idealized form as a foundational template. Observations of entire setal fields of geckos and anoles have, however, revealed extensive, predictable variation in setal form. Some filaments of these fields do not fulfil the morphological criteria that characterize setae and, problematically, recent authors have applied the term ‘seta’ to structurally simpler and likely non-adhesively competent fibrils. Herein we briefly review the history of the definition of squamate setae and propose a standardized classificatory scheme for epidermal outgrowths based on a combination of whole animal performance and morphology. Our review is by no means comprehensive of the literature regarding the form, function, and development of the adhesive setae of squamates and we do not address significant advances that have been made in many areas (e.g. cell biology of setae) that are largely tangential to their classification and identification. We contend that those who aspire to simulate the form and function of squamate setae will benefit from a fuller appreciation of the diversity of these structures, thereby assisting in the identification of features most relevant to their objectives.
An aptasensor using ceria electrodeposited-screen-printed carbon electrode for detection of epithelial sodium channel protein as a hypertension biomarker
Authors: Hartati Yeni Wahyuni , Komala Dina Ratna , Hendrati Diana , Gaffar Shabarni , Hardianto Ari , Sofiatin Yulia , Bahti Husein Hernandi
Published: February 2021

Epithelial sodium channel (ENaC) is a transmembrane protein that has an essential role in maintaining the levels of sodium in blood plasma. A person with a family history of hypertension has a high enough amount of ENaC protein in the kidneys or other organs, so that the ENaC protein acts as a marker that a person is susceptible to hypertension. An aptasensor involves aptamers, which are oligonucleotides that function similar to antibodies, as sensing elements. An electrochemical aptasensor for the detection of ENaC was developed using a screen-printed carbon electrode (SPCE) which was modified by electrodeposition of cerium oxide (CeO
2
). The aptamer immobilization was via the streptavidin–biotin system. The measurement of changes in current of the active redox [Fe(CN)
6
]
3−/4−
was carried out by differential pulse voltammetry. The surfaces of SPCE and SPCE/CeO
2
were characterized using scanning electron microscopy, voltammetry and electrochemical impedance spectroscopy. The Box–Behnken experimental optimization design revealed the streptavidin incubation time, aptamer incubation time and streptavidin concentrations were 30 min, 30 min and 10.8 µg ml
−1
, respectively. Various concentrations of ENaC were used to obtain the linearity range of 0.05–3.0 ng ml
−1
, and the limits of detection and quantification were 0.012 ng ml
−1
and 0.038 ng ml
−1
, respectively. This aptasensor method has the potential to measure the ENaC protein levels in urine samples as well as to be a point-of-care device.
Molecular and cellular insight into Escherichia coli SslE and its role during biofilm maturation
Authors: Corsini Paula M. , Wang Sunjun , Rehman Saima , Fenn Katherine , Sagar Amin , Sirovica Slobodan , Cleaver Leanne , Edwards-Gayle Charlotte J. C. , Mastroianni Giulia , Dorgan Ben , Sewell Lee M. , Lynham Steven , Iuga Dinu , Franks W. Trent , Jarvis James , Carpenter Guy H. , Curtis Michael. A. , Bernadó Pau , Darbari Vidya C. , Garnett James A.
Published: February 2021

Escherichia coli is a Gram-negative bacterium that colonizes the human intestine and virulent strains can cause severe diarrhoeal and extraintestinal diseases. The protein SslE is secreted by a range of pathogenic and some commensal E. coli strains. It can degrade mucins in the intestine, promotes biofilm maturation and it is a major determinant of infection in virulent strains, although how it carries out these functions is not well understood. Here we examine SslE from the E. coli Waksman and H10407 strains and reveal that it has a novel and dynamic structure. In response to acidification within mature biofilms we show how SslE forms a unique functional aggregate that interacts with cellulose and regulates the distribution of exopolysaccharides in macrocolony biofilms. Our data indicates that the spatial organization of SslE polymers and local pH are critical for biofilm maturation and SslE is a key factor that drives persistence of SslE-secreting bacteria during acidic stress.
Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.
Authors: De La Vega Francisco M. , Chowdhury Shimul , Moore Barry , Frise Erwin , McCarthy Jeanette , Hernandez Edgar J. , Wong Terrence , James Kiely , Guidugli Lucia , Agrawal Pankaj B. , Genetti Casie A. , Brownstein Catherine A. , Beggs Alan H. , Loscher Britt-Sabina , Franke Andre , Boone Braden , Levy Shawn E. , Ounap Katrin , Pajusalu Sander , Huentelman Matt , Ramsey Keri , Naymik Marcus , Narayanan Vinodh , Veeraraghavan Narayanan , Billings Paul , Reese Martin G. , Yandell Mark , Kingsmore Stephen F.
Published: February 2021

Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed interpretation by comprehensively evaluating genetic variants for pathogenicity in the context of the growing knowledge of genetic disease. We assess the diagnostic performance of GEM, a new, AI-based, clinical decision support tool, compared with expert manual interpretation. We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole genome sequencing (WGS) at Rady Children's Hospital. We also performed a replication study in a separate cohort of 60 cases diagnosed at five additional academic medical centers. For comparison, we also analyzed these cases with commonly used variant prioritization tools (Phevor, Exomiser, and VAAST). Included in the comparisons were WGS and whole exome sequencing (WES) as trios, duos, and singletons. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted either manually or by automated clinical natural language processing (CNLP) from clinical notes. Finally, 14 previously unsolved cases were re-analyzed. GEM ranked >90% of causal genes among the top or second candidate, using manually curated or CNLP derived phenotypes, and prioritized a median of 3 genes for review per case. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top or second candidate irrespective of whether SV calls where provided or inferred ab initio by GEM when absent. Analysis of 14 previously unsolved cases provided novel findings in one, candidates ultimately not advanced in 3, and no new findings in 10, demonstrating the utility of GEM for reanalysis. GEM enables automated diagnostic interpretation of WES and WGS for all types of variants, including SVs, nominating a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing the cost and speeding case review.
Moderators of changes in smoking, drinking, and quitting behaviour associated with the first Covid-19 lockdown in England
Authors: Jackson Sarah E. , Beard Emma , Angus Colin , Field Matt , Brown Jamie
Published: February 2021

Aim

To estimate changes in smoking, drinking, and quitting behaviour from before to during the first Covid-19 lockdown in England, and whether changes differed by age, sex, or social grade.

Design

Representative cross-sectional surveys of adults, collected monthly between August 2018 and July 2020.

Setting

England.

Participants

36,980 adults (≥18y).

Measurements

Independent variables were survey month (pre-lockdown: August-February vs. lockdown months: April-July) and year (pandemic: 2019/20 vs. comparator: 2018/19). Smoking outcomes were smoking prevalence, cessation, quit attempts, quit success, and use of evidence-based or remote cessation support. Drinking outcomes were high-risk drinking prevalence, alcohol reduction attempts, and use of evidence-based or remote support. Moderators were age, sex, and occupational social grade (ABC1=more advantaged/C2DE=less advantaged).

Findings

Relative to changes over the same time period in 2018/19, lockdown was associated with significant increases in smoking prevalence (+24.7% in 2019/20 vs. 0.0% in 2018/19, ORadj=1.35[95%CI=1.12-1.63]) and quit attempts (+39.9% vs. −22.2%, ORadj=2.48[1.76-3.50]) among 18-34 year-olds, but not older groups. Increases in cessation (+156.4% vs. −12.5%, ORadj=3.08[1.86-5.09]) and the success rate of quit attempts (+99.2% vs. +0.8%, ORadj=2.29[1.31-3.98]) were also observed, and did not differ significantly by age, sex, or social grade. Lockdown was associated with a significant increase in high-risk drinking prevalence across all sociodemographic groups (+39.5% vs. −7.8%, ORadj=1.80[1.64-1.98]), with particularly high increases among women (ORadj=2.17[1.87-2.53]) and social grades C2DE (ORadj=2.34[2.00-2.74]). Alcohol reduction attempts increased significantly among high-risk drinkers from social grades ABC1 (ORadj=2.31[1.78-3.00]) but not C2DE (ORadj=1.25[0.83-1.88]), with larger increases among those aged 18-34 (ORadj=2.56[1.72-3.81]) and ≥60 (ORadj=1.43[1.05-1.95]) than 35-59 (ORadj=2.51[1.51-4.18]). There were few significant changes in use of support for smoking cessation or alcohol reduction, although samples were small.

Conclusions

In England, the first Covid-19 lockdown was associated with increased smoking prevalence among younger adults, and increased high-risk drinking prevalence among all adults. Smoking cessation activity also increased: more younger smokers made quit attempts during lockdown and more smokers quit successfully. Socioeconomic disparities in drinking behaviour were evident: high-risk drinking increased by more among women and those from less advantaged social grades (C2DE) but the rate of reduction attempts increased only among the more advantaged social grades (ABC1).
Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU-based disease: the Multi-Targeting Drug DREAM Challenge
Authors: Xiong Zhaoping , Jeon Minji , Allaway Robert J , Kang Jaewoo , Park Donghyeon , Lee Jinhyuk , Jeon Hwisang , Ko Miyoung , Jiang Hualiang , Zheng Mingyue , Tan Aik Choon , Guo Xindi ,   The Multi-Targeting Drug DREAM Challenge Community, Dang Kristen K , Tropsha Alex , Hecht Chana , Das Tirtha K. , Carlson Heather A. , Abagyan Ruben , Guinney Justin , Schlessinger Avner , Cagan Ross
Published: February 2021

A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (‘polypharmacology’). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.

Author Summary

Many modern drugs are developed with the goal of modulating a single cellular pathway or target. However, many drugs are, in fact, ‘dirty;’ they target multiple cellular pathways or targets. This phenomenon is known as multi-targeting or polypharmacology. While some strive to develop ‘cleaner’ therapeutics that eliminate secondary targets, recent work has shown that multi-targeting therapeutics have key advantages for a variety of diseases. However, while multi-targeting drugs that affect a precisely-defined profile of targets may be more effective, it is difficult to computationally predict which molecules have desirable target profiles. Here, we report the results of a competitive crowdsourcing project (the Multi-Targeting Drug DREAM Challenge), where we challenged participants to predict chemicals that have desired target profiles for cancer and neurodegenerative disease.
CONSTAX2: Improved taxonomic classification of environmental DNA markers
Authors: Liber Julian , Bonito Gregory , Benucci Gian Maria Niccolò
Published: February 2021

CONSTAX - the CONSensus TAXonomy classifier - was developed for accurate and reproducible taxonomic annotation of fungal rDNA amplicons and is based upon a consensus approach of RDP, SINTAX and UTAX algorithms. CONSTAX2 can be used to classify prokaryotes and incorporates BLAST-based classifiers to reduce classification errors. Additionally, CONSTAX2 implements a conda-installable, command line tool with improved classification metrics, faster training, multithreading support, capacity to incorporate external taxonomic databases, new isolate matching and high-level taxonomy tools, replete with documentation and example tutorials.

Availability and Implementation

CONSTAX2 is available athttps://github.com/liberjul/CONSTAXv2, and is packaged for Linux and MacOS from Bioconda. A tutorial and documentation are available athttps://constax.readthedocs.io/en/latest/.
A glycan gate controls opening of the SARS-CoV-2 spike protein
Authors: Sztain Terra , Ahn Surl-Hee , Bogetti Anthony T. , Casalino Lorenzo , Goldsmith Jory A. , Seitz Evan , McCool Ryan S. , Kearns Fiona L. , Acosta-Reyes Francisco , Maji Suvrajit , Mashayekhi Ghoncheh , McCammon J. Andrew , Ourmazd Abbas , Frank Joachim , McLellan Jason S. , Chong Lillian T. , Amaro Rommie E.
Published: February 2021

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded “down” to an exposed “up” state in order to bind the human ACE2 receptor and infect cells. While snapshots of the “up” and “down” states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Together with ManifoldEM analysis of cryo-EM data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408, and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.
Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV
Authors: Alrubayyi Aljawharah , Gea-Mallorquí Ester , Touizer Emma , Hameiri-Bowen Dan , Kopycinski Jakub , Charlton Bethany , Fisher-Pearson Natasha , Muir Luke , Rosa Annachiara , Roustan Chloe , Earl Christopher , Cherepanov Peter , Pellegrino Pierre , Waters Laura , Burns Fiona , Kinloch Sabine , Dong Tao , Dorrell Lucy , Rowland-Jones Sarah , McCoy Laura E. , Peppa Dimitra
Published: February 2021

There is an urgent need to understand the nature of immune responses generated against SARS-CoV-2, to better inform risk-mitigation strategies for people living with HIV (PLWH). Although not all PLWH are considered immunosuppressed, residual cellular immune deficiency and ongoing inflammation could influence COVID-19 disease severity, the evolution and durability of protective memory responses. Here, we performed an integrated analysis, characterizing the nature, breadth and magnitude of SARS-CoV-2-specific immune responses in PLWH, controlled on ART, and HIV negative subjects. Both groups were in the convalescent phase of predominately mild COVID-19 disease. The majority of PLWH mounted SARS-CoV-2 Spike- and Nucleoprotein-specific antibodies with neutralizing activity and SARS-CoV-2-specific T cell responses, as measured by ELISpot, at levels comparable to HIV negative subjects. T cell responses against Spike, Membrane and Nucleocapsid were the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. Notably, the overall magnitude of SARS-CoV-2-specific T cell responses related to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses were observed. Both humoral and cellular responses to SARS-CoV-2 were detected at 5-7 months post-infection, providing evidence of medium-term durability of responses irrespective of HIV serostatus. Incomplete immune reconstitution on ART and a low CD4:CD8 ratio could, however, hamper the development of immunity to SARS-CoV-2 and serve as a useful tool for risk stratification of PLWH. These findings have implications for the individual management and potential effectiveness of vaccination against SARS-CoV-2 in PLWH.

One Sentence Summary

Adaptive immune responses to SARS-CoV-2 in the setting of HIV infection
Hepatitis C Virus E1 Protein Enhances Macrophage iNOS Expression In Vitro
Authors: Munkhjargal Batkhishig , Enkhtuvshin Bilguun , Ulziisaikhan Uranbileg , Tuvdenjamts Baljinnyam , Unurbuyan Khulan , Sandagdorj Dolgorsuren , Baasandalai Tuul , Enkhjargal Baasansuren , Sandag Tsogtsaikhan , Tsolmon Bilegtsaikhan , Lkhagvasuren Enkhsaikhan
Published: February 2021

Objective

Hepatitis C virus (HCV) is a single-stranded RNA virus that causes chronic hepatitis, cirrhosis, and liver cancer. Approximately 170 million individuals are infected with HCV worldwide. The pathogenesis of HCV-associated liver injury is thought to be due to the host antiviral immune response, including the T cell response, and excessive production of proinflammatory cytokines, reactive oxygen species, and nitric oxide (NO).

Interferon-γ (IFN-γ) is a key cytokine in the adaptive immune response that is primarily secreted from CD4+ T helper cells to induce cytotoxic T lymphocyte (CTL) cell response against HCV infection. Another important role of IFN-γ is the activation of macrophages in the liver resulting in inhibition of viral replication and increased NO production.

Enhanced inducible nitric oxide synthase (iNOS) expression and NO production observed in the liver of HCV-infected patients is positively correlated with viral load and hepatic inflammation. HCV-infected macrophages are major producers of NO in the liver. It is not completely understood how HCV proteins affect iNOS expression and what the role of IFN-γ is in HCV protein expression in HCV-infected macrophages. In this study, we examined the effect of INF-γ and HCV proteins on iNOS expression in the Raw264.7 cell line.

Results

Consistent with other studies, HCV core and NS5A proteins induced iNOS expression in macrophages. Moreover, HCV E1 protein-enhanced iNOS expression is highest in the presence and absence of IFN-γ activation.

Conclusion

These results indicate that hepatitis C virus core, NS5A, E1 protein regulates iNOS protein expression in IFN-γ-activated and resting macrophage cell lines. These findings points to a future research direction for understanding the pathogenesis of HCV-related liver inflammation.
“A compressed representation of spatial distance in the rodent hippocampus’’
Authors: Sheehan Daniel J. , Charczynski Stephen , Fordyce Blake A. , Hasselmo Michael E. , Howard Marc W.
Published: February 2021

Principal cells in the rodent hippocampus often fire in response to traversal through a specific spatial location (place cells), as well as elapsed time during an imposed temporal delay or after stimulus offset (time cells). Sequences of time cells unfold rapidly at first, with many time cells with narrow time fields. As the triggering event recedes into the past, time cells are fewer and have broader fields. This means that the representation of time in the hippocampus is compressed with greater resolution for time points near the present. Using tetrode recordings we measured individual CA1 units while rats traveled along a track that could be changed in length. Consistent with previous results, most place cells coded for distance from the starting point of the trajectory. Critically, place cells became less numerous and showed gradually widening fields with distance from the starting location. These results suggest that as the animal leaves a landmark, the hippocampal place code forms a compressed representation of distance from the starting location. The representation of time and space in the hippocampus have similar properties suggesting that they arise from similar computational mechanisms.

Significance Statement

The hippocampus represents relationships between events in time and space. It has been hypothesized that temporal and spatial relationships are the result of a common computational mechanism. Previous work has shown that the representation of time in the hippocampus is compressed, with less neural resolution for more temporally remote events, consistent with the observation that temporal memory is worse for events further in the past. This paper shows an analogous result for spatial relationships. Place cells coded for distance from the start of a journey. As distance increased, place fields became broader and less numerous, showing a decrease in spatial resolution. This result suggests a unified coding scheme for the dimensions of time and space in the rodent hippocampus.
Human primed endothelial colony forming cells exert neuroprotective effects in the growth restricted newborn piglet
Authors: Chand Kirat K. , Patel Jatin , Bjorkman Tracey , Sim Seen-Ling , Miller Stephanie M. , Teo Elliot , Jones Lara , Sun Jane , Colditz Paul B. , Khosrotehrani Kiarash , Wixey Julie A.
Published: February 2021

The fetal brain is particularly vulnerable to the detrimental effects of fetal growth restriction (FGR) with subsequent abnormal neurodevelopment being common. There are no current treatments to protect the FGR newborn from lifelong neurological disorders. This study examines whether pure fetal mesenchymal stem cells and endothelial colony forming cells (ECFC) from the human term placenta are neuroprotective through modulating neuroinflammation and supporting the brain vasculature. We determined that one dose of these primed ECFCs (pECFC) on the first day of life to the newborn FGR piglet improved damaged vasculature, restored the neurovascular unit, reduced brain inflammation and improved adverse neuronal and white matter changes present in the FGR newborn piglet brain. These findings could not be reproduced using mesenchymal stromal cells alone. These results demonstrate pECFC treatment exerts beneficial effects on multiple cellular components in the FGR brain and act as a neuroprotectant.

One Sentence Summary

Stem cell treatment improves brain outcomes in the growth restricted newborn
Computational Fluid Dynamics Modeling of Cough Transport in an Aircraft Cabin
Authors: Zee Malia , Davis Angela C. , Clark Andrew D. , Wu Tateh , Jones Stephen P. , Waite Lindsay L. , Cummins Joshua J. , Olson Nels A.
Published: February 2021

To characterize the transport of respiratory pathogens during commercial air travel, Computational Fluid Dynamics simulations were performed to track particles expelled by coughing by a passenger assigned to different seats on a Boeing 737 aircraft. Simulation data were post-processed to calculate the amounts of particles inhaled by nearby passengers. Different airflow rates were used, as well as different initial conditions to account for random fluctuations of the flow field. Overall, 80% of the particles were removed from the cabin in 1.3 to 2.6 minutes, depending on conditions, and 95% of the particles were removed in 2.4 to 4.6 minutes. Reducing airflow increased particle dispersion throughout the cabin but did not increase the highest exposure of nearby passengers. The highest exposure was 0.3% of the nonvolatile mass expelled by the cough, and the median exposure for seats within 3 feet of the cough discharge was 0.1%, which was in line with recent experimental testing.
Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics
Authors: Chu Xiakun , Wang Jin
Published: February 2021

Cancer reflects the dysregulation of the underlying gene network, which is intimately related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosomal structural transition during the can-cerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanded structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on chromosome. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosomal structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization, which contains initial reprogramming towards the stem cell followed by differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of cell stemness.
Dynamin is primed at endocytic sites for ultrafast endocytosis
Authors: Imoto Yuuta , Raychaudhuri Sumana , Fenske Pascal , Sandoval Eduardo , Itoh Kie , Blumrich Eva-Maria , Mamer Lauren , Zarebidaki Fereshteh , Söhl-Kielczynski Berit , Trimbuch Thorsten , Nayak Shraddha , Iwasa Janet H. , Jorgensen Erik M. , Cousin Michael A. , Rosenmund Christian , Watanabe Shigeki
Published: February 2021

Dynamin mediates fission of vesicles from the plasma membrane during endocytosis. Typically, dynamin is recruited from the cytosol to endocytic sites, requiring seconds to tens of seconds. However, ultrafast endocytosis in neurons internalizes vesicles as quickly as 50 ms during synaptic vesicle recycling. Here we demonstrate that Dynamin 1 is pre-recruited to endocytic sites for ultrafast endocytosis. Specifically, Dynamin 1xA, a splice variant of Dynamin 1, interacts with Syndapin 1 to form molecular condensates on the plasma membrane when the proline-rich domain of this variant is dephosphorylated. When this domain is mutated to include phosphomimetic residues or Syndapin 1’s dynamin-interacting domain is mutated, Dynamin 1xA becomes diffuse, and consequently, ultrafast endocytosis slows down by ∼100-fold. Mechanistically, Syndapin 1 acts as an adaptor by binding the plasma membrane and stores Dynamin 1xA at endocytic sites. This cache bypasses the recruitment step and accelerates endocytosis at synapses.
Impacts of COVID-19 on long-term health and health care use
Authors: Skyrud Katrine , Hernæs Kjersti Helene , Telle Kjetil , Magnusson Karin
Published: February 2021

Aim

To explore the temporal impact of mild COVID-19 on need for primary and specialist health care services.

Methods

In all persons tested for SARS-CoV-2 in Norway March 1st 2020 to February 1st 2021 (N=1 401 922), we contrasted the monthly all-cause health care use before and up to 6 months after the test (% relative difference), for patients with a positive test for SARS-CoV-2 (non-hospitalization, i.e. mild COVID-19) and patients with a negative test (no COVID-19).

Results

We found a substantial short-term elevation in primary care use in all age groups, with men generally having a higher relative increase (men 20-44 years: 522%, 95%CI=509-535, 45-69 years: 439%, 95%CI=426-452, ≥ 70 years: 199%, 95%CI=180-218) than women (20-44 years: 342, 95%CI=334-350, 45-69 years=375, 95%CI=365-385, ≥ 70 years: 156%, 95%CI=141-171) at 1 month following positive test. At 2 months, this sex difference was less pronounced, with a (20-44 years: 21%, 95%CI=13-29, 45-69 years=38%, 95%CI=30-46, ≥ 70 years: 15%, 95%CI=3-28) increase in primary care use for men, and a (20-44 years: 30%, 95%CI=24-36, 45-69 years=57%, 95%CI=50-64, ≥ 70 years: 14%, 95%CI=4-24) increase for women. At 3 months after test, only women aged 45-70 years still had an increased primary care use (14%, 95%CI=7-20). The increase was due to respiratory- and general/unspecified conditions. We observed no long-term (4-6 months) elevation in primary care use, and no elevation in specialist care use.

Conclusion

Mild COVID-19 gives an elevated need for primary care that vanishes 2-3 months after positive test. Middle-aged women had the most prolonged increased primary care use.
Osmolarity-regulated swelling initiates egg activation inDrosophila
Authors: York-Andersen Anna H. , Wood Benjamin W. , Wilby Elise L. , Berry Alexander S. , Weil Timothy T.
Published: February 2021

Egg activation is a series of highly coordinated processes that prepare the mature oocyte for embryogenesis. Typically associated with fertilisation, egg activation results in many downstream outcomes, including the resumption of the meiotic cell cycle, translation of maternal mRNAs and cross-linking of the vitelline membrane. While some aspects of egg activation, such as initiation factors in mammals and environmental cues in sea animals, have been well-documented, the mechanics of egg activation in insects are less well understood. For many insects, egg activation can be triggered independently of fertilisation. InDrosophila melanogaster, egg activation occurs in the oviduct resulting in a single calcium wave propagating from the posterior pole of the oocyte.

Here we use physical manipulations, genetics and live imaging to demonstrate the requirement of a volume increase for calcium entry at egg activation in matureDrosophilaoocytes. The addition of water, modified with sucrose to a specific osmolarity, is sufficient to trigger the calcium wave in the mature oocyte and the downstream events associated with egg activation. We show that the swelling process is regulated by the conserved osmoregulatory channels, aquaporins (AQPs) and DEGenerin/Epithelial Na+(DEG/ENaC) channels. Furthermore, through pharmacological and genetic disruption, we reveal a concentration-dependent requirement of Trpm channels to transport calcium, most likely from the perivitelline space, across the plasma membrane into the mature oocyte.

Our data establishes osmotic pressure as the mechanism that initiates egg activation inDrosophilaand is consistent with previous work from evolutionarily distant insects, including dragonflies and mosquitos, and shows remarkable similarities to the mechanism of egg activation in some plants.
The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs
Authors: Sheikh Zeshan P. , Wulf Matthias , Friis Søren , Althaus Mike , Lynagh Timothy , Pless Stephan A.
Published: February 2021

The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium around 10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). The most obvious explanation for this discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we use conventional and non-canonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that they contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work supports the notion that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. The results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.
The evolution of the cytochromec6family of photosynthetic electron transfer proteins
Authors: Slater Barnaby , Kosmützky Darius , Nisbet R. Ellen R. , Howe Christopher J.
Published: February 2021

During photosynthesis, electrons are transferred between the cytochromeb6fcomplex and photosystem I. This is carried out by the protein plastocyanin in plant chloroplasts. In contrast, electron transfer can be carried out by either plastocyanin or cytochromec6in many cyanobacteria and eukaryotic algal species. There are three further cytochromec6homologues: cytochromec6Ain plants and green algae, and cytochromesc6Bandc6Cin cyanobacteria. The function of these proteins is unknown. Here, we present a comprehensive analysis of the evolutionary relationship between the members of the cytochromec6family in photosynthetic organisms. Our phylogenetic analyses show that cytochromec6Band cytochromec6Care likely to be orthologues that arose from a duplication of cytochromec6, but that there is no evidence for separate origins for cytochromec6Bandc6C. We therefore propose re-naming cytochromec6Cas cytochromec6B. We show that cytochromec6Ais likely to have arisen from cytochromec6Brather than by an independent duplication of cytochromec6, and present evidence for an independent origin of a protein with some of the features of cytochromec6Ain peridinin dinoflagellates. We conclude with a new comprehensive model of the evolution of the cytochromec6family which is an integral part of understanding the function of the enigmatic cytochromec6homologues.
Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization
Authors: Turner Hannah L. , Andrabi Raiees , Cottrell Christopher A. , Richey Sara T. , Song Ge , Callaghan Sean , Anzanello Fabio , Moyer Tyson J. , Abraham Wuhbet , Melo Mariane , Silva Murillo , Scaringi Nicole , Rakasz Eva G. , Sattentau Quentin , Irvine Darrell J. , Burton Dennis R. , Ward Andrew B.
Published: February 2021

Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non or weakly neutralizing (“off-target”) antibodies. Using our recently developed electron microscopy epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.
Effectiveness of Joint Species Distribution Models in the Presence of Imperfect Detection
Authors: Hogg Stephanie , Wang Yan , Stone Lewi
Published: February 2021

Joint species distribution models (JSDMs) are a recent development in biogeography and enable the spatial modelling of multiple species and their interactions and dependencies. However, most models do not consider imperfect detection, which can significantly bias estimates. This is one of the first papers to account for imperfect detection when fitting data with JSDMs and to explore the complications that may arise.

A multivariate probit JSDM that explicitly accounts for imperfect detection is proposed, and implemented using a Bayesian hierarchical approach. We investigate the performance of the JSDM in the presence of imperfect detection for a range of factors, including varied levels of detection and species occupancy, and varied numbers of survey sites and replications. To understand how effective this JSDM is in practice, we also compare results to those from a JSDM that does not explicitly model detection but instead makes use of “collapsed data”. A case study of owls and gliders in Victoria Australia is also illustrated.

Using simulations, we found that the JSDMs explicitly accounting for detection can accurately estimate intrinsic correlation between species with enough survey sites and replications. Reducing the number of survey sites decreases the precision of estimates, while reducing the number of survey replications can lead to biased estimates. For low probabilities of detection, the model may require a large number of survey replications to remove bias from estimates. However, JSDMs not explicitly accounting for detection may have a limited ability to dis-entangle detection from occupancy, which substantially reduces their ability to accurately infer the species distribution spatially. Our case study showed positive correlation between Sooty Owls and Greater Gliders, despite a low number of survey replications.

To avoid biased estimates of inter-species correlations and species distributions, imperfect detection needs to be considered. However, for low probability of detection, the JSDMs explicitly accounting for detection is data hungry. Estimates from such models may still be subject to bias. To overcome the bias, researchers need to carefully design surveys and choose appropriate modelling approaches. The survey design should ensure sufficient survey replications for unbiased inferences on species inter-dependencies and occupancy.