bluuebunny/crossref_metadata_2025 huggingface dataset:
The epidemiological characteristics of COVID-19 in Libya during the ongoing-armed conflict
Authors: Daw Mohamed Ali , El-Bouzedi Abdallah Hussean , Ahmed Mohamed Omar , Alejenef Ali Ali
Published: September 2020

Introduction

COVID-19 can have even more dire consequences in countries with ongoing armed conflict. Libya, the second largest African country, has been involved in a major conflict since 2011. This study analyzed the epidemiological situation of the COVID-19 pandemic in Libya, examined the impact of the armed conflict in Libya on the spread of the pandemic, and proposes strategies for dealing with the pandemic during this conflict.

Methods

We collected the available information on all COVID-19 cases in the different regions of Libya, covering the period from March 25 to May 25, 2020. The cumulative number of cases and the daily new cases are presented in a way to illustrate the patterns and trends of COVID-19 and the effect of the ongoing armed conflict was assessed regionally.

Results

A total of 698 cases of COVID-19 were reported in Libya during a period of three months. The number of cases varied from one region to another and was affected by the fighting. The largest number of cases was reported in the southern part of the country, which has been severely affected by the conflict in comparison to the eastern and western parts of the country.

Conclusion

This study describes the epidemiological pattern of COVID-19 in Libya and how it has been affected by the ongoing armed conflict. This conflict seems to have hindered access to populations and thereby masked the true dimensions of the pandemic. Hence, efforts should be combined to combat these consequences.
Aerosol emission of child voices during speaking, singing and shouting
Authors: Mürbe Dirk , Kriegel Martin , Lange Julia , Schumann Lukas , Hartmann Anne , Fleischer Mario
Published: September 2020

Since the outbreak of the COVID-19 pandemic, singing activities for children and young people have been strictly regulated with far-reaching consequences for music education in schools and ensemble and choir singing in some places. This is also due to the fact, that there has been no reliable data available on aerosol emissions from children’s speaking, singing, and shouting. By utilizing a laser particle counter in cleanroom conditions we show, that children emit fewer aerosols during singing than what has been known so far for adults. In our data, the emission rates ranged from 16 P/s to 267 P/s for speaking, 141 P/s to 1240 P/s for singing, and 683 P/s to 4332 P/s for shouting. The data advocate an adaptation of existing risk management strategies and rules of conduct for groups of singing children, like gatherings in an educational context, e.g. singing lessons or choir rehearsals.
Ductal Carcinoma In Situ with Diffuse Growth Distribution: A Potentially Lethal Subtype of “Preinvasive” Disease
Authors: O’Keefe Thomas J , Harismendy Olivier , Wallace Anne M
Published: September 2020

PURPOSE

The current trend in ductal carcinoma in situ (DCIS) research is towards treatment de-escalation. Problematically, prognostic indicators for patients at high risk of breast cancer mortality (BCM), rather than recurrence, have not been identified. We aim to identify prognostic factors for the development of metastatic disease and mortality.

EXPERIMENTAL DESIGN

Patients diagnosed with DCIS in a local cancer registry as well as in the National Cancer Database (NCDB) and the Surveillance, Epidemiology and End Results (SEER) program were assessed for factors prognostic of metastatic disease, overall, and breast-cancer specific survival. Cox and competing risks regressions were developed.

RESULTS

Among 5 patients who developed distant metastatic disease in the cancer registry, 3 had identifiable growth distribution; all 3 were diffuse type. None had in-breast invasive or DCIS recurrences before metastasis. In NCDB and SEER, cumulative incidence of any cause mortality (ACM) and BCM at 10 years was 12%/5.0% for diffuse lesions; 8%/3.6% for patients with microinvasive disease, 7.4%/2.3% for lesions >5 cm, 5.6%/1.4% for lesions 2-5 cm and 5.5%/1.5% for lesions <2 cm. Multivariate hazard ratios for ACM in NCDB and BCM in SEER were 2.0 and 5.3 (p=0.03 and 0.02, respectively). Among patients with diffuse lesions, cumulative incidence ACM at 10 years was 15.0% among those undergoing unilateral mastectomy vs. 2.5% among those undergoing bilateral mastectomy (p=0.11).

CONCLUSION

Diffuse DCIS represents an uncommon but deadly subtype for whom treatment escalation, rather than de-escalation, is likely necessary. Further studies elucidating the mechanism of metastasis and best treatment course are needed.
In-concert immune dynamics during natural influenza virus infection and recovery in acute hospitalized patients
Authors: Nguyen Thi H.O. , Koutsakos Marios , van de Sandt Carolien E. , Crawford Jeremy Chase , Loh Liyen , Sant Sneha , Grzelak Ludivine , Allen Emma K. , Brahm Tim , Clemens E. Bridie , Auladell Maria , Hensen Luca , Wang Zhongfang , Nüssing Simone , Jia Xiaoxiao , Günther Patrick , Wheatley Adam K. , Kent Stephen J. , Aban Malet , Deng Yi-Mo , Laurie Karen L. , Hurt Aeron C. , Gras Stephanie , Rossjohn Jamie , Crowe Jane , Xu Jianqing , Jackson David , Brown Lorena E. , Gruta Nicole La , Chen Weisan , Doherty Peter C. , Turner Stephen J. , Kotsimbos Tom C. , Thomas Paul G. , Cheng Allen C. , Kedzierska Katherine
Published: September 2020

We report in-concert dynamics of 18 key immune parameters, related to clinical, genetic and virological factors, in patients hospitalized with influenza across different severity levels. Influenza disease was associated with correlated increases in IL6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells (cTfhs) correlated with peak antibody-secreting cells (ASC) and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differed from vaccination-induced B-cell responses. Influenza-specific CD8+/CD4+T-cells increased early in disease and remained activated during patient recovery. Here, we describe the broadest to-date immune cellular networks underlying recovery from influenza infection, highly relevant to other infectious diseases.
WASP: A software package for correctly characterizing the topological development of ribbon structures
Authors: Sierzega Zachary , Wereszczynski Jeff , Prior Chris
Published: September 2020

We introduce the Writhe Application Software Package (WASP) which can be used to characterise the topology of ribbon structures, the underlying mathematical model of DNA, Biopolymers, superfluid vorticies, elastic ropes and magnetic flux ropes. This characterisation is achieved by the general twist-writhe decomposition of both open and closed ribbons, in particular through a quantity termed the polar writhe. We demonstrate how this decomposition is far more natural and straightforward than artificial closure methods commonly utilized in DNA modelling. In particular, we demonstrate how the decomposition of the polar writhe in local and non-local components distinctly characterizes local helical structure and knotting/linking of the ribbon. This decomposition provides additional information not given by alternative approaches. As an example application, the WASP routines are used to characterise the evolving topology (writhe) of DNA minicircle and open ended plectoneme formation magnetic/optical tweezer simulations. Finally it is demonstrated that a number of well known alternative writhe expressions are actually simplifications of the polar writhe measure.
Deorphanisation of novel biogenic amine-gated ion channels identifies a new serotonin receptor for learning
Authors: Morud Julia , Hardege Iris , Liu He , Wu Taihong , Basu Swaraj , Zhang Yun , Schafer William R
Published: September 2020

Pentameric ligand-gated ion channels (LGCs) play conserved, critical roles in fast synaptic transmission, and changes in LGC expression and localisation are thought to underlie many forms of learning and memory. TheC. elegansgenome encodes a large number of LGCs without a known ligand or function. Here, we deorphanize five members of a family of Cys-loop LGCs by characterizing their diverse functional properties that are activated by biogenic amine neurotransmitters. To analyse the neuronal function of these LGCs, we show that a novel serotonin-gated cation channel, LGC-50, is essential for aversive olfactory learning.lgc-50mutants show a specific defect in learned olfactory avoidance of pathogenic bacteria, a process known to depend on serotonergic neurotransmission. Remarkably, the expression of LGC-50 in neuronal processes is enhanced by olfactory conditioning; thus, the regulated expression of these receptors at synapses appears to represent a molecular cornerstone of the learning mechanism.
High-sensitivity vision restoration via ectopic expression of chimeric rhodopsin in mice
Authors: Katada Yusaku , Yoshida Kazuho , Serizawa Naho , Kobayashi Kenta , Neghisi Kazuno , Okano Hideyuki , Kandori Hideki , Tsubota Kazuo , Kurihara Toshihide
Published: September 2020

Photoreception requires amplification by mammalian rhodopsin through G protein activation, which requires a visual cycle. To achieve this in retinal gene therapy, we incorporated human rhodopsin cytoplasmic loops intoGloeobacterrhodopsin, thereby generatingGloeobacterand human chimeric rhodopsin (GHCR). In a murine model of inherited retinal degeneration, we induced retinal GHCR expression by intravitreal injection of a recombinant adeno-associated virus vector. Retinal explant and visual thalamus electrophysiological recordings, behavioral tests, and histological analysis showed that GHCR restored dim-environment vision and prevented the progression of retinal degeneration. Thus, GHCR may be a potent clinical tool for the treatment of retinal disorders.

One Sentence Summary

Optogenetic therapy with Gloeobacter and human chimeric rhodopsin resulted in highly sensitive visual restoration and protection effects.
DNA Methylation Reprogramming during Sex Determination and Transition in Zebrafish
Authors: Wang Xinxin , Ma Xin , Wei Gaobo , Ma Weirui , Zhang Zhen , Chen Xuepeng , Gao Lei , Liu Zhenbo , Yuan Yue , Yi Lizhi , Wang Jun , Tokumoto Toshinobu , Huang Junjiu , Chen Dahua , Zhang Jian , Liu Jiang
Published: September 2020

It is a mystery about sex determination and sexual plasticity in species without sex chromosomes. DNA methylation is a prevalent epigenetic modification in vertebrates, which has been shown to involve in the regulation of gene expression and embryo development. However, it remains unclear about how DNA methylation regulates sexual development. To elucidate it, we used zebrafish to investigate DNA methylation reprogramming during juvenile germ cell development and adult female-to-male sex transition. We revealed that primordial germ cells (PGCs) undergo significant DNA methylation reprogramming during germline development and set to an oocyte/ovary-like pattern at 9 days post fertilization (9 dpf). When blocking DNMTs activity in juveniles after 9 dpf, the zebrafish preferably develops into females. We also show thatTet3involves in PGC development. Notably, we find that DNA methylome reprogramming during adult zebrafish sex transition is similar to the reprogramming during the sex differentiation from 9 dpf PGCs to sperm. Furthermore, inhibiting DNMTs activity can prevent the female-to-male sex transition, suggesting that methylation reprogramming is required for zebrafish sex transition. In summary, DNA methylation plays important roles in zebrafish germline development and sexual plasticity.
Conserved Arginine Residues in Synaptotagmin 1 Regulate Fusion Pore Expansion Through Membrane Contact
Authors: Nyenhuis Sarah B. , Karandikar Nakul , Kiessling Volker , Kreutzberger Alex , Thapa Anusa , Liang Binyong , Tamm Lukas , Cafiso David S.
Published: September 2020

Synaptotagmin 1 is a vesicle-anchored membrane protein that functions as the Ca2+sensor for synchronous neurotransmitter release. In this work, an arginine containing region in the second C2 domain of synaptotagmin 1 (C2B) is shown to control the expansion of the fusion pore and thereby the concentration of neurotransmitter released. This arginine apex, which is opposite the Ca2+binding sites, interacts with membranes or membrane reconstituted SNAREs; however, only the membrane interactions occur under the conditions in which fusion takes place. Other regions of C2B influence the probably and kinetics of fusion but do not control the expansion of the fusion pore. These data indicate that the C2B domain has at least two distinct molecular roles in the fusion event, and the data are consistent with a novel model where the arginine apex of C2B positions the domain at the curved membrane surface of the expanding fusion pore.
Including intraspecific trait variability to avoid distortion of functional diversity and ecological inference: lessons from natural assemblages
Authors: Wong Mark K. L. , Carmona Carlos P.
Published: September 2020

Functional diversity assessments are crucial and increasingly used for understanding ecological processes and managing ecosystems. The functional diversity of a community is assessed by sampling traits at one or more scales (individuals, populations, species) and calculating a summary index of the variation in trait values. However, it remains unclear how the scale at which traits are sampled and the indices used to estimate functional diversity may alter the patterns observed and inferences about ecological processes.

For 40 plant and 61 ant communities, we assess functional diversity using six methods – encompassing various mean-based and probabilistic methods – chosen to reflect common scenarios where different levels of detail are available in trait data. We test whether including trait variability at different scales (from individuals to species) alter functional diversity values calculated using volume-based and dissimilarity-based indices, Functional Richness (FRic) and Rao, respectively. We further test whether such effects alter the functional diversity patterns observed across communities and their relationships with environmental drivers such as abiotic gradients and occurrences of invasive species.

Intraspecific trait variability strongly determined FRic and Rao. Methods using only species’ mean trait values to calculate FRic (convex hulls) and Rao (Gower-based dissimilarity) distorted the patterns observed when intraspecific trait variability was considered. These distortions generated Type I and Type II errors for the effects of environmental factors structuring the plant and ant communities.

The high sensitivity of FRic to individuals with extreme trait values was revealed in comparisons of different probabilistic methods including among-individual and among-population trait variability in functional diversity. By contrast, values and ecological patterns in Rao were consistent among methods including different scales of intraspecific trait variability.

Decisions about where traits are sampled and how trait variability is included in functional diversity can drastically change the patterns observed and conclusions about ecological processes. We recommend sampling the traits of multiple individuals per species and capturing their intraspecific trait variability using probabilistic methods. We discuss how intraspecific trait variability can be reasonably estimated and included in functional diversity in the common circumstance where only limited trait data are available.
Release of insulin granules by simultaneous, high-speed correlative SICM-FCM
Authors: Bednarska Joanna , Novak Pavel , Korchev Yuri , Rorsman Patrik , Tarasov Andrei I. , Shevchuk Andrew
Published: September 2020

Exocytosis of peptides and steroids stored in a dense core vesicular (DCV) form is the final step of every secretory pathway, indispensable for the function of nervous, endocrine and immune systems. The lack of live imaging techniques capable of direct, label-free visualisation of DCV release makes many aspects of the exocytotic process inaccessible to investigation. We describe the application of correlative scanning ion conductance and fluorescence confocal microscopy (SICM-FCM) to study the exocytosis of individual granules of insulin from the top, non-adherent, surface of pancreatic β-cells. Using SICM-FCM, we were first to directly follow the topographical changes associated with physiologically-induced release of insulin DCVs. This allowed us to report the kinetics of the full fusion of the insulin vesicle as well as the subsequent solubilisation of the released insulin crystal.
Identification and Characterization of a Residual Host Cell Protein Hexosaminidase B Associated with N-glycan Degradation During the Stability Study of a Therapeutic Recombinant Monoclonal Antibody Product
Authors: Li Xuanwen , An Yan , Liao Jing , Xiao Li , Swanson Michael , Martinez-Fonts Kirby , Pavon Jorge Alexander , Sherer Edward C. , Jawa Vibha , Gao Xinliu , Letarte Simon , Richardson Douglas D.
Published: September 2020

Host cell proteins (HCPs) are process-related impurities derived from host organisms, which need to be controlled to ensure adequate product quality and safety. In this study, product quality attributes were tracked for several mAbs under the intended storage and accelerated stability conditions. One product quality attribute not expected to be stability indicating is the N-glycan heterogeneity profile. However, significant N-glycan degradation was observed for one mAbs under accelerated and stressed stability conditions. The root cause for this instability was attributed to Hexosaminidase B (HEXB), an enzyme known to remove terminal N-acetylglucosamine (GlcNAc). HEXB was identified by liquid chromatography–mass spectrometry (LC-MS) based proteomics approach to be enriched in the impacted stability batches from mAb-1. Subsequently, enzymatic and targeted multiple reaction monitoring (MRM) MS assays were developed to support process and product characterization. A potential interaction between HEXB and mAb-1 was initially observed from the analysis of process intermediates by proteomics among several mAbs and later supported by computational modeling. An improved bioprocess was developed to significantly reduce HEXB levels in the final drug substance. A risk assessment was conducted by evaluating thein silicoimmunogenicity risk and the impact on product quality. To the best of our knowledge, HEXB is the first residual HCP reported to have impact on the glycan profile of a formulated drug product. The combination of different analytical tools, mass spectrometry and computational modeling provide a general strategy on how to study residual HCP for biotherapeutics development.
Genomic insights into adaptations of TMA-utilizing methanogens to diverse habitats including the human gut
Authors: de la Cuesta-Zuluaga Jacobo , Spector Timothy D. , Youngblut Nicholas D. , Ley Ruth E.
Published: September 2020

Archaea of the orderMethanomassiliicoccalesuse methylated-amines such as trimethylamine as a substrate for methane production. They form two large phylogenetic clades and reside in diverse environments, from soil to the human gut. Two genera, one from each clade, inhabit the human gut:Methanomassiliicoccus, which has one cultured representative, and “candidatusMethanomethylophilus”, which has none. Questions remain regarding their distribution across different biomes and human populations, their association with other taxa in the human gut, and whether host genetics correlate with their abundance. To gain insight into theMethanomassiliicoccales, and the human-associated members in particular, we performed a genomic comparison of 72Methanomassiliicoccalesgenomes and assessed their presence in metagenomes derived from the human gut (n=4472 representing 25 populations), nonhuman animal gut (n=145) and nonhost environments (n=160). Our analyses showed that all taxa are generalists: they were detected in animal gut and environmental samples. We confirmed two large clades, one enriched in the gut, the other enriched in the environment, with notable exceptions. Genomic adaptations to the gut include genome reduction, a set of adhesion factors distinct from that of environmental taxa, and genes involved in the shikimate pathway and bile resistance. Genomic adaptations differed by clade, not habitat preference, indicating convergent evolution between the clades. In the human gut, the relative abundance ofMethanomassiliicoccalescorrelated with trimethylamine-producing bacteria and was unrelated to host genotype. Our results shed light on the microbial ecology of this group may help guideMethanomassiliicoccales-basedstrategies for trimethylamine mitigation in cardiovascular disease.

Importance

Methanomassiliicoccalesare a lesser known component of the human gut microbiota. This archaeal order is composed of methane producers that use methylated amines, such as trimethylamine, in methane production. This group has only one cultured representative; how they adapted to inhabit the mammalian gut and how they interact with other microbes is largely unknown. Using bioinformatics methods applied to DNA from a wide range of samples, we profiled the relative abundances of these archaea in environmental and host-associated microbial communities. We observed two groups ofMethanomassiliicoccales, one largely host-associated and one largely found in environmental samples, with some exceptions. When host-associated, these archaea have a distinct set of genes related to adhesion and possess genes related to bile resistance. We did not detectMethanomassiliicoccalesin all human populations tested but when present, they are correlated withBacteriaknown to produce trimethylamine. Since trimethylamine is linked to cardiovascular disease risk, these intriguing Archaea may also be involved.
Histidine-rich Ca2+-binding protein stimulates the transport cycle of SERCA through a conformation-dependent fuzzy complex
Authors: Ayeotan Temitope I. , Hansen Line Cecilie , Boesen Thomas , Olesen Claus , Møller Jesper V. , Nissen Poul , Kjaergaard Magnus
Published: September 2020

The histidine-rich Ca2+-binding protein (HRC) stimulates the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) to increase Ca2+-uptake into the lumen. HRC also binds the triadin scaffold in a Ca2+-dependent manner, and HRC tunes both the uptake and release of Ca2+depending on the concentration in the intracellular Ca2+-stores. We investigated how HRC stimulates SERCA pumping using biochemical and biophysical assays, and show that HRC is an intrinsically disordered protein that binds directly to SERCA via electrostatic interactions. The affinity of the interaction depends on the conformation of SERCA, and HRC binds most tightly in the calcium-released E2P state. This state marks the end of the rate-limiting [Ca2]E1P to E2P transition of SERCA, and suggests that HRC stimulates SERCA by preferentially stabilizing the end point of this transition. HRC remains disordered in the bound state and thus binds in a dynamic, fuzzy complex. The binding of HRC to SERCA shows that fuzzy complexes formed by disordered proteins may be conformation-specific, and use this specificity to modulate the functional cycle of complex molecular machines such as a P-type ATPase.
Metabolic stress and disease-stage specific basigin expression of peripheral blood immune cell subsets in COVID-19 patients
Authors: Siska Peter J. , Singer Katrin , Klitzke Jana , Kauer Nathalie , Decking Sonja-Maria , Bruss Christina , Matos Carina , Kolodova Kristina , Peuker Alice , Schönhammer Gabriele , Raithel Johanna , Lunz Dirk , Graf Bernhard , Geismann Florian , Lubnow Matthias , Mack Matthias , Hau Peter , Bohr Christopher , Burkhardt Ralph , Gessner Andre , Salzberger Bernd , Hanses Frank , Hitzenbichler Florian , Heudobler Daniel , Lüke Florian , Pukrop Tobias , Herr Wolfgang , Wolff Daniel , Poeck Hendrik , Brochhausen Christoph , Hoffmann Petra , Rehli Michael , Kreutz Marina , Renner Kathrin
Published: September 2020

Coronavirus disease 2019 (COVID-19) is driven by dysregulated immune responses yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 47 patients with confirmed SARS-CoV-2 infection and 16 uninfected controls, we found an immunometabolic dysregulation specific for patients with progressed disease that was reversible in the recovery phase. Specifically, T cells and monocytes exhibited increased mitochondrial mass, accumulated intracellular ROS and these changes were accompanied by disrupted mitochondrial architecture. Basigin (CD147), but not established markers of T cell activation, was up-regulated on T cells from progressed COVID-19 patients and correlated with ROS accumulation, reflected in the transcriptome. During recovery, basigin and ROS decreased to match the uninfected controls.In vitroanalyses confirmed the correlation and showed a down-regulation of ROS by dexamethasone treatment. Our findings provide evidence of a basigin-related and reversible immunometabolic dysregulation in COVID-19.
Mental health in higher-education students and non-students: evidence from a nationally representative panel study
Authors: Tabor Evangeline , Patalay Praveetha , Bann David
Published: September 2020

Despite increasing policy focus on mental health provision for higher education students, it is unclear whether they have worse mental health outcomes than their non-student peers. In a nationally-representative UK study spanning 2010-2019 (N=11,519), 17-24 year olds who attended higher education had lower average psychological distress (GHQ score difference=–0.37, 95%CI: −0.60, −0.08) and lower odds of case-level distress than those who did not (OR=0.91, 95%CI: 0.81, 1.02). Increases in distress between 2010 and 2019 were similar in both groups. Accessible mental health support outside higher education settings is necessary to prevent further widening of socioeconomic inequalities in mental health.
Relationships between demographic, geographic, and environmental statistics and the spread of novel coronavirus disease (COVID-19) in Italy
Authors: Rovetta Alessandro , Castaldo Lucia
Published: September 2020

Background

Since January 2020, the COVID-19 pandemic has raged around the world, causing nearly a million deaths and hundreds of severe economic crises. In this scenario, Italy has been one of the most affected countries.

Objective

This study investigated significant correlations between COVID-19 cases and demographic, geographical, and environmental statistics of each Italian region from February 26 to August 12, 2020. We further investigated the link between the spread of SARS-CoV-2 and particulate matter (PM) 2.5 and 10 concentrations before the lockdown in Lombardy.

Methods

All demographic data were obtained from the AdminStat Italia website, and geographic data were from the Il Meteo website. The collection frequency was one week. Data on PM2.5 and PM10 average daily concentrations were collected from previously published articles. We used Pearson’s coefficients to correlate the quantities that followed a normal distribution, and Spearman’s coefficient to correlate quantities that did not follow a normal distribution.

Results

We found significant strong correlations between COVID-19 cases and population number in 60.0% of the regions. We also found a significant strong correlation between the spread of SARS-CoV-2 in the various regions and their latitude, and with the historical averages (last 30 years) of their minimum temperatures. We identified a significant strong correlation between the number of COVID-19 cases until August 12 and the average daily concentrations of PM2.5 in Lombardy until February 29, 2020. No significant correlation with PM10 was found in the same periods. However, we found that 40 μg/m3 for PM2.5 and 50 μg/m3 PM10 are plausible thresholds beyond which particulate pollution clearly favors the spread of SARS-CoV-2.

Conclusion

Since SARS-CoV-2 is correlated with historical minimum temperatures and PM10 and 2.5, health authorities are urged to monitor pollution levels and to invest in precautions for the arrival of autumn. Furthermore, we suggest creating awareness campaigns for the recirculation of air in enclosed places and to avoid exposure to the cold.
Symptoms of pediatric feeding disorders among individuals with 3q29 deletion syndrome
Authors: Wawrzonek Addam J. , Burrell T. Lindsey , Sharp William , Gillespie Scott E. , Pollak Rebecca M ,   The Emory 3q29 Project, Murphy Melissa , Mulle Jennifer Gladys
Published: September 2020

Objective

To evaluate symptoms of pediatric feeding disorders in a sample of individuals with 3q29 Deletion Syndrome. Previous research has found that individuals with 3q29 deletion syndrome (3q29Del) may experience elevated feeding concerns in early childhood; however, the specificity of these feeding concerns in this pediatric population is not well understood.

Methods

We compared individuals with 3q29Del (n = 60) to matched controls (n = 59) using an 11-item survey that assessed commonly reported symptoms associated with pediatric feeding disorders. An exploratory analysis also examined individuals with 3q29Del with and without a comorbid autism spectrum disorder (ASD) diagnosis.

Results

Caregivers of 3q29Del cases reported higher incidences of feeding concerns on all 11 items included in the survey. This included statistically significant differences in food refusal behaviors, rejection of one or more food group, and a history of failure to thrive. Parents of children with comorbid autism were more likely to report concerns regarding rejection of one or more food group compared to children with 3q29Del without autism.

Conclusions

Results suggest individuals with 3q29Del experience increased symptoms of pediatric feeding disorders. Future research should include a more thorough multidisciplinary evaluation to further document the severity and identify optimal remediation strategies.
In the long shadow of our best intentions: model-based assessment of the consequences of school reopening during the COVID-19 pandemic
Authors: Johnson Kaitlyn E. , Stoddard Madison , Nolan Ryan P. , White Douglas E. , Hochberg Natasha S. , Chakravarty Arijit
Published: September 2020

As the United States grapples with the ongoing COVID-19 pandemic, a particularly thorny set of questions surrounds the reopening of K-12 schools and universities. The benefits of in-person learning are numerous, in terms of education quality, mental health, emotional well-being, equity and access to food and shelter. Early reports suggested that children might have reduced susceptibility to COVID-19, and children have been shown to experience fewer complications than older adults. Over the past few months, our understanding of COVID-19 has been further shaped by emerging data, and it looks increasingly likely that children are as susceptible to infection as adults and have a similar viral load during infection. While the higher prevalence of asymptomatic disease among children makes symptom-based isolation strategies ineffective, asymptomatic patients do not in fact carry a reduced viral load. Using assumptions consistent with the emerging understanding of the disease, we conducted epidemiological modeling to explore the feasibility and consequences of school reopening in the face of differing rates of COVID-19 prevalence and transmission. Our findings indicate that, regardless of the initial prevalence of the disease, and in the absence of systematic surveillance testing, most schools in the United States can expect 20-60 days without a major cluster emerging. Without testing or contact tracing, the true extent of these disease clusters may not be apparent, and our research suggests that the case count will underestimate the true size of the clusters by a large margin. These disease clusters, in turn, can be expected to propagate silently through the community, with potentially hundreds to thousands of additional cases resulting from each individual school cluster. Thus, our findings suggest that the debate between the risks to student safety and benefits of in-person learning frames a false dual choice. Given the current circumstances in the United States, the most likely outcome in the late fall is that students will be deprived of the benefits of in-person learning while having incurred a significant risk to themselves and their communities.
Regulation of protein abundance in genetically diverse mouse populations
Authors: Keele Gregory R , Zhang Tian , Pham Duy T , Vincent Matthew , Bell Timothy A , Hock Pablo , Shaw Ginger D , Munger Steven C , de Villena Fernando Pardo-Manuel , Ferris Martin T , Gygi Steven P , Churchill Gary A
Published: September 2020

Proteins constitute much of the structure and functional machinery of cells, forming signaling networks, metabolic pathways, and large multi-component complexes. Protein abundance is regulated at multiple levels spanning transcription, translation, recycling, and degradation to maintain proper balance and optimal function. To better understand how protein abundances are maintained across varying genetic backgrounds, we analyzed liver proteomes of three genetically diverse mouse populations. We observe strong concordance of genetic and sex effects across populations. Differences between the populations arise from the contributions of additive, dominance, and epistatic components of heritable variation. We find that the influence of genetic variation on proteins that form complexes relates to their co-abundance. We identify effects on protein abundance from mutations that arose and became fixed during breeding and can lead to unique regulatory responses and disease states. Genetically diverse mouse populations provide powerful tools for understanding proteome regulation and its relationship to whole-organism phenotypes.
Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice
Authors: Lozoya Oswaldo A. , Xu Fuhua , Grenet Dagoberto , Wang Tianyuan , Stevanovic Korey D. , Cushman Jesse D. , Jensen Patricia , Hernandez Bairon , Riadi Gonzalo , Moy Sheryl S. , Santos Janine H. , Woychik Richard P.
Published: September 2020

The peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1α) is known as a transcriptional co-activator in peripheral tissues but its function in the brain remains poorly understood. Various brain-specificPgc1αisoforms have been reported in mice and humans, including transcripts derived from a novel promoter about ∼580 Kb upstream from the reference gene. These isoforms incorporate repetitive sequences from the simple sequence repeat (SSR) and short interspersed nuclear element (SINE) classes and are predicted to give rise to proteins with distinct amino-termini. In this study, we show that a SINE-containing isoform is the predominant form ofPgc1αexpressed in neurons. We then generated a mouse carrying a mutation within the SINE to study its functional role in the brain. By combining genomics, biochemical and behavioural approaches, we show that this mutation leads to impaired motor coordination in females, but not male mice, associated with the upregulation of hundreds of cerebellar genes. Moreover, our analysis suggests that known nuclear receptors interact with this isoform of PGC1α in the brain to carry out the female transcriptional program. These data expand our knowledge on the role ofPgc1αin the brain and help explain its conflicting roles in neurological disease and behavioural outcomes.
A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent in vitro
Authors: Xiao Tianshu , Lu Jianming , Zhang Jun , Johnson Rebecca I. , McKay Lindsay G.A. , Storm Nadia , Lavine Christy L. , Peng Hanqin , Cai Yongfei , Rits-Volloch Sophia , Lu Shen , Quinlan Brian D. , Farzan Michael , Seaman Michael S. , Griffiths Anthony , Chen Bing
Published: September 2020

Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that forms a dimer and serves as the cellular receptor for SARS-CoV-2. It is also a key negative regulator of the renin-angiotensin system (RAS), conserved in mammals, which modulates vascular functions. We report here the properties of a trimeric ACE2 variant, created by a structure-based approach, with binding affinity of ~60 pM for the spike (S) protein of SARS-CoV-2, while preserving the wildtype peptidase activity as well as the ability to block activation of angiotensin II receptor type 1 in the RAS. Moreover, the engineered ACE2 potently inhibits infection of SARS-CoV-2 in cell culture. These results suggest that engineered, trimeric ACE2 may be a promising anti-SARS-CoV-2 agent for treating COVID-19.
Loss of CIB2 causes non-canonical autophagy deficits and visual impairment
Authors: Sethna Saumil , Scott Patrick A. , Giese Arnaud P.J. , Duncan Todd , Redmond T. Michael , Riazuddin Saima , Ahmed Zubair M.
Published: September 2020

Non-canonical autophagy or LC3-associated phagocytosis (LAP) is essential for the maintenance and functioning of the retinal pigment epithelium (RPE) and photoreceptors. Although molecular mechanisms still remain elusive, deficits in LAP have been found to be associated with age-related retinal pathology in both mice and humans. In this study, we found that calcium and integrin-binding protein 2 (CIB2) regulates LAP in the RPE. Mice lacking CIB2, both globally and specifically within RPE, have an impaired ability to process the engulfed photoreceptor outer segments due to reduced lysosomal capacity, which leads to marked accumulation of improperly digested remnants, lipid droplets, fused phago-melanosomes in RPE, and impaired visual function. In aged mice, we also found marked accumulation of drusen markers APOE, C3, and Aβ, along with esterified cholesterol. Intriguingly, we were able to transiently rescue the photoreceptor function inCib2mutant mice by exogenous retinoid delivery. Our study links LAP and phagocytic clearance with CIB2, and their relevance to the sense of sight.
Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells
Authors: Nguyenla Xammy , Wehri Eddie , Van Dis Erik , Biering Scott B. , Yamashiro Livia H. , Stroumza Julien , Dugast-Darzacq Claire , Graham Thomas , Stanley Sarah , Schaletzky Julia
Published: September 2020

The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir’s apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis C therapeutics Epclusa (velpatasvir/sofosbuvir) and Zepatier (elbasvir/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections.
Piperacillin/tazobactam resistant, cephalosporin susceptibleEscherichia colibloodstream infections are driven by multiple acquisition of resistance across diverse sequence types
Authors: Edwards Thomas , Heinz Eva , van Aartsen Jon , Howard Alex , Roberts Paul , Corless Caroline , Fraser Alice J. , Williams Christopher T. , Bulgasim Issra , Cuevas Luis E. , Parry Christopher M. , Roberts Adam P. , Adams Emily R. , Mason Jenifer , Hubbard Alasdair T. M.
Published: September 2020

Resistance to piperacillin/tazobactam (TZP) inEscherichia colihas predominantly been associated with mechanisms that confer resistance to third generation cephalosporins. Recent reports have identifiedE. colistrains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype inE. coli(n= 58) isolated between 2014-2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasiveE. coliisolates(n= 1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype(n= 68), a piperacillin/tazobactam and third generation cephalosporin-susceptible (TZP-S/3GC-S,n= 1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasiveE. coliisolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor resistant β-lactamases, and an S133Gb/aCTX-M-15mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.
A meta-analysis and experiment assessing phage-based FMDV vaccine
Authors: Wu Peng , Yang Ningning , Wang Yueli , Xu Mingguo , Zhang Yunfeng , Chen Chuangfu
Published: September 2020

Foot-and-mouth disease (FMD) is a pathological disease caused by the foot- and-mouth disease virus (FMDV), which mainly affects cloven-hoofed animals. This study was conducted to a meta-analysis and experiment on the effect of bacteriophages used in the development of FMDV vaccines. A systematic search was conducted for the collection of the protection effect for the phage-based FMDV vaccine using sensitive search strategies. The extracted data were analyzed using Rev-Man 5.4 software. This experiment used the T7 phage to express the capsid protein VP1 of the OHM-02 strain, and the recombinant VP1 phage was termed OHM-T7. Antibodies and cytokines levels were assessed after immunizing BALB/C mice with OHM-T7. The results showed that a total of 115 articles were retrieved, and 4 of them met the inclusion criteria. There was no heterogeneity with I2= 0%, 20% or 43%. We used a fixed-effect model for meta-analysis, and the results showed a protective effect on FMDV between the phage group and control group (P<0.01) and between FMDV group and control group (P<0.01). Furthermore, when the phage group was compared to the FMDV group, there was also no significant difference (P>0.05). After successfully obtained the ohm-t7 strain and immunized the mice, it could induce high levels of IFN-γ levels in mice with little effect on IL-4 levels. OHM-T7 could be used to detect antibodies produced by mice immunized with different FMDV antigens and produce high levels of anti-FMD antibodies. In summary, these results showed the potential of phage-based FMDV vaccines in FMDV prevention.
Population genomic evidence for a repeated introduction and rapid expansion in Europe of a maize fungal pathogen
Authors: Vidal-Villarejo Mireia , Freund Fabian , Hanekamp Hendrik , von Tiedemann Andreas , Schmid Karl
Published: September 2020

Modern agricultural practices and the climate change foster the rapid spread of plant pathogens like the maize fungal pathogenSetosphaeria turcica, which causes Northern corn leaf blight and expanded into Central Europe since the 1980s. To investigate the rapid expansion ofS. turcicawe sequenced 121 isolates from Europe and Kenya. Population genomic inference revealed a single genetically diverse cluster in Kenya and three clonal lineages with low diversity and one cluster of multiple clonal sublineages in Europe. Phylogenetic dating suggests that all European lineages originated by sexual reproduction outside Europe and subsequently were subsequently introgressed multiple times. In contrast to Kenyan isolates, European isolates did not show sexual recombination despite the presence of bothMAT1-1andMAT1-2mating types. Coalescent analysis of the geographically most widespread European lineage supported a neutral, strongly exponential population growth model over models with natural selection caused by host defence resistance or environmental adaptation. Within clonal lineages, we observed phenotypic variation in virulence to different monogenic resistances that may originate from repeated mutations in virulence genes. Association mapping between genetic clusters did not identify genomic regions associated with pathogen races but uncovered strongly differentiated genomic regions between clonal lineages that harbor putative effector genes. In conclusion, the expansion and population growth ofS. turcicain Europe was mainly driven by the expansion of maize cultivation area and not by rapid adaptation.

Significance statement

The geographic expansion and plant pathogens caused by modern agricultural practices and climate change is a major problem in modern agriculture. We investigated the rapid spread of the maize fungal pathogen Setosphaeria turcica by whole genome sequencing of isolates from Kenya and Europe and demonstrated that the rapid expansion in Central Europe since the 1980s mainly reflects the rapid growth of the maize cultivation area in this region and not a rapid adaptation to resistant maize varieties. Our analyses show that by monitoring whole genome sequence diversity of plant pathogens and their invasion history, agricultural management and breeding strategies can be developed to control the evolution and future spread of plant pathogens.
NBR1 directly promotes the formation of p62 – ubiquitin condensates via its PB1 and UBA domains
Authors: Savova Adriana , Romanov Julia , Martens Sascha
Published: September 2020

Selective autophagy removes harmful intracellular structures such as ubiquitinated, aggregated proteins ensuring cellular homeostasis. This is achieved by the encapsulation of this cargo material within autophagosomes. The cargo receptor p62/SQSTM1 mediates the phase separation of ubiquitinated proteins into condensates, which subsequently become targets for the autophagy machinery. NBR1, another cargo receptor, is a crucial regulator of condensate formation. The mechanisms of the interplay between p62 and NBR1 are not well understood. Employing a fully reconstituted system we show that two domains of NBR1, the PB1 domain which binds to p62 and the UBA domain which binds to ubiquitin, are required to promote p62-ubiquitin condensate formation. In cells, acute depletion of endogenous NBR1 reduces formation of p62 condensates, a phenotype that can be rescued by re-expression of wild-type NBR1, but not PB1 or UBA domain mutants. Our results provide mechanistic insights into the role of NBR1 in selective autophagy.