bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxin-like neuropeptides in the sea anemoneNematostellaunravel recruitment from the nervous system to venom
Authors: Sachkova Maria Y. , Landau Morani , Surm Joachim M. , Macrander Jason , Singer Shir , Reitzel Adam M. , Moran Yehu
Published: May 2020

The sea anemoneNematostella vectensis(Anthozoa, Cnidaria) is a powerful model system for characterizing the evolution of genes functioning in venom and nervous systems. Despite being an example for evolutionary novelty, the evolutionary origin of most toxins remains unknown. Here we report the first bona fide case of protein recruitment from the cnidarian nervous to venom system. The ShK-like1 peptide has ShKT cysteine motif, is lethal for fish larvae and packaged into nematocysts, the cnidarian venom-producing stinging capsules. Thus, ShK-like1 is a toxic venom component. Its paralog, ShK-like2, is a neuropeptide localized to neurons and is involved in development. Interestingly, both peptides exhibit similarities in their functional activities: both of them provoke contraction inNematostellapolyps and are toxic to fish. Because ShK-like2 but not ShK-like1 is conserved throughout sea anemone phylogeny, we conclude that the two paralogs originated due to aNematostella-specific duplication of a ShK-like2 ancestor, a neuropeptide-encoding gene, followed by diversification and partial functional specialization. Strikingly, ShK-like2 is represented by two gene isoforms controlled by alternative promoters conferring regulatory flexibility throughout development. Additionally, we characterized the expression patterns of four other peptides with structural similarities to studied venom components, and revealed their unexpected neuronal localization. Thus, we employed genomics, transcriptomics and functional approaches to reveal one new venom component, five neuropeptides with two different cysteine motifs and an evolutionary pathway from nervous to venom system in Cnidaria.
Auditory Corticothalamic Neurons are Recruited by Motor Preparatory Inputs
Authors: Clayton Kameron K. , Williamson Ross S. , Hancock Kenneth E. , Hackett Troy , Polley Daniel B
Published: May 2020

Optogenetic activation ofNtsr1+ layer 6 corticothalamic (L6 CT) neurons modulates thalamocortical sensory processing and perception for hundreds of milliseconds following laser offset. Naturally occurring sources of extrasensory inputs that could recruit L6 CTs prior to upcoming sensory stimuli have not been identified. Here, we found that 100% of L6 CTs in mouse primary auditory cortex (A1) expressed FoxP2, a protein marker found in brain areas that coordinate sensory inputs with movement. To test the idea that motor preparatory inputs could be a natural extrasensory activator of L6 CTs, we combined quantitative videography, optogenetically targeted single unit recordings, and two-photon imaging during self-initiated behavior. We found that A1 L6 CTs were activated hundreds of milliseconds prior to orofacial movements, but not whole-body movements associated with locomotion. These findings identify new local circuit arrangements for routing motor corollary discharge into A1 and suggest new roles for CT neurons in active sensing.
Cell type-specific proteogenomic signal diffusion for integrating multi-omics data predicts novel schizophrenia risk genes
Authors: Torshizi Abolfazl Doostparast , Duan Jubao , Wang Kai
Published: May 2020

Accumulation of diverse types of omics data on schizophrenia (SCZ) requires a systems approach to jointly modeling the interplay between genome, transcriptome and proteome. Proteome dynamics, as the definitive cellular machinery in human body, has been lagging behind the research on genome/transcriptome in the context of SCZ, both at tissue and single-cell resolution. We introduce a Markov Affinity-based Proteogenomic Signal Diffusion (MAPSD) method to model intra-cellular protein trafficking paradigms and tissue-wise single-cell protein abundances. MAPSD integrates multi-omics data to amplify the signals at SCZ risk loci with small effect sizes, and reveal convergent disease-associated gene modules in the brain interactome as well as more than 130 tissue/cell-type combinations. We predicted a set of high-confidence SCZ risk genes, the majority of which are not directly connected to SCZ susceptibility risk genes. We characterized the subcellular localization of proteins encoded by candidate SCZ risk genes in various brain regions, and illustrated that most are enriched in neuronal and Purkinje cells in cerebral cortex. We demonstrated how the identified gene set may be involved in different developmental stages of the brain, how they alter SCZ-related biological pathways, and how they can be effectively leveraged for drug repurposing. MAPSD can be applied to other polygenic diseases, yet our case study on SCZ signifies how tissue-adjusted protein-protein interaction networks can assist in generating deeper insights into the orchestration of polygenic diseases.
Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis
Authors: Wang Yinu , Zhao Guangyuan , Condello Salvatore , Huang Hao , Cardenas Horacio , Tanner Edward , Wei Jian-Jun , Ji Yanrong , Li Junjie , Tan Yuying , Davuluri Ramana , Cheng Ji-Xin , Matei Daniela
Published: May 2020

Defining traits of platinum tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum tolerant cells and tumors were identified by usingin vitroandin vivoovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were found to be enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors highly expressed the Wnt receptor,Frizzled 7(FZD7). FZD7 knock down improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells includedepithelial-to-mesenchymal (EMT), stemness, andoxidative phosphorylationenriched gene sets. Overexpression ofFZD7activated the oncogenic factorTp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protects cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors.FZD7, Tp63and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-β-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum tolerant cancer cells and provide new insight into a potential “persister cancer cell” phenotype.
Silk Fibroin as an Additive for Cell-Free Protein Synthesis
Authors: Lee Marilyn S. , Hung Chia-Suei , Phillips Daniel A. , Buck Chelsea C. , Gupta Maneesh K. , Lux Matthew W.
Published: May 2020

Cell-free systems contain many proteins and metabolites required for complex functions such as transcription and translation or multi-step metabolic conversions. Research into expanding the delivery of these systems by drying or by embedding into other materials is enabling new applications in sensing, point-of-need manufacturing, and responsive materials. Meanwhile, silk fibroin from the silk worm,Bombyx mori, has received attention as a protective additive for dried enzyme formulations and as a material to build biocompatible hydrogels for controlled localization or delivery of biomolecular cargoes. In this work, we explore the effects of silk fibroin as an additive in cell-free protein synthesis (CFPS) reactions. Impacts of silk fibroin on CFPS activity and stability after drying, as well as the potential for incorporation of CFPS into hydrogels of crosslinked silk fibroin are assessed. We find that simple addition of silk fibroin increased productivity of the CFPS reactions by up to 42%, which we attribute to macromolecular crowding effects. However, we did not find evidence that silk fibroin provides a protective effects after drying as previously described for purified enzymes. Further, the enzymatic crosslinking transformations of silk fibroin typically used to form hydrogels are inhibited in the presence of the CFPS reaction mixture. Crosslinking attempts did not impact CFPS activity, but did yield localized protein aggregates rather than a hydrogel. We discuss the mechanisms at play in these results and how the silk fibroin-CFPS system might be improved for the design of cell-free devices.
Polymorphisms in STING affect human innate immune responses to poxviruses
Authors: Kennedy Richard B. , Haralambieva Iana H. , Ovsyannikova Inna G. , Voigt Emily A. , Larrabee Beth R. , Schaid Daniel J. , Zimmermann Michael T. , Oberg Ann L. , Poland Gregory A.
Published: May 2020

We conducted a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination in a combined cohort of > 1,600 subjects. We identified a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated (p-value: 1.3 × 10−12– 1.5×10−36) with IFNα response toin vitropoxvirus stimulation. Examination of these SNPs led to the functional testing of rs1131769, a non-synonymous SNP inTMEM173causing an Arg-to-His change at position 232 in the STING protein—a major regulator of innate immune responses to viral infections. Our findings demonstrate important functional differences between the two alleles, where the major allele (R232) more effectively induces IFNα secretion. Molecular modeling of both alleles identified altered ligand binding characteristics between the two variants, providing a potential mechanism underlying differences in inter-individual responses to poxvirus vaccination. Our data demonstrate that possession of the H232 variant impairs STING-mediated innate immunity to poxviruses. These results clarify prior studies evaluating functional effects of genetic variants inTMEM173and provide novel data regarding genetic control of poxvirus immunity.

Contribution to the Field

Here we report that a single nucleotide non-synonymous polymorphism in theTMEM173gene encodes for a STING variant conferring a reduced IFN stimulated response compared to wild type. Our results suggest that, upon binding of the STING H232 variant to its ligand, activation of downstream signaling proteins is impaired, resulting in decreased production of IFNα and a weaker interferon-stimulated gene response. Molecular modeling indicates that the diminished functional activity of this variant is likely due to an altered physical structure of the STING protein. STING controls the innate, type I IFN response to double-stranded DNA and cyclic dinucleotides. Individuals with the H232 variant of STING have a much weaker innate immune response to vaccinia virus. Our data help resolve ongoing controversies regarding the role of genetic variants in STING function. Because STING plays an important role in our immune response to DNA viruses and bacteria, our results can be used to predict who will and will not respond to vaccines and treatments, and to design more effective vaccine candidates. Given the role of the STING protein in innate responses to DNA viruses and bacterial pathogens, these data may also be useful in developing novel treatment options for multiple infectious diseases.
Homeostatic plasticity triggered by rod photoreceptor degenerative disease is associated with maintenance of sensitive night vision
Authors: Leinonen Henri , Pham Nguyen C , Boyd Taylor , Santoso Johanes , Palczewski Krzysztof , Vinberg Frans
Published: May 2020

Neuronal plasticity of the inner retina has been observed in response to photoreceptor degeneration. Typically, this phenomenon has been considered maladaptive and may preclude vision restoration in the blind. However, several recent studies utilizing triggered photoreceptor ablation have shown adaptive responses in bipolar cell dendrites expected to support normal vision. Whether such homeostatic plasticity occurs during progressive photoreceptor degenerative disease to help maintain normal visual behavior is unknown. We addressed these issues in an established mouse model of Retinitis Pigmentosa caused by the P23H mutation in rhodopsin. We show robust modulation of the retinal transcriptomic network reminiscent of the neurodevelopmental state as well as potentiation of rod – rod bipolar cell signaling following rod photoreceptor degeneration. Additionally, we found highly sensitive night vision in P23H mice even when more than half of the rod photoreceptors were lost. The results implicate retinal adaptation leading to persistent visual function during photoreceptor degenerative disease.
Benchmarking Risk Predictions and Uncertainties in the NSCR Model of GCR Cancer Risks with Revised Low LET Risk Coefficients
Authors: Cucinotta Francis A. , Cacao Eliedonna , Kim Myung-Hee Y. , Saganti Premkumar B.
Published: May 2020

We report on the contributions of model factors that appear in fatal cancer risk projection models to the overall uncertainty in cancer risks predictions for exposures to galactic cosmic ray (GCR) in deep space. Annual GCR exposures to astronauts at solar minimum are considered. Uncertainties in low LET risk coefficients, dose and dose-rate modifiers, quality factors (QFs), space radiation organ doses, non-targeted effects (NTE) and increased tumor lethality at high LET compared to low LET radiation are considered. For the low LET reference radiation parameters we use a revised assessment of excess relative risk (ERR) and excess additive risk (EAR) for radiation induced cancers in the Life-Span Studies (LSS) of the Atomic bomb survivors that was recently reported, and also consider ERR estimates for males from the International Study of Nuclear Workers (INWORKS). For 45-y old females at mission age the risk of exposure induced death (REID) per year and 95% confidence intervals is predicted as 1.6% [0.71, 1.63] without QF uncertainties and 1.64% [0.69, 4.06] with QF uncertainties. However, fatal risk predictions increase to 5.83% [2.56, 9.7] with non-targeted effects. For males a comparison application to GCR using LSS or INWORKS lead to predictions of 1.24% [0.58, 3.14] and 2.45% [1.23, 5.9] without NTEs. The major conclusion of our report is that high LET risk prediction uncertainties due to QFs parameters, NTEs, and possible increase lethality at high LET are dominant contributions to GCR uncertainties and should be the focus of space radiation research.
GalaxyCloudRunner: enhancing scalable computing for Galaxy
Authors: Goonasekera N , Mahmoud A , Chilton J , Afgan E
Published: May 2020

The existence of more than 100 public Galaxy servers with service quotas is indicative of the need for an increased availability of compute resources for Galaxy to use. The GalaxyCloudRunner enables a Galaxy server to easily expand its available compute capacity by sending user jobs to cloud resources. User jobs are routed to the acquired resources based on a set of configurable rules and the resources can be dynamically acquired from any of 4 popular cloud providers (AWS, Azure, GCP, or OpenStack) in an automated fashion.

Availability and implementation

GalaxyCloudRunner is implemented in Python and leverages Docker containers. The source code is MIT licensed and available athttps://github.com/cloudve/galaxycloudrunner. The documentation is available athttp://gcr.cloudve.org/.

Contact

Enis Afgan (enis.afgan@jhu.edu)

Supplementary information

None
Ventral tegmental area GABA neurons mediate stress-induced anhedonia
Authors: Lowes Daniel C. , Chamberlin Linda A. , Kretsge Lisa N. , Holt Emma S. , Abbas Atheir I. , Park Alan J. , Yusufova Lyubov , Bretton Zachary H. , Firdous Ayesha , Gordon Joshua A. , Harris Alexander Z.
Published: May 2020

Stressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.
Population structure of the invasive golden mussel (Limnoperna fortunei) on reservoirs from five Brazilian drainage basins
Authors: Ferreira João G. R. N. , Soares-Souza Giordano Bruno , Americo Juliana A. , Dumaresq Aline , Rebelo Mauro F.
Published: May 2020

The golden mussel (Limnoperna fortunei) is a freshwater bivalve that was introduced in South America almost 30 years ago, likely through ballast water of Asian ships. Since then, it has spread across the continent, causing both economic and environmental impacts. The study of the population structure of an invasive species may bring valuable insights towards understanding its pattern of dispersion, which in turn will help to create more effective management plans. Here, we have compared mussel populations from 5 different Brazilian reservoirs and tested for the presence of geographic genetic structure. In order to obtain a high number of single nucleotide variants (SNVs) at good cost-benefit, we have for the first time applied the double digest restriction-site associated DNA sequencing (ddRAD-seq) protocol for the golden mussel. The ddRAD-seq protocol allowed us to obtain 2046 SNVs, which were then used to assess population structure by applying three independent methodologies: Principal Component Analysis (PCA), Bayesian Clustering and Phylogenetic Tree. All methodologies have indicated absent geographic structure.
ATP-binding cassette protein ABCF1 couples gene transcription with maintenance of genome integrity in embryonic stem cells
Authors: Choi Eun-Bee , Vodnala Munender , Zerbato Madeleine , Wang Jianing , Ho Jaclyn J. , Inouye Carla , Fong Yick W.
Published: May 2020

OCT4 and SOX2 confer pluripotency by recruiting coactivators to activate stem cell-specific gene expression programs. However, the composition of coactivator complexes and their roles in maintaining stem cell fidelity remain unclear. Here we report the identification of ATP-binding cassette subfamily F member 1 (ABCF1) as a critical coactivator for OCT4/SOX2. ABCF1 is required for pluripotency gene expression and stem cell self-renewal. ABCF1 binds co-dependent coactivators XPC and DKC1 via its intrinsically disordered region and stimulates transcription by linking SOX2 to the transcription machinery. Furthermore, in response to pathogen infection and DNA damage, ABCF1 binds intracellular DNAs accumulated in cells, concomitant with loss of SOX2 interaction and pluripotency gene transcription. This results in spontaneous differentiation of compromised stem cells and elimination from the self-renewing population. Thus, ABCF1 directly couples pluripotency gene transcription with sensing aberrant DNAs and acts as a checkpoint for self-renewal to safeguard stem cell fidelity and genome integrity.
Kin recognition in guppies uses self-referencing on olfactory cues
Authors: Daniel Mitchel J. , Rodd F. Helen
Published: May 2020

Kin recognition plays an important role in social evolution, but the proximate mechanisms by which individuals recognize kin remain poorly understood. In many species, individuals form a “kin template” that they compare against conspecifics’ phenotypes to assess phenotypic similarity–and by association, relatedness. Individuals may form a kin template through self-inspection (i.e. self-referencing) and/or by observing their rearing associates (i.e. family-referencing). However, despite much interest, few empirical studies have successfully disentangled self- and family-referencing. Here, we use a novel set of breeding crosses in the Trinidadian guppy (Poecilia reticulata) to definitively disentangle referencing systems by manipulating exposure to kin from conception onwards. We show that guppies discriminate among their full- and maternal half-siblings, which can only be explained by self-referencing. Additional behavioral experiments revealed no evidence that guppies incorporate the phenotypes of their broodmates or mother into the kin template. Finally, by manipulating the format of our behavioral tests, we show that olfactory communication is both necessary and sufficient for kin discrimination. These results demonstrate that individuals recognize kin by comparing the olfactory phenotypes of conspecifics against their own. This study resolves key questions about the proximate mechanisms underpinning kin recognition, with implications for the ontogeny and evolution of social behavior.
Macrophages drive the inflammatory phase in experimental osteoarthritis
Authors: Montgomery Anna , Fahy Niamh , Hamilton Samuel , Eckman Blair , De Almeida Lucia , Ishihara Shingo , Mayr Maximilian G , Chen Shang Yang , Gadhvi Gaurav , Cuda Carla , Malfait Anne-Marie , Bastiaansen-Jenniskens Yvonne , Winter Deborah R.
Published: May 2020

Macrophages fulfill critical functions in maintaining tissue homeostasis in steady-state, as well as in inflammation and immune response. Inflammation is not considered a major driver of osteoarthritis (OA), but macrophages have been implicated in its pathogenesis. Here, we use two mouse models of experiment OA – collagenase-induced osteoarthritis (CIOA) and destabilization of the medial meniscus (DMM) – to quantify the immune cell infiltration into the knee joint during the early stages of disease. We find that the peak of inflammation occurs at day 3 in CIOA and is characterized by a transitory increase in neutrophils and monocytes and a longer-lived expansion of synovial macrophages. Macrophage sub-populations are disproportionally expanded with CX3CR1+ cells accounting for a larger proportion of the macrophage compartment. Transcriptional profiling demonstrates that synovial macrophages up-regulate inflammatory genes coinciding with peak inflammation and down-regulate genes associated with homeostasis and tissue-residence. Female mice exhibit a similar expansion of macrophages post-CIOA indicating that the inflammatory phase is not sex-specific. Finally, we find day 7 post-DMM is also characterized by increases in neutrophil, monocyte, and macrophage sub-population numbers. These results support a role for macrophages in early stages of OA through driving the inflammatory phase. Further investigation may elucidate potential targets for the prevention or attenuation of OA-associated cartilage damage.
The immunophilin Zonda controls regulated exocytosis in endocrine and exocrine tissues
Authors: de la Riva Carrasco Rocío , Pandolfo Sebastián Perez , Freire Sofía Suarez , Romero Nuria M. , Bhujabal Zambarlal , Johansen Terje , Wappner Pablo , Melani Mariana
Published: May 2020

Exocytosis is a fundamental process in physiology, communication between cells, organs and even organisms. Hormones, neuropeptides and antibodies, among other cargoes are packed in exocytic vesicles that need to reach and fuse with the plasma membrane to release their content to the extracellular milieu. Hundreds of proteins participate in this process and several others in its regulation. We report here a novel component of the exocytic machinery, theDrosophilatransmembrane immunophilin Zonda (Zda), previously found to participate in autophagy. Zda is highly expressed in secretory tissues, and regulates exocytosis in at least three of them: the ring gland, insulin-producing cells and the salivary gland. Using the salivary gland as a model system, we found that Zda is required at final steps of the exocytic process for fusion of secretory granules to the plasma membrane. In a genetic screen we identified the small GTPase RalA as a crucial regulator of secretory granule exocytosis that operates upstream of Zda in the process.
Competition and Caries on Enamel of a Dual-species Biofilm Model ofStreptococcus mutansandStreptococcus sanguinis
Authors: Díaz-Garrido Natalia , Lozano Carla P. , Kreth Jens , Giacaman Rodrigo A.
Published: May 2020

Imbalances within the dental biofilm trigger dental caries, currently considered a dysbiosis and the most prevalent non-communicable disease. There is still a gap in knowledge about the dynamics of enamel colonization by bacteria from the dental biofilm in caries. The aim, therefore, was to test whether the sequence of enamel colonization by a typically commensal and a cariogenic species modifies biofilm’s cariogenicity. Dual-species biofilms ofStreptococcus mutans(Sm) andStreptococcus sanguinis(Ss) on saliva-coated enamel slabs were inoculated in different sequences: Sm followed by Ss (Sm-Ss), Ss followed by Sm (Ss-Sm), Sm and Ss inoculated at the same time (Sm=Ss) and the single-species controls Sm followed by Sm (Sm-Sm) and Ss followed by Ss (Ss-Ss). Biofilms were exposed to 10% sucrose, 3x/day for 5 days and the slabs/biofilms were retrieved to assess demineralization, viable cells, biomass, proteins, polysaccharides and H2O2production. When compared with Sm-Sm, primary inoculation with Ss reduced demineralization (p<0.05). Both Ss-Sm and Sm=Ss sequences showed reduction in biomass, protein and polysaccharide content (p<0.05). The highestS. sanguinisviable cells and H2O2production and the lowest acidogenicity were observed when Ss colonized enamel before Sm (p<0.05). Initial enamel adherence with commensal biofilms seems to induce more intense competition against more typically cariogenic species, reducing cariogenicity.

Importance

The concept of caries as an ecological disease implies the understanding of the intricate relationships among the populating microorganisms. Under frequent sugars exposure, some the bacteria from the oral biofilm develop pathogenic traits that lead to oral imbalances, known as dysbiosis. Depending on which microorganism colonizes the dental surface first, different competition strategies may be developed. Since the study of the interactions in the entire dental biofilm is not an easy task, in this article we model the interplay among these microorganisms using a caries-inducing (S. mutans) and a health-associated species (S. sanguinis). Initial enamel adherence with S. sanguinis seems to induce more intense competition against more typically caries-inducing species. Besides continuous exposure with sugars, early colonization of the enamel by highly cariogenic species, likeS. mutans, appears to be needed to develop caries lesions, as well. Promoting early colonization by health-associated bacteria, such asS. sanguinis, could help maintaining oral health, delaying dysbiosis.
Step-specific adaptation and trade-off over the course of an infection by GASP-mutation small colony variants
Authors: Christian Faucher , Vincent Mazana , Marion Kardacz , Nathalie Parthuisot , Jean-Baptiste Ferdy , David Duneau
Published: May 2020

During an infection, parasites face a succession of challenges, each decisive for disease outcome. The diversity of challenges requires a series of parasite adaptations to successfully multiply and transmit from host to host. Thus, the pathogen genotypes which succeed during one step might be counter-selected in later stages of the infection. Using the bacteriaXenorhabdus nematophilaand adultDrosophila melanogasteras hosts, we showed that such step-specific adaptations, here linked to GASP mutations in theX. nematophilamaster gene regulatorlrp, exist and can trade-off with each other. We found that nonsenselrpmutations had lowered ability to resist the host immune response, while all classes of mutations inlrpwere associated with a decrease in the ability to proliferate during early infection. We demonstrate that reduced proliferation ofX. nematophilabest explains diminished virulence in this infection model. Finally, decreased proliferation during the first step of infection is accompanied with improved proliferation during late infection, suggesting a trade-off between the adaptations to each step. Step-specific adaptations could play a crucial role in the chronic phase of infections in any diseases that show similar small colony variants (also known as SCV) toX. nematophila.

Importance

Within-host evolution has been described in many bacterial diseases, and the genetic basis behind the adaptations stimulated a lot of interest. Yet, the studied adaptations are generally focused on antibiotic resistance, rarely on the adaptation to the environment given by the host, and the potential trade-off hindering adaptations to each step of the infection are rarely considered. Those trade-offs are key to understand intra-host evolution, and thus the dynamics of the infection. However, the understanding of these trade-offs supposes a detailed study of host-pathogen interactions at each step of the infection process, with for each step an adapted methodology. UsingDrosophila melanogasteras host and the bacteriaXenorhabdus nematophila, we investigated the bacterial adaptations resulting from GASP mutations known to induce small colony variant (SCV) phenotype positively selected within-the-host over the course of an infection, and the trade-off between step-specific adaptations.
A survey of the psychological status of primary school students who were quarantined at home during the coronavirus disease 2019 epidemic in Hangzhou China
Authors: Zheng Yanghao , Li Jianhua , Zhang Maiyan , Jin Bicheng , Li Xiaoyi , Cao Zhiyong , Wu Nanping , Jin Changzhong
Published: May 2020

Objective: To investigate the presence of social anxiety and depression and the risk factors for them among primary school students who were quarantined at home during the coronavirus disease 2019 (COVID-19) epidemic in Hangzhou China.
Methods: A total of 1620 students who were quarantined at home for at least one month were recruited from two primary schools in Hangzhou. Students completed a questionnaire on a mobile App with help from their guardians; the measures included demographic and general information, the Social Anxiety Scale for Children (SASC), and the Depression Self-rating Scale for Children (DSRSC).
Results: The mean SASC score of the participants was 3.90±3.73, which was higher than the mean norm score of Chinese urban children (3.48±3.47) (P < 0.01). The mean DSRSC score of the participants (5.67±4.97) was much lower than the mean norm score of Chinese urban children (9.84±4.73) (P < 0.05). A total of 279 (17.2%) students had social anxiety, with a mean score of 10.41±2.59, and 102 (6.3%) students had depression, with a mean score of 18.96±3.89. The following variables were found to be significant risk factors for social anxiety during home quarantine: deterioration of the parent-child relationship, increased conflicts with parents, irregular work and rest, and worrying more about being infected. Deterioration of the parent-child relationship, less physical activity, irregular work and rest, and negative mood during home quarantine were significant risk factors for depression.
Conclusion: Primary school students who were quarantined at home during the COVID-19 epidemic were more likely to have social anxiety but less likely to have depressive symptoms. Poor parent-child relationships, irregularity of work and rest, and epidemic-related problems were the main reasons for psychological problems. Families, schools, and social organizations need to pay more attention to the psychological status of primary school students quarantined at home.
Clinical Assessment of the Utility of Metagenomic Next-Generation Sequencing in Pediatric Patients of Hematology Department
Authors: Shen Heping , Shen Diying , Song Hua , Wu Xueqin , Xu Cong , Su Guangyu , Liu Chao , Zhang Jingying
Published: May 2020

Metagenomic Next-Generation Sequencing (mNGS) is an emerging technique for microbial identification and diagnosis of infectious diseases. The clinical utility of mNGS in the management of infections, especially its real-world impact on antimicrobial therapy and patient outcome has not been systematically evaluated. To that end, we prospectively assessed the effectiveness of mNGS in 70 febrile inpatients with suspected infections at the Hematology department of the Childrens Hospital, National Clinical Research Center for Child Health. 69/70 patients were given empirical antibiotics prior to mNGS. A total of 104 samples (62 plasma, 34 throat swabs, 4 bone marrow, 4 bronchoalveolar lavage) were collected on day 1-28 (mean 6.9) after symptom onset and underwent mNGS testing. Traditional microbial tests such as culture identified causal microorganisms in 5/70 (7.14%) patients that were in accordance with mNGS. In addition, mNGS reported possible pathogens when routine tests were negative. Antimicrobial treatment was adjusted in 55/70 (78.6%) patients that led to improvement/relief of symptoms within 3 days. On the other hand, in 15/70 (21.4%) patients, mNGS reports were considered irrelevant by a board of clinicians based on biochemical, serological, imaging evidence and experiences. We concluded that mNGS not only expanded the clinical capacity of pathogen detection, but also yielded positive impact on handling suspected infections through 1) differential diagnosis which may rule out infectious diseases and 2) modification and de-escalation of the empirical antibiotic regimen.
Analyzing Covid-19 Data using SIRD Models
Authors: Chakraborty Abhijit , Chen Jiaying , Desvars-Larrive Amélie , Klimek Peter , Tames Erwin Flores , Garcia David , Horstmeyer Leonhard , Kaleta Michaela , Lasser Jana , Reddish Jenny , Pinior Beate , Wachs Johannes , Turchin Peter
Published: May 2020

The goal of this analysis is to estimate the effects of the diverse government intervention measures implemented to mitigate the spread of the Covid-19 epidemic. We use a process model based on a compartmental epidemiological framework Susceptible-Infected-Recovered-Dead (SIRD). Analysis of case data with such a mechanism-based model has advantages over purely phenomenological approaches because the parameters of the SIRD model can be calibrated using prior knowledge. This approach can be used to investigate how governmental interventions have affected the Covid-19-related transmission and mortality rate during the epidemic.
Prognostic value of visual quantification of lesion severity at initial chest CT in confirmed Covid-19 infection: a retrospective analysis on 216 patients
Authors: Taieb Elias , Labani Aïssam , Ruch Yvon , Danion François , Bilbault Pascal , Oberlin Mathieu , Leyendecker Pierre , Roy Catherine , Ohana Mickaël
Published: May 2020

Rationale and Objectives

Studies suggest an association between chest CT findings assessed with semi-quantitative CT score and gravity of Covid-19. The objective of this work is to analyze potential correlation between visual quantification of lesion severity at initial chest CT and clinical outcome in confirmed Covid-19 patients.

Materials and Methods

From March 5th to March 21st, 2020, all consecutive patients that underwent chest CT for clinical suspicion of Covid-19 at a single tertiary center were retrospectively evaluated for inclusion. Patients with lung parenchyma lesions compatible with Covid-19 and positive RT-PCR were included.

Global extensiveness of abnormal lung parenchyma was visually estimated and classified independently by 2 readers, following the European Society of Thoracic Imaging Guidelines. Death and/or mechanical ventilation within 30 days following the initial chest CT was chosen as the primary hard endpoint.

Results

216 patients (124 men, 62 years-old ± 16.5, range 22 – 94 yo) corresponding to 216 chest CT were included. Correlation between lesion severity and percentage of patients that met the primary endpoint was high, with a coefficient ρ of 0.87 (p = 0.05).

A greater than 25% involvement was significantly associated with a higher risk of mechanical ventilation or death at 30 days, with a Risk Ratio of 5.00 (95% CI [3.59–6.99]).

Conclusion

This retrospective cohort confirms a correlation between visual evaluation of lesions severity at initial chest CT and the 30 days clinical outcome of Covid-19 patients and suggests using a threshold of greater than 25% involvement to identify patients at risk.
Spread of COVID-19 through Georgia, USA. Near-term projections and impacts of social distancing via a metapopulation model
Authors: Beckett Stephen J , Dominguez-Mirazo Marian , Lee Seolha , Andris Clio , Weitz Joshua S
Published: May 2020

Epidemiological forecasts of COVID-19 spread at the country and/or state level have helped shape public health interventions. However, such models leave a scale-gap between the spatial resolution of actionable information (i.e. the county or city level) and that of modeled viral spread. States and nations are not spatially homogeneous and different areas may vary in disease risk and severity. For example, COVID-19 has age-stratified risk. Similarly, ICU units, PPE and other vital equipment are not equally distributed within states. Here, we implement a county-level epidemiological framework to assess and forecast COVID-19 spread through Georgia, where 1,933 people have died from COVID-19 and 44,638 cases have been documented as of May 27, 2020. We find that county-level forecasts trained on heterogeneity due to clustered events can continue to predict epidemic spread over multi-week periods, potentially serving efforts to prepare medical resources, manage supply chains, and develop targeted public health interventions. We find that the premature removal of physical (social) distancing could lead to rapid increases in cases or the emergence of sustained plateaus of elevated fatalities.
Future scenarios for the SARS-CoV-2 epidemic in Switzerland: an age-structured model
Authors: Estill Janne , Venkova-Marchevska Plamenna , Roelens Maroussia , Orel Erol , Temerev Alexander , Flahault Antoine , Keiser Olivia
Published: May 2020

The recent lifting of COVID-19 related restrictions in Switzerland causes uncertainty about the future of the epidemic. We developed a compartmental model for SARS-CoV-2 transmission in Switzerland and projected the course of the epidemic until the end of year 2020 under various scenarios. The model was age-structured with three categories, children (0-17), adults (18-64) and seniors (65- years). Lifting all restrictions according to the plans disclosed by the Swiss federal authorities by mid-May resulted in a rapid rebound in the epidemic, with the peak expected in July. Measures equivalent to at least 90% reduction in all contacts were able to eradicate the epidemic; 56% reduction in contacts could keep the intensive care unit occupancy under the critical level, and delay the next wave until October. Scenarios where strong contact reductions were only applied in selected age groups could not suppress the epidemic, increasing the risk of a next wave in July, and another stronger wave in September. Future interventions need to cover all age groups to keep the SARS-CoV-2 epidemic under control.
Use of Skin Cancer Procedures, Medicare Reimbursement, and Overall Expenditures, 2012-2017
Authors: Puri Pranav , Baliga Sujith , Pittelkow Mark R. , Bhullar Puneet K. , Mangold Aaron R.
Published: May 2020

The treatment of skin cancers represents a growing share of healthcare expenditures. However, little is known about how variations in payment rates relate to the use of different skin cancer procedures. This study describes recent trends in payment rates, use rates, and overall expenditures for skin cancer procedures in the Medicare Part B population. In this ecological study, we used the Medicare Physician Supplier and Other Provider Public Use File (POSPUF) to analyze trends in Medicare payment rates, use rates, and overall Medicare expenditures for skin cancer procedures from 2012 to 2017. We adjusted reimbursement rates for inflation by converting payment amounts into units of 2017 dollars. From 2012 to 2017, overall inflation-adjusted Medicare expenditure on skin cancer procedures increased 9%. Over this time period, inflation-adjusted Medicare reimbursement rates declined for each procedure class, with the exception of shave excision. Concurrently, the use rate of Mohs micrographic surgery increased 21%, while the use rate for all other skin cancer procedure classes declined. In summary, the results of this study suggest that increased use of Mohs has displaced use of other skin cancer procedures in the Medicare population.
Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety
Authors: Takla Michael , Jeevaratnam Kamalan
Published: May 2020

Background

The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the repurposing of existing drugs. Several drugs are now being repurposed with the aim of identifying if these drugs provide some level of disease resolution. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ), first developed as an antimalarial therapy. There is increasing concern with regards to the efficacy and safety of these agents. The aims of this review are to systematically identify and collate studies describing the use of CQ and HCQ in human clinical trials and provide a detailed synthesis of evidence of its efficacy and safety.

Methods and Findings

Searches for (“COVID” AND “chloroquine”[title/abstract] AND “outcomes”[full text]) and two (“COVID” AND “hydroxychloroquine”[title/abstract] AND “outcomes”[full text]) yielded 272 unique articles. Unique articles were manually checked for inclusion and exclusion criteria and also subjected to a quality appraisal assessment. A total of 19 articles were included in the systematic review. Seventy-five percent of observational studies employing an endpoint specific to efficacy recorded no significant difference in the attainment of outcomes, between COVID-19 patients given a range of CQ and/or HCQ doses, and the control groups. All clinical trials and 82% of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Seventy-five percent of the total papers focusing on cardiac side-effects found a greater incidence among patients administered a wide range of CQ and/or HCQ doses, with QTc prolongation the most common finding, in addition to its consequences of VT and cardiac arrest. Of the total studies using mortality rate as an end-point, 60% reported no significant change in the risk of death, while 30% showed an elevation, and 10% a depression, in treated relative to control patients.

Conclusion

The strongest available evidence suggests that, relative to standard in-hospital management of symptoms, the use of CQ and HCQ to treat hospitalised COVID-19 patients has likely been unsafe. At the very least, the poor quality of data failing to find any significant changes in the risk of VT should preclude definitive judgment on drug safety until the completion of high-quality randomised clinical trials.
An inflammatory cytokine signature helps predict COVID-19 severity and death
Authors: Del Valle Diane Marie , Kim-schulze Seunghee , Hsin-hui Huang , Beckmann Noam D , Nirenberg Sharon , Wang Bo , Lavin Yonit , Swartz Talia , Madduri Deepu , Stock Aryeh , Marron Thomas , Xie Hui , Patel Manish Kumar , van Oekelen Oliver , Rahman Adeeb , Kovatch Patricia , Aberg Judith , Schadt Eric , Jagannath Sundar , Mazumdar Madhu , Charney Alexander , Firpo-Betancourt Adolfo , Mendu Damodara Rao , Jhang Jeffrey , Reich David , Sigel Keith , Cordon-Cardo Carlos , Feldmann Marc , Parekh Samir , Merad Miriam , Gnjatic Sacha
Published: May 2020

The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-α, and IL-1β in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival. Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF-α levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.
Monitoring sick leave data for early detection of influenza outbreaks
Authors: Duchemin Tom , Bastard Jonathan , Ante-Testard Pearl Anne , Assab Rania , Daouda Oumou Salama , Duval Audrey , Garsi Jérôme-Philippe , Lounissi Radowan , Nekkab Narimane , Neynaud Helene , Smith David R.M. , Dab William , Jean Kévin , Temime Laura , Hocine Mounia N
Published: May 2020

Background - Workplace absenteeism increases significantly during influenza epidemics. Sick leave records may facilitate more timely detection of influenza outbreaks, as trends in increased sick leave may precede alerts issued by sentinel surveillance systems by days or weeks. Sick leave data have not been comprehensively evaluated in comparison to traditional surveillance methods.
Aim - To study the performance and the feasibility of using a detection system based on sick leave data to detect influenza outbreaks
Methods - Sick leave records were extracted from private French health insurance data, covering on average 209,932 companies per year across a wide range of sizes and sectors. We used linear regression to estimate the weekly number of new sick leave spells from 2010 to 2017 in 12 French regions, adjusting for trend, seasonality and worker leaves. Outbreaks were detected using a 95%-prediction interval. This method was compared to results from the French Sentinelles network, a gold-standard primary care surveillance system currently in place.
Results - Using sick leave data, we detected 92% of reported influenza outbreaks between 2016 and 2017, on average 5.88 weeks prior to outbreak peaks. Compared to the existing Sentinelles model, our method had high sensitivity (89%) and specificity (86%), and detected outbreaks on average 2.5 weeks earlier.
Conclusion - Sick leave surveillance could be a sensitive, specific and timely tool for detection of influenza outbreaks.