bluuebunny/crossref_metadata_2025 huggingface dataset:
Doxycycline is a safe alternative to Hydroxychloroquine + Azithromycin to prevent clinical worsening and hospitalization in mild COVID-19 patients: An open label randomized clinical trial (DOXYCOV)
Authors: Sobngwi Eugene , Zemsi Sylvain , Guewo-Fokeng Magellan , Katte Jean-Claude , Kounfack Charles , Mfeukeu-Kuate Liliane , Zemsi Armel , Wasnyo Yves , Ntsama Antoinette Assiga , Ndi-Manga Arnaud , Sobngwi-Tambekou Joelle , Ngatchou William , Omgba Charlotte Moussi , Mbanya Jean Claude , Zogo Pierre Ongolo , Fouda Pierre Joseph
Published: July 2021

Objective

We aimed to compare the safety and efficacy of a doxycycline-based regimen against the national standard guidelines (Hydroxychloroquine plus Azithromycin) for the treatment of mild symptomatic COVID-19.

Methods

We conducted an open-label, randomized, non-inferiority trial, in Cameroon comparing Doxycycline 100mg, twice daily for 7 days versus Hydroxychloroquine, 400 mg daily for 5 days and Azithromycin 500mg at day 1 and 250mg from day 2 through 5, in mild COVID-19 patients. Clinical improvement, biological parameters and adverse events were assessed. The primary outcome was the proportion of clinical cure at day 3, 10 and 30. Non-inferiority was determined by the clinical cure rate between protocols with a 20 percentage points margin.

Results

194 participants underwent randomization and were treated with Doxycycline (n=97) or Hydroxychloroquine-Azithromycin (n=97). At day 3, 74/92 (80.4%) participants on Doxycycline versus 77/95 (81.1%) on Hydroxychloroquine-Azithromycin -based protocols were asymptomatic (p=0.91). At day 10, 88/92 (95.7%) participants on Doxycycline versus 93/95 (97.9%) on Hydroxychloroquine-Azithromycin were asymptomatic (p=0.44). At day 30 all participants were asymptomatic. SARS-CoV2 PCR was negative at Day 10 in 60/92 (65.2%) participants allocated to Doxycycline and 63/95 (66.3%) participants allocated to Hydroxychloroquine-Azithromycin. None of the participants were admitted for worsening of the disease after treatment initiation.

Conclusion

Doxycycline 100 mg twice daily for 7 days is as effective and safe as Hydroxychloroquine-Azithromycin, for preventing clinical worsening of mild symptomatic or asymptomatic COVID-19, and achieving virological suppression.

Strengths and Limitations

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This study is one of the first randomized trial, assessing the efficacy and tolerance of Doxycycline to treat COVID-19

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It is one of the first to evaluate disease progression and need to hospitalization in mild or asymptomatic COVID-19

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Patients will not receive identical treatments

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Doxycycline has advantages in terms of availability, safety and cost compared to Hydroxychloroquine and Azytromycin

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Though this study has encounter 7 lost to follow-up, this does not have a major influence on our results

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These data will assist clinicians in their daily practice, and provide a new tool for the fight against COVID-19
Effectiveness of BNT162b2 and ChAdOx1 vaccines against symptomatic COVID-19 among Healthcare Workers in Kuwait: A retrospective cohort study
Authors: Alali Walid Q. , Ali Lamiaa A. , AlSeaidan Mohammad , Al-Rashidi Mohammad
Published: July 2021

Background

The COVID-19 BNT162b2 vaccination roll-out in Kuwait started on 24 December 2020 followed by ChAdOx1 on 3 February 2021. The study objectives were to assess the factors associated with vaccine coverage and determine vaccine effectiveness (VE) against SARS-CoV-2 infection in a healthcare worker (HCW) population.

Methods

This retrospective cohort study was conducted among HCW working at a public secondary hospital in Kuwait. The follow-up period was from 24 December 2020 to 15 June 2021. The primary outcomes were vaccine coverage and PCR-confirmed SARS-CoV-2 infection for the VE analysis. Data on new SARS-CoV-2 infections (with or without symptoms) during study period in addition to HCWs characteristics (sex, age, nationality, and occupation) were extracted from the hospital records. The vaccine coverage and PCR-confirmed SARS-CoV-2 infections were cross-tabulated by the HCWs characteristics. Furthermore, we used Cox regression to estimate time-to-infection hazard ratios in vaccinated (first and second dose) compared to unvaccinated HCWs. Only one ChAdOx1 dose was given during the study period.

Results

There were 3246 HCWs included in the analysis. The median age was 38 years (IQR = 33 - 44), 63.4% were females, 46.8% aged 31-40, and 82.3% were non-Kuwaitis. Overall, 82.1% of HCWs received at least one vaccine dose (50.4% received only one dose of ChAdOx1, 3.3% received one dose of BNT162b2, and 28.3% received two doses of BNT162b2). 17.9% of HCWs remained unvaccinated by the end of the study. A significantly lower vaccination coverage percentage was amongst female HCWs, younger age group (20 – 30 years old), and administrative/executive staff. Symptomatic SARS-CoV-2 PCR-confirmed infection prevalence was 7.3%. No asymptomatic infections were reported. The SARS-CoV-2 infection incidence rate was 126 per 100,000 person-days in the unvaccinated group; whereas, the incidence rates in the partially vaccinated groups (≥ 28 days after ChAdOx1 first dose) and (≥ 14 days after receiving BNT162b2 through receipt of second dose) were 31.4 and 10.9 per 100,000 person-days, respectively. In the fully vaccinated group (≥ 14 days after BNT162b2 second dose), the incidence rate was 6.3 per 100,000 person-days. The estimated adjusted vaccine effectiveness of fully vaccinated was 94.5% (95% confidence interval [CI] = 89.4%–97.2%). The VE of partially vaccinated for ChAdOx1 and BNT162b2 was 75.4% (95% CI = 67.2%–81.6%) and 91.4% (95% CI = 65.1%–97.9%), respectively.

Conclusions

Both BNT162b2 and ChAdOx1 vaccines prevented most symptomatic infections in this population across age groups, nationalities, and occupations. A significant proportion (17.9%) of HCWs were unvaccinated despite the vaccine accessibility. The findings complement other VE studies and demonstrate the vaccine benefit among HCWs.
Parent attitudes about childhood vaccines: a vaccine hesitancy point prevalence study
Authors: Marshall Sarah , Moore Anne C , Sahm Laura J , Fleming Aoife
Published: July 2021

Objectives

The aim of this study was to measure the prevalence of vaccine hesitancy using Parent Attitudes about Childhood Vaccines (PACV) survey regarding paediatric vaccines for their children, in a population of parents attending a STEM (Science, Technology, Engineering and Mathematics) outreach event in Cork, Ireland.

Study design

Cross-sectional survey study.

Methods

This study was conducted in November 2018 at the “Community Festival of Science” STEM event. Eligible attendees were invited to read the participant information leaflet, provide written informed consent, and complete the validated Parent Attitudes about Childhood Vaccines (PACV) survey. Each of the 15 PACV survey items was scored. A score ≥50 identified vaccine hesitant parents.

Results

A total of 105 parents participated in the study. A small number of participants (6.7%, n = 7) were identified as vaccine hesitant. There were no statistically significant differences between the vaccine hesitant and non-hesitant groups based on age, education, or number of children. Parents had concerns around vaccine side effects (36.2%, n=38) and vaccine safety (20%, n=21). Parents trusted the information they received on vaccines (85.6%, n=90) and 81.9% (n=86) believed that the vaccine schedule was good for their child.

Conclusions

The findings of this research indicate the presence of vaccine hesitancy in parents in Ireland regarding paediatric vaccines. Parents had concerns regarding vaccine side effects and the number of vaccines on the paediatric immunisation schedule. Further research is necessary to understand how these issues may contribute to vaccine hesitancy, and to develop evidence-based interventions to build on parents existing trust in the vaccination schedule.

Key points

A low level of vaccine hesitancy regarding childhood vaccinations was reported in a sample of parents at a science outreach event in Ireland using the PACV survey.

Areas of parents’ concerns were around vaccine side effects and number of vaccines.

Most parents trusted their doctors regarding vaccines, trusted vaccines information and followed the vaccine schedule.

The PACV survey could be used as a screening tool to identify vaccine hesitant parents by healthcare providers and provide them with additional information and support, to support public health vaccination campaigns.
Tracking Cryptic SARS-CoV-2 Lineages Detected in NYC Wastewater
Authors: Smyth Davida S. , Trujillo Monica , Gregory Devon A. , Cheung Kristen , Gao Anna , Graham Maddie , Guan Yue , Guldenpfennig Caitlyn , Hoxie Irene , Kannoly Sherin , Kubota Nanami , Lyddon Terri D. , Markman Michelle , Rushford Clayton , San Kaung Myat , Sompanya Geena , Spagnolo Fabrizio , Suarez Reinier , Teixeiro Emma , Daniels Mark , Johnson Marc C. , Dennehy John J.
Published: July 2021

Tracking SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To monitor New York City (NYC) for the presence of novel variants, we amplified regions of the SARS-CoV-2 Spike protein gene from RNA acquired from all 14 NYC wastewater treatment plants (WWTPs) and ascertained the diversity of lineages from these samples using high throughput sequencing. Here we report the detection and increasing frequencies of novel SARS-CoV-2 lineages not recognized in GISAID’s EpiCoV database. These lineages contain mutations rarely observed in clinical samples, including Q493K, Q498Y, H519N and T572N. Many of these mutations were found to expand the tropism of SARS-CoV-2 pseudoviruses by allowing infection of cells expressing the human, mouse, or rat ACE2 receptor. In addition, pseudoviruses containing the Spike amino acid sequence of these lineages were found to be resistant to many different classes of receptor binding domain (RBD) binding neutralizing monoclonal antibodies. We offer several hypotheses for the anomalous presence of these mutations, including the possibility of a non-human animal reservoir. Although wastewater sampling cannot provide direct inference of SARS-CoV-2 clinical sequences, our research revealed several lineages that could be relevant to public health and they would not have been discovered if not for wastewater surveillance.
Wastewater surveillance for infectious disease: a systematic review
Authors: Kilaru Pruthvi , Hill Dustin , Anderson Kathryn , Collins Mary B. , Green Hyatt , Kmush Brittany L. , Larsen David A.
Published: July 2021

Wastewater surveillance of SARS-CoV-2 has shown to be a valuable source of information regarding SARS-CoV-2 transmission and COVID-19 cases. Though the method has been used for several decades to track other infectious diseases, there has not been a comprehensive review outlining all of the pathogens surveilled through wastewater. The aim of this study is to identify what infectious diseases have been previously studied via wastewater surveillance prior to the COVID-19 Pandemic and identify common characteristics between the studies, as well as identify current gaps in knowledge. Peer-reviewed articles published as of August 1, 2020 that examined wastewater for communicable and infectious human pathogens on 2 or more occasions were included in the study. Excluded from this list were all reviews and methods papers, single collection studies, and non-human pathogens. Infectious diseases and pathogens were identified in studies of wastewater surveillance, as well as themes of how wastewater surveillance and other measures of disease transmission were linked. This review did not include any numerical data from individual studies and thus no statistical analysis was done. 1005 articles were identified but only 100 were included in this review after applying the inclusion criteria. These studies came from 38 countries with concentration in certain countries including Italy, Israel, Brazil, Japan, and China. Twenty-five separate pathogen families were identified in the included studies, with the majority of studies examining pathogens from the family Picornaviridae, including polio and non-polio enteroviruses. Most studies of wastewater surveillance did not link what was found in the wastewater to other measures of disease transmission. Among those studies that did compare wastewater surveillance to other measures of disease transmission the value observed was dependent upon pathogen and varied by study. Wastewater surveillance has historically been used to assess water-borne and fecal-orally transmitted pathogens causing diarrheal disease. However, numerous other types of pathogens have been surveilled using wastewater and wastewater surveillance should be considered as a potential tool for many infectious diseases. Wastewater surveillance studies can be improved by incorporating other measures of disease transmission at the population-level including disease incidence and hospitalizations.
Small Patient Datasets Reveal Genetic Drivers of Non-Small Cell Lung Cancer Subtypes Using a Novel Machine Learning Approach
Authors: Moses Cook , Bessi Qorri , Amruth Baskar , Jalal Ziauddin , Luca Pani , Shashibushan Yenkanchi , Geraci Joseph
Published: July 2021

Background

There are many small datasets of significant value in the medical space that are being underutilized. Due to the heterogeneity of complex disorders found in oncology, systems capable of discovering patient subpopulations while elucidating etiologies is of great value as it can indicate leads for innovative drug discovery and development.

Materials and Methods

Here, we report on a machine intelligence-based study that utilized a combination of two small non-small cell lung cancer (NSCLC) datasets consisting of 58 samples of adenocarcinoma (ADC) and squamous cell carcinoma (SCC) and 45 samples (GSE18842). Utilizing a set of standard machine learning (ML) methods which are described in this paper, we were able to uncover subpopulations of ADC and SCC while simultaneously extracting which genes, in combination, were significantly involved in defining the subpopulations. We also utilized a proprietary interactive hypothesis-generating method designed to work with machine learning methods, which provided us with an alternative way of pinpointing the most important combination of variables. The discovered gene expression variables were used to train ML models. This allowed us to create methods using standard methods and to also validate our in-house methods for heterogeneous patient populations, as is often found in oncology.

Results

Using these methods, we were able to uncover genes implicated by other methods and accurately discover known subpopulations without being asked, such as different levels of aggressiveness within the SCC and ADC subtypes. Furthermore, PIGX was a novel gene implicated in this study that warrants further study due to its role in breast cancer proliferation.

Conclusion

Here we demonstrate the ability to learn from small datasets and reveal well-established properties of NSCLC. This demonstrates the utility for machine learning techniques to reveal potential genes of interest, even from small data sets, and thus the driving factors behind subpopulations of patients.
Short Report –Consumption of multiple sources of protein is associated with gestational diabetes mellitus in the Chinese population
Authors: Wang Wei-Qin , Chiang Vic Shao-Chih , Wen Jing-Yuan , Hu Ji-Fen , Xu Rong-Xian
Published: July 2021

Background

Gestational diabetes mellitus (GDM) is a hyperglycemic state during pregnancy that results in disruptions of insulin sensitivity and secretion. It affects 7% of all pregnancies and lead to adverse maternal and offspring outcomes. GDM has many risk factors, such as ethnicity special, hereditary. However Nutritional factors offer key strategies against GDM, but this is less characterized for the Chinese population.

Methods

A case control study of GDM pregnant women (n=49, 29.88±3.92 years of age) and healthy pregnant women (n=77, 27.63±4.83 years of age) from 1st Affiliated Hospital of Fujian Medical University were studied. Diagnosis was made using oral glucose tolerance test. Dietary data were collected using food frequency questionnaires. Data for use of dietary supplements, occupation, education, income, meal expenditure and smoking history were also recorded.

Results

No differences were found between GDM and control subjects for their age, education, occupation, monthly income, grocery expenditure and smoking (p>0.05). GDM subjects were associated with higher quantities of dairy products (p<0.05) and seafood (p<0.01) intake. There were also higher number of GDM subjects using protein powder supplementation (p<0.05).

Conclusions

Dietary recommendation guidelines for pregnant Chinese women should consider possible risks with excessive consumption of dairy products, seafood and protein powder. They should also assess the quality of the nutrition factor, other dietary interactions and their nutritional status further to minimize adverse outcomes caused by GDM.
Genetic and neurophysiological biomarkers of neuroplasticity inform post-stroke language recovery
Authors: Dresang Haley C. , Harvey Denise Y. , Shah-Basak Priyanka P. , DeLoretta Laura , Wurzman Rachel , Parchure Shreya Y. , Sacchetti Daniela , Faseyitan Olufunsho , Lohoff Falk W. , Hamilton Roy H.
Published: July 2021

Background

There is high variability in post-stroke aphasia severity and predicting recovery remains imprecise. Standard prognostics do not include neurophysiological indicators or genetic biomarkers of neuroplasticity, which may be critical sources of variability.

Objective

To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF) contributes to variability in post-stroke language recovery, and to assess whether BDNF polymorphism interacts with neurophysiological indicators of neuroplasticity to improve estimates of aphasia severity.

Methods

Saliva samples and motor-evoked potentials (MEPs) were collected from participants with chronic aphasia subsequent to left-hemisphere stroke. MEPs were collected prior to continuous theta burst stimulation (cTBS; index for cortical excitability) and 10 minutes following cTBS (index for stimulation-induced neuroplasticity) to the left primary motor cortex. Analyses assessed the extent to which BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to predict aphasia severity beyond established predictors.

Results

Val66Val carriers showed less aphasia severity than Met allele carriers, after controlling for lesion volume and time post-stroke. Furthermore, Val66Val carriers showed expected effects of age on aphasia severity, and positive associations between both cortical excitability and stimulation-induced neuroplasticity and severity. In contrast, Met allele carriers showed weaker effects of age and negative associations between cortical excitability, stimulation-induced neuroplasticity and aphasia severity.

Conclusions

Neurophysiological indicators and genetic biomarkers of neuroplasticity improved ability to predict aphasia severity. Furthermore, BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to improve predictions. These findings provide novel insights into mechanisms of variability in stroke recovery and may improve aphasia prognostics.
The Vaccination Threshold for SARS-CoV-2 Depends on the Indoor Setting and Room Ventilation
Authors: Mikszewski A. , Stabile L. , Buonanno G. , Morawska L.
Published: July 2021

Background

Effective vaccines are now available for SARS-CoV-2 in the second year of the COVID-19 pandemic, but there remains significant uncertainty surrounding the necessary vaccination rate to safely lift occupancy controls in public buildings and return to pre-pandemic norms. The aim of this paper is to estimate setting-specific vaccination thresholds for SARS-CoV-2 to prevent sustained community transmission using classical principles of airborne contagion modeling. We calculated the airborne infection risk in three settings, a classroom, prison cell block, and restaurant, at typical ventilation rates, and then the expected number of infections resulting from this risk at varying levels of occupant susceptibility to infection.

Results

We estimate the vaccination threshold for control of SARS-CoV-2 to range from a low of 40% for a mechanically ventilation classroom to a high of 85% for a naturally ventilated restaurant.

Conclusions

If vaccination rates are limited to a theoretical minimum of approximately two-thirds of the population, enhanced ventilation above minimum standards for acceptable air quality is needed to reduce the frequency and severity of SARS-CoV-2 superspreading events in high-risk indoor environments.
Uncovering the Bromodomain Interactome using Site-Specific Azide-Acetyllysine Photochemistry, Proteomic Profiling and Structural Characterization
Authors: Wagner Shana , Fedorov Elena , Sudhamalla Babu , Jnawali Hum Nath , Debiec Ronald , Ghosh Agnidipta , Islam Kabirul
Published: July 2021

Protein-protein interactions mediated by acetyllysines and bromodomains are essential for the regulation of eukaryotic gene expression. Diagramming the bromodomain interactome network and molecular characterization of these interactions are key to unraveling context-dependent signaling pathways. Herein, we employ a chemoproteomic platform, called interaction-based protein profiling (IBPP), to map the acetylome of the bromodomain and extra terminal domain (BET) family of bromodomains. We developed photo-responsive bromodomain analogues to carry out UV light-induced azide-acetyllysine crosslinking within the recognition cavity of the domain to capture transient interacting partners present in human cells. Subsequent proteomic and biochemical analyses lead to the identification of an array of acetylated interacting factors, which extend the potential function of BET family proteins beyond transcription. We present here eight high-resolution crystal structures of interactome-bound bromodomains that underscore the atypical binding modes and sequence motifs by which BET members recognize an expanded repertoire of acetylated proteins. In addition, we report an acetyllysine-dependent interaction between BRD4 and interleukin enhancer binding factor 3 (ILF3) in human cells, and uncover its role in recruiting transcriptional regulators to the promoter of the Survivin gene, an anti-apoptotic factor overexpressed in a wide range of human neoplasia. Collectively, our work provides a blueprint for engineering bromodomains, establishes IBPP as a robust chemoproteomic tool to characterize bromodomain interactome, and reveals distinctive recognition modes by which such associations may take place in order to modulate signaling pathways. Furthermore, these structural snapshots offer clues to design specific small-molecule inhibitors against the novel BET interactions and paves the path for exploring the biological significance of this newly identified signaling network.
Early Life Adversity in Male Mice Sculpts Reward Circuits
Authors: Wendel Kara M. , Short Annabel K. , Noarbe Brenda P. , Haddad Elizabeth , Palma Anton M. , Yassa Michael A. , Baram Tallie Z. , Obenaus Andre
Published: July 2021

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA- NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.
Estimating dispersal using close kin dyads: The kindisperse R package
Authors: Jasper Moshe E , Hoffmann Ary A , Schmidt Thomas L
Published: July 2021

Investigating dispersal in animal populations can be difficult, particularly for taxa that are hard to directly observe such as those that are small or rare. A promising solution may come from new approaches that use genome-wide sequence data to detect close kin dyads and estimate dispersal parameters from the distribution of these dyads. These methods have so far only been applied to mosquito populations. However, they should have broad applicability to a range of taxa, although no assessment has yet been made on their performance under different dispersal conditions and study designs. Here we develop an R package and Shiny app, kindisperse, that can be used to estimate dispersal parameters from the spatial distribution of close kin. Kindisperse can handle study designs that target different life stages and allows for a range of dispersal kernel shapes and organismal life histories; we provide implementation examples for a vertebrate (Antechinus) and an invertebrate (Aedes). We use simulations run in kindisperse to compare the performance of two published close kin methodologies, showing that one method produces unbiased estimates whereas the other produces downward-biased estimates. We also use kindisperse simulations to investigate how study design affects dispersal estimates, and we provide guidelines for the size and shape of sample sites as well as the number of close kin needed for accurate estimates. kindisperse is easily adaptable for application to a variety of research contexts ranging from invasive pests to threatened species where non-invasive DNA sampling can be used to detect close kin.
EffectorP 3.0: prediction of apoplastic and cytoplasmic effectors in fungi and oomycetes
Authors: Sperschneider Jana , Dodds Peter N.
Published: July 2021

Many fungi and oomycete species are devasting plant pathogens. These eukaryotic filamentous pathogens secrete effector proteins to facilitate plant infection. Fungi and oomycete pathogens have diverse infection strategies and their effectors generally do not share sequence homology. However, they occupy similar host environments, either the plant apoplast or plant cytoplasm, and may therefore share some unifying properties based on the requirements of these host compartments. Here we exploit these biological signals and present the first classifier (EffectorP 3.0) that uses two machine learning models: one trained on apoplastic effectors and one trained on cytoplasmic effectors. EffectorP 3.0 accurately predicts known apoplastic and cytoplasmic effectors in fungal and oomycete secretomes with low estimated false positive rates of 3% and 8%, respectively. Cytoplasmic effectors have a higher proportion of positively charged amino acids, whereas apoplastic effectors are enriched for cysteine residues. The combination of fungal and oomycete effectors in training leads to a higher number of predicted cytoplasmic effectors in biotrophic fungi. EffectorP 3.0 expands predicted effector repertoires beyond small, cysteine-rich secreted proteins in fungi and RxLR-motif containing secreted proteins in oomycetes. We show that signal peptide prediction is essential for accurate effector prediction, as EffectorP 3.0 recognizes a cytoplasmic signal also in intracellular, non-secreted proteins. EffectorP 3.0 is available at http://effectorp.csiro.au.
Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify its “Epidemic Rates”
Authors: Torres Elizabeth B
Published: July 2021

In the last decade, Autism has broadened and often shifted its diagnostics criter a, allowing several neuropsychiatric and neurological disorders of known etiology. This has resulted in a highly heterogeneous spectrum with apparent exponential rates in prevalence. I ask if it is possible to leverage existing genetic information about those disorders making up Autism today and use it to stratify this spectrum. To that end, I combine genes linked to Autism in the SFARI database and genomic information from the DisGeNet portal on 25 diseases, inclusive of non-neurological ones. I use the GTEx data on genes’ expression on 54 human tissues and ask if there are overlapping genes across those associated to these diseases and those from SFARI-Autism. I find a compact set of genes across all brain-disorders which express highly in tissues fundamental for somatic-sensory-motor function, self-regulation, memory, and cognition. Then, I offer a new stratification that provides a distance-based orderly clustering into possible Autism subtypes, amenable to design personalized targeted therapies within the framework of Precision Medicine. I conclude that viewing Autism through this physiological (Precision) lens, rather than viewing it exclusively from a psychological behavioral construct, may make it a more manageable condition and dispel the Autism epidemic myth.
Catalytic cycling of human mitochondrial Lon protease
Authors: Mohammed Inayathulla , Schmitz Kai A. , Schenck Niko , Topitsch Annika , Maier Timm , Abrahams Jan Pieter
Published: July 2021

The mitochondrial Lon protease homolog (LonP1) hexamer controls mitochondrial health by digesting proteins from the mitochondrial matrix that are damaged or must be removed. Understanding how it is regulated requires characterizing its mechanism. Here, we show how human LonP1 functions, based on eight different conformational states that we determined by cryo-EM with a resolution locally extending to 3.6 Å for the best ordered states. LonP1 has a poorly ordered N-terminal part with apparent threefold symmetry, which apparently binds substrate protein and feeds it into its AAA+ unfoldase core. This translocates the extended substrate protein into a proteolytic cavity, in which we report an additional, previously unidentified Thr-type proteolytic center. Threefold rocking movements of the flexible N-terminal assembly likely assist thermal unfolding of the substrate protein. Our data suggest LonP1 may function as a sixfold cyclical Brownian ratchet controlled by ATP hydrolysis.
Inferring the intrinsic mutational fitness landscape of influenza-like evolving antigens from temporally ordered sequence data
Authors: Doelger Julia , Kardar Mehran , Chakraborty Arup K.
Published: July 2021

There still are no effective long-term protective vaccines against viruses that continuously evolve under immune pressure such as seasonal influenza, which has caused, and can cause, devastating epidemics in the human population. For finding such a broadly protective immunization strategy it is useful to know how easily the virus can escape via mutation from specific antibody responses. This information is encoded in the fitness landscape of the viral proteins (i.e., knowledge of the viral fitness as a function of sequence). Here we present a computational method to infer the intrinsic mutational fitness landscape of influenza-like evolving antigens from yearly sequence data. We test inference performance with computer-generated sequence data that are based on stochastic simulations mimicking basic features of immune-driven viral evolution. Although the numerically simulated model does create a phylogeny based on the allowed mutations, the inference scheme does not use this information. This provides a contrast to other methods that rely on reconstruction of phylogenetic trees. Our method just needs a sufficient number of samples over multiple years. With our method we are able to infer single-as well as pairwise mutational fitness effects from the simulated sequence time series for short antigenic proteins. Our fitness inference approach may have potential future use for design of immunization protocols by identifying intrinsically vulnerable immune target combinations on antigens that evolve under immune-driven selection. This approach may in the future be applied to influenza and other novel viruses such as SARS-CoV-2, which evolves and, like influenza, might continue to escape the natural and vaccine-mediated immune pressures.
Muscarinic receptors mediate motivation via preparatory neural activity in humans
Authors: Grogan John P. , Raemaekers Matthias , Van Swieten Maaike M. H. , Green Alexander L. , Gillies Martin J. , Manohar Sanjay G.
Published: July 2021

Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson’s disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using electroencephalography (EEG). We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivation effects, suggesting that muscarinic receptors facilitate invigoration by reward.

Preparatory EEG build-up (contingent negative variation; CNV) was strengthened by high incentives and by muscarinic blockade, although THP reduced the incentive-effect. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions; frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. The incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug’s effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.
PLB-985 neutrophil-like cells as a model to studyAspergillus fumigatuspathogenesis
Authors: Rafiq Muhammad , Rivieccio Flora , Zimmermann Ann-Kathrin , Visser Corissa , Bruch Alexander , Krüger Thomas , Rojas Katherine González , Kniemeyer Olaf , Blango Matthew G. , Brakhage Axel A.
Published: July 2021

Fungal infections remain a major global concern. Emerging fungal pathogens and increasing rates of resistance mean that additional research efforts and resources must be allocated to advancing our understanding of fungal pathogenesis and developing new therapeutic interventions. Neutrophilic granulocytes are a major cell type involved in protection against the important fungal pathogenAspergillus fumigatus, where they employ numerous defense mechanisms, including production of antimicrobial extracellular vesicles. A major draw-back to work with neutrophils is the lack of a suitable cell line system for the study of fungal pathogenesis. To address this problem, we assessed the feasibility of using differentiated PLB-985 neutrophil-like cells as anin vitromodel to studyA. fumigatusinfection. We find that dimethylformamide-differentiated PLB-985 cells provide a useful recapitulation of many aspects ofA. fumigatusinteractions with primary human polymorphonuclear leukocytes. We show that differentiated PLB-985 cells phagocytose fungal conidia and acidify conidia-containing phagolysosomes similar to primary neutrophils, release neutrophil extracellular traps, and also produce antifungal extracellular vesicles in response to infection. In addition, we provide an improved method for the isolation of extracellular vesicles produced during infection by employing a size-exclusion chromatography-based approach. Advanced LC-MS/MS proteomics revealed an enrichment of extracellular vesicle marker proteins and a decrease of cytoplasmic proteins in extracellular vesicles isolated using this improved method. Ultimately, we find that differentiated PLB-985 cells can serve as a genetically tractable model to study many aspects ofA. fumigatuspathogenesis.

IMPORTANCE

Polymorphonuclear leukocytes are an important defense against human fungal pathogens, yet our model systems to study this group of cells remains very limited in scope. In this study, we established that differentiated PLB-985 cells can serve as a model to recapitulate several important aspects of human polymorphonuclear leukocyte interactions with the important human fungal pathogenAspergillus fumigatus. The proposed addition of a cultured neutrophil-like cell line to the experimental toolbox to study fungal pathogenesis will allow for a more mechanistic description of neutrophil antifungal biology. In addition, the easier handling of the cell line compared to primary human neutrophils allowed us to use PLB-985 cells to provide an improved method for isolation of neutrophil-derived extracellular vesicles using size-exclusion chromatography. Together, these results provide significant tools and a baseline knowledge for the future study of neutrophil-derived extracellular vesicles in the laboratory.
Environmental drivers of body size in North American bats
Authors: Alston J.M. , Keinath D.A. , Willis C.K.R. , Lausen C.L. , O’Keefe J.M. , Tyburec J.D. , Broders H.G. , Moosman P.R. , Carter T.C. , Chambers C.L. , Gillam E.H. , Geluso K. , Weller T.J , Burles D.W. , Fletcher Q.E. , Norquay K.J.O. , Goheen J.R.
Published: July 2021

Bergmann’s Rule—which posits that larger animals live in colder areas—is thought to influence variation in body size within species across space and time, but evidence for this claim is mixed. We tested four competing hypotheses for spatio-temporal variation in body size within bat species during the past two decades across North America. Bayesian hierarchical models revealed that spatial variation in body mass was most strongly (and negatively) correlated with mean annual temperature, supporting the heat conservation hypothesis (historically believed to underlie Bergmann’s Rule). Across time, variation in body mass was most strongly (and positively) correlated with net primary productivity, supporting the resource availability hypothesis. Climate change could influence body size in animals through both changes in mean annual temperature and in resource availability. Rapid reductions in body size associated with increasing temperatures have occurred in short-lived, fecund species, but such reductions likely transpire more slowly in longer-lived species.
Sensory computations in the cuneate nucleus of macaques
Authors: Suresh Aneesha K. , Greenspon Charles M. , He Qinpu , Rosenow Joshua M. , Miller Lee E. , Bensmaia Sliman J.
Published: July 2021

Abstract

Tactile nerve fibers fall into a few classes that can be readily distinguished based on their spatiotemporal response properties. Because nerve fibers reflect local skin deformations, they individually carry ambiguous signals about object features. In contrast, cortical neurons exhibit heterogeneous response properties that reflect computations applied to convergent input from multiple classes of afferents, which confer to them a selectivity for behaviorally relevant features of objects. The conventional view is that these complex response properties arise within the cortex itself, implying that sensory signals are not processed to any significant extent in the two intervening structures – the cuneate nucleus (CN) and the thalamus. To test this hypothesis, we recorded the responses evoked in CN to a battery of stimuli that have been extensively used to characterize tactile coding in both the periphery and cortex, including skin indentations, vibrations, random dot patterns, and scanned edges. We found that CN responses are more similar to their cortical counterparts than they are to their inputs: CN neurons receive input from multiple classes of nerve fibers, they have spatially complex receptive fields, and they exhibit selectivity for object features. Contrary to consensus, then, CN plays a key role in processing tactile information.

Significance

Perception is the outcome of the sequential processing of sensory signals at multiple stages along the neuraxis. The conventional view is that tactile signals are processed predominantly in the cerebral cortex. We tested this view by investigating the response properties of neurons in the cuneate nucleus (CN), the first potential stage of processing along the primary touch neuraxis. We found that CN responses more nearly resemble those of cortical neurons than they do those of nerve fibers: CN neurons have spatially complex receptive fields reflecting convergent input from multiple classes of nerve fibers and exhibit a selectivity for object features, absent in the nerve. We conclude that CN plays a key, early role in the processing of tactile information.
Long term conservation of DNA at ambient temperature. Implications for DNA data storage
Authors: Coudy Delphine , Colotte Marthe , Luis Aurélie , Tuffet Sophie , Bonnet Jacques
Published: July 2021

DNA conservation is central to many applications. This leads to an ever-increasing number of samples which are more and more difficult and costly to store or transport. A way to alleviate this problem is to develop procedures for storing samples at room temperature while maintaining their stability. A variety of commercial systems have been proposed but they fail to completely protect DNA from deleterious factors, mainly water. On the other side, Imagene company has developed a procedure for long-term conservation of biospecimen at room temperature based on the confinement of the samples under an anhydrous and anoxic atmosphere maintained inside hermetic capsules. The procedure has been validated by us and others for purified RNA, and DNA in buffy coat or white blood cells lysates, but a precise determination of purified DNA stability is still lacking. We used the Arrhenius law to determine the DNA degradation rate at room temperature. We found that extrapolation to 25 °C gave a degradation rate constant equivalent to about 1 cut/century/100 000 nucleotides, a stability several orders of magnitude larger than the current commercialized processes. Such a stability is fundamental for many applications such as the preservation of very large DNA molecules (particularly interesting in the context of genome sequencing) or oligonucleotides for DNA data storage. Capsules are also well suited for this latter application because of their high capacity. One can calculate that the 64 zettabytes of data produced in 2020 could be stored, standalone, for centuries, in about 20 kg of capsules.
An active RNA transport mechanism into plant vacuoles
Authors: Floyd BE , Wong MM , Liu AY , Morriss SC , Mugume Y , Kazibwe Z , Ridout V , Luo X , MacIntosh GC , Bassham DC
Published: July 2021

RNA degradation inside the plant vacuole by the ribonuclease RNS2 is essential for maintaining nucleotide concentrations and cellular homeostasis via the nucleotide salvage pathway. However, the mechanisms by which RNA is transported into the vacuole are not well understood. While selective macroautophagy may contribute to this transport, macroautophagy-independent transport pathways also exist. Here we demonstrate a mechanism for direct RNA transport into vacuoles that is active in purified vacuoles and is ATP hydrolysis-dependent. We identify the RNA helicase SKI2 as a factor required for this transport pathway, asski2mutant vacuoles are defective in transport.ski2mutants have an increased autophagy phenotype that can be rescued by exogenous addition of inosine, consistent with a function in nucleotide salvage. This newly-described transport mechanism is therefore critical for RNA degradation, recycling and cytoplasmic nucleotide homeostasis.
Synaptotagmin 1 oligomerization via the juxtamembrane linker regulates spontaneous and evoked neurotransmitter release
Authors: Courtney Kevin C. , Li Yueqi , Vevea Jason D. , Wu Zhenyong , Zhang Zhao , Chapman Edwin R.
Published: July 2021

Synaptotagmin-1 (syt1) is a Ca2+sensor that regulates synaptic vesicle exocytosis. Cell-based experiments suggest that syt1 functions as a multimer, however biochemical and electron microscopy studies have yielded contradictory findings regarding putative self-association. Here, we performed dynamic light scattering on syt1 in solution, followed by electron microscopy, and used atomic force microscopy to study syt1 self-association on supported lipid bilayers under aqueous conditions. Ring-like multimers were clearly observed. Multimerization was enhanced by Ca2+and required anionic phospholipids. Large ring-like structures (∼180 nm) were reduced to smaller rings (∼30 nm) upon neutralization of a cluster of juxtamembrane lysine residues; further substitution of residues in the second C2-domain completely abolished self-association. When expressed in neurons, syt1 mutants with graded reductions in self-association activity exhibited concomitant reductions in: a) clamping spontaneous release, and b) triggering and synchronizing evoked release. Thus, the juxtamembrane linker of syt1 plays a crucial role in exocytosis by mediating multimerization.
The complete genome of carbapenem-resistant Escherichia coli ST410 harbored blaNDM-5 isolated from reservoir water in Singapore
Authors: Zhong Yang , Guo Siyao , Ming Glendon Ong Hong , Schlundt Joergen
Published: July 2021

Objective

Escherichia coli ST410 with blaNDM-5 has been increasingly detected as multidrug resistance pathogens globally, even though there are very few reports of infections caused by blaNDM-5 producing E. coli in Singapore[1]. And significantly limit sequencing information of blaNDM-5 carried E. coli strain from Singapore. In 2018, our group obtained a carbapenem resistance E. coli ST410 strain SrichA-1 isolated from reservoir water in Singapore, determined to harbor the NDM-5 gene. (BioSample Accession: SAMN18579051).

Methods

The susceptibility test to antimicrobials was performed with microdilution minimum inhibitory concentration (MIC) test and interpreted according to the Clinical And Laboratory Standards Institute (CLSI) -M100 standards. The genomic DNA of this strain was extracted and send for Whole-genome sequencing(WGS) with the Illumina platform. The WGS analysis was processed with the Center for Genomic Epidemiology (CGE, DTU) server.

Results

During the minimum inhibitory concentration (MIC) test, SrichA-1 has shown strong resistance to all the beta-lactams, including cephalosporin and carbapenem, which can not be inhibited by the clavulanic acid. Further whole genome sequencing analysis has shown that the strain harboring five beta-lactamase genes covers all class A to D, including the carbapenemase genes as blaNDM-5.

Conclusion

Here, we reported the complete chromosome sequence of this isolate as well as the sequence of a cycler plasmid. The pSGNDM-5 plasmid was furtherly identified to carry four beta-lactamase genes, including blaNDM-5, blaCTX-M-15, blaTEM-1B, blaOXA-1, while a blaCMY-2 was detected to be located on the chromosome.