bluuebunny/crossref_metadata_2025 huggingface dataset:
Trait divergence and trade-offs among Brassicaceae species differing in elevational distribution
Authors: Maccagni Alessio , Willi Yvonne
Published: February 2022

Species have restricted geographic distributions and the causes are still largely unknown. Temperature has long been associated with distribution limits, suggesting that there are ubiquitous constraints to the evolution of the climate niche. Here we investigated the traits involved in such constraints by macroevolutionary comparisons involving around 100 Brassicaceae species differing in elevational distribution. Plants were grown under three temperature treatments (regular frost, mild, regular heat) and phenotyped for phenological, morphological and thermal resistance traits. Trait values were analysed by assessing the effect of temperature and elevational distribution, by comparing models of evolutionary trajectories, and by correlative approaches to identify trade-offs. Analyses pointed to size, leaf morphology and growth under heat as among the most discriminating traits between low- and high-elevation species, with high-elevation species growing faster under the occurrence of regular heat bouts, at the cost of much reduced size. Mixed models and evolutionary models supported adaptive divergence for these traits, and correlation analysis indicated their involvement in moderate trade-offs. Finally, we found asymmetry in trait evolution, with evolvability across traits being 50% less constrained under regular frost. Overall, results suggest that trade-offs between traits under adaptive divergence contribute to the disparate distribution of species along the elevational gradient.
Top-down control of the left visual field bias in cued visual spatial attention
Authors: Meyyappan Sreenivasan , Rajan Abhijit , Mangun George R , Ding Mingzhou
Published: February 2022

A left visual field (LVF) bias in perceptual judgements, response speed and discrimination accuracy are well documented in humans. However, LVF bias can be modulated by perceptual and task demands. For example, cuing spatial attention can reduce or eliminate the LVF bias, suggesting that attentional control can compensate for the LVF bias. We investigated this possibility directly by recording pupillometry together with fMRI in a cued visual spatial attention task. Prior to the onset of a task-relevant target stimulus, we observed that the pupil was significantly more dilated following attend-right than attend-left cues even though task performance did not differ. This difference in pupil dilation was inversely related to the corresponding difference in later target-evoked pupil dilation and in the reaction times to those targets, suggesting that an increased attentional effort was triggered by the attend-right cues, and this offset the LVF bias, equating behavioral performance. The differences in pupil dilation to the right versus left hemifield were correlated with corresponding fMRI differences primarily in the right hemisphere, supporting the idea that the increased attentional effort for rightward attention is mediated by activity in right hemisphere networks, which illuminates how attentional control mediates attentional biases in vision.
A novel rhesus macaque model of Huntington’s disease recapitulates key neuropathological changes along with progressive motor and cognitive decline
Authors: Weiss Alison R. , Liguore William A. , Brandon Kristin , Wang Xiaojie , Liu Zheng , Domire Jacqueline S. , Button Dana , Kroenke Christopher D. , McBride Jodi L.
Published: February 2022

We created a new nonhuman primate model of the genetic neurodegenerative disorder, Huntington’s disease (HD), by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This novel modeling strategy results in robust expression of mutant huntingtin protein (mHTT) in the injected brain regions, as well as dozens of other cortical and subcortical brain regions that are also affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 20-months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed progressive working memory decline and motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. This novel model will aid in the development of disease biomarkers and therapeutic strategies for this devastating disorder.
Comparative evaluation of Oral lesions: “Tale - the Covid 19 Tells”
Authors: Bhavasar Rashmi , Ajith Namratha A. , Bhavasar Rahul , Shah Arti , Vaswani Vivek
Published: February 2022

Introduction & Objectives

The COVID-19 pandemic has been raging across the globe since early January 2020. India has reported over 27 million cases and more than 3, 00,000 deaths. This study was planned to analyze the differences in demographic, clinical features and oral manifestations of COVID 19 patients hospitalized during COVID-19 pandemic.

Methods

This observational pilot study had total 36 participants, 12 each of mild, moderate and severe RT-PCR positive COVID cases hospitalized during COVID 19 pandemic. All demographic, clinical features, treatment details and oral manifestations were noted from first day of admission to hospital till treatment completion with follow up of minimum 7 days.

Results

Mean age of the patients was 39.44 ±9.13 years with M: F ratio of 5:4. Most common clinical presentation was fever, shortness of breath and treatment involved was symptomatic with supplemental oxygen & mechanical ventilation. Most common oral site involved was tongue & oral lesions observed were herpes labialis, mucositis, burning sensation, dryness of oral cavity, angular chelitis, aphthous ulcers, geographic tongue, fissuring of tongue, candidiasis, coated tongue, sublingual varicosity, & scalloped tongue.

Interpretation and Conclusion

All demographic, clinical and oral manifestations were significantly different in mild, moderate and severe cases of covid hospitalized patients. Though clinical symptoms were improved, oral lesions were worsened. Oral Lesions seen in covid patients were associated with multiple drug therapy for illness along with poor oral hygiene, but further etiology for lesions needs to be evaluated. Sublingual varicosity was observed in our hospitalised covid patients, but large sample observation is required for confirmation of findings and may be an early oral feature for covid detection. Prevention is always better than cure, so all patients positive for Covid should have a full mouth examination. Oral health should be priority during overall management of COVID patients and dentists should be a part of Covid management team.
Cross-sectional equity analysis of accessibility by automobile to tertiary care emergency services in Cali, Colombia in 2020
Authors: Cuervo Luis Gabriel , Martinez Herrera Eliana , Osorio Lyda , Hatcher Roberts Janet , Cuervo Daniel , Bula María Olga , Pinilla Luis Fernando , Piquero Felipe , Jaramillo Ciro
Published: February 2022

This study provides data on equity in accessibility to tertiary care emergency services in Cali, accounting for traffic congestion, in two separate weeks in 2020.

This cross-sectional study builds on a proof-of-concept, the AMORE Project(1) and provides a baseline assessment of accessibility to urgent tertiary care at peak and free flow traffic times in Cali.1 It makes the case for assessing travel time over distance, and accounting for traffic congestion.

This study indicates that people in vulnerable situations have to travel longer and therefore invest more of their personal direct and indirect resources to access tertiary care emergency departments than the average population. This study emphasizes the added value of integrating new data sources that can inform health services and urban planning. These new data sources merit future testing by concerned stakeholders.1

This study used the digital AMORE Platform to show the effects of traffic congestion on equitable access to tertiary care emergency departments. The data shows which populations take longer to reach a facility within a time threshold under different traffic congestion levels.

The broader proof-of-concept assesses the value of new data obtained by integrating secondary data from publicly available sources. These sources combine geospatial analysis with census microdata, health services location data, and bigdata for travel times.

The analysis covered the city of Cali, which has 2.258 million residents and is the third-largest city in Colombia. The analysis shows the projected accessibility assessments for two weeks during the COVID-19 pandemic, 6 – 12 July 2020, and 23 – 29 November 2020. Restrictions on car travel had been lifted before the July assessment, but stay-at-home orders were in place during the November assessment, which showed substantially less traffic.

This assessment found that traffic congestion sharply reduces accessibility to tertiary emergency care. Reduced access has the greatest impact on people with less education, those living in low-income households or on the periphery of Cali, and specific ethnic groups (e.g., nomadic people like the Rrom, and Afro-descendants). This assessment also identifies the concentration of tertiary care emergency departments in areas of lower population density, leaving large swaths of the population with poor accessibility.

Data was reported in dashboards that used simple univariate and bivariate analyses. In July 2020, the estimated overall accessibility at peak traffic hours was 37% and in November 2020 it increased to 57% due to reduced traffic congestion. These results illustrate the value of the proposed tools in monitoring and adjusting to changing conditions.
Use of machine learning for comparing disease risk scores and propensity scores under complex confounding and large sample size scenarios: a simulation study
Authors: Guo Yuchen , Strauss Victoria Y , Prieto-Alhambra Daniel , Khalid Sara
Published: February 2022

Background

The surge of treatments for COVID-19 in the ongoing pandemic presents an exemplar scenario with low prevalence of a given treatment and high outcome risk. Motivated by that, we conducted a simulation study for treatment effect estimation in such scenarios. We compared the performance of two methods for addressing confounding during the process of estimating treatment effects, namely disease risk scores (DRS) and propensity scores (PS) using different machine learning algorithms.

Methods

Monte Carlo simulated data with 25 different scenarios of treatment prevalence, outcome risk, data complexity, and sample size were created. PS and DRS matching with 1: 1 ratio were applied with logistic regression with least absolute shrinkage and selection operator (LASSO) regularization, multilayer perceptron (MLP), and eXtreme Gradient Boosting (XgBoost). Estimation performance was evaluated using relative bias and corresponding confidence intervals.

Results

Bias in treatment effect estimation increased with decreasing treatment prevalence regardless of matching method. DRS resulted in lower bias compared to PS when treatment prevalence was less than 10%, under strong confounding and nonlinear nonadditive data setting. However, DRS did not outperform PS under linear data setting and small sample size, even when the treatment prevalence was less than 10%. PS had a comparable or lower bias to DRS when treatment prevalence was common or high (10% - 50%). All three machine learning methods had similar performance, with LASSO and XgBoost yielding the lowest bias in some scenarios. Decreasing sample size or adding nonlinearity and non-additivity in data improved the performance of both PS and DRS.

Conclusions

Under strong confounding with large sample size DRS reduced bias compared to PS in scenarios with low treatment prevalence (less than 10%), whilst PS was preferable for the study of treatments with prevalence greater than 10%, regardless of the outcome prevalence.

Key Messages

When handling nonlinear nonadditive data with strong confounding, DRS estimated by machine learning methods outperforms PS in scenarios with low treatment prevalence (less than 10%).

However, if having linear data and small sample size data with strong confounding, we did not observe DRS outperformed PS even when treatment prevalence was less than 10%.

Our results suggested that using PS performed better compared to DRS in tackling strong confounding problems with treatment prevalence greater than 10%.

Small sample size increased bias for both DRS and PS methods, and it affected DRS more than PS.
Investigating the genetic pathways of insomnia in Autism Spectrum Disorder
Authors: Niarchou Maria , Singer Emily V. , Straub Peter , Malow Beth A. , Davis Lea K.
Published: February 2022

Background

Sleep problems are common in children with autism spectrum disorder (autism). There is sparse research to date to examine whether insomnia in people with autism is related to autism genetics or insomnia genetics. Moreover, there is a lack of research examining whether circadian-rhythm related genes share potential pathways with autism.

Aims

To address this research gap, we tested whether polygenic scores of insomnia or autism are related to risk of insomnia in people with autism, and to test whether the circadian genes are associated with insomnia in people with autism.

Methods and procedures

We tested these questions using the phenotypically and genotypically rich MSSNG dataset (N=1,049) as well as incorporating in the analyses data from the Vanderbilt University Biobank (BioVU) (N=349).

Outcomes and results

In our meta-analyzed sample, there was no evidence of associations between the polygenic scores (PGS) for insomnia and a clinical diagnosis of insomnia, or between the PGS of autism and insomnia. We also did not find evidence of a greater burden of rare and disruptive variation in the melatonin and circadian genes in individuals with autism and insomnia compared to individuals with autism without insomnia.

Conclusions and implications

Overall, we did not find evidence for strong effects of genetic scores influencing sleep in people with autism, however, we cannot rule out the possibility that smaller genetic effects may play a role in sleep problems. Our study indicated the need for a larger collection of data on sleep problems and sleep quality among people with autism.
An evaluation of metabolic, dietetic, and nutritional status reveals impaired nutritional outcomes in breast cancer patients undergoing chemotherapy compared with a matched control group
Authors: da Silva Bruna Ramos , Rufato Sarah , Mialich Mirele S. , Cruz Loris P. , Gozzo Thais , Jordao Alceu A.
Published: February 2022

Purpose

Nutritional status changes in breast cancer patients during treatment are prevalent. However, the metabolic implications of those alterations are poorly understood. We aimed to characterize body composition, lipids, glucose levels, and indices that express cardiovascular risk in breast cancer patients after completion of chemotherapy and then to compare those results with a matched control group.

Methods

A cross-sectional study was performed. Women who completed their chemotherapy were recruited (BC group) and compared with a group of non-malignant age- and body mass index-matched (MC group), as well as a group of healthy, non-malignant women (HC group). Body composition by bioelectrical impedance analysis, handgrip strength, and blood sample were collected. Visceral adiposity, triglyceride glucose and lipid accumulation product indices were calculated. Food consumption was assessed.

Results

88 women were included (BC=36, MC=36, HC=16). BC patients demonstrated worse values of phase angle, nutritional risk index, extracellular body water to total body water ratio and lower handgrip strength. Additionally, those women had impairments in lipids, worst glucose levels, visceral fat dysfunction and consequently higher cardiovascular risk, presenting important unhealthy dietary patterns with higher carbohydrate and caloric intake and insufficient protein and fiber ingestion. No differences were observed between MC and HC.

Conclusion

Breast cancer patients present unhealthy metabolic, nutritional, and dietetic features when compared to a group of age- and BMI-matched non-malignant females. Also, breast cancer patients had higher levels of cardiovascular risk. Further investigations are required to examine the underlying mechanisms and the potential longitudinal changes during surveillance time.
Risk of severe COVID-19 from the Delta and Omicron variants in relation to vaccination status, sex, age and comorbidities – surveillance results from southern Sweden
Authors: Kahn Fredrik , Bonander Carl , Moghaddassi Mahnaz , Rasmussen Magnus , Malmqvist Ulf , Inghammar Malin , Björk Jonas
Published: February 2022

The risk of severe COVID-19 disease requiring hospitalization with extensive oxygen supply was compared among infected cases during two calendar periods when Delta and Omicron, respectively, were the dominating virus variants in Scania county, Sweden. Adjustments were made for differences among cases in comorbidities, prior infection, vaccination status, age and sex. Markedly lower risks were observed from Omicron among the vaccinated in the present study. The risk of severe disease was also lower for unvaccinated during Omicron than during Delta, but remained high among older people and middle-aged males with comorbidities. Efforts to increase vaccination uptake across countries, populations and subgroups should thus remain a public health priority.
Associations between prenatal exposure to gestational diabetes mellitus and child adiposity markers: mediating effects of brain structure
Authors: Luo Shan , Hsu Eustace , Lawrence Katherine E. , Adise Shana , Pickering Trevor A. , Herting Megan M. , Buchanan Thomas , Page Kathleen A. , Thompson Paul M.
Published: February 2022

Objectives

To investigate neural mechanisms underlying increased obesity risk in children prenatally exposed to gestational diabetes mellitus (GDM).

Research Design and Methods

This was a cross-sectional study of 9-10-year-old participants and siblings across the United States. Data was obtained from the baseline assessment of the Adolescent Brain and Cognitive Development (ABCD) Study® in which brain structure was evaluated by magnetic resonance imaging. Adiposity markers included age- and sex-specific body mass index (BMIz-scores), waist circumference and waist-to-height ratio. GDM exposure was self-reported, and discordance for GDM exposure within biological siblings was identified. Mixed effects and mediation models were used to examine associations between prenatal GDM exposure, brain structure, and adiposity markers with sociodemographic covariates.

Results

The sample included 8,521 children (age: 9.9±0.6 years; 51% males; 7% GDM-exposed), among whom there were 28 sibling pairs discordant for GDM exposure. Across the entire study sample, prenatal exposure to GDM was associated with lower global and regional cortical gray matter volume (GMV) in the bilateral rostral middle frontal gyrus and superior temporal gyrus. In a subset of sample only including siblings, GDM-exposed siblings also demonstrated lower global cortical GMV than un-exposed siblings. Global cortical GMV partially mediated the associations between prenatal GDM exposure and child adiposity markers.

Conclusions

Our results establish robust and generalizable brain markers of prenatal GDM exposure and suggest that low cortical GMV may explain increased obesity risk for offspring prenatally exposed to GDM.

Twitter summary

Prenatal exposure to gestational diabetes mellitus #GDM is associated with smaller cortical gray matter volume #brain, which in turn relates to larger adiposity markers #BMI in a large and diverse cohort of 8521 children.

Article Highlights

Prenatal exposure to gestational diabetes mellitus (GDM) is associated with smaller cortical gray matter volume (GMV) in a large and diverse cohort of 8521 children, independent from genetics and shared environment.

Cortical GMV partially mediated the associations of prenatal GDM exposure and adiposity markers in children.

These results establish robust and generalizable brain markers of prenatal GDM exposure and provide neurobiological underpinnings of increased obesity risk in offspring prenatally exposed to GDM.
Influence of meteorological factors and drought on coccidioidomycosis incidence in California, 2000–2020
Authors: Head Jennifer R. , Sondermeyer-Cooksey Gail , Heaney Alexandra K. , Yu Alexander T. , Jones Isabel , Bhattachan Abinash , Campo Simon , Wagner Robert , Mgbara Whitney , Phillips Sophie , Keeney Nicole , Taylor John , Eisen Ellen , Lettenmaier Dennis P. , Hubbard Alan , Okin Gregory S. , Vugia Duc J. , Jain Seema , Remais Justin V.
Published: February 2022

Background

Coccidioidomycosis is an emerging infection in the southwestern United States. We examined the effects of precipitation and temperature on the incidence of coccidioidomycosis in California during 2000-2020, and estimated incident cases attributable to the California droughts of 2007-09 and 2012-15.

Methods

We analyzed monthly California coccidioidomycosis surveillance data from 2000–2020 at the census tract-level using generalized additive models. Models included distributed lags of precipitation and temperature within each endemic county, pooled using fixed-effects meta-analysis. An ensemble prediction algorithm of incident cases per census tract was developed to estimate the impact of drought on expected cases.

Results

Across 14 counties examined, coccidioidomycosis was strongly suppressed during, and amplified following, the 2007-2009 and 2012-2015 droughts. An estimated excess of 1,358 and 2,461 drought-attributable cases were observed in California in the two years following the 2007-2009 and 2012-2015 droughts, respectively. These post-drought excess cases more than offset the drought-attributable declines of 1,126 and 2,192 cases, respectively, that occurred during the 2007-2009 and 2012-2015 droughts. Across counties, a temperature increase from the 25thto 75thpercentile (interquartile range) in the summer was associated with a doubling of incidence in the following fall (incidence rate ratio (IRR): 2.02, 95% CI: 1.84, 2.22), and a one IQR increase in precipitation in the winter was associated with 1.45 (95% CI: 1.36, 1.55) times higher incidence in the fall. The effect of winter precipitation was stronger (interaction coefficient representing ratio of IRRs: 1.36, 95% CI: 1.25, 1.48) when preceded by two dry rather than average winters. Incidence in arid lower San Joaquin Valley counties was most sensitive to winter precipitation fluctuations, while incidence in wetter coastal counties was most sensitive to summer temperature fluctuations.

Conclusions

In California, wet winters along with hot summers, particularly those following previous dry years, increased risk of coccidioidomycosis in California. Drought conditions may suppress incidence, then amplify incidence in subsequent years. With anticipated increasing frequency of drought in California, continued expansion of incidence, particularly in wetter, coastal regions, is expected.
Fairness and efficiency considerations in COVID-19 vaccine allocation strategies: a case study comparing front-line workers and 65-74 year olds in the United States
Authors: Rumpler Eva , Feldman Justin M. , Bassett Mary T. , Lipsitch Marc
Published: February 2022

1

The COVID-19 epidemic in the United States has been characterized by two stark disparities. COVID-19 burden has been unequally distributed among racial and ethnic groups and at the same time the mortality rates have been sharply higher among older age groups. These disparities have led some to suggest that inequalities could be reduced by vaccinating front-line workers before vaccinating older individuals, as older individuals in the US are disproportionately Non-Hispanic White.

We compare the performance of two distribution policies, one allocating vaccines to front-line workers and another to older individuals aged 65-74-year-old. We estimate both the number of lives saved and the number of years of life saved under each of the policies, overall and in every race/ethnicity groups, in the United States and every state.

We show that prioritizing COVID-19 vaccines for 65-74-year-olds saves both more lives and more years of life than allocating vaccines front-line workers in each racial/ethnic group, in the United States as a whole and in nearly every state. When evaluating fairness of vaccine allocation policies, the overall benefit to impact of each population subgroup should be considered, not only the proportion of doses that is distributed to each subgroup. Further work can identify prioritization schemes that perform better on multiple equity metrics.
Deceiving The Big Eaters: Salmonella Typhimurium SopB subverts host cell Xenophagy through Akt-TFEB axis in macrophages
Authors: Chatterjee Ritika , Chaudhuri Debalina , Setty Subba Rao Gangi , Chakravortty Dipshikha
Published: February 2022

Salmonella, a stealthy facultative intracellular pathogen, harbors an array of host immune evasion strategies. This facilitates successful survival and replicative niches establishment in otherwise hostile host innate immune cells such as macrophages. Salmonella survives and utilizes macrophages for effective dissemination throughout the host causing systemic infection. One of the central host defense mechanisms in macrophages is bacterial xenophagy or macro-autophagy. Here we report for the first time that Salmonella pathogenicity island-1 (SPI-1) effector SopB is involved in subverting host autophagy through dual mechanisms. SopB is known to act as a phosphoinositide phosphatase and thereby can alter the phosphoinositide dynamics of the host cell. Here we demonstrate that this activity helps the bacterium escape autophagy by inhibiting terminal fusion of Salmonella containing vacuole (SCV) with both lysosomes and autophagosomes. We also report the second mechanism, wherein SopB downregulates overall lysosomal biogenesis through Akt- transcription factor EB (TFEB) axis. TFEB is a master regulator of lysosomal biogenesis and autophagy, and SopB restricts the nuclear localization of TFEB. This reduces the overall lysosome content inside host macrophages, further facilitating survival in macrophages and systemic dissemination of Salmonella in the host.
Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age-associated retinal degeneration
Authors: Ramírez-Pardo Ignacio , Villarejo-Zori Beatriz , Jiménez-Loygorri Juan Ignacio , Sierra-Filardi Elena , Alonso-Gil Sandra , Mariño Guillermo , de la Villa Pedro , Fitze Patrick S , Fuentes José Manuel , García-Escudero Ramón , Gomez-Sintes Raquel , Boya Patricia
Published: February 2022

Autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE–retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we describe a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency forAmbra1, a pro-autophagic gene. These mice show protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover,Ambra1+/gtmice are more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.
Re-sensitising XDR biofilms using a combination of bacteriophage cocktails and colistin: a natural approach
Authors: Devanga Ragupathi Naveen Kumar , Muthuirulandi Sethuvel Dhiviya Prabaa , Gopikrishnan Mohanraj , Murugan Dhivya , Juliet Ramya , Majhi Monalisa , Murugesan Malathi , C George Priya Doss , Wannigama Leshan , Monk Peter N. , Karunakaran Esther , Veeraraghavan Balaji
Published: February 2022

Persistent antibiotic use results in the rise of antimicrobial resistance with limited or no choice for multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria. This necessitates a need for alternative therapy to effectively combat clinical pathogens that are resistant to last resort antibiotics. The study investigates hospital sewage as a potential source of bacteriophages to control MDR/XDR bacterial pathogens. 81 samples were screened for phages against selected clinical pathogens. 10 phages were isolated against A. baumannii, 5 phages against K. pneumoniae and 16 phages obtained against P. aeruginosa. The novel phages were observed to be strain-specific with a complete growth inhibition of up to 6 hrs. Phage plus colistin combinations further reduced the MBEC of colistin up to 16 folds. Notably, cocktail of phages exhibited supreme efficacy with complete killing at 0.5-1 µg/ml colistin concentrations. Thus, phages specific to clinical strains has a higher edge in treating nosocomial pathogens with their proven anti-biofilm efficacy. In addition, analysis of phage genomes revealed close phylogenetic relations with phages reported from Europe, China and other neighbouring countries. This study serves as a reference and can be extended to other antibiotics and phage types to assess optimum synergistic combinations to combat various drug resistant pathogens in the ongoing AMR crisis.
Frequency of a nucleotide overhang at the 5’ end of hemorrhagic fever mammarenavirus genomes in public sequence data
Authors: Neriya Yutaro , Kojima Shohei , Kishimoto Mai , Sakiyama Arata , Iketani Takao , Watanabe Tadashi , Abe Yuichi , Shimoda Hiroshi , Nakagawa Keisuke , Koma Takaaki , Matsumoto Yusuke
Published: February 2022

Mammarenaviruses, such as Lassa virus and South American hemorrhagic fever (SAHF) virus, cause severe hemorrhagic fevers in humans, and pose major threats to public health. Mammarenaviruses consist of a bi-segmented negative-sense RNA genome in which the 5’ and 3’ ends form complementary strands that serve as a replication promoter. Some mammarenaviruses have a nucleotide overhang at the 5’ genome end. By examining the complementarity of 5’ and 3’ genome ends using public mammarenavirus genome sequences, we found that the 5’ guanine overhang (5’-G overhang) was present more frequently in Lassa and SAHF viruses than in other viruses. The 5’-G overhang in the Lassa and SAHF virus sequences was found to be restricted to the L and S segments, respectively. If the genome end sequence data in the public database are accurate, the 5’-G overhang may be related to the high pathogenicity of mammarenaviruses in humans.
Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes
Authors: Besson Benoit , Lezcano Oscar M. , Overheul Gijs J. , Janssen Kirsten , Spruijt Cornelia G. , Vermeulen Michiel , Qu Jieqiong , van Rij Ronald P.
Published: February 2022

Efficient virus replication in Aedes vector mosquitoes is essential for the transmission of arboviral diseases such as dengue virus (DENV) in human populations. Like in vertebrates, virus-host protein-protein interactions are essential for viral replication and immune evasion in the mosquito vector. Here, 79 mosquito host proteins interacting with DENV non-structural proteins NS1 and NS5 were identified by label-free mass spectrometry, followed by a functional screening. We confirmed interactions with host factors previously observed in mammals, such as the oligosaccharyltransferase complex, and we identified protein-protein interactions that seem to be specific for mosquitoes. Among the interactors, the double-stranded RNA (dsRNA) binding protein Loquacious (Loqs), an RNA interference (RNAi) cofactor, was found to be essential for efficient replication of DENV and Zika virus (ZIKV) in mosquito cells. Loqs did not affect viral RNA stability or translation of a DENV replicon and its proviral activity was independent of its RNAi regulatory activity. Interestingly, Loqs colocalized with DENV dsRNA in viral replication organelles in infected cells and directly interacted with high affinity with DENV RNA in the 3’ untranslated region in vitro (KD = 100-200 nM). Our study provides an interactome for DENV NS1 and NS5 and identifies Loqs as a key proviral host factor in mosquitoes. We propose that DENV hijacks a factor of the RNAi mechanism for replication of its own RNA.

AUTHOR SUMMARY

Dengue virus is a mosquito-transmitted virus endemic to the tropics and subtropics, affecting an estimated 390 million people yearly. While the mechanisms of infection, pathogenesis and immune evasion have been extensively studied in humans, replication in Aedes mosquitoes has received much less attention, despite being a critical step in the arbovirus transmission cycle. Here, we used a proteomic approach to identify Aedes mosquito proteins recruited by dengue virus non- structural proteins NS1 and NS5. In addition to previously established host proteins that interact with DENV in mammals, we identified Loquacious, a double-stranded RNA binding protein involved in the antiviral RNAi immune response of mosquitoes. Unexpectedly, our data showed Loquacious functions as a proviral factor that is recruited to replication organelles to facilitate viral RNA replication. We propose that DENV exploits host immune components, such as Loquacious, for its own benefit.
Habitat Suitability Modeling and Ecological Forecasting of Northern Goshawk Nesting Habitat
Authors: Wright Marylin. E. , Jackson Jenelle. , Tornberg Risto. , Higa Erica. , Clayton A. , McCartney Sean. , Ranglack Dustin H , Bickford Nate
Published: February 2022

Northern Goshawks (Accipiter gentilis) are dynamic forest raptors often used as a management indicator species in forest management planning. Despite their use as indicators, there is a limited understanding of habitat requirements for goshawks, especially in dry forested landscapes as climate change occurs. We examined goshawk nesting habitat on the Helena-Lewis and Clark National Forest (HLCNF) in central Montana to further understand climate change on goshawk nesting habitat. The HLCNF receives low annual precipitation, making this forest useful to understand climate change in dry forest in structure and ecology. We measured characteristics of nest sites throughout the HLCNF and used principle component analysis to predict important variables for nest trees and nesting habitat for goshawks in this landscape. We also used remote sensing and GIS to create a composite map predicting areas of high, medium and low suitability for nesting habitat for goshawks in the HLCNF. We used the composite map to predict potential impacts of mountain pine beetle (Dendroctonus ponderosae), fire, and climate change to Northern Goshawk habitat in the HLCNF. The best indicators of a chosen nest tree were diameter at breast height, tree height, and tree status, which can be considered indicative of trees preferred for nesting by goshawks. The best indicators for nest forest were canopy closure, slope angle, and slope position, which indicate habitat areas of high suitability for goshawk nesting. Two forecast models where developed based on climate change predictions. After overlapping a projected mountain pine beetle risk map and fire frequency risk map onto the modeled of high suitability goshawk nesting habitat, we calculated that 52 % of modeled high suitability habitat may be at risk for mountain pine beetle blight and 66 % high suitability habitat at risk for frequent wildfires, which will reduce goshawk habitat quality.
Air pollution induces Staphylococcus aureus USA300 respiratory tract colonisation mediated by specific bacterial genetic responses dependent on the global virulence gene regulators Agr and Sae
Authors: Purves Jo , Hussey Shane. J. K. , Corscadden Louise , Purser Lillie , Hall Andie , Misra Raju , Monks Paul S. , Ketley Julian M. , Andrew Peter W. , Morrissey Julie A.
Published: February 2022

Exposure to particulate matter (PM), a major component of air pollution, is associated with exacerbation of chronic respiratory disease, and infectious diseases such as community acquired pneumonia. Although PM can cause adverse health effects through direct damage to host cells, our previous study showed that PM can also impact bacterial behaviour by promoting in vivo colonisation. In this study we describe the genetic mechanisms involved in the bacterial response to exposure to black carbon (BC), a constituent of PM found in most sources of air pollution. We show that Staphylococcus aureus strain USA300 LAC grown in BC prior to inoculation showed increased murine respiratory tract colonisation and pulmonary invasion in vivo, as well as adhesion and invasion of human epithelial cells in vitro. Global transcriptional analysis showed that BC has a widespread effect on S. aureus transcriptional responses, altering the regulation of the major virulence gene regulators Sae and Agr and causing increased expression of genes encoding toxins, proteases, and immune evasion factors. Together these data describe a previously unrecognised causative mechanism of air pollution-associated infection, in that exposure to BC can increase bacterial colonisation and virulence factor expression by acting directly on the bacterium rather than via the host.

Originality-Significance Statement

This study shows that exposure to air pollution results in a global change in gene expression in bacteria. Specifically, our data show that in the important human pathogen Staphylococcus aureus, exposure to a major constituent of air pollution, black carbon (BC) results in widespread changes in global gene expression, altering the expression of key virulence determinants. Furthermore, S. aureus that are exposed to BC prior to inoculation show increased colonisation of the murine nasopharynx and lungs in vivo, and increased adhesion and invasion in lung epithelial cells in vitro. These findings indicate that air pollution has a significant and direct impact on bacteria, altering their behaviour and their potential to colonise and invade during infection. While many studies have taken a host-focussed approach to studying the impact of air pollution on human health, this study takes a pathogen-focussed approach to further the understanding of these fundamental interactions to identify new causative mechanisms of the detrimental effects of air pollution. This is critical for understanding the adverse health effects caused by exposure to air pollution, the single largest environmental risk to human health in the world.
Model-free prediction of microbiome compositions
Authors: Asher Eitan E. , Bashan Amir
Published: February 2022

The recent recognition of the importance of the microbiome to the host’s health and well-being, has yielded efforts to develop therapies that aim to shift the microbiome from a disease-associated steady-state to a healthier one. Direct manipulation techniques of the species’ assemblage are currently available, e.g., using probiotics or narrow-spectrum antibiotics to introduce or eliminate specific taxa. However, predicting the species’ abundances at the new steady-state remains a challenge, mainly due to the difficulties of deciphering the delicate underlying network of ecological interactions or constructing a predictive model for such complex ecosystems. Here, we propose a model-free method to predict the species’ abundances at the new steady state based on their presence/absence configuration by utilizing a multi-dimensional k-nearest-neighbors (kNN) regression algorithm. By analyzing data from numeric simulations of ecological dynamics, we show that our predictions, which consider the presence/absence of all species holistically, outperform both the null model that uses the statistics of each species independently and a predictive neural network model. We analyze real metagenomic data of human-associated microbial communities and found that by relying on a small number of ‘neighboring’ samples, i.e., samples with similar species assemblage, the kNN predicts the species abundance better than the whole-cohort average. By studying both real metagenomic and simulated data, we show that the predictability of our method is tightly related to the dissimilarity-overlap relationship of the training data. Our results demonstrate how model-free methods can prove useful in predicting microbial communities and may facilitate the development of microbial-based therapies.
Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR
Authors: Gustafsson H. Tobias , Galan Carolina , Yu Tianxiong , Upton Heather E. , Ferguson Lucas , Kaymak Ebru , Weng Zhiping , Collins Kathleen , Rando Oliver J.
Published: February 2022

Among the major classes of RNAs in the cell, tRNAs remain the most difficult to characterize via deep sequencing approaches, as tRNA secondary structure and nucleotide modifications can both interfere with cDNA synthesis by commonly-used reverse transcriptases (RTs). Here, we benchmark a recently-developed RNA cloning protocol, termed Ordered Two-Template Relay (OTTR), to characterize intact tRNAs and tRNA fragments in budding yeast and in mouse tissues. We find that OTTR robustly captures full-length tRNAs in budding yeast and in mouse testis, with relatively low levels of premature termination at known barriers – 1-methylguanine, N2,N2-dimethylguanine, and 1-methyladenine – to typical reverse transcriptases. Moreover, these and several other nucleotide modifications leave misincorporation signatures in OTTR datasets which enables their detection without any additional protocol steps. Turning to analysis of small RNAs such as tRNA cleavage products, we compare OTTR with several standard small RNA-Seq protocols, finding that OTTR provides the most accurate picture of tRNA fragment levels by comparison to “ground truth” Northern blots. Applying this protocol to mature mouse spermatozoa, our data dramatically alter our understanding of the small RNA cargo of mature mammalian sperm, revealing a far more complex population of tRFs – including both 5’ and 3’ tRNA halves derived from the majority of tRNAs – than previously appreciated. Taken together, our data confirm the superior performance of OTTR to commercial protocols in analysis of tRNA fragments, and force a reappraisal of potential epigenetic functions of the sperm small RNA payload.
Human XIST RNA acts early to condense architecture which facilitates A-repeat density-dependent initiation of gene silencing
Authors: Valledor Melvys , Byron Meg , Dumas Brett , Carone Dawn M. , Hall Lisa L. , Lawrence Jeanne B.
Published: February 2022

XIST RNA triggers gene silencing chromosome-wide and transforms a euchromatic chromosome into a condensed Barr body. XIST is heavily studied in mouse ES cells, but here an inducible iPSC system allows analysis of initial steps in human chromosome silencing, revealing key points not known in either system. XIST RNA distribution was examined relative to biochemical and transcriptional changes directly within architecture of individual chromosome territories. Within a few hours of induction, XIST transcripts distribute as a large “sparse zone” and a smaller “dense zone”, which, importantly, exhibit different effects on chromatin. Very sparse transcripts immediately trigger bright staining for H2AK119ub and CIZ1, a structural matrix protein. In contrast, H3K27me3 enrichment comes hours later and is much more restricted to the smaller dense RNA zone, which enlarges as the chromosome condenses. Importantly, silencing of several genes examined occurred well after architectural condensation, suggesting a possibly separable step. Surprisingly, we show the small A-repeat fragment of XIST can alone silence endogenous genes; however, results indicate this requires high local RNA density for effective histone deacetylation. Results support a concept whereby XIST RNA acts directly to condense the chromosome territory, comprised largely of non-coding DNA, which facilitates a required step to initiate gene silencing by the A-repeat. Hence, compacted architecture is not a consequence of collective gene silencing, but an early step required for chromosome-wide gene silencing.
Understanding the Separation of Timescales in Rhodococcus erythropolis Proteasome Core Particle Assembly
Authors: Itagi Pushpa , Kante Anupama , Lagunes Leonila , Deeds Eric J.
Published: February 2022

The 20S proteasome Core Particle (CP) is a molecular machine that is a key component of cellular protein degradation pathways. Like other molecular machines, it is not synthesized in an active form, but rather as a set of subunits that assemble into a functional complex. The CP is conserved across all domains of life and is composed of 28 subunits, 14 α and 14 β, arranged in four stacked 7-member rings (α7β7β7α7). While details of CP assembly vary across species, the final step in the assembly process is universally conserved: two half proteasomes (HP: α7β7) dimerize to form the CP. In the bacterium Rhodococcus erythropolis, experiments have shown that the formation of the HP is completed within minutes, while the dimerization process takes hours. The N-terminal propeptide of the β subunit, which is autocatalytically cleaved off after CP formation, plays a key role in regulating this separation of time scales. However, the detailed molecular mechanism of how the propeptide achieves this regulation is unclear. In this work, we used Molecular Dynamics (MD) simulations to characterize HP conformations and found that the HP exists in two states: one where the propeptide interacts with key residues in the HP dimerization interface and likely blocks dimerization, and one where this interface is free. We found that a propeptide mutant that dimerizes extremely slowly is essentially always in the non-dimerizable state, while the WT rapidly transitions between the two. Based on these simulations, we designed a propeptide mutant that favored the dimerizable state in MD simulations. In vitro assembly experiments confirmed that this mutant dimerizes significantly faster than WT. Our work thus provides unprecedented insight into how this critical step in CP assembly is regulated, with implications both for efforts to inhibit proteasome assembly and for the evolution of hierarchical assembly pathways.
A centromeric RNA-associated protein complex affects germ line development in Drosophila melanogaster
Authors: Höcker Saskia L. , Akan Izlem Su , Simon Alexander M. , Yildirim Kerem , Kenéz Lili A. , Lohmann Ingrid , Erhardt Sylvia
Published: February 2022

In many metazoans, centromeres are embedded in large blocks of highly repetitive (peri-) centromeric heterochromatin from which non-coding RNAs emanate that have been assigned diverse functions in different species. However, little is known about their functional details or regulation. The pericentromere of the X chromosome in Drosophila melanogaster contains a multi mega-base array of the 359 bp satellite repeats from the 1.688 family, which is transcribed into a lncRNA (SAT III RNA). We performed a SAT III RNA pulldown assay and identified a SAT III RNA-associated complex of four previously uncharacterized proteins and show that they affect germline development. These factors not only interact with each other and with SAT III RNA but also co-regulate each other. RNAi depletion of any of the factors leads to severe defects in the developing germline and sterility. Moreover, we show that the complex plays a crucial role in SAT III RNA repression, as RNAi depletion of the factors leads to a drastic increase of SAT III RNA levels. Importantly, genetic reduction of SAT III RNA level in the RNAi-depleted flies partially rescued the germ line defects and infertility phenotype. Based on our results we hypothesize that the identified complex functions in the germline to regulate SAT III RNA levels, possibly to offset effects of chromatin remodelling taking place in the developing germline.