bluuebunny/crossref_metadata_2025 huggingface dataset:
Uranium Aerosol Activity Size Distributions at a Nuclear Fuel Fabrication Plant
Authors: Hansson Edvin , Pettersson Håkan B.L. , Eriksson Mats
Published: July 2020

Inhalation of uranium aerosols is a concern in nuclear fuel fabrication. Determination of committed effective doses and lung equivalent doses following inhalation intake requires knowledge about aerosol characteristics; e.g., the activity median aerodynamic diameter (AMAD). Cascade impactor sampling of uranium aerosols in the breathing zone of nuclear operators was carried out at a nuclear fuel fabrication plant producing uranium dioxide via ammonium uranyl carbonate. Complementary static sampling was carried out at key process steps. Uranium on impaction substrates was measured using gross alpha counting and alpha spectrometry. Activity size distributions were evaluated for both unimodal and bimodal distributions. When a unimodal distribution was assumed, the average AMAD in the operator breathing zone at the workshops was 12.9–19.3 μm, which is larger than found in previous studies. Certain sampling occasions showed variable isotope ratios (234U/238U) at different impactor stages, indicating more than one population of particles; i.e., a multimodal activity size distribution. When a bimodal distribution (coarse and fine fraction) was assumed, 75–88% of the activity was associated with an AMAD of 15.2–18.9 μm (coarse fraction). Quantification of the AMAD of the fine fraction was associated with large uncertainties. Values of 1.7–7.1 μm were obtained. Static sampling at key process steps in the workshops showed AMADs of 4.9–17.2 μm, generally lower than obtained by breathing zone sampling, when a unimodal distribution was assumed. When a bimodal distribution was assumed, a smaller fraction of the activity was associated with the coarse fraction compared to breathing zone sampling. This might be due to impactor positioning during sampling and sedimentation of large particles. The average committed effective dose coefficient for breathing zone sampling and a bimodal distribution was 1.6–2.6 μSv Bq−1 for 234U when Type M/S absorption parameters were assumed (5.0 μSv Bq−1 for an AMAD of 5 μm). The corresponding lung equivalent dose coefficient was 3.6–10.7 μSv Bq−1 (29.9 μSv Bq−1 for an AMAD of 5 μm). The predicted urinary excretion level 100 d after inhalation intake was found to be 13-34% of that corresponding to an AMAD of 5 μm. Uranium aerosols generated at a nuclear fuel fabrication plant using ammonium uranyl carbonate route of conversion were associated with larger AMADs compared to previous work, especially when sampling of aerosols was carried out in the operator breathing zone. A bimodal activity size distribution can be used in calculations of committed effective doses and lung equivalent doses, but parameters associated with the fine fraction must be interpreted with care due to large uncertainties.
Analysis of common glucocorticoid response genes in childhood acute lymphoblastic leukemia in vivo identifies cell cycle but not apoptosis genes
Authors: Aneichyk Tatsiana , Schmidt Stefan , Bindreither Daniel , Kroesbacher Armin , Mueller Nikola S , Meister Bernhard , Crazzolara Roman , Mann Georg , Panzer-Gruemayer Renate , Kofler Reinhard , Rainer Johannes , Geley Stephan
Published: July 2020

Glucocorticoids (GCs) are an essential component of acute lymphoblastic leukemia (ALL) therapy. To identify genes mediating the anti-leukemic GC effectsin vivo, we performed gene expression profiling of lymphoblasts from 46 children during the first 6-24h of systemic GC mono-therapy. Differential gene expression analysis across all patients revealed a considerable number of GC-regulated genes (190 induced, 179 repressed at 24h). However, when 4 leukemia subtypes (T-ALL, ETV6-RUNX1+, hyperdiploid, other preB-ALLs) were analyzed individually only 17 genes were regulated in all of them showing subtype-specificity of the transcriptional response. “Cell cycle-related” genes were down-regulated in the majority of patients, while no common changes in apoptosis genes could be identified. Surprisingly, none of the cell cycle or apoptosis genes correlated well with the reduction of peripheral blasts used as parameter for treatment response. These data suggest that (a) GC effects on cell cycle are independent of the cell death response and (b) GC-induced cell death cannot be explained by a single transcriptional pathway conserved in all subtypes. To unravel more complex, potentially novel pathways, we employed machine learning algorithms using an iterative elastic net approach, which identified gene expression signatures that correlated with the clinical response.
The Infectious Nature of Patient-Generated SARS-CoV-2 Aerosol
Authors: Santarpia Joshua L. , Herrera Vicki L. , Rivera Danielle N. , Ratnesar-Shumate Shanna , Reid St. Patrick , Denton Paul W. , Martens Jacob W.S. , Fang Ying , Conoan Nicholas , Callahan Michael V. , Lawler James V. , Brett-Major David M. , Lowe John J.
Published: July 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission causing coronavirus disease 2019 (COVID-19) may occur through multiple routes. We collected aerosol samples around six patients admitted into mixed acuity wards in April of 2020 to identify the risk of airborne SARS-CoV-2. Measurements were made to characterize the size distribution of aerosol particles, and size-fractionated, aerosol samples were collected to assess the presence of infectious virus in particles sizes of >4.1 µm, 1-4 µm, and <1 µm in the patient environment. Samples were analyzed by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), cell culture, western blot, and transmission electron microscopy (TEM). SARS-CoV-2 RNA was detected in all six rooms in all particle size fractions (>4.1 µm, 1-4 µm, and <1 µm). Increases in viral RNA during cell culture of the virus from recovered aerosol samples demonstrated the presence of infectious, replicating virions in three <1 µm aerosol samples (P<0.05). Viral replication of aerosol was also observed in the 1-4 µm stage but did not reach statistical significance (0.05<P<0.10). Western blot and TEM analysis of these samples also showed evidence of viral proteins and intact virions. The infectious nature of aerosol collected in this study further suggests that airborne transmission of COVID-19 is possible, and that aerosol prevention measures are necessary to effectively stem the spread of SARS-CoV-2.
Practical Strategies for Extreme Missing Data Imputation in Dementia Diagnosis
Authors: McCombe Niamh , Liu Shuo , Ding Xuemei , Prasad Girijesh , Bucholc Magda , Finn David P. , Todd Stephen , McClean Paula L. , Wong-Lin KongFatt ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: July 2020

Accurate computational models for clinical decision support systems require clean and reliable data but, in clinical practice, data are often incomplete. Hence, missing data could arise not only from training datasets but also test datasets which could consist of a single undiagnosed case, an individual. This work addresses the problem of extreme missingness in both training and test data by evaluating multiple imputation and classification workflows based on both diagnostic classification accuracy and computational cost. Extreme missingness is defined as having ∼50% of the total data missing in more than half the data features. In particular, we focus on dementia diagnosis due to long time delays, high variability, high attrition rates and lack of practical data imputation strategies in its diagnostic pathway. We identified and replicated the extreme missingness structure of data from a real-world memory clinic on a larger open dataset, with the original complete data acting as ground truth. Overall, we found that computational cost, but not accuracy, varies widely for various imputation and classification approaches. Particularly, we found that iterative imputation on the training dataset combined with a reduced-feature classification model provides the best approach, in terms of speed and accuracy. Taken together, this work has elucidated important factors to be considered when developing a predictive model for a dementia diagnostic support system.
Observational Study of Haloperidol in Hospitalized Patients with Covid-19
Authors: Hoertel Nicolas , Rico Marina Sanchez , Vernet Raphaël , Jannot Anne-Sophie , Neuraz Antoine , Blanco Carlos , Lemogne Cédric , Airagnes Guillaume , Paris Nicolas , Daniel Christel , Gramfort Alexandre , Lemaitre Guillaume , Bernaux Mélodie , Bellamine Ali , Beeker Nathanaël , Limosin Frédéric
Published: July 2020

Background

Haloperidol, a widely used antipsychotic, has been suggested as potential effective treatment for Covid-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2.

Methods

We examined the association between haloperidol use and respiratory failure at AP-HP Greater Paris University hospitals. Data were obtained regarding all adult patients hospitalized with Covid-19 since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. We compared outcomes between patients who were exposed to haloperidol and those who were not, using a multivariable Cox regression model with inverse probability weighting according to the propensity score.

Results

Of the 13,279 hospitalized adult patients with positive Covid-19 RT-PCR test, 667 patients (5.0%) were excluded because of missing data. Of the remaining 12,612 patients, 104 (0.8%) were exposed to haloperidol. Over a mean follow-up of 20.8 days, the primary endpoint of respiratory failure respectively occurred in 27 patients (26.0%) exposed to haloperidol and 1,700 patients (13.6%) who were not. Among survivors, the secondary endpoint of discharge home occurred in 26 patients (32.1%) who received haloperidol and 6,110 patients (55.3%) who did not. In the main analysis, there were no significant associations between haloperidol use and the primary (HR, 1.09; 95% CI, 0.60 to 1.97, p=0.772) and secondary (HR, 0.88; 95% CI, 0.50 to 1.53, p=0.643) endpoints. Results were similar in multiple sensitivity analyses.

Conclusion

In this observational study involving patients with Covid-19 who had been admitted to the hospital, haloperidol use was not associated with risk of intubation or death, or with time to hospital discharge home. These results suggest that haloperidol is unlikely to have a clinical efficacy for Covid-19.
Epidemiological Profile and Transmission Dynamics of COVID-19 in the Philippines
Authors: Haw N. J. L. , Uy J. , Sy K. T. L. , Abrigo M. R. M.
Published: July 2020

The Philippines confirmed local transmission of COVID-19 on 7 March 2020. We described the characteristics and epidemiological time-to-event distributions for laboratory-confirmed cases in the Philippines. The median age of 8,212 cases was 46 years (IQR: 32-61), with 46.2% being female and 68.8% living in the National Capital Region. Health care workers represented 24.7% of all detected infections. Mean length of hospitalization for those who were discharged or died were 16.00 days (95% CI: 15.48, 16.54) and 7.27 days (95% CI: 6.59, 8.24). Mean duration of illness was 26.66 days (95% CI: 26.06, 27.28) and 12.61 days (95% CI: 11.88, 13.37) for those who recovered or died. Mean serial interval was 6.90 days (95% CI: 5.81, 8.41). Epidemic doubling time pre-quarantine (11 February and 19 March) was 4.86 days (95% CI: 4.67, 5.07) and the reproductive number was 2.41 (95% CI: 2.33, 2.48). During quarantine (March 20 to April 9), doubling time was 12.97 days (95% CI: 12.57, 13.39) and the reproductive number was 0.89 (95% CI: 0.78, 1.02).
An Optimization Framework to Study the Balance Between Expected Fatalities due to COVID-19 and the Reopening of U.S. Communities
Authors: Chen Victoria C. P. , Zhou Yuan , Fallahi Alireza , Viswanatha Amith , Yang Jingmei , Ghasemi Yasaman , Ohol Nilabh. S. , Rosenberger Jay M. , Liu Feng , Ju Xinglong , Guild Jeffrey B.
Published: July 2020

As communities reopen following shelter-in-place orders, they are facing two conflicting objectives. The first is to keep the COVID-19 fatality rate down. The second is to revive the U.S. economy and the livelihood of millions of Americans. In this paper, a team of researchers from the Center on Stochastic Modeling, Optimization, & Statistics (COSMOS) at the University of Texas at Arlington, in collaboration with researchers from University of Texas Southwestern Medical Center and Harvard Medical School, has formulated a computationally-efficient optimization framework, referred to as COSMOS COVID-19 Linear Programming (CC19LP), to study the delicate balance between the expected fatality rate and the level of normalcy in the community. Given the disproportionate fatality characteristics of COVID-19 among those in different age groups or with an underlying medical condition or those living with crowding, the key to the CC19LP framework is a focus on “key contacts” that separate individuals at higher risk from the rest of the population. The philosophy of CC19LP lies in maximizing protection of key contacts, so as to shield high-risk individuals from infection. Given the lack of pharmaceutical solutions, i.e., a vaccine or cure, the CC19LP framework minimizes expected fatalities by optimizing the use of non-pharmaceutical interventions, namely COVID-19 testing; personal protective equipment; and social precautions, such as distancing, hand-washing, and face coverings. Low-risk individuals that are not key contacts, including most children, are unrestricted and can choose to participate in pre-pandemic normal activities, which eliminates the need for compliance across the entire population. Consequently, the CC19LP framework demonstrates optimal strategies for protecting high-risk individuals while reopening communities.
Evaluation of efficiency and sensitivity of 1D and 2D sample pooling strategies for SARS-CoV-2 RT-qPCR screening purposes
Authors: Verwilt Jasper , Hellemans Jan , Sante Tom , Mestdagh Pieter , Vandesompele Jo
Published: July 2020

To increase the throughput, lower the cost, and save scarce test reagents, laboratories can pool patient samples before SARS-CoV-2 RT-qPCR testing. While different sample pooling methods have been proposed and effectively implemented in some laboratories, no systematic and large-scale evaluations exist using real-life quantitative data gathered throughout the different epidemiological stages. Here, we use anonymous data from 9673 positive cases to simulate and compare 1D and 2D pooling strategies. We show that the optimal choice of pooling method and pool size is an intricate decision with a testing population-dependent efficiency-sensitivity trade-off and present an online tool to provide the reader with custom real-time pooling strategy recommendations.
Phenotypic plasticity explains apparent reverse evolution of fat synthesis in parasitoid insects
Authors: Visser Bertanne , Alborn Hans T. , Rondeaux Suzon , Haillot Manon , Hance Thierry , Rebar Darren , Riederer Jana M. , Tiso Stefano , van Eldijk Timo J.B. , Weissing Franz J. , Nieberding Caroline M.
Published: July 2020

Over the last few decades, numerous examples have been described where a trait that was once lost during the course of evolution had been regained. Here, we argue that such reverse evolution can also become apparent when trait expression is plastic in response to the environment. We tested this hypothesis for the loss and regain of fat synthesis in parasitic wasps. Wasps from lineages that supposedly regained lipogenic ability ~80 million years ago were grown under a fat-poor or fat-rich environment. In line with our hypothesis, it turned out that fat synthesis had not been lost and regained, but was only switched on in low-fat environments. Functional protein domains of key lipogenesis genes were also found in other parasitoid species, suggesting that plasticity of fat synthesis may be more widespread in parasitoids. Individual-based simulations then revealed that a switch for plastic expression can remain functional in the genome for thousands of generations, even if it is only used sporadically. The evolution of plasticity may thus also explain other examples of apparent reverse evolution.
Visual mode switching learned through experience
Authors: Li Yanjun , Tregillus Katherine EM. , Luo Qiongsha , Engel Stephen A.
Published: July 2020

When the environment changes, vision adapts to maintain accurate perception. For repeatedly encountered environments, learning to switch immediately to prior adaptive states would be beneficial, but past work remains inconclusive. We tested if the visual system can learn such visual mode switching for a strongly tinted environment, where adaptation causes the dominant hue to fade over time. Eleven observers wore red glasses for five one-hour periods per day, for five days. Color adaptation was measured by asking observers to identify “unique yellow”, appearing neither reddish nor greenish. As expected, the world appeared less and less reddish during the one-hour periods of glasses wear. Critically, across days the world also appeared significantly less reddish immediately after donning the glasses. This indicates that the visual system learned to shift rapidly to a partially adapted state, switching modes to stabilize color vision. Mode switching likely provides a general strategy to optimize perceptual processes.
Is methylation of the CTLA-4 gene promoter region an epigenetic mechanism of autoimmune thyroiditis in hepatitis C?In silicoexperimental observation
Authors: de Oliveira Gabriela Correia Matos , Teles Aragão Aline Zamira Freire , de Oliveira Andrade Luís Jesuíno
Published: July 2020

Introduction

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a crucial immune control point receptor that regulates T cell activation. Epigenetic mechanisms, such as DNA methylation and histone modifications, modulate DNA packaging in the nucleus and influence Gene expression. Autoimmune thyroiditis may be associated with hepatitis C virus (HCV) infection as well as the CTLA-4 Gene.

Objective

To in silico simulate the methylation of the promoter region of CTLA-4 gene as an epigenetic factor triggering autoimmune thyroiditis by HCV.

Methods

We analyzed by in silico simulation the hypermethylation scenarios of the CTLA-4 Gene promoter region, aligning CTLA-4 and HCV sequences (genotypes 1, 2 and 3) through BLAST software -http://blast.ncbi.nlm.nih.gov/Blast.cgi, and identifying their methylated and unmethylated CpG sites. After the sequences obtained with the alignment of the methylation points by MultAlin program, the consensus sequences obtained were submitted to the BLAST similarity search. The GC content calculation and HCV annotation were performed using ENDMEMO (http://www.endmemo.com/bio/gc.php). The MethPrimer was used to identify and locate the methylation CpGi within the HCV genome.

Results

The location of CTLA-4 on chromosome 2 and the alignment of the amino acid sequences are presented: CTLA-4 and HCV genotype 1, CTLA-4 and HCV genotype 2 and CTLA-4 and HCV genotype 3 are presented, as well as the methylation sites.

Conclusion

In susceptible individuals, hypermethylation promotes reduced CTLA-4 expression and increases the risk of autoimmune thyroiditis in HCV-infected individuals.
Providing breastfeeding support during the COVID-19 pandemic: Concerns of mothers who contacted the Australian Breastfeeding Association
Authors: Hull Naomi , Kam Renee L , Gribble Karleen D
Published: July 2020

Concerns of mothers seeking breastfeeding support during the COVID-19 pandemic, and the experiences of Australian Breastfeeding Association (ABA) volunteers who assisted them, were explored via an online survey. Surveys were completed 16th March to 18th of May 2020 and described the COVID-19 related concerns of 340 individuals. One hundred and thirty six mothers (64%) sought support to protect their infants by continuing breastfeeding, increasing milk supply, or restarting breastfeeding. Mothers were commonly stressed, isolated and needing reassurance. Thirty four (10%) raised concerns about COVID-19 and breastfeeding safety. One hundred and twenty nine (61%) informed volunteers they were unable to access face-to-face health services because of fear or unavailability. Most common breastfeeding concerns were related to insufficient milk or weight gain, painful breasts, relactation, and reducing supplemental milk. Volunteers reported mothers were worried stress had reduced milk supply, that milk supply concerns were exacerbated by the inability to weigh infants, and that seeking medical treatment was being delayed. ABA volunteers stated they felt supported and confident assisting mothers while also expressing distress at mothers’ situation. ABA’s role in emergency response should be recognised and national planning for infant and young child feeding in emergencies, must be urgently developed, funded, and implemented.
Dynamics and significance of the antibody response to SARS-CoV-2 infection
Authors: Iyer Anita S. , Jones Forrest K. , Nodoushani Ariana , Kelly Meagan , Becker Margaret , Slater Damien , Mills Rachel , Teng Erica , Kamruzzaman Mohammad , Garcia-Beltran Wilfredo F. , Astudillo Michael , Yang Diane , Miller Tyler E. , Oliver Elizabeth , Fischinger Stephanie , Atyeo Caroline , Iafrate A. John , Calderwood Stephen B. , Lauer Stephen A. , Yu Jingyou , Li Zhenfeng , Feldman Jared , Hauser Blake M. , Caradonna Timothy M. , Branda John A. , Turbett Sarah E. , LaRocque Regina C. , Mellon Guillaume , Barouch Dan H. , Schmidt Aaron G. , Azman Andrew S. , Alter Galit , Ryan Edward T , Harris Jason B. , Charles Richelle C.
Published: July 2020

BACKGROUND

Characterizing the humoral immune response to SARS-CoV-2 and developing accurate serologic assays are needed for diagnostic purposes and estimating population-level seroprevalence.

METHODS

We measured the kinetics of early antibody responses to the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 in a cohort of 259 symptomatic North American patients infected with SARS-CoV-2 (up to 75 days after symptom onset) compared to antibody levels in 1548 individuals whose blood samples were obtained prior to the pandemic.

RESULTS

Between 14-28 days from onset of symptoms, IgG, IgA, or IgM antibody responses to RBD were all accurate in identifying recently infected individuals, with 100% specificity and a sensitivity of 97%, 91%, and 81% respectively. Although the estimated median time to becoming seropositive was similar across isotypes, IgA and IgM antibodies against RBD were short-lived with most individuals estimated to become seronegative again by 51 and 47 days after symptom onset, respectively. IgG antibodies against RBD lasted longer and persisted through 75 days post-symptoms. IgG antibodies to SARS-CoV-2 RBD were highly correlated with neutralizing antibodies targeting the S protein. No cross-reactivity of the SARS-CoV-2 RBD-targeted antibodies was observed with several known circulating coronaviruses, HKU1, OC 229 E, OC43, and NL63.

CONCLUSIONS

Among symptomatic SARS-CoV-2 cases, RBD-targeted antibodies can be indicative of previous and recent infection. IgG antibodies are correlated with neutralizing antibodies and are possibly a correlate of protective immunity.
Maternal blood and amnionic oxytocin receptor gene expression and serum oxytocin levels in preterm birth: a case control study
Authors: Anukriti Kumari , Guleria Kiran , Tyagi Vipin , Suneja Amita , Banerjee B D
Published: July 2020

Background

The oxytocin (OXT)-oxytocin receptor (OXTR) system provides promising candidate gene for studies of genetic contributions to prematurity.

Objective

Quantification and comparison of oxytocin receptor (OXTR) gene expression and serum OXT levels in the blood and amnion of women delivering preterm and evaluation of the correlation between OXTR gene expression in blood and amnion with serum OXT levels in them.

Methods

70 pregnant women in spontaneous labor delivering vaginally preterm i.e < 37 weeks and equal number of matched controls delivering spontaneously at term (37-42 weeks) were recruited. Maternal serum OXT levels taken in active stage of labor i.e 4 cm cervical dilatation were quantified by ELISA. Gene expression studies in the maternal blood and amnion were done by using real time quantitative polymerase chain reaction (RT-qPCR).

Results

The mean serum OXT level in PTL was 48.56 ± 6.97 pg/ml; significantly higher than in controls (43.00 ± 3.96 pg/ml), p<0.001. OXTR gene expression both in maternal blood (2.5 times) and amnion (3.5 times) were significantly higher in PTL. A significant positive correlation was observed between serum OXT levels and OXTR gene expression in amnion (r = −0.190, p = 0.025).

Conclusions

The serum OXT levels and OXTR gene expression in amnion surge significantly in active phase of PTL. Thus, amnion probably links OXT-PTGs autocrine paracrine circuit to facilitate PTL. Future studies are needed to devise better OXTR receptor antagonists preferably acting on amnionic OXTRs to prevent PTL.
High expression of angiotensin-converting enzyme-2 (ACE2) on tissue macrophages that may be targeted by virus SARS-CoV-2 in COVID-19 patients
Authors: Song Xiang , Hu Wei , Yu Haibo , Zhao Laura , Zhao Yeqian , Zhao Yong
Published: July 2020

Angiotensin-converting enzyme-2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects host cells, causing the development of the new coronavirus infectious disease (COVID-19). To better understand the pathogenesis of COVID-19 and build up the host anti-viral immunity, we examined the levels of ACE2 expression on different types of immune cells including tissue macrophages. Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood-derived immune cells including CD4+T, CD8+T, activated CD4+T, activated CD8+T, CD4+CD25+CD127low/−regulatory T cells (Tregs), Th17 cells, NKT cells, B cells, NK cells, monocytes, dendritic cells (DCs), and granulocytes. Additionally, there was no ACE2 expression (< 1%) found on platelets. Compared with interleukin-4-treated type 2 macrophages (M2), the ACE2 expression was markedly increased on the activated type 1 macrophages (M1) after the stimulation with lipopolysaccharide (LPS). Immunohistochemistry demonstrated that high expressions of ACE2 were colocalized with tissue macrophages, such as alveolar macrophages found within the lungs and Kupffer cells within livers of mice. Flow cytometry confirmed the very low level of ACE2 expression on human primary pulmonary alveolar epithelial cells. These data indicate that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS-CoV-2 infection and therefore need to be considered for the prevention and treatment of COVID-19.
Deep learning neural network prediction method improves proteome profiling of vascular sap of grapevines during Pierce’s disease development
Authors: Sagawa Cíntia H. D. , Zaini Paulo A. , Assis Renata de A. B. , Saxe Houston , Salemi Michelle , Jacobson Aaron , Phinney Brett S. , Dandekar Abhaya M.
Published: July 2020

Plant secretome studies have shown the importance of plant defense proteins in the vascular system against pathogens. Studies on Pierce’s disease of grapevines caused by the xylem-limited bacteriaXylella fastidiosa(Xf) have detected proteins and pathways associated to its pathobiology. Despite the biological importance of the secreted proteins in the extracellular space to plant survival and development, proteome studies are scarce due to technical and technological challenges. Deep learning neural network prediction methods can provide powerful tools for improving proteome profiling by data-independent acquisition (DIA). We aimed to explore the potential of this strategy by combining it within silicospectral library prediction tool, Prosit, to analyze the proteome of vascular leaf sap of grapevines with Pierce’s disease. The results demonstrate that the combination of DIA and Prosit increased the total number of identified proteins from 145 to 360 for grapevines and 18 to 90 forXf. The new proteins increased the range of molecular weight, assisted on the identification of more exclusive peptides per protein, and increased the identification of low abundance proteins. These increases allowed the identification of new functional pathways associated with cellular responses to oxidative stress to be further investigated.
Dynamic regulatory module networks for inference of cell type-specific transcriptional networks
Authors: Siahpirani Alireza Fotuhi , Knaack Sara , Chasman Deborah , Seirup Morten , Sridharan Rupa , Stewart Ron , Thomson James , Roy Sushmita
Published: July 2020

Multi-omic datasets with parallel transcriptomic and epigenomic measurements across time or cell types are becoming increasingly common. However, integrating these data to infer regulatory network dynamics is a major challenge. We present Dynamic Regulatory Module Networks (DRMNs), a novel approach that uses multi-task learning to infer cell type-specific cis-regulatory networks dynamics. Compared to existing approaches, DRMN integrates expression, chromatin state and accessibility, accurately predicts cis-regulators of context-specific expression and models network dynamics across linearly and hierarchically related contexts. We apply DRMN to three dynamic processes of different experimental designs and predict known and novel regulators driving cell type-specific expression patterns.
Proprioceptive afferents differentially contribute to effortful perception of object heaviness and mass distribution
Authors: Mangalam Madhur , Desai Nisarg , Singh Tarkeshwar
Published: July 2020

When humans handle a tool, such as a tennis racket or hammer, for the first time, they often wield it to determine its inertial properties, however, the mechanisms that contribute to perception of inertial properties are not fully understood. The goal of the present study was to investigate how proprioceptive afferents contribute to effortful perception of heaviness and mass distribution of a manually wielded object in the absence of vision. Blindfolded participants manually wielded a set of specially-designed experimental objects of different mass and mass distribution about the wrist at different wrist angles and wrist angular kinematics. By independently manipulating these variables, we aimed to elicit different levels of tonic and rhythmic activity in the muscle spindles of the wrist flexors and extensors and relate them to reported perceptual judgments of heaviness and length. Perception of heaviness and length were predominantly dependent on an object’s static moment and the moment of inertia, respectively. Manipulations of wrist angle and wrist angular kinematics affected perceptual judgments of heaviness and length in relatively opposite ways. As for wrist angle, ulnar deviation consistently resulted in an object being perceived heavier but shorter. Compared to static holding, wielding the object resulted in it being perceived heavier but wielding did not affect perceived length. These results suggest that proprioceptive afferents differentially contribute to effortful perception of object heaviness and mass distribution.
Reproductive effort of intertidal tropical seagrass as an indicator of habitat disturbance
Authors: Mishra Amrit Kumar , Apte Deepak
Published: July 2020

Habitat disturbance is one of the major causes of seagrass loss around the Andaman Sea in the Indian Ocean bioregion. Assessing the seagrass response to these disturbances is of utmost importance in planning effective conservation measures. Here we report about seagrass reproductive effort (RE) as an indicator to assess seagrass response to habitat disturbances. Quadrat sampling was used to collect seagrass samples at three locations (a disturbed and undisturbed site per location) of the Andaman and Nicobar Islands. The health of seagrass meadows was quantified based on density-biomass indices of the disturbed sites. A change ratio (D/U) was derived by contrasting the RE of disturbed (D) sites with the undisturbed (U) sites of all three locations. The relationship between RE and plant morphometrics were also quantified. Reproductive density of T.hemprichiiwas higher and significant at the three disturbed sites. The average reproductive density ofT. hemprichiiat the disturbed sites was 3.3-fold higher than the undisturbed sites. The reproductive density consisted around 52% of the total shoot density ofT. hemprichiiat the disturbed sites. In general, the increase in the plant RE was site-specific and was 4-fold higher at the three disturbed sites. Positive and significant correlations was observed between the change ratio of RE and the plant morphometrics, suggesting an active participation of seagrass morphometrics in the reproductive process. Increase in seagrass RE can contribute to the increase in population genetic diversity, meadow maintenance and various ecosystem functions under the influence of anthropogenic disturbance scenarios.
Exome-wide association studies in general and long-lived populations identify genetic variants related to human age
Authors: Sin-Chan Patrick , Gosalia Nehal , Gao Chuan , Van Hout Cristopher V. , Ye Bin , Marcketta Anthony , Li Alexander H. , O’Dushlaine Colm , Li Dadong , Overton John D. , Reid Jeffrey D. , Baras Aris ,   Regeneron Genetics Center, Carey David J. , Ledbetter David H. , Rader Daniel , Ritchie Marylyn D. , Damrauer Scott M. , Milman Sofiya , Barzilai Nir , Glass David J. , Economides Aris N. , Shuldiner Alan R.
Published: July 2020

Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition toAPOE, we identified rareDISP2rs183775254 (p = 7.40×10−10) andZYG11Ars74227999 (p = 2.50×10−08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males ≥ 92 years, Females ≥ 95years) were compared to 482 controls. Our results showed variants inAPOE(rs429358, rs6857), andTMTC2(rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.
Protein homeostasis imprinting across evolution
Authors: Koutsandreas Thodoris , Felden Brice , Chevet Eric , Chatziioannou Aristotelis
Published: July 2020

Protein homeostasis (a.k.a. proteostasis) is associated with the primary functions of life, and therefore with evolution. However, it is unclear how the cellular proteostasis machines have evolved to adjust the protein biogenesis needs to environmental constraints. Herein, we describe a novel computational approach, based on semantic network analysis, to evaluate proteostasis differentiation during evolution. We show that the molecular components of the proteostasis network (PN) are reliable metrics to deconvolute the life forms into Archaea, Bacteria and Eukarya and to assess the evolution rates among species. Topological properties of semantic graphs were used as new criteria to evaluate PN complexity of 93 Eukarya, 250 Bacteria and 62 Archaea, thus representing a novel strategy for taxonomic classification. This functional analysis provides information about species divergence and pointed towards taxonomic clades that evolved faster than others. Kingdom-specific PN were identified, suggesting that PN complexity correlates evolution. Through the analysis of gene conservation, we found that the gains or losses that occurred throughout PN evolution revealed a dichotomy within both the PN conserved modules and within kingdom-specific modules. Since the PN is implicated in cell fitness, aging and disease onset, it could be used as a new metric to tackle mechanisms underlying ‘gain-of-functions’, and their biological ramifications.
Carotenogenesis ofStaphylococcus aureus: new insights and impact on membrane biophysical properties
Authors: López Gerson-Dirceu , Suesca Elizabeth , Álvarez-Rivera Gerardo , Rosato Adriana , Ibáñez Elena , Cifuentes Alejandro , Leidy Chad , Carazzone Chiara
Published: July 2020

Staphyloxanthin (STX) is a saccharolipid derived from a carotenoid inStaphylococcus aureusinvolved in oxidative-stress tolerance and antimicrobial peptide resistance. In this work, a targeted metabolomics and biophysical study was carried out on native and knock-outS. aureusstrains to investigate the biosynthetic pathways of STX and related carotenoids. Identification of 34 metabolites at different growth phases (8, 24 and 48h), reveal shifts of carotenoid populations during progression towards stationary phase. Six of the carotenoids in the STX biosynthetic pathway and three menaquinones (Vitamin K2) were identified in the same chromatogram. Furthermore, other STX homologues with varying acyl chain structures reported herein for the first time, which reveal the extensive enzymatic activity of CrtO/CrtN. Fourier Transform infrared spectroscopy show that STX increases acyl chain order and shifts the cooperative melting of the membrane indicating a more rigid lipid bilayer. This study shows the diversity of carotenoids inS. aureus, and their influence on membrane biophysical properties.
A Whole Blood Thrombus Mimic: Constitutive Behavior Under Simple Shear
Authors: Sugerman Gabriella P. , Kakaletsis Sotirios , Thakkar Parin , Chokshi Armaan , Parekh Sapun H. , Rausch Manuel K.
Published: July 2020

Deep vein thrombosis and pulmonary embolism affect 300,000-600,000 patients each year in the US. The progression from deep vein thrombus to pulmonary embolism occurs when blood clots, as a whole or partially, break off from the deep veins and eventually occlude the pulmonary arteries. Venous thromboembolism is the cause of up to 100,000 deaths per year in the US alone. To date, we don’t fully understand this mechanical process among other reasons because in-vivo samples are difficult to obtain, highly heterogeneous, and their shapes are inappropriate for most mechanical tests. Toward overcoming these obstacles, we have set out to develop an in-vitro thrombus mimic and to test this mimic under large deformation simple shear. In addition to reporting on the mechanics of our mimics under simple shear, we explore the sensitivity of their mechanics to coagulation conditions and blood storage time, and compare three hyperelastic material models for their ability to fit our data. We found that thrombus mimics made from whole blood demonstrate strain-stiffening, a negative Poynting effect, and hysteresis when tested quasi-statically to 50% strain under simple shear. Additionally, we found that the stiffness of these mimics does not significantly vary with coagulation conditions or blood storage times. Of the three hyperelastic constitutive models that we tested, the Ogden model provided the best fits to both shear stress and normal stress. In conclusion, we developed a robust protocol to generate regularly-shaped, homogeneous thrombus mimics that lend themselves to simple shear testing under large deformation. Future studies will extend our model to include the effect of maturation and explore its fracture properties toward a better understanding of embolization.
Evidence for a system in the auditory periphery that may contribute to linking sounds and images in space
Authors: Murphy David LK , King Cynthia D , Lovich Stephanie N , Landrum Rachel E , Shera Christopher A , Groh Jennifer M
Published: July 2020

Eye movements alter the relationship between the visual and auditory spatial scenes. Signals related to eye movements affect the brain’s auditory pathways from the ear through auditory cortex and beyond, but how these signals might contribute to computing the locations of sounds with respect to the visual scene is poorly understood. Here, we evaluated the information contained in the signals observed at the earliest processing stage, eye movement-related eardrum oscillations (EMREOs). We report that human EMREOs carry information about both horizontal and vertical eye displacement as well as initial/final eye position. We conclude that all of the information necessary to contribute to a suitable coordinate transformation of auditory spatial cues into a common reference frame with visual information is present in this signal. We hypothesize that the underlying mechanism causing EMREOs could impose a transfer function on any incoming sound signal, which could permit subsequent processing stages to compute the positions of sounds in relation to the visual scene.
Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans
Authors: Zapata Isain , Hecht Erin E. , Serpell James A. , Alvarez Carlos E.
Published: July 2020

Genetic studies show a general factor associated with all human psychopathology and strongly correlated with personality and intelligence, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and six of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, cognition, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because body size and behavior are correlated in dogs, we isolated the effect of body size in the dog mapping and in the comparative human UK Biobank analyses. Our dog findings are consistent with pleiotropy of diverse brain traits with energy metabolism and growth, and suggest behavioral variations often affect neurogenesis. There is support for such pleiotropy in humans and well-powered genetic studies of human psychiatric traits consistently implicate neurogenesis. We propose a genetic network which underlies neuron birth and development throughout life is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for genetic and environmental contributions to psychiatric disease. We discuss how canine translational models can further accelerate the study of psychopathology.

Author summary

We genetically mapped diverse normal and problem behaviors in dogs. The well-established approach we used is ideally suited for finding variation that is common across dog breeds and for pin-pointing the most likely gene candidates. Our analysis of the genes implicated at 90 genome regions shows they are enriched for i) genes mapped for diverse brain functions and pathologies in humans; ii) genes involved in brain development throughout life; and iii) footprints of evolution in dogs, humans and other animals. We propose that is consistent with evolutionary conservation of the general genetic factor of mental health in humans, which is correlated with personality and intelligence. The implications are that this super-network of genes is preferentially targeted by evolutionary adaptation for behavior and that its dysregulation increases risk of mental health disorders.
How to characterize a strain? The neglected influence of clonal heterogeneity on the phenotypes of industrialSaccharomyces
Authors: Rácz Hanna Viktória , Mukhtar Fezan , Imre Alexandra , Rádai Zoltán , Gombert Andreas Károly , Rátonyi Tamás , Nagy János , Pócsi István , Pfliegler Walter P.
Published: July 2020

Populations of microbes are constantly evolving heterogeneity that selection acts upon, yet heterogeneity is non-trivial to assess methodologically. The practice of isolating single cell colonies for establishing, transferring, and using a strain results in single-cell bottlenecks with a generally neglected effect on the characteristics of the strain. We used six industrial yeasts to assess the level of heterogeneity in clonal populations, especially in terms of stress tolerance. First, we uncovered the existence of genome structure variants in available sequenced genomes of clonal lineages of thes strains. Subsequent phenotyping of strains and their newly isolated subclones showed that single-cell bottlenecks during isolation can considerably influence the observable phenotype. Next, we decoupled fitness distributions on the level of individual cells from clonal interference by plating single cell colonies. We used the obtained data on colony area for statistical modeling of the heterogeneity in phenotypes. One strain was further used to show how individual subclonal lineages are remarkably different not just in phenotype, but also in the level of heterogeneity. Thereby we call attention to the fact that choosing an initial clonal lineage from an industrial yeast strain may vastly influence downstream performances and observations on geno- and phenotype, and also on heterogeneity.