bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Pluronic-F68 fog solution on performance and morbidity of newly received heifer calves
Authors: Sowers Consuelo A , Gouvêa Vinicius N , Barnes Michael L , Duff Glenn C
Published: December 2020

Morbidity and mortality from bovine respiratory disease (BRD) of newly received feedlot cattle continue to be problems for the feedlot industry. The objective of this study was to evaluate the effects of utilizing a novel breathing treatment containing a nonionic surfactant (Pluronic-F68) on performance and morbidity of high-risk calves during a 45-d receiving period. Angus/Angus-cross heifer calves (n = 240) were acquired in Delhi, LA, and transported (14 h) to the research facility. Heifers were allowed 21-h rest with access to water and RAMP prior to processing. Heifers were sorted into 16 pens by processing order and randomized by pen into one of two treatments: novel breathing treatment containing 6.25% Pluronic-F68 solution, 28.13% glycerin, and 65.62% water (FOG; n = 8 pens per treat and 15 heifers per pen) and control (CON; n = 8 pens per treat and 15 heifers per pen). Control heifers were held in an enclosed stock trailer for 10 min and followed by FOG heifers, during which time treatment was administered. The person responsible for identifying signs of morbidity was blinded to treatment assignments. Data were analyzed as a completely randomized design using MIXED (continuous) or GLIMIX (binomial) models of SAS 9.4. Average daily gain was similar between treatments (P = 0.91). No differences were found in dry matter intake (P = 0.14) nor in gain efficiency (P = 0.58). There were no differences (P = 0.74) in final body weights. Morbidity was similar at first, second, and third antimicrobial administration regardless of treatment (P ≥ 0.34). The number of antimicrobial treatments required or the management of BRD was similar between treatments (P = 0.72). There was no difference (P = 0.44) in mortality between FOG and CON groups. The Pluronic-F68 solution did not improve performance or reduce morbidity of newly received heifer calves; however, further research with a different concentration and/or duration of fogging may be warranted.
Evaluation of Organ Dysfunction Scores for Allocation of Scarce Resources in Critically Ill Children and Adults During a Healthcare Crisis*
Authors: Sanchez-Pinto L. Nelson , Parker William F. , Mayampurath Anoop , Derrington Sabrina , Michelson Kelly N.
Published: December 2020

Objectives:

When healthcare systems are overwhelmed, accurate assessments of patients’ predicted mortality risks are needed to ensure effective allocation of scarce resources. Organ dysfunction scores can serve this essential role, but their evaluation in this context has been limited so far. In this study, we sought to assess the performance of three organ dysfunction scores in both critically ill adults and children at clinically relevant mortality thresholds and timeframes for resource allocation and compare it with two published prioritization schemas.

Design:

Retrospective observational cohort study.

SETTING:

Three large academic medical centers in the United States.

PATIENTS:

Critically ill adults and children.

Interventions:

None.

Measurements and Main Results:

We calculated the daily Sequential Organ Failure Assessment score in adults and the Pediatric Logistic Organ Dysfunction 2 score and the Pediatric Sequential Organ Failure Assessment score in children. There were 49,290 (11.6% mortality) and 19,983 children (2.5% mortality) included in the analysis. Both the Sequential Organ Failure Assessment and Pediatric Sequential Organ Failure Assessment scores had adequate discrimination across relevant timeframes and adequate distribution across relevant mortality thresholds. Additionally, we found that the only published state prioritization schema that includes pediatric and adult patients had poor alignment of mortality risks, giving adults a systematic advantage over children.

Conclusions:

In the largest analysis of organ dysfunction scores in a general population of critically ill adults and children to date, we found that both the Sequential Organ Failure Assessment and Pediatric Sequential Organ Failure Assessment scores had adequate performance across relevant mortality thresholds and timeframes for resource allocation. Published prioritization schemas that include both pediatric and adult patients may put children at a disadvantage. Furthermore, the distribution of patient and mortality risk in the published schemas may not adequately stratify patients for some high-stakes allocation decisions. This information may be useful to bioethicists, healthcare leaders, and policy makers who are developing resource allocation policies for critically ill patients.
Brief Report: The Impact of Disease Stage on Early Gaps in ART in the “Treatment for All” Era—A Multisite Cohort Study
Authors: Katz Ingrid T. , Musinguzi Nicholas , Bell Kathleen , Cross Anna , Bwana Mwebesa B. , Amanyire Gideon , Asiimwe Stephen , Orrell Catherine , Bangsberg David R. , Haberer Jessica E. ,   On Behalf of the META (Measuring Early Treatment Adherence) Team Investigators
Published: December 2020

Background:

Adoption of “Treat All” policies has increased antiretroviral therapy (ART) initiation in sub-Saharan Africa; however, unexplained early losses continue to occur. More information is needed to understand why treatment discontinuation continues at this vulnerable stage in care.

Methods:

The Monitoring Early Treatment Adherence Study involved a prospective observational cohort of individuals initiating ART at early-stage versus late-stage disease in South Africa and Uganda. Surveys and HIV-1 RNA levels were performed at baseline, 6, and 12 months, with adherence monitored electronically. This analysis included nonpregnant participants in the first 6 months of follow-up; demographic and clinical factors were compared across groups with χ2, univariable, and multivariable models.

Results:

Of 669 eligible participants, 91 (14%) showed early gaps of ≥30 days in ART use (22% in South Africa and 6% in Uganda) with the median time to gap of 77 days (interquartile range: 43–101) and 87 days (74, 105), respectively. Although 71 (78%) ultimately resumed care, having an early gap was still significantly associated with detectable viremia at 6 months (P ≤ 0.01). Multivariable modeling, restricted to South Africa, found secondary education and higher physical health score protected against early gaps [adjusted odds ratio (aOR) 0.4, 95% confidence interval (CI): 0.2 to 0.8 and (aOR 0.93, 95% CI: 0.9 to 1.0), respectively]. Participants reporting clinics as “too far” had double the odds of early gaps (aOR 2.2: 95% CI: 1.2 to 4.1).

Discussion:

Early gaps in ART persist, resulting in higher odds of detectable viremia, particularly in South Africa. Interventions targeting health management and access to care are critical to reducing early gaps.
Split-Dose Regimen With Bisacodyl Increases the Quality of Bowel Preparation for Colonoscopy
Authors: Kallestrup Kirsten , Møller Jensen Thomas , Grode Louise Bang , Behrndtz Brandsborg Søren , Dige Anders Kirch , Brix Lone Dragnes
Published: December 2020

The aim of the present study was to compare 2 different bowel preparations procedures (split-dose with PicoPrep and bisacodyl vs. same-day preparation with PicoPrep) in patients undergoing colonoscopy with regard to quality of bowel preparation, compliance, and willingness to repeat. A retrospective quasi-experimental investigation was conducted. Adults with outpatient diagnostic and surveillance colonoscopies were included. A total of 540 patients participated: group ‘split-dose with bisacodyl’ (n = 293) and group ‘same-day’ (n = 247). Patients in group ‘split-dose with bisacodyl’ had a higher chance for having an excellent quality of bowel preparation (21.2%; 95% CI [13.5, 28.9]) and a reduced risk of an incomplete colonoscopy (4.1%; 95% CI [1.2, 7.0]). Group ‘split-dose with bisacodyl’ drank more fluid, had more nightly visits to the bathroom, and had more bathroom stops on the way to the endoscopic site. No differences were found between groups regarding adenoma detection rate, withdrawal time, overall time of colonoscopy, well-being during cleansing, patient satisfaction, the professional's assessment of the patient's tolerability of colonoscopy, and willingness to repeat the bowel preparation process. The split-dose regimen with PicoPrep and bisacodyl is now the standard bowel preparation procedure for patients undergoing elective colonoscopy as it is superior to the same-day regimen with PicoPrep regarding colon cleansing and incomplete colonoscopy. Hence, the written and verbal information at our institution regarding the bowel preparation procedure was altered according to the split-dose regimen, emphasizing the importance of adequate oral fluid intake and complete intake of the solution in order to ensure a safe and effective procedure.
Validity and Reliability of the Japanese Version of the Morisky Medication Adherence Scale-8 in Patients With Ulcerative Colitis
Authors: Tanaka Makoto , Kawakami Aki , Maeda Shin , Kunisaki Reiko , Morisky Donald E.
Published: December 2020

The Morisky Medication Adherence Scale is a clinically relevant tool used to evaluate medication adherence. In the current study, the validity and reliability of a Japanese version of the Morisky Medication Adherence Scale and factors related to low adherence were investigated in patients with ulcerative colitis. The original English version was translated into Japanese and then 3 institutions in Japan administered that Japanese version to 428 patients taking medication. Factor validity, internal consistency, and correlations between the Morisky Medication Adherence Scale and adherence were calculated on the basis of patients' own reports of skipped medication, and known group validity between clinically different groups was assessed. Logistic regression was used to assess relationships between low adherence and other factors. The Morisky Medication Adherence Scale identified 184 of 428 patients (43.0%) who exhibited low adherence. Confirmed factor analysis indicated one-dimensionality of the scale. Cronbach's α was 0.74. The Morisky Medication Adherence Scale score was significantly correlated with self-reported missed medication. Patients who were on concomitant induction therapy exhibited significantly better Morisky Medication Adherence Scale scores than those who were not. Patients with low adherence reported difficulty taking medicine, having proctitis, and ulcerative colitis duration of less than 5 years, and were of younger age. The Japanese Morisky Medication Adherence Scale yielded clinically relevant measures of adherence in patients with ulcerative colitis and may promote further international comparative studies.
Clinical and Economic Outcomes of Enhanced Recovery Dissemination in Michigan Hospitals
Authors: Regenbogen Scott E. , Cain-Nielsen Anne H. , Syrjamaki John D. , Norton Edward C.
Published: December 2020

Objective:

To evaluate real-world effects of enhanced recovery protocol (ERP) dissemination on clinical and economic outcomes after colectomy.

Summary Background Data:

Hospitals aiming to accelerate discharge and reduce spending after surgery are increasingly adopting perioperative ERPs. Despite their efficacy in specialty institutions, most studies have lacked adequate control groups and diverse hospital settings and have considered only in-hospital costs. There remain concerns that accelerated discharge might incur unintended consequences.

Methods:

Retrospective, population-based cohort including patients in 72 hospitals in the Michigan Surgical Quality Collaborative clinical registry (N = 13,611) and/or Michigan Value Collaborative claims registry (N = 14,800) who underwent elective colectomy, 2012 to 2018. Marginal effects of ERP on clinical outcomes and risk-adjusted, price-standardized 90-day episode payments were evaluated using mixed-effects models to account for secular trends and hospital performance unrelated to ERP.

Results:

In 24 ERP hospitals, patients Post-ERP had significantly shorter length of stay than those Pre-ERP (5.1 vs 6.5 days, P < 0.001), lower incidence of complications (14.6% vs 16.9%, P < 0.001) and readmissions (10.4% vs 11.3%, P = 0.02), and lower episode payments ($28,550 vs $31,192, P < 0.001) and postacute care ($3,384 vs $3,909, P < 0.001). In mixed-effects adjusted analyses, these effects were significantly attenuated—ERP was associated with a marginal length of stay reduction of 0.4 days (95% confidence interval 0.2–0.6 days, P = 0.001), and no significant difference in complications, readmissions, or overall spending.

Conclusions:

ERPs are associated with small reduction in postoperative length of hospitalization after colectomy, without unwanted increases in readmission or postacute care spending. The real-world effects across a variety of hospitals may be smaller than observed in early-adopting specialty centers.
Interim evaluation of Google AI forecasting for COVID-19 compared with statistical forecasting by human intelligence in the first week
Authors: Kurita Junko , Sugawara Tamie , Ohkusa Yasushi
Published: December 2020

Background

Since June, Google (Alphabet Inc.) has provided forecasting for COVID-19 outbreak by artificial intelligence (AI) in the USA. In Japan, they provided similar services from November, 2020.

Object

We compared Google AI forecasting with a statistical model by human intelligence.

Method

We regressed the number of patients whose onset date was day t on the number of patients whose past onset date was 14 days prior, with information about traditional surveillance data for common pediatric infectious diseases including influenza, and prescription surveillance 7 days prior. We predicted the number of onset patients for 7 days, prospectively. Finally, we compared the result with Googles AI-produced forecast. We used the discrepancy rate to evaluate the precision of prediction: the sum of absolute differences between data and prediction divided by the aggregate of data.

Results

We found Google prediction significantly negative correlated with the actual observed data, but our model slightly correlated but not significant. Moreover, discrepancy rate of Google prediction was 27.7% for the first week. The discrepancy rate of our model was only 3.47%.

Discussion and Conclusion

Results show Googles prediction has negatively correlated and greater difference with the data than our results. Nevertheless, it is noteworthy that this result is tentative: the epidemic curve showing newly onset patients was not fixed.
Soil Chemistry and Microbiome Determine N2O Emission Potential in Soils
Authors: Highton Matthew P. , Bakken Lars R. , Dörsch Peter , Tobias-Hunefeldt Sven , Molstad Lars , Morales Sergio E.
Published: December 2020

Microbial nitrogen (N) transformations in soil, notably denitrification, result in the production of the potent greenhouse and ozone depleting gas nitrous oxide (N2O). Soil chemistry and microbiome composition impact N2O emission potential but the relative importance of these factors as determinants of N2O emission in denitrifying systems is rarely tested. In addition, previous linkages between microbiome composition and N2O emission potential rarely demonstrate causality. Here, we determined the relative impact of microbiome composition (i.e. soil extracted cells) and chemistry (i.e. water extractable chemicals) on N2O emission potential utilizing an anoxic cell based assay system. Cells and chemistry for assays were sourced from soils with contrasting N2O/N2O+N2ratios, combined in various combinations and denitrification gas production was measured in response to nitrate addition. Average directionless effects of cell and chemical extract on N2O/N2O+N2(Cell: Δ0.16, Chemical extract: Δ0.22) and total N2O hypothetically emitted (Cell: Δ2.62 μmol-N, Chemical extract: Δ4.14 μmol-N) indicated chemistry is the most important determinant of N2O emissions. Independent pH differences of just 0.6 points impacted N2O/N2O+N2on par with independent chemical extract differences, supporting the dominance of this variable in previous studies. However, impacts on overall N2O hypothetically emitted were smaller suggesting that soil pH manipulation may not necessarily be a successful approach to mitigate emissions over a fixed time period. In addition, we observed increased N2O accumulation and emission potential at the end of incubations concomitant with predicted decreases in carbon availability suggesting that carbon limitation increases N2O emission transiently with the magnitude of emission dependent on the both chemical and microbiome controls.
Oxygen saturation instability in suspected covid-19 patients; contrasting effects of reduced VA/Q and shunt
Authors: Jones J.Gareth
Published: December 2020

Patients in the UK at risk of Covid-19 pneumonia, but not needing immediate hospital attention, are to be given pulse oximeters to identify a fall in oxygen saturation (SaO2 or SpO2) at home. A recent finding in Covid-19 pneumonia is a dominant reduction in ventilation to perfused alveoli (VA/Q). A mathematical model of gas exchange was used to predict the effect of shunt or reduced VA/Q on SaO2 stability inferred from the slope of the PIO2 vs SaO2 curve as it intersected the line representing ambient PIO2. A ±1 kPa variation in PIO2 predicted a 1.5% and 8% change in SpO2 with 15% shunt and 0.4 VA/Q respectively. As a consistency check, two patients with pre-existing lung disease and 12 hour continuous SpO2 monitoring breathing air had gas exchange impairment analysed in terms of shunt and reduced VA/Q. The patient with 16% shunt and normal VA/Q had a stable but reduced SpO2 (circa 93±1%) throughout the 12 hr period. The patient with a VA/Q reduced to 0.48 had SpO2 ranging from 75-95% during the same period. SpO2 monitoring in suspected covid-19 patients should focus on SpO2 varying >5% in 30 minutes. Such instability in at risk patients is not diagnostic of Covid-19 pneumonia but this may be suspected from a dominant reduction in VA/Q if episodic hypoxaemia has progressed from a stable SpO2.
Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses
Authors: Llibre Alba , Smith Nikaïa , Rouilly Vincent , Musvosvi Munyaradzi , Nemes Elisa , Posseme Céline , Mabwe Simba , Charbit Bruno , Mbandi Stanley Kimbung , Filander Elizabeth , Africa Hadn , Saint-André Violaine , Bondet Vincent , Bost Pierre , Mulenga Humphrey , Bilek Nicole , Albert Matthew L , Scriba Thomas J , Duffy Darragh
Published: December 2020

Tuberculosis (TB) remains a major public health problem with host-directed therapeutics offering potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of howMycobacterium tuberculosis(M.tb) infection impacts immune responses. To address this challenge, we applied standardised immunomonitoring tools to compare TB antigen, BCG and IL-1β induced immune responses between individuals with latentM.tbinfection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. Elevated IL-1 antagonist responses were explained by upstream differences in TNF responses, while for IL-1 agonists it was due to downstream differences in granzyme mediated cleavage. Finally, the immune response to IL-1β driven signalling was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how immune responses are altered during TB disease, and may support design of improved diagnostic, prophylactic and therapeutic tools.
KwARG: Parsimonious Reconstruction of Ancestral Recombination Graphs with Recurrent Mutation
Authors: Ignatieva Anastasia , Lyngsø Rune B. , Jenkins Paul A. , Hein Jotun
Published: December 2020

Abstract

The reconstruction of possible histories given a sample of genetic data in the presence of recombination and recurrent mutation is a challenging problem, but can provide key insights into the evolution of a population. We present KwARG, which implements a parsimony-based greedy heuristic algorithm for finding plausible genealogical histories (ancestral recombination graphs) that are minimal or near-minimal in the number of posited recombination and mutation events. Given an input dataset of aligned sequences, KwARG outputs a list of possible candidate solutions, each comprising a list of mutation and recombination events that could have generated the dataset; the relative proportion of recombinations and recurrent mutations in a solution can be controlled via specifying a set of ‘cost’ parameters. We demonstrate that the algorithm performs well when compared against existing methods. The software is made available on GitHub.
Activation of the type 3 secretion system of enteropathogenicE. colileads to remodeling of its membrane composition and function
Authors: Zacharia Anish , Pal Ritesh Ranjan , Katsowich Naama , Mannully Chanchal Thomas , ibrahim Aida , Alfandary Sivan , Serruya Raphael , Baidya Amit K , Ben-Yehuda Sigal , Rosenshine Ilan , Moussaieff Arieh
Published: December 2020

The cell envelope of gram-negative bacteria is a complex structure, essential for bacterial survival and for resistance to many antibiotics. Channels that cross the bacterial envelope and the host cell membrane form secretion systems that are activated upon attachment to host, enabling bacteria to inject effector molecules into the host cell, required for bacterial-host interaction. The type III secretion system (T3SS) is critical for the virulence of several pathogenic bacteria, including enteropathogenicE. coli(EPEC). The EPEC T3SS activation is associated with repression of carbon storage regulator (CsrA), resulting in gene expression remodeling, which is known to affect EPEC central carbon metabolism and contributes to the adaptation to a cell-adherent lifestyle in a poorly understood manner. We reasoned that the changes in bacterial envelope upon attachment to host and the activation of a secretion system may involve a modification of the lipid composition of bacterial envelope. Accordingly, we performed a lipidomics analysis on mutant strains that simulate T3SS activation. We saw a shift in glycerophospholipid metabolism towards the formation of lysophospholipids, attributed to corresponding upregulation of the phospholipasepldAand the acyltransferaseygiHupon T3SS activation in EPEC. We also detected a shift from menaquinones and ubiquinones to undecaprenyl lipids, concomitant to abnormal synthesis of O-antigen. The remodeling of lipid metabolism is mediated by CsrA and associated with increased bacteria cell size and Zeta potential, and a corresponding alteration in EPEC permeability to vancomycin, increasing the sensitivity of T3SS-activated strains and of adherent wild type EPEC to the antibiotic.

Importance

The characterization of EPEC membrane lipid metabolism upon attachment to host is an important step towards a better understanding the shift of EPEC, a notable human pathogen, from a planktonic to adherent life style. It may also apply to other pathogenic bacteria that use this secretion system. We predict that upon attachment to host cells the lipid remodeling upon T3SS activation contributes to bacterial fitness and promotes host colonization, and show that it is associated with increased cell permeability and higher sensitivity to vancomycin.

To the best of our knowledge, this is the first demonstration of a bacterial lipid remodeling due to activation of a secretion system.
Gastrointestinal ulceration in calves presented to a central Iowa veterinary referral facility: An underappreciated morbidity?
Authors: Mosichuk Allison , Smith Joe , Tatarniuk Dane , Kreuder Amanda
Published: December 2020

Summary and Implications

The objective of this retrospective investigation is to identify the incidence of gastrointestinal ulceration as a co-morbidity in calves presenting to a referral veterinary hospital. Approximately 24% of calves presented to the hospital that died or were euthanized had evidence of gastrointestinal ulceration. Previous administration of an NSAID was significantly associated with the presence of ulcers, whereas antibiotic administration, age at presentation, gender, or breed were not. Clinicians and producers should consider the risk of ulceration in calves treated with NSAIDs, in light of antiulcer therapies.
TIPS: Trajectory Inference of Pathway Significance through Pseudotime Comparison for Functional Assessment of single-cell RNAseq Data
Authors: Zheng Zihan , Xin Qiu , Wu Haiyang , Chang Ling , Tang Xiangyu , Zou Liyun , Li Jingyi , Wu Yuzhang , Zhou Jianzhi , shan jiang , Wan Ying , Ni Qingshan
Published: December 2020

Recent advances in bioinformatics analyses have led to the development of novel tools enabling the capture and trajectory mapping of single-cell RNA sequencing (scRNAseq) data. However, there is a lack of methods to assess the contributions of biological pathways and transcription factors to an overall developmental trajectory mapped from scRNAseq data. In this manuscript, we present a simplified approach for trajectory inference of pathway significance (TIPS) that leverages existing knowledgebases of functional pathways and transcription factor targets to enable further mechanistic insights into a biological process. TIPS returns both the key pathways whose changes are associated with the process of interest, as well as the individual genes that best reflect these changes. TIPS also provides insight into the relative timing of pathway changes, as well as a suite of visualizations to enable simplified data interpretation of scRNAseq libraries generated using a wide range of techniques. The TIPS package can be run through either a web server, or downloaded as a user-friendly GUI run in R, and may serve as a useful tool to help biologists perform deeper functional analyses and visualization of their single-cell and/or large cohort RNAseq data.
Public adherence to governmental recommendations regarding quarantine and testing for COVID-19 in two Norwegian cohorts
Authors: Carlsen Ellen Ø , Caspersen Ida Henriette , Trogstad Lill , Gjessing Håkon K , Magnus Per
Published: December 2020

Background

Combatting the COVID-19 pandemic relies at present on non-pharmacological interventions. Governments are using various approaches from general advice to full lockdown. There is a need to describe and understand adherence to public health actions.

Methods

Participants from two ongoing cohorts, the Norwegian Mother, Father and Child Cohort Study (MoBa) and The Norwegian Influenza Pregnancy Cohort (NorFlu), answered questionnaires every 14 days since March 2020. From the summer of 2020, testing for presence of SARS-CoV-2 became easily available. Recommendations were that respiratory symptoms should lead to testing, and that confirmed or suspected COVID-19 should be followed by quarantine. We estimated the adherence to these guidelines in responses from cohort participants in the period August to October 2020.

Results

Less than 40% of men who were ill and less than 45% of women who were ill, tested themselves for SARS-CoV-2 during the same 14-day periods. Among subjects tested for COVID-19, about 53% of men and 59% of women reported quarantine. For subjects with a confirmed or suspected COVID-19 diagnosis, the proportions quarantined were 65% for men and 72% for women.

Conclusions

Public adherence to governmental recommendations regarding testing and quarantine were lower than expected in a country with high trust in government. This leaves considerable room for improvement in adherence, possibly reducing the need for more restrictive interventions.
The Easter Egg Weevil (Pachyrhynchus) genome reveals synteny in Coleoptera across 200 million years of evolution
Authors: Van Dam Matthew H. , Cabras Analyn Anzano , Henderson James B. , Pérez Estrada Cynthia , Omer Arina D. , Dudchenko Olga , Aiden Erez Lieberman , Lam Athena W.
Published: December 2020

Patterns of genomic architecture across insects remain largely undocumented or decoupled from a broader phylogenetic context. For instance, it is unknown whether translocation rates differ between insect orders? We address broad scale patterns of genome architecture across Insecta by examining synteny in a phylogenetic framework from open source insect genomes. To accomplish this, we add a chromosome level genome to a crucial lineage, Coleoptera. Our assembly of thePachyrhynchus sulphureomaculatusgenome is the first chromosome scale genome for the hyperdiverse Phytophaga lineage and currently the largest insect genome assembled to this scale. The genome is significantly larger than those of other weevils, and this increase in size is caused by repetitive elements. Our results also indicate that, among beetles, there are instances of long-lasting (>200 Ma) localization of genes to a particular chromosome with few translocation events. While some chromosomes have a paucity of translocations, intra-chromosomal synteny was almost absent, with gene order thoroughly shuffled along a chromosome. To place our findings in an evolutionary context, we compared syntenic patterns across Insecta. We find that synteny largely scales with clade age, with younger clades, such as Lepidoptera, having especially high synteny. However, we do find subtle differences in the maintenance of synteny and its rate of decay among the insect orders.
FBW7 couples structural integrity with functional output of primary cilia
Authors: Petsouki Eleni , Gerakopoulos Vasileios , Szeto Nicholas , Chang Wenhan , Humphrey Mary Beth , Tsiokas Leonidas
Published: December 2020

Structural defects in cilia have robust effects in diverse tissues and systems. However, how ciliary length changes influence signaling output are unknown. Here, we examined the functional role of a ciliary length control mechanism whereby FBW7-mediated destruction of NDE1 positively regulated ciliary length, in mesenchymal stem cell differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on cilia formation, MSC differentiation, and bone architecture. Deletion ofFbxw7suppresses ciliation, Hedgehog activity, and differentiation, which are rescued inFbxw7/Nde1-null cells. However, despite formation of abnormally long cilia inNde1-null cells, MSC differentiation is suppressed. NDE1 promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that ciliary structure-function coupling is determined by intricate interactions of structural and functional proteins.
Increased functional connectivity of the intraparietal sulcus underlies the attenuation of numerosity estimations for self-generated words
Authors: Stripeikyte Giedre , Pereira Michael , Rognini Giulio , Potheegadoo Jevita , Blanke Olaf , Faivre Nathan
Published: December 2020

Previous studies have shown that self-generated stimuli in auditory, visual, and somatosensory domains are attenuated, producing decreased behavioral and neural responses compared to the same stimuli that are externally generated. Yet, whether such attenuation also occurs for higher-level cognitive functions beyond sensorimotor processing remains unknown. In this study, we assessed whether cognitive functions such as numerosity estimations are subject to attenuation. We designed a task allowing the controlled comparison of numerosity estimations for self (active condition) and externally (passive condition) generated words. Our behavioral results showed a larger underestimation of self-compared to externally-generated words, suggesting that numerosity estimations for self-generated words are attenuated. Moreover, the linear relationship between the reported and actual number of words was stronger for self-generated words, although the ability to track errors about numerosity estimations was similar across conditions. Neuroimaging results revealed that numerosity underestimation involved increased functional connectivity between the right intraparietal sulcus and an extended network (bilateral supplementary motor area, left inferior parietal lobule and left superior temporal gyrus) when estimating the number of self vs. externally generated words. We interpret our results in light of two models of attenuation and discuss their perceptual versus cognitive origins.
A recombinant fragment of Human surfactant protein D binds Spike protein and inhibits infectivity and replication of SARS-CoV-2 in clinical samples
Authors: Madan Taruna , Biswas Barnali , Varghese Praveen M. , Subedi Rambhadur , Pandit Hrishikesh , Idicula-Thomas Susan , Kundu Indra , Rooge Sheetalnath , Agarwal Reshu , Tripathi Dinesh M. , Kaur Savneet , Gupta Ekta , Gupta Sanjeev K. , Kishore Uday
Published: December 2020

Rationale

COVID-19 is an acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Human surfactant protein D (SP-D) is known to interact with spike protein of SARS-CoV, but its immune-surveillance against SARS-CoV-2 is not known.

Objective

This study aimed to examine the potential of a recombinant fragment of human SP-D (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2.

Methods

rfhSP-D interaction with spike protein of SARS-CoV-2 and hACE-2 receptor was predicted via docking analysis. The inhibition of interaction between spike protein and ACE-2 by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was studied by measuring the expression of RdRp gene of the virus using qPCR.

Measurements and Main Results

In-silicointeraction studies indicated that three amino acid residues in the RBD of spike of SARS-CoV-2 were commonly involved in interacting with rfhSP-D and ACE-2. Studies using clinical samples of SARS-CoV-2 positive cases (asymptomatic, n=7 and symptomatic, n=8 and negative controls n=15) demonstrated that treatment with 5μM rfhSP-D inhibited viral replication by ~5.5 fold and was more efficient than Remdesivir (100 μM). Approximately, a 2-fold reduction in viral infectivity was also observed after treatment with 5μM rfhSP-D.

Conclusions

These results conclusively demonstrate that the calcium independent rfhSP-D mediated inhibition of binding between the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein and human ACE-2, its host cell receptor, and a significant reduction in SARS-CoV-2 infection and replicationin-vitro.
Human Surfactant Protein D Binds S1 and Receptor Binding Domain of Spike protein and acts as an entry inhibitor of SARS-CoV-2 Pseudotyped viral particlesin vitro
Authors: Hsieh Miao-Hsi , beirag Nazar , Murugaiah Valarmathy , Chou Yu-Chi , Kuo Wen-Shuo , Kao Hui-Fan , Madan Taruna , Kishore Uday , Wang Jiu-Yao
Published: December 2020

Human SP-D is a potent innate immune molecule whose presence at pulmonary mucosal surfaces allows immune surveillance role against pulmonary pathogens. Higher levels of serum SP-D have been reported in patients with severe acute respiratory syndrome coronavirus-1 (SARS-CoV). Studies have suggested the ability of human SP-D to recognise spike glycoprotein of SARS-CoV; its interaction with HCoV-229E strain leads to viral inhibition in human bronchial epithelial (16HBE) cells. Previous studies have reported that a recombinant fragment of human SP-D (rfhSP-D) composed of 8 Gly-X-Y repeats, neck and CRD region, can act against a range of viral pathogens including influenza A Virus and Respiratory Syncytial Virusin vitro, in vivoandex vivomodels. In this context, this study was aimed at examining the likely protective role of rfhSP-D against SARS-CoV-2 infection. rfhSP-D showed a dose-responsive binding to S1 spike protein of SARS-CoV-2 and its receptor binding domain. Importantly, rfhSP-D inhibited interaction of S1 protein with the HEK293T cells overexpressing Angiotensin Converting Enzyme 2. The protective role of rfhSP-D against SARS-CoV-2 infection as an entry inhibitor was further validated by the use of pseudotyped lentiviral particles expressing SARS-CoV-2 S1 protein; ~0.5 RLU fold reduction in viral entry was seen following rfhSP-D treatment (10 μg/ml). The results highlight the therapeutic potential of rfhSP-D in SARS-CoV-2 infection and merits pre-clinical studies in murine models.
SARS-CoV-2 spike protein interacts with and activates TLR4
Authors: Zhao Yingchi , Kuang Ming , Zhu Ling , Li Junhong , Jia Zijing , Guo Xuefei , Wang Xiangxi , You Fuping
Published: December 2020

The onset of sepsis is an important feature of COVID19 and a main cause of death. It is unknown how SARS-CoV-2 infection results in viral sepsis in human. We recently found that SARS-CoV-2 provoked an anti-bacterial like response and activation of TLR4 pathway at the very early stage of infection in animal models. This abnormal immune response led to emergency granulopoiesis and sepsis. However, the original trigger of TLR4 signaling by SARS-CoV-2 is unknown. We here identified that the trimeric spike protein of SARS-CoV-2 could bind to TLR4 directly and robustly activate downstream signaling in monocytes and neutrophils. Moreover, specific TLR4 or NFKB inhibitor, or knockout of MyD88 could significantly block IL-1B induction by spike protein. We thus reveal that spike protein of SARS-CoV-2 functions as a potent stimulus causing TLR4 activation and sepsis related abnormal responses.
Molecular fluctuations as a ruler of force-induced protein conformations
Authors: Stannard Andrew , Mora Marc , Beedle Amy E.M. , Castro-Lopez Marta , Board Stephanie , Garcia-Manyes Sergi
Published: December 2020

Molecular fluctuations directly reflect the underlying energy landscape. Variance analysis can probe protein dynamics in several biochemistry-driven approaches, yet measurement of probe-independent fluctuations in proteins exposed to mechanical forces remains only accessible through steered molecular dynamics simulations. Using single molecule magnetic tweezers, here we conduct variance analysis to show that individual unfolding and refolding transitions occurring in dynamic equilibrium in a single protein under force are hallmarked by a change in the protein's end-to-end fluctuations, revealing a change in protein stiffness. By unfolding and refolding three structurally distinct proteins under a wide range of constant forces, we demonstrate that the associated change in protein compliance to reach force-induced thermodynamically-stable states scales with the protein's contour length, in agreement with the sequence-independent FJC model of polymer physics. Our findings will help probe the conformational dynamics of proteins exposed to mechanical force at high resolution, of central importance in mechanosensing and mechanotransduction.
A common genetic architecture enables the lossy compression of large CRISPR libraries
Authors: Zhao Boyang , Rao Yiyun , Gilbert Luke , Pritchard Justin
Published: December 2020

There are thousands of ubiquitously expressed mammalian genes, yet a genetic knockout can be lethal to one cell, and harmless to another. This context specificity confounds our understanding of genetics and cell biology. 2 large collections of pooled CRISPR screens offer an exciting opportunity to explore cell specificity. One explanation, synthetic lethality, occurs when a single “private” mutation creates a unique genetic dependency. However, by fitting thousands of machine learning models across millions of omic and CRISPR features, we discovered a “public” genetic architecture that is common across cell lines and explains more context specificity than synthetic lethality. This common architecture is built on CRISPR loss-of-function phenotypes that are surprisingly predictive of other loss-of-function phenotypes. Using these insights and inspired by thein silicolossy compression of images, we use machine learning to identify small “lossy compression” sets ofin vitroCRISPR constructs where reduced measurements produce genome-scale loss-of-function predictions.
Rapid local adaptation in both sexual and asexual invasive populations of monkeyflowers (Mimulus spp.)
Authors: Simón-Porcar Violeta I. , Silva Jose L. , Vallejo-Marín Mario
Published: December 2020

Background and Aims

Traditionally, local adaptation has been seen as the outcome of a long evolutionary history, particularly in sexual lineages. In contrast, phenotypic plasticity has been thought to be most important during the initial stages of population establishment and in asexual species. We evaluated the roles of adaptive evolution and phenotypic plasticity in the invasive success of two closely related species of invasive monkeyflowers (Mimulus) in the United Kingdom (UK) that have contrasting reproductive strategies:M. guttatuscombines sexual (seeds) and asexual (clonal growth) reproduction whileM. × robertsiiis entirely asexual.

Methods

We compared the clonality (number of stolons), floral and vegetative phenotype, and phenotypic plasticity of native (M. guttatus) and invasive (M. guttatusandM. ×robertsii) populations grown in controlled environment chambers under the environmental conditions at each latitudinal extreme of the UK. The goal was to discern the roles of temperature and photoperiod on the expression of phenotypic traits. Next, we tested the existence of local adaptation in the two species within the invasive range with a reciprocal transplant experiment at two field sites in the latitudinal extremes of the UK, and analysed which phenotypic traits underlie potential local fitness advantage in each species.

Key Results

Populations ofM. guttatusin the UK showed local adaptation through sexual function (fruit production), whileM. ×robertsiishowed local adaptation via asexual function (stolon production). Phenotypic selection analyses revealed that different traits are associated with fitness in each species. Invasive and native populations ofM. guttatushad similar phenotypic plasticity and clonality.M. ×robertsiipresents greater plasticity and clonality than nativeM. guttatus, but most populations have restricted clonality under the warm conditions of the south of UK.

Conclusions

Our study provides experimental evidence of local adaptation in a strictly asexual invasive species with high clonality and phenotypic plasticity. This indicates that even asexual taxa can rapidly (< 200 years) adapt to novel environmental conditions in which alternative strategies may not ensure the persistence of populations.
Neuroanatomy of the grey seal brain: bringing pinnipeds into the neurobiological study of vocal learning
Authors: Hoeksema Nienke , Verga Laura , Mengede Janine , van Roessel Corne , Villanueva Stella , Salazar-Casals Anna , Rubio-Garcia Ana , Curcic-Blake Branislava , Vernes Sonja , Ravignani Andrea
Published: December 2020

Comparative studies of vocal learning and vocal non-learning animals can increase our understanding of the neurobiology and evolution of vocal learning and human speech. Mammalian vocal learning is understudied: most research has either focused on vocal learning in songbirds or its absence in non-human primates. Here we focus on a highly promising model species for the neurobiology of vocal learning: grey seals. We provide a neuroanatomical atlas (based on dissected brain slices and magnetic resonance images), a labelled MRI template, a 3D model with volumetric measurements of brain regions, and histological cortical stainings. Four main features of the grey seal brain stand out. (1) It is relatively big and highly convoluted. (2) It hosts a relatively large temporal lobe and cerebellum, structures which could support developed timing abilities and acoustic processing. (3) The cortex is similar to humans in thickness and shows the expected six-layered mammalian structure. (4) Expression of FoxP2 - a gene involved in vocal learning and spoken language - is present in deeper layers of the cortex. Our results could facilitate future studies targeting the neural and genetic underpinnings of mammalian vocal learning, thus bridging the research gap from songbirds to humans and non-human primates.
Sleep leads to system-wide neural changes independent of allo- and egocentric spatial training in humans and rats
Authors: Samanta Anumita , van Rongen Laurens S , Rossato Janine I. , Jacobse Justin , Schoenfeld Robby , Genzel Lisa
Published: December 2020

Sleep is important for memory consolidation, especially the process of systems consolidation should occur during sleep. While a significant amount of research has been done in regards to the effect of sleep on behavior and certain mechanisms during sleep, until now evidence is lacking that sleep leads to consolidation across the system. Here, we investigated the role of sleep in consolidation of spatial memory in the watermaze in both rats and humans using allocentric and egocentric based training. Combining behavior with immediate early gene expression analysis in rodents and functional MR imaging in humans, elucidated similar behavioral and neural effects in both species. Rats and humans showed a benefit of sleep on behavior. Interestingly, sleep led to systems-wide retrieval network in both species in both training conditions. Thus, we provide cross-species evidence for memory consolidation on the system-level occurring during sleep.

Significance Statement

Processes occurring during sleep such as memory reactivations are proposed to lead to consolidation from the initial hippocampal memory representation to long-lasting cortical representations, this is known as systems consolidation. By combining behavioral measurements in the watermaze with immediate early gene expression analysis in rats and function magnetic resonance imaging in humans, we could show a benefit of sleep on behavioral memory performance. And, sleep lead to systems-wide changes in the retrieval network. These results are the first direct evidence supporting the role of sleep for systems-wide memory consolidation in both rats and humans.
Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE
Authors: Chaudhary P , Marracci GH , Calkins E , Pocius E , Bensen AL , Scanlan TS , Emery B , Bourdette DN
Published: December 2020

We have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4mg/kg), Sob (5mg/kg) or Sob-AM2 (5mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.

Highlights

Thyroid hormone, the thyromimetic Sob and its CNS penetrating prodrug, Sob-AM2, reduce disease severity, reduce myelin and axonal degeneration and protect oligodendrocytes in EAE.

The benefits of Sob and Sob-AM2 may be via direct protective effects on oligodendrocytes and reduction in activity of microglia/macrophages.