bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual Activity and Dyspareunia 1 Year After Surgical Repair of Pelvic Organ Prolapse
Authors: Lukacz Emily S. , Sridhar Amaanti , Chermansky Christopher J. , Rahn David D. , Harvie Heidi S. , Gantz Marie G. , Varner R. Edward , Korbly Nicole B. , Mazloomdoost Donna
Published: February 2021

(Abstracted from Obstet Gynecol 2020;136:492–500)

A significant concern for women and their surgeons is sexual function after pelvic organ prolapse (POP) surgery. Women who prioritize goals and expectations after prolapse surgery rate sexual function just below resolution of bulge symptoms and improvement in physical function.
When to Operate, Hesitate and Reintegrate: Society of Gynecologic Oncology Surgical Considerations During the COVID-19 Pandemic
Authors: Fader Amanda N. , Huh Warner K. , Kesterson Joshua , Pothuri Bhavana , Wethington Stephanie , Wright Jason D. , Bakkum-Gamez Jamie N. , Soliman Pamela T. , Sinno Abdulrahman K. , Leitao Mario , Martino Martin A. , Karam Amer , Rossi Emma , Brown Jubilee , Blank Stephanie , Burke William , Goff Barbara , Yamada S. Diane , Uppal Shitanshu , Dowdy Sean C.
Published: February 2021

(Abstracted from Gynecol Oncol 2020;158:236–243)

The COVID-19 pandemic has challenged our abilities to provide timely surgical care for patients, including women with gynecologic cancer. In March 2020, the American College of Surgeons, The US Surgeon General, and many medical and surgical academic societies recommended postponing elective surgical interventions.
Microscopy of Stained Urethral Smear in Male Urethritis; Which Cutoff Should be Used?
Authors: Moi Harald , Hartgill Usha , Skullerud Kristin Helene , Reponen Elina J. , Syvertsen Line , Moghaddam Amir
Published: February 2021

Background

The microscopical diagnosis of male urethritis was recently questioned by Rietmeijer and Mettenbrink, lowering the diagnostic criteria of the diagnosis to ≥2 polymorphonuclear leucocytes (PMNL) per high power field (HPF), and adopted by Centers for Disease Control and Prevention in their 2015 STD Treatment Guidelines. The European Non-Gonococcal Urethritis Guideline advocates a limit of ≥5 PMNL/HPF.

Objective

To determine if syndromic treatment of urethritis should be considered with a cutoff value of ≥2 PMNL/HPF in urethral smear.

Methods

The design was a cross-sectional study investigating the presence and degree of urethritis relative to specific infections in men attending an STI clinic as drop-in patients.

Results

The material included 2 cohorts: a retrospective study of 13,295 men and a prospective controlled study including 356 men. We observed a mean chlamydia prevalence of 2.3% in the 0–9 stratum, and a 12-fold higher prevalence (27.3%) in the strata above 9. Of the chlamydia cases, 89.8% were diagnosed in strata above 9. For Mycoplasma genitalium, the prevalence was 1.4% in the 0–9 stratum and 11.2% in the stratum ≥10, and 83.6% were diagnosed in strata above 9. For gonorrhea, a significant increase in the prevalence occurred between the 0–30 strata and >30 strata from 0.2% to 20.7%. The results of the prospective study were similar.

Conclusions

Our data do not support lowering the cutoff to ≥2 PMNL/HPF. However, a standardization of urethral smear microscopy seems to be impossible. The cutoff value should discriminate between low and high prevalence of chlamydia, mycoplasma, and gonorrhea to include as many as possible with a specific infection in syndromic treatment, without overtreating those with few PMNL/HPF and high possibility of having nonspecific or no urethritis.
Incidentally Diagnosed Esophago-Pulmonary Fistula on 18F-FDG PET/CT in a Case of Carcinoma Esophagus
Authors: Ravina Mudalsha , Bansal Himanshu , Lukose Tinu Thadiyananickal , Mishra Ajit Kumar , Moideen Amal
Published: February 2021

Esophago-pulmonary fistulas are very less reported in literature. 18F-FDG PET/CT scan is routinely used for evaluation of patients of carcinoma esophagus. We present a case of carcinoma esophagus with acquired esophago-pulmonary fistula diagnosed on 18F-FDG PET/CT scan.
Therapeutic Methods for Gut Microbiota Modification in Lipopolysaccharide-Associated Encephalopathy
Authors: Li Suyan , Guo Hui , Xu Xin , Hua Ranliang , Zhao Qian , Li Jian , Lv Jian , Li Jianguo
Published: February 2021

Objective:

To compare the efficacy of four therapeutic methods to modify gut microbiota dysbiosis and brain dysfunction in septic rats.

Methods:

Rats were treated with fecal microbiota transplantation, prebiotics, probiotics, and synbiotics after exposure to lipopolysaccharide. The diversity and composition of gut microbiota, electroencephalogram values, and the concentrations of TNF-α, IL-1β, and IL-6 in the cortex were analyzed.

Results:

Fecal microbiota transplantation was the most efficacious method to restore intestinal microbial diversity and exert the best corrective effects in modulating microbial composition in septic rats. More interestingly, fecal microbiota transplantation exerted the best protective effects in brain dysfunction in septic rats.

Conclusion:

Among the four methods, fecal microbiota transplantation was the most useful method to modify the dysbiosis of intestinal microbiota and improve brain function in septic rats. These findings reveal the protective consequence of microbiota modification, and the findings suggest opportunities to improve brain function in sepsis.
Estimating the Impact of Extended Delay to Surgery for Stage I Non-small-cell Lung Cancer on Survival
Authors: Mayne Nicholas R. , Elser Holly C. , Darling Alice J. , Raman Vignesh , Liou Douglas Z. , Colson Yolonda L. , D’Amico Thomas A. , Yang Chi-Fu Jeffrey
Published: February 2021

Objective:

The purpose of this study is to evaluate the impact of extended delay to surgery for stage I NSCLC.

Summary of Background Data:

During the COVID-19 pandemic, patients with NSCLC may experience delays in care, and some national guidelines recommend delays in surgery by >3 months for early NSCLC.

Methods:

Using data from the National Lung Screening Trial, a multi-center randomized trial, and the National Cancer Data Base, a multi-institutional oncology registry, the impact of “early” versus “delayed” surgery (surgery received 0–30 vs 90–120 days after diagnosis) for stage I lung adenocarcinoma and squamous cell carcinoma (SCC) was assessed using multivariable Cox regression analysis with penalized smoothing spline functions and propensity score-matched analyses.

Results:

In Cox regression analysis of the National Lung Screening Trial (n = 452) and National Cancer Data Base (n = 80,086) cohorts, an increase in the hazard ratio was seen the longer surgery was delayed. In propensity score-matched analysis, no significant differences in survival were found between early and delayed surgery for stage IA1 adenocarcinoma and IA1-IA3 SCC (all P > 0.13). For stage IA2-IB adenocarcinoma and IB SCC, delayed surgery was associated with worse survival (all P < 0.004).

Conclusions:

The mortality risk associated with an extended delay to surgery differs across patient subgroups, and difficult decisions to delay care during the COVID-19 pandemic should take substage and histologic subtype into consideration.
Postacute Care Utilization and Episode of Care Payments Following Common Elective Operations
Authors: Ehlers Anne P. , Howard Ryan , Lai Yen-Ling , Waljee Jennifer F. , Delaney Lia D. , Nathan Hari , Dimick Justin B. , Telem Dana A.
Published: February 2021

Objective:

To describe PAC utilization and associated payments for patients undergoing common elective procedures.

Summary of Background Data:

Utilization and costs of PAC are well described for benchmarked conditions and operations but remain understudied for common elective procedures.

Methods:

Cross-sectional study of adult patients in a statewide administrative claims database undergoing elective cholecystectomy, ventral or incisional hernia repair (VIHR), and groin hernia repair from 2012 to 2019. We used multivariable logistic regression to estimate the odds of PAC utilization, and multivariable linear regression to determine the association of 90-day episode of care payments and PAC utilization.

Results:

Among 34,717 patients undergoing elective cholecystectomy, 0.7% utilized PAC resulting in significantly higher payments ($19,047 vs $7830, P < 0.001). Among 29,826 patients undergoing VIHR, 1.7% utilized PAC resulting in significantly higher payments ($19,766 vs $9439, P < 0.001). Among 37,006 patients undergoing groin hernia repair, 0.3% utilized PAC services resulting in significantly higher payments ($14,886 vs $8062, P < 0.001). We found both modifiable and non-modifiable risk factors associated with PAC utilization. Morbid obesity was associated with PAC utilization following VIHR [odds ratio (OR) 1.61, 95% confidence interval (CI) 1.29–2.02, P < 0.001]. Male sex was associated with lower odds of PAC utilization for VIHR (OR 0.43, 95% CI 0.35–0.51, P < 0.001) and groin hernia repair (OR 0.62, 95% CI 0.39–0.98, P = 0.039).

Conclusions:

We found both modifiable (eg, obesity) and nonmodifiable (eg, female sex) patient factors that were associated with PAC. Optimizing patients to reduce PAC utilization requires an understanding of patient risk factors and systems and processes to address these factors.
Epidemiological and Genomic analysis of a Sydney Hospital COVID-19 Outbreak
Authors: Tennant Elaine , Figtree Melanie , Tallon Jo , Bull Rowena A , Yeang Malinna , Deveson Ira W , Ferguson James M , Adikari Thiruni , Holmes Edward C , Hal Sebastiaan Van , Hammond Jillian M , Stevanovski Igor , Mitsakos Katerina , Hilditch-Roberts Drew , Rawlinson William , Hudson Bernard
Published: February 2021

Australia’s early COVID-19 experience involved clusters in northern Sydney, including hospital and aged-care facility (ACF) outbreaks. We explore transmission dynamics, drivers and outcomes of a metropolitan hospital COVID-19 outbreak that occurred in the context of established local community transmission. A retrospective cohort analysis is presented, with integration of viral genome sequencing, clinical and epidemiological data. We demonstrate using genomic epidemiology that the hospital outbreak (n=23) was linked to a concurrent outbreak at a local aged care facility, but was phylogenetically distinct from other community clusters. Thirty day survival was 50% for hospitalised patients (an elderly cohort with significant comorbidities) and 100% for staff. Staff who acquired infection were unable to attend work for a median of 26.5 days (range 14-191); an additional 140 staff were furloughed for quarantine. Transmission from index cases showed a wide dispersion (mean 3.5 persons infected for every patient case and 0.6 persons infected for every staff case). One patient, who received regular nebulised medication prior to their diagnosis being known, acted as an apparent superspreader. No secondary transmissions occurred from isolated cases or contacts who were quarantined prior to becoming infectious. This analysis elaborates the wide-ranging impacts on patients and staff of nosocomial COVID-19 transmission and highlights the utility of genomic analysis as an adjunct to traditional epidemiological investigations. Delayed case recognition resulted in nosocomial transmission but once recognised, prompt action by the outbreak management team and isolation with contact and droplet (without airborne) precautions were sufficient to prevent transmission within this cohort. Our findings support current PPE recommendations in Australia but demonstrate the risk of administering nebulised medications when COVID-19 is circulating locally.
Association between Functional Inhibitors of Acid Sphingomyelinase and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: results from an observational multicenter study
Authors: Hoertel Nicolas , Sánchez-Rico Marina , Gulbins Erich , Kornhuber Johannes , Carpinteiro Alexander , Lenze Eric J. , Reiersen Angela M. , Abellán Miriam , de la Muela Pedro , Vernet Raphaël , Blanco Carlos , Beeker Nathanaël , Neuraz Antoine , Gorwood Philip , Alvarado Jesús M. , Meneton Pierre , Limosin Frédéric
Published: February 2021

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.
Risk of death among teachers in England and Wales during the Covid19 pandemic
Authors: Lewis Sarah J , Dack Kyle , Relton Caroline L , Munafò Marcus R , Smith George Davey
Published: February 2021

Objectives

To estimate occupation risk from Covid19 among teachers and others working in schools using publicly available data on mortality in England and Wales.

Design

Analysis of national death registration data from the Office for National Statistics.

Setting

England and Wales, March 20th to 28th December 2020, during the Covid19 pandemic.

Participants

The total working age population in England and Wales plus those still working aged over 65.

Primary and Secondary outcomes

Death with Covid19 as a primary outcome and death from all causes as a secondary outcome.

Results

Across occupational groups there was a strong correlation between Covid19 mortality and both non-Covid19 and all-cause mortality. The absolute mortality rates for deaths with Covid19 were low amongst those working in schools (from 10 per 100,000 in female primary school teachers to 39 per 100,000 male secondary school teachers) relative to many other occupations (range: 10 to 143 per 100,000 in men; 9 to 50 per 100,000 in women).There was weak evidence that secondary school teachers had slightly higher risks of dying with Covid19 compared to the average for all working aged people, but stronger evidence of a higher risk compared to the average for all professionals; primary school teachers had a lower risk. All-cause mortality was also higher amongst all teachers compared to all professionals. Teaching and lunchtime assistants were not at higher risk of death from Covid19 compared with all working aged people.

Conclusion

There was weak evidence that Covid19 mortality risk for secondary school teachers was above expectation, but in general school staff had Covid19 mortality risks which were proportionate to their non-covid mortality risk.

Strengths and limitations of this study

We used routinely collected data on all deaths in England and Wales;, which are near-complete and not susceptible to serious ascertainment biases.

We were able to compare mortality data for teachers and other school workers with all other occupational groups and with the working-age population.

The number of deaths due to Covid19 were small and thus differences between the specific occupational groups were imprecisely estimated.

We did not have access to individual level mortality data so were not able to account for potential confounders such as comorbidities or household size.

For those working in school aged over 65 we had neither mortality rates per 100,000 nor total numbers within the group; we only had number of deaths and a 5-year average and we do not know whether the denominators have changed for this group over the last 5 years.
The Public Health Impact of Delaying a Second Dose of the BNT162b2 or mRNA-1273 COVID-19 Vaccine
Authors: Romero-Brufau Santiago , Chopra Ayush , Ryu Alex J , Gel Esma , Raskar Ramesh , Kremers Walter , Anderson Karen , Subramanian Jayakumar , Krishnamurthy Balaji , Singh Abhishek , Pasupathy Kalyan , Dong Yue , O’Horo John C , Wilson Walter R , Mitchell Oscar , Kingsley Thomas C
Published: February 2021

Objectives

To estimate population health outcomes under delayedsecond dose versus standard schedule SARS-CoV-2 mRNA vaccination.

Design

Agent-based modeling on a simulated population of 100,000 based on a real-world US county. The simulation runs were replicated 10 times. To test the robustness of these findings, simulations were performed under different estimates for single-dose efficacy and vaccine administration rates, and under the possibility that a vaccine prevents only symptoms but not asymptomatic spread.

Setting

population level simulation.

Participants

100,000 agents are included in the simulation, with a representative distribution of demographics and occupations. Networks of contacts are established to simulate potentially infectious interactions though occupation, household, and random interactions

Interventions

we simulate standard Covid-19 vaccination, versus delayed-second-dose vaccination prioritizing first dose. Sensitivity analyses include first-dose vaccine efficacy of 70%, 80% and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread; and an alternative vaccination strategy that implements delayed-second-dose only for those under 65 years of age.

Main outcome measures

cumulative Covid-19 mortality over 180 days, cumulative infections and hospitalizations.

Results

Over all simulation replications, the median cumulative mortality per 100,000 for standard versus delayed second dose was 226 vs 179; 233 vs 207; and 235 vs 236; for 90%, 80% and 70% first-dose efficacy, respectively. The delayed-second-dose strategy was optimal for vaccine efficacies at or above 80%, and vaccination rates at or below 0.3% population per day, both under sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100,000. The delayed-second-dose for those under 65 performed consistently well under all vaccination rates tested.

Conclusions

A delayed-second-dose vaccination strategy, at least for those under 65, could result in reduced cumulative mortality under certain conditions.
Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death
Authors: Geldsetzer P. , Mukama T. , Jawad N. , Riffe T. , Rogers A. , Sudharsanan N.
Published: February 2021

Men are more likely than women to die due to coronavirus disease 2019 (COVID-19). This paper sets out to examine whether the magnitude of the sex differences in the COVID-19 mortality rate are unusual when compared to other common causes of death. In doing so, we aim to provide evidence as to whether the causal pathways for the sex differences in the mortality rate of COVID-19 likely differ from those for other causes of death. We found that sex differences in the age-standardized COVID-19 mortality rate were substantially larger than for the age-standardized all-cause mortality rate and most other common causes of death. These differences were especially large in the oldest age groups.

One Sentence Summary

The sex difference in the mortality rate of coronavirus disease 2019 is substantially larger than for other common causes of death.
HDAC6 promote HCCLM3 cell migration and invasion by regulating TGF-β1 pathway
Authors: Yu Zeyu , Yang Xiaoxiao , Yin Guowen
Published: February 2021

Histone deacetylase 6 (HDAC6) have been demonstrated to play critical roles in the progression of tumor migration and invasion in recent years.However, little research has been done on hepatocellular carcinoma (HCC). This study investigated the role of HDAC6 in the migration and invasion of HCCLM3 cells and its potential mechanism. Western blot and immunohistochemistry were used to detect the expression of HDAC6 in normal hepatic cell line LO2 and HCC cell line HCCLM3. Transforming growth factor 1 (TGF-β1) was proved as a direct target of HDAC6 by Western blot and qRT-PCR.The changes of migration and invasion ability of HCCLM3 cells were confirmed by wound healing and Transwell assays.Morphological changes of HCCLM3 cells were observed by microscope.Our study proved that drownregulated HDAC6 supress HCCLM3 cells metastasis and invasion. Meanwhile, our study verified that HDAC6 regulate EMT by targeting TGF-β1.In conclusion, HDAC6 inhibits the EMT of HCCLM3 cells and further inhibits the migration and invasion of HCCLM3 cells by downregulating the expression of TGF-β1.
Epidemiological Philosophy of Pandemics
Authors: Raham Tareef Fadhil
Published: February 2021

Objectives

Current estimates of the total number of cases of COVID-19 are largely based on previously-determined case fatality rates (CFRs). In this study, we aim to find an association between the Covid-19 number of cases / million inhabitants (M) and mortality rate (MR), and the association of Covid MR −19 and CFR. The background theory in this study is based on two factors: (1) There is no evidence that the CFR is fixed throughout time or place during an epidemic and (2) there is evidence that an increased viral load (density of infection) leads to more fatalities.

Study Design

We chose 31 countries with testing coverage levels of > 400,0000 tests /M and populations greater than 1 million inhabitants.

Methods

We used ANOVA regression analyses to test the associations.

Results

There was a very highly significant correlation between MR and the total number of cases/ million population inhabitants(M) (P-value 0.0000).

The CRF changed with a change in the MR. A very high positive influence of the COVID-19 MR on the CFR (P-value = 0.0002).

Conclusions

Increased number of cases per million inhabitants is associated with increased MR. Increased MR is associated with increased CFR. This finding might explain variable mortality rates that happened during this pandemic and possibly previous pandemics. This evidence will give us an idea of the behavior of epidemics in general.
Predicting hospitalizations related to ambulatory care sensitive conditions with machine learning for population health planning: derivation and validation cohort study
Authors: Yi Seung Eun , Harish Vinyas , Gutierrez Jahir M. , Ravaut Mathieu , Kornas Kathy , Watson Tristan , Poutanen Tomi , Ghassemi Marzyeh , Volkovs Maksims , Rosella Laura
Published: February 2021

Objective

To predict older adults’ risk of avoidable hospitalization related to ambulatory care sensitive conditions (ACSC) using machine learning applied to administrative health data of Ontario, Canada.

Design, Setting, and Participants

A retrospective cohort study was conducted on a large cohort of all residents covered under a single-payer system in Ontario, Canada over the period of 10 years, between 2008 and 2017. The study included 1.85 million Ontario residents between 65 and 74 years old at any time throughout the study period.

Data sources

Administrative health data from Ontario, Canada obtained from the ICES Data Repository.

Main outcome measures

Risk of hospitalizations due to ACSCs one year after the observation period.

Results

The study used a total of 1,854,116 patients, split into train, validation, and test sets. The ACSC incidence rates among the data points were 1.1% for all sets. The final XGBoost model achieved an AUC of 80.5% on the held-out test set, and the predictions were well-calibrated. When ranking the predictions made by the model, those at the top 5% of risk as predicted by the model captured 37.4% of those presented with an ACSC-related hospitalization. A variety of features such as the previous number of ambulatory care visits, presence of ACSC-related hospitalizations during the observation window, age, rural residence, and prescription of certain medications were contributors to the prediction. Our model was also able to capture the geospatial heterogeneity of ACSC risk in the province of Ontario, and especially the elevated risk in rural and marginalized regions.

Conclusions

This study aimed to predict the 1-year risk of hospitalization from a series of ambulatory-care sensitive conditions in seniors aged 65 to 74 years old with a single, large-scale machine learning model. The model shows the potential to inform population health planning and interventions to reduce the burden of ACSC-related hospitalizations.
SARS-CoV-2 Viremia is Associated with Distinct Proteomic Pathways and Predicts COVID-19 Outcomes
Authors: Li Yijia , Schneider Alexis M. , Mehta Arnav , Sade-Feldman Moshe , Kays Kyle R. , Gentili Matteo , Charland Nicole C. , Gonye Anna L.K. , Gushterova Irena , Khanna Hargun K. , LaSalle Thomas J. , Lavin-Parsons Kendall M. , Lilly Brendan M. , Lodenstein Carl L. , Manakongtreecheep Kasidet , Margolin Justin D. , McKaig Brenna N. , Parry Blair A. , Rojas-Lopez Maricarmen , Russo Brian C. , Sharma Nihaarika , Tantivit Jessica , Thomas Molly F. , Regan James , Flynn James P. , Villani Alexandra-Chloé , Hacohen Nir , Goldberg Marcia B. , Filbin Michael R. , Li Jonathan Z.
Published: February 2021

Background

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) plasma viremia has been associated with severe disease and death in coronavirus disease 2019 (COVID-19) in small-scale cohort studies. The mechanisms behind this association remain elusive.

Methods

We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using qRT-PCR based platform. Proteomic data were generated with Proximity Extension Assay (PEA) using the Olink platform.

Results

Three hundred participants with nucleic acid test-confirmed COVID-19 were included in this study. Levels of plasma SARS-CoV-2 viremia at the time of presentation predicted adverse disease outcomes, with an adjusted odds ratio (aOR) of 10.6 (95% confidence interval [CI] 4.4, 25.5, P<0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and aOR of 3.9 (95%CI 1.5, 10.1, P=0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, endothelium/vasculature and alterations in coagulation pathways.

Conclusions

These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.
Identification of mutations associated with Macozinone-resistant inMycobacterium Tuberculosis
Authors: Chen Xi , Li Yuanyuan , Wang Bin , Lu Yu
Published: February 2021

AbSTRACT

Macozinone is identified as a drug candidate and is currently under clinical development for the treatment of tuberculosis, but the mutations conferring resistance to Macozinone remain inadequately characterized. Herein, we investigated the Macozinone -resistance -associated mutations through selecting resistant isolatesin vitro. Macozinone-resistant isolates were obtained through inductionin vitro. The level of Macozinone -resistant strains was confirmed by MABA test. PCR sequencing analysis was carried out on dprE1 gene. Whole Genome Sequencing was performed to identify mutations associated with Macozinone -resistance. The totals of isolates obtained at Macozinone concentrations of 6.4ng/ml, 25.6ng/ml, 50ng/ml and 100ng/ml were 49, 20, 20 and 4 respectively. Among the 49 strains obtained by 6.4ng/ml Macozinone only one strain had C387S mutation in dprE1. C387S is only occurred in high-level resistant isolates (MIC > 500ng/ml). Meanwhile high-level resistance to Macozinone can occur in strains induced at 6.4ng/ml and the frequency of occurrence is low (1/49, 2.04%). The MIC90of other strains except the strains carrying C387S mutation is at the same level (11.5ng/ml > MIC90> 2ng/ml). The G61A or G248A mutations in dprE1 was discovered for the first time. Other gene mutations (rv0678, rrs, mbtF, rv2956,et al) were found in low-level resistant strains.

Conclusions

High-level resistant isolates can be produced at low concentration of Macozinone. C387S mutation in dprE1 is directly related to high-level resistance. There may be new mechanisms involved in Macozinone-resistance independent of dprE1 mutations.
Aryl Hydrocarbon Receptor Blocks Aging-Induced Senescence in the Liver and Fibroblast Cells
Authors: Nacarino-Palma Ana , Rico-Leo Eva M. , Campisi Judith , Ramanathan Arvind , Merino Jaime M. , Fernández-Salguero Pedro M.
Published: February 2021

Aging induces progressive organ degeneration and worsening of tissue homeostasis leading to multiple pathologies. Yet, little is known about the mechanisms and molecular intermediates involved. Here, we report that aged aryl hydrocarbon receptor-null mice (AhR-/-) had exacerbated senescence and larger numbers of liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16Ink4aand p21Cip1and genes of the senescence-associated secretory phenotype (SASP) TNF and IL1 were overexpressed in agedAhR-/-livers. AhR binding to the promoter of those genes, as shown by chromatin immunoprecipitation, likely had a repressive effect maintaining their physiological levels inAhR+/+livers. Furthermore, factors secreted by senescent cells MCP-2, MMP12 and FGF were also produced at higher levels in aged AhR-null livers. Supporting the linkage between senescence and stemness, liver progenitor cells were more abundant inAhR-/-mice, which could probably contribute to their increased hepatocarcinoma burden. These roles of AhR are not liver-specific since adult and embryonic AhR-null fibroblasts acquired cellular senescence upon culturing with overexpression of SA-β-Gal, p16Ink4aand p21Cip1. Notably, depletion of senescent cells with the senolytic agent navitoclax restored basal expression of senescent markers inAhR-/-fibroblasts. Oppositely, senescence promoter palbociclib induced an AhR-null like phenotype inAhR+/+fibroblasts. Moreover, doxycycline-induced senescence reduced AhR levels while depletion of p16Ink4a-expressing senescent cells restored basal AhR levels in mouse lungs. Thus, AhR is needed to restrict age-induced senescence, and such activity seems to correlate with a more differentiated phenotype and with increased resistance to liver tumorigenesis.
Positional and Compositional Analysis of Saturated, Monounsaturated and Polyunsaturated Fatty acids in Human Adipose Tissue Triglyceride by13C NMR
Authors: Torres Alejandra N. , Tavares Ludgero , Pereira Maria J. , Eriksson Jan W. , Jones John G.
Published: February 2021

Objectives and new findings, ends with short conclusion, no references

The synthesis and turnover of triglyceride in adipose tissue involves enzymes with preferences for specific fatty acid classes and/or regioselectivity with regard to the fatty acid position within the glycerol moiety. The focus of the present study was to characterize both the fatty acid composition and their positional distribution in triglycerides of biopsied human subcutaneous adipose tissue using13C NMR spectroscopy. The triglyceridesn2 position was significantly more enriched with monounsaturated fatty acids compared to thesn1,3 sites, while saturated fatty acids abundance was significantly lower in thesn2 position compared to that ofsn1,3. Furthermore, the analysis revealed significant positive correlations between the total fraction of palmitoleic acid with both BMI and HOMA-IR scores. Additionally, we established that13C NMR chemical shifts for ω −3 signals, centered at 31.9 ppm, provided superior resolution of the most abundant FA species, including palmitoleate, compared to the ω −2 signals that were used previously.13C NMR spectroscopy reveals for the first time a highly non-homogenous distribution of FA in the glycerol sites of human adipose tissue triglyceride and that these distributions are correlated with different phenotypes such as BMI and insulin resistance.
Withaferin A promotes white adipose browning and prevents obesity through sympathetic nerve-activated Prdm16-FATP1 axis
Authors: Guo Bingbing , Liu Jiarui , Wang Bingwei , Zhang Chenyu , Su Zhijie , Zhao Miao , Zheng Ruimao
Published: February 2021

The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. The Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. Here, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure (EE), decreased respiratory exchange ratio (RER), and prevented high-fat diet (HFD)-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly up-regulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA, and restored the weight gain and the adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis; and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.
Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
Authors: Meyer James O. , Dolphin Annette C.
Published: February 2021

N-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in part, to increased CaVexpression at the plasma membrane. In the present study we provide evidence that α2δ-1, like α2δ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that α2δ-1 increases plasma membrane CaV2.2 expression by increasing the rate and extent of net forward CaV2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α2δ-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, α2δ-3 does not enhance rapid forward CaV2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell CaV2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α2δ-1, but not α2δ-3. Taken together these data suggest that α2δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2.

Summary statement

The calcium channel auxiliary subunit α2δ-1 but not α2δ-3 participates in Rab11a-dependent recycling, which in turn influences the localisation and function of CaV2.2.
Underlying environmental factors and geomagnetic fields linked to 45 pilot whalesGlobicephala macrorhynchusstranding in Modung white beach, Indonesian coast on 19thFebruary 2021
Authors: Wibowo Andri
Published: February 2021

The reason whale and dolphin stranding is not fully understood and it is not linked to a standalone variable. Theories assume intertwined factors including sickness, underwater noise, navigational error, geographical features, the presence of predators, poisoning from pollution or algal blooms, geomagnetic field, and extreme weather are responsible to whale stranding. On 19thFebruary 2021, a pod consists of 45 pilot whalesGlobicephala macrorhynchuswas stranded in a remote 7050 m2Modung white beach of Indonesian coast. This paper aims to assess the environmental factors that may be can explain and link to this stranding cases. Those factors include bathymetry, plankton cell density measured using MODIS, water sediment load measured using Sentinel 2 Bands 4,3,1, vessel traffic, precipitation (inch) and thunder (CAPE index J/kg), water salinity and temperature, and geomagnetic field (nT). The results show the water near stranding sites were shallow, has sediment load, high plankton density, warmer, receiving torrential rain prior stranding, having weak geomagnetic field and high total magnetic field change/year. The combination of those environmental covariates may influence the behavior, navigation, and echolocation of the said stranded pilot whale.
Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival
Authors: Vashisth Manasvita , Cho Sangkyun , Irianto Jerome , Xia Yuntao , Wang Mai , Hayes Brandon , Jafarpour Farshid , Wells Rebecca , Liu Andrea , Discher Dennis E.
Published: February 2021

Spatiotemporal relationships between genes expressed in tissues likely reflect physicochemical principles that range from stoichiometric interactions to co-organized fractals with characteristic scaling. For key structural factors within the nucleus and extracellular matrix (ECM), gene-gene power laws are found to be characteristic across several tumor types in The Cancer Genome Atlas (TCGA) and across single-cell RNA-seq data. The nuclear filamentLMNB1scales with many tumor-elevated proliferation genes that predict poor survival in liver cancer, and cell line experiments showLMNB1regulates cancer cell cycle. Also high in the liver, lung, and breast tumors studied here are the main fibrosis-associated collagens,COL1A1andCOL1A2, that scale stoichiometrically with each other and super-stoichiometrically with a pan-cancer fibrosis gene set. However, high fibrosis predicts prolonged survival of patients undergoing therapy and does not correlate withLMNB1. Single-cell RNA-seq data also reveal scaling consistent with the pan-cancer power laws obtained from bulk tissue, allowing new power law relations to be predicted. Lastly, although noisy data frustrate weak scaling, concepts such as stoichiometric scaling highlight a simple, internal consistency check to qualify expression data.

Classification

Applied Physical Sciences (major) and Cell Biology (minor)

Significance Statement

Non-linear scaling analyses pervade polymer physics and chemistry and conceivably provide new insight into polymeric assemblies of genes expressed in tissues as well as co-regulated gene sets. Fractal scaling and stoichiometric scaling are among the gene-gene power law results identified here for key structural polymers in nuclei or extracellular matrix in human cancer data. Among nuclear envelope factors that might scale with DNA mass, only one nuclear filament scales with tumor proliferation and predicts poor survival in some cancer types. Collagen-1 scales with fibrosis and also tends to increase in multiple tumor types, but patients in therapy surprisingly survive longest with the highest levels of fibrosis, consistent with a therapeutic response.
Aerobic growth physiology ofSaccharomyces cerevisiaeon sucrose is strain-dependent
Authors: Rodrigues Carla Inês Soares , Wahl Aljoscha , Gombert Andreas K.
Published: February 2021

Present knowledge on the quantitative aerobic physiology of the yeastSaccharomyces cerevisiaeduring growth on sucrose as sole carbon and energy source is limited to either adapted cells or to the model laboratory strain CEN.PK113-7D. To broaden our understanding of this matter and open novel opportunities for sucrose-based biotechnological processes, we characterized three strains, with distinct backgrounds, during aerobic batch bioreactor cultivations. Our results reveal that sucrose metabolism inS. cerevisiaeis a strain-specific trait. Each strain displayed a distinct extracellular hexose concentration and invertase activity profiles. Especially, the inferior maximum specific growth rate (0.21 h−1) of the CEN.PK113-7D strain, with respect to that of strains UFMG-CM-Y259 (0.37 h−1) and JP1 (0.32 h−1), could be associated to its low invertase activity (0.04 to 0.09 U mgDM−1). Moreover, comparative experiments with glucose or fructose alone, or in combination, suggest mixed mechanisms of sucrose utilization by the industrial strain JP1, and points out the remarkable ability of the wild isolate UFMG-CM-259 to grow faster on sucrose than on glucose in a well-controlled cultivation system. This work hints to a series of metabolic traits that can be exploited to increase sucrose catabolic rates and bioprocess efficiency.

Abstract Figure
A triple threat: theParastagonospora nodorumSnTox267 effector exploits three distinct host genetic factors to cause disease in wheat
Authors: Richards Jonathan K. , Kariyawasam Gayan , Seneviratne Sudeshi , Wyatt Nathan A. , Xu Steven S. , Liu Zhaohui , Faris Justin D. , Friesen Timothy L.
Published: February 2021

Parastagonospora nodorumis a fungal pathogen of wheat. As a necrotrophic specialist, it deploys a suite of effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Nine effector – host susceptibility gene interactions have been reported in this pathosystem, presumed to be governed by unique pathogen effectors. This study presents the characterization of the SnTox267 necrotrophic effector that hijacks two separate host pathways to cause necrosis. An association mapping approach identifiedSnTox267and the generation of gene-disrupted mutants and gain-of-function transformants confirmed its role inSnn2-,Snn6-, andSnn7-mediated necrosis. TheSnn2andSnn6host susceptibility genes were complementary, and together they functioned cooperatively to elicit SnTox267-induced necrosis in the same light-dependent PCD pathway. Additionally, we showed that SnTox267 targetedSnn7, resulting in light-independent necrosis. Therefore, SnTox267 co-opts two distinct host pathways to elicit PCD.SnTox267sequence comparison among a natural population of 197 North AmericanP. nodorumisolates revealed 20 protein isoforms conferring variable levels of virulence, indicating continuing selection pressure on this gene. Protein isoform prevalence among discrete populations indicated that SnTox267 has likely evolved in response to local selection pressures and has diversified more rapidly in the Upper Midwest. Deletion ofSnTox267resulted in the upregulation of the unrelated effector genesSnToxA,SnTox1, andSnTox3, providing evidence for a complex genetic compensation mechanism. These results illustrate a novel evolutionary path by which a necrotrophic fungal pathogen uses a single proteinaceous effector to hijack two host pathways to induce cell death.
Graphene oxide/silver nanoparticle ink formulations rapidly inhibit influenza A virus and OC43 coronavirus infectionin vitro
Authors: Crane Meredith J. , Devine Stephen , Jamieson Amanda M.
Published: February 2021

Respiratory tract infections present a significant risk to the human population, both through seasonal circulation and novel introductions with pandemic potential. There is a strong need for antiviral compounds with broad antimicrobial activity that can be coated onto filtration systems and personal protective equipment to augment their ability to remove infectious particles from the environment. Graphene oxide and silver nanoparticles are both materials with documented antimicrobial properties. Here, we tested thein vitroantiviral properties of several graphene oxide–silver nanoparticle composite materials, which were prepared through three different methods: reduction with silver salt, direct addition of silver nanospheres, and direct addition of silver nanospheres to thiolized graphene. These materials were tested over short time scales for their antiviral activity against two enveloped RNA viruses, influenza A virus and OC43 coronavirus, by performing viral plaque assays after exposure of the viruses to each material. It was found that the graphene oxide – silver nanoparticle materials generated by direct addition of the silver nanospheres were able to completely inhibit plaque formation by both viruses within one minute of exposure. Materials generated by the other two methods had varying levels of efficacy against influenza A virus. These studies indicate that graphene oxide-silver nanoparticle composite materials can rapidly neutralize RNA viruses and demonstrate their potential for use in a wide range of applications.

Abstract Figure
High-resolution, genome-wide mapping of positive supercoiling in chromosomes
Authors: Guo Monica S. , Kawamura Ryo , Littlehale Megan , Marko John F. , Laub Michael T.
Published: February 2021

Supercoiling impacts DNA replication, transcription, protein binding to DNA, and the three-dimensional organization of chromosomes. However, there are currently no methods to directly interrogate or map positive supercoils, so their distribution in genomes remains unknown. Here, we describe a method, GapR-seq, based on the chromatin immunoprecipitation of GapR, a bacterial protein that preferentially recognizes overtwisted DNA, for generating high-resolution maps of positive supercoiling. Applying this method toE. coliandS. cerevisiae, we find that positive supercoiling is widespread, associated with transcription, and particularly enriched between convergently-oriented genes, consistent with the “twin-domain” model of supercoiling. In yeast, we also find positive supercoils associated with centromeres, cohesin binding sites, autonomously replicating sites, and the borders of R-loops (DNA-RNA hybrids). Our results suggest that GapR-seq is a powerful approach, likely applicable in any organism, to investigate aspects of chromosome structure and organization not accessible by Hi-C or other existing methods.
Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia
Authors: Badran Mohammad , Abuyassin Bisher , Ayas Najib , Sin Don D. , Laher Ismail
Published: February 2021

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). There is increased biomarkers of aging, such as telomere shortening, in patients with OSA. We assessed telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH using a PCR protocol, and demonstrate significant telomere shortening in both tissues. This data indicates that IH, a hallmark of OSA, can accelerate vascular and renal aging that may contribute to OSA-induced CVD and CKD