bluuebunny/crossref_metadata_2025 huggingface dataset:
Murine Typhus Outbreak Presenting as Multisystem Inflammatory Syndrome in Children During SARS-CoV-2 Pandemic
Authors: Alamarat Zain , Pérez Norma , Wootton Susan , Kamdar Ankur , Smith Keely , Heresi Gloria P. , Chang Michael
Published: October 2020

Multisystem inflammatory syndrome in children is a severe illness associated with the SARS-CoV-2 pandemic that possesses features overlapping with other pediatric diseases causing systemic inflammation. Significant diagnostic and treatment uncertainty remain, and clinicians should maintain a broad differential when evaluating patients for multisystem inflammatory syndrome in children, as antibiotic-susceptible infections such as murine typhus may present similarly.
Comparison of Rapid Antidepressant and Antisuicidal Effects of Intramuscular Ketamine, Oral Ketamine, and Electroconvulsive Therapy in Patients With Major Depressive Disorder
Authors: Kheirabadi Dorna , Kheirabadi Gholam Reza , Mirlohi Zahra , Tarrahi Mohammad Javad , Norbaksh Amir
Published: October 2020

Purpose/Background

This study was devised to compare the antidepressant and antisuicidal effects of oral and intramuscular (IM) ketamine versus electroconvulsive therapy (ECT).

Methods/Procedures

In our pilot study, 45 patients with major depressive disorder (based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria) in the age range of 18 to 70 years who were determined suitable candidates for ECT got randomly divided into 3 equal groups. Each group received one of these treatment modalities: 0.5 mg/kg of IM ketamine; 1 mg/kg of oral ketamine; and ECT in 6 to 9 sessions during 3 weeks. Depression and suicidal ideation scores were recorded using the Hamilton Depression Rating Scale and the Beck Scale for Suicidal Ideation, respectively, at baseline, 24 hours, 1 week, 2 weeks, and 3 weeks within the intervention. The measurements were repeated 1 week and 1 month after the end of the intervention as well. Vital signs and adverse effects were noted. Finally, satisfaction levels of patients for each method were recorded and compared between groups.

Findings/Results

The Hamilton Depression Rating Scale and the Beck Scale for Suicidal Ideation scores significantly improved in all groups compared with baseline with no significant differences between the 3 groups. The adverse effects for ketamine-consuming groups such as dissociative symptoms were brief and transient, whereas memory loss for the ECT group remained up to 1 month in some patients. Ketamine-receiving groups preferred it more than ECT.

Implications/Conclusions

Oral and IM ketamine probably have equal antidepressant in addition to more antisuicidal effects compared with ECT but had less cognitive adverse effects and higher preference by patients. Thereby, ketamine can be an alternative method in the treatment of patients with severe and/or suicidal MDD.
Gender Differences in Mortality After Left Ventricular Assist Device Implant: A Causal Mediation Analysis Approach
Authors: Nayak Aditi , Hu Yingtian , Ko Yi-An , Mehta Anurag , Liu Chang , Pennington John , Xie Rongbing , Cowger Jennifer , Kirklin James K. , Kormos Robert L. , Simon Marc A. , Morris Alanna A.
Published: October 2020

We used the International Society for Heart and Lung Transplantation (ISHLT) Registry for Mechanically Assisted Circulatory Support (IMACS) database to examine 1) gender differences in post-left ventricular assist device (LVAD) mortality in the contemporary era and 2) preimplant clinical factors that might mediate any observed differences. Adults who received continuous-flow (CF)-LVAD from January 2013 to September 2017 (n = 9,565, age: 56.2 ± 13.2 years, 21.6% female, 31.1% centrifugal pumps) were analyzed. An inverse probability weighted Cox proportional hazards model was used to estimate association of female gender with all-cause mortality, adjusting for known covariates. Causal mediation analysis was performed to test plausible preimplant mediators mechanistically underlying any association between female gender and mortality. Females had higher mortality after LVAD (adjusted hazard ratio [HR]: 1.36; p < 0.0001), with significant gender × time interaction (p = 0.02). An early period of increased risk was identified, with females experiencing a higher risk of mortality during the first 4 months after implant (adjusted HR: 1.74; p < 0.0001), but not after (adjusted HR: 1.18; p = 0.16). More severe tricuspid regurgitation and smaller left ventricular end-diastolic diameter at baseline mediated ≈21.9% of the increased early hazard of death in females; however, most of the underlying mechanisms remain unexplained. Therefore, females have increased mortality only in the first 4 months after LVAD implantation, partially driven by worsening right ventricular dysfunction and LV-LVAD size mismatch.
Older Patients With Hepatocellular Carcinoma Are Less Knowledgeable About Survivorship Issues
Authors: Winters Adam C. , Viramontes Matthew , Buch Adam , Najarian Lisa , Yum Jung , Yang Liu , Saab Sammy
Published: October 2020

Background and Aims:

As the incidence and survival for hepatocellular carcinoma increase, the number of patients having been treated for liver cancer would be expected to increase as well. Little is known about the experience of the survivors of hepatocellular carcinoma.

Methods:

The authors conducted a 3-tool survey of hepatocellular carcinoma survivors at a large, academic, and tertiary referral medical center to assess potential areas of disparities in the survivorship experience. The instruments aimed to assess knowledge of survivorship issues (Perceived Efficacy in Patient‐Physician Interactions Questionnaire-1), preparedness for the survivorship experience (Perceived Efficacy in Patient‐Physician Interactions Questionnaire-2), and self-efficacy in procuring medical information while navigating the patient-provider relationship (Perceived Efficacy in Patient‐Physician Interactions Questionnaire). The authors compared mean test scores for each instrument, with higher scores indicating a more positive response, by patient characteristics and used s linear regression model to examine associations between sociodemographics and survey scores.

Results:

In total, 110 patients took at least 1 survey. In the multiple linear regression model, the authors found that for every increase in patient age by 10 years, knowledge of survivorship issues decreased by a total score of 1.3 (P=0.02). In this model, the authors found no significant differences between male and female respondents, English and non-English speakers, and liver transplant recipients and nonliver transplant recipients. Survivors who had completed a 4-year college degree had significantly higher knowledge of survivorship issues than those who did not use χ2 testing, but this finding did not maintain significance in the multiple linear regression model.

Conclusions:

In a population of 110 ethnically diverse hepatocellular carcinoma survivors, the authors found older patients had gaps in knowledge of survivorship issues. Particular attention should be paid to older populations during liver cancer treatment.
Involvement of MTHFR rs1801133 in the Susceptibility of Acute Lymphoblastic Leukemia: A Preliminary Study
Authors: Frikha Rim , Turki Fatma , Frikha Fakher , Elloumi Moez , Rebai Tarek
Published: October 2020

Background:

Acute lymphoblastic leukemia (ALL), a common blood cancer, is characterized by the interaction between genetic and environmental factors. Several variants of the Methylenetetrahydrofolate reductase (MTHFR), mainly the C677T (rs1801133), may affect susceptibility to ALL.

Aim of the Study:

The authors conducted this case-control study to evaluate the relationship between this variant of the MTHFR gene and the risk of ALL.

Materials and Methods:

Forty-one patients with ALL and 35 non-ALL controls recruited in this study were genotyped utilizing polymerase chain reaction-restriction fragment length polymorphism methodology.

Results:

The MTHFR 677CT genotype was significantly more frequently found in patients with ALL having a 2-fold increase in risk (P <0.01).

Conclusion:

Our results suggest that rs1801133 of MTHFR is a predictive risk marker to ALL in Tunisian ALL.
Intimate Partner Violence Among Chinese Transwomen: Associations With Sexual Risk Behaviors and HIV Testing
Authors: Wang Liying , Barile John P. , Simoni Jane M. , Harris Rachel , Yue Qing , Fu Jie , Zheng Huang , Ning Zhen , Wong Frank Y.
Published: October 2020

Background

Intimate partner violence (IPV) is an emerging risk factor for HIV infection. Given the high vulnerability of and limited research on transwomen in China, we described IPV, sexual risk behaviors, HIV, and sexually transmitted infection (STIs) testing rates and results, and investigated the pathways that link IPV to HIV infection among this population.

Methods

We conducted a cross-sectional survey and collected blood samples for HIV and syphilis testing among transwomen in Shanghai, China (n = 199). With logistic regression, we examined sexual risk behaviors and HIV/STI testing history among participants with and without IPV experience.

Results

More than half of the respondents reported IPV (57.3%), and the prevalence of unprotected sex ranged from 51.9% (with sex workers) to 87.8% (oral sex); 85.9% had ever tested for HIV and 49.3% for other STIs. Self-reported positivity results were as follows: HIV (2.3%), herpes simplex virus type 2 (8.3%), gonorrhea (18.8%), and syphilis (17.8%). Laboratory-confirmed positivity values were 5.0% for HIV and 6.5% for syphilis. Respondents with a history of IPV were significantly less likely to report HIV testing in the past 12 months (adjusted odds ratio, 0.20; 95% confidence interval, 0.10–0.38).

Conclusions

Transwomen self-reported a high prevalence of IPV, which was related to a lower probability of HIV testing. The prevalence of HIV and other STIs was lower than reported in previous studies of Chinese transwomen, whereas the HIV/STI testing rates were higher. Findings suggest transwomen in China are at risk for IPV and need enhanced HIV prevention services to promote HIV testing in an IPV setting.
The Effect of Pediatric Early Warning Score Use on Emergency Response Calls After Admission From the Pediatric Emergency Department
Authors: Frascogna Melissa Nan , Merkle Eric , Dowdy Kristin , Seals Samantha
Published: October 2020

Objectives

Pediatric Early Warning Scores (PEWS) are an easy-to-use diagnostic tool for patient evaluation. The goal of this study was to determine if using PEWS in our pediatric emergency department (PED) at the time of admission to the hospital was associated with a decrease in the number of emergency response calls within 6 hours of admission.

Methods

A retrospective chart review of 6 months before (May 2013–October 2013) and after (December 2013–May 2014) initiation of PEWS upon inpatient admission from our urban, tertiary care PED was conducted to determine the number of patients who had emergency response calls within 6 hours of admission.

Results

The percentage of patients admitted from the PED who required an emergency response call within 6 hours of admission dropped from 1.77% in the 6 months before assigning PEWS to 0.79% in the 6 months after, a 55% reduction (P = 0.0070).

Conclusions

Assigning PEWS to patients being admitted to our hospital from the PED was associated with a reduced number of emergency response calls in the period immediately after admission.
Treatment of extended-spectrum β-lactamases infections: what is the current role of new β-lactams/β-lactamase inhibitors?
Authors: Bassetti Matteo , Giacobbe Daniele R. , Robba Chiara , Pelosi Paolo , Vena Antonio
Published: October 2020

Purpose of review

The widespread diffusion of extended-spectrum β-lactamases (ESBLs)-producing Enterobacteriales currently represents a major threat for public health worldwide. Carbapenems are currently considered the first-line choice for serious ESBL infections. However, the dramatic global increase in ESBL prevalence has led to a significant overuse of carbapenems that has promoted the selection and spread of carbapenemases, which might further prejudicated our ability to treat infections due to multidrug-resistant pathogens. Therefore, strategies to limit the use of carbapenems should be implemented.

Recent findings

Although piperacillin–tazobactam should no longer be considered an alternative to carbapenems for definitive treatment of bloodstream infections due to ESBL-producing strains, it might still represent an alternative for step-down therapy or for low-to-moderate severity infection originating from urinary or biliary sources and when piperacillin–tazobactam minimum inhibitory concentration of 4 mg/l or less. Ceftazidime–avibactam and ceftolozane–tazobactam are both carbapenem sparing agents that appear interesting alternatives for treatment of serious ESBL infections. New β-lactams/β-lactamase inhibitors (BL/BLI), including cefepime–enmetazobactam, ceftaroline fosamil–avibactam, aztreonam–avibactam and cefepime–zidebactam, are also promising agents for treatment of ESBL infections, but further clinical data are needed to establish their efficacy relative to carbapenems. The role of carbapenems/β-lactamase inhibitors remain to be clarified.

New BL/BLI have distinctive specificities and limitations that require further investigations. Future randomized clinical trials are required to define the best strategy for their administering for ESBL infections.
A Comparison of Outcomes After Palatoplasty in Patients With Non-Syndromic Pierre Robin Sequence Versus Patients With Non-Syndromic Isolated Cleft Palate
Authors: Taku Maeda , Yamamoto Yuhei , Oyama Akihiko , Sasaki Satoru , Hayashi Toshihiko , Murao Naoki , Osawa Masayuki , Funayama Emi
Published: October 2020

The purpose of this retrospective study was to compare outcomes of cleft palate repair in patients with non-syndromic Pierre Robin sequence (NS-PRS) versus those with non-syndromic isolated cleft palate (NS-ICP). Pierre Robin sequence (PRS) was defined as a diagnosis of the triad of microretrognathia, glossoptosis, and cleft palate, and the severity of PRS was assessed based on the presence of respiratory and feeding problems. All patients underwent palatoplasty between January 2000 and December 2011. The authors examined age at palatoplasty, type of cleft palate, fistula rate, velopharyngeal (VP) function, nasal emission, hypernasality, and need for secondary speech surgery, in addition to PRS severity in the NS-PRS patients. A total of 15 NS-PRS patients and 40 NS-ICP patients were reviewed. The incidence of VP dysfunction, nasal emission, hypernasality, and secondary speech surgery was not significantly different between the NS-PRS patients and NS-ICP patients. Age at palatoplasty was significantly different between the 2 groups (P = 0.012) but type of CP was not (P = 1.00). Only 2 NS-PRS patients were classified as category III (severe), and all of the NS-PRS patients who had VP insufficiency were classified as PRS severity category I (not severe). The findings of this study indicate that NS-PRS patients may not have worse outcomes than NS-ICP patients.
Muscle-Derived Mitochondrial Transplantation Reduces Inflammation, Enhances Bacterial Clearance, and Improves Survival in Sepsis
Authors: Zhang Zhanqin , Yan Chaoying , Miao Jiwen , Pu Kairui , Ma Hongli , Wang Qiang
Published: October 2020

Background:

Mitochondrial transplantation is a promising strategy for the treatment of several diseases. However, the effects of mitochondrial transplantation on the outcome of polymicrobial sepsis remain unclear.

Methods:

The distribution of transplanted mitochondria in cecal ligation and puncture (CLP)-operated mice was detected at 2 and 12 h after intravenous injection in the tail (n = 3). Then, the effects of mitochondrial transplantation on bacterial clearance (n = 7), systemic inflammation (n = 10), organ injury (n = 8), and mortality (n = 19) during CLP-induced sepsis were explored. Microarray analysis (n = 3) was used to testify the molecular changes associated with decreased systemic inflammation and multiorgan dysfunction in sepsis.

Results:

The extraneous mitochondria were distributed in the lung, liver, kidney, and brain of CLP-operated mice at 2 and 12 h after intravenous injection in the tail. Mitochondrial transplantation increased the survival rate of septic mice, which was associated with decreased bacterial burden, systemic inflammation, and organ injury. Spleen samples were utilized for microarray analysis. Pathway analysis revealed that in polymicrobial sepsis, gene expression was significantly changed in processes related to inflammatory response, complement and coagulation cascades, and rejection reaction.

Conclusions:

These data displayed that mitochondrial replenishment reduces systemic inflammation and organ injury, enhances bacterial clearance, and improves the survival rate in sepsis. Thus, extraneous mitochondrial replenishment may be an effective adjunctive treatment to reduce sepsis-related mortality.
Survival Benefit Associated With the Use of Extracorporeal Life Support for Neonates With Congenital Diaphragmatic Hernia
Authors: Jancelewicz Tim , Langham Max R. , Brindle Mary E. , Stiles Zachary E. , Lally Pamela A. , Dong Lei , Wan Jim Y. , Guner Yigit S. , Harting Matthew T.
Published: October 2020

Objective:

To measure the survival among comparable neonates with CDH supported with and without ECLS.

Summary of Background Data:

Despite widespread use in the management of newborns with CDH, ECLS has not been consistently associated with improved survival.

Methods:

A retrospective cohort study was performed using ECLS-eligible CDH Study Group registry patients born between 2007 and 2019. The primary outcome was in-hospital mortality. Neonates who did and did not receive ECLS were matched based on variables affecting risk for the primary outcome. Iterative propensity score-matched, survival (Cox regression and Kaplan-Meier), and center effects analyses were performed to examine the association of ECLS use and mortality.

Results:

Of 5855 ECLS-eligible CDH patients, 1701 (29.1%) received ECLS. “High-risk” patients were best defined as those with a lowest achievable first-day arterial partial pressure of CO2 of ≥60 mm Hg. After propensity score matching, mortality was higher with ECLS (47.8% vs 21.8%, odds ratio 3.3, 95% confidence interval 2.7–4.0, hazard ratio 2.3, P < 0.0001). For the subgroup of high-risk patients, there was lower mortality observed with ECLS (64.2% vs 84.4%, odds ratio 0.33, 95% confidence interval 0.17–0.65, hazard ratio 0.33, P = 0.001). This survival advantage was persistent using multiple matching approaches. However, this ECLS survival advantage was found to occur primarily at high CDH volume centers that offer frequent ECLS for the high-risk subgroup.

Conclusions:

Use of ECLS is associated with excess mortality for low- and intermediate-risk neonates with CDH. It is associated with a significant survival advantage among high-risk infants, and this advantage is strongly influenced by center CDH volume and ECLS experience.
Rapid, accurate, precise and reproducible ligand–protein binding free energy prediction
Authors: Wan Shunzhou , Bhati Agastya P. , Zasada Stefan J. , Coveney Peter V.
Published: October 2020

A central quantity of interest in molecular biology and medicine is the free energy of binding of a molecule to a target biomacromolecule. Until recently, the accurate prediction of binding affinity had been widely regarded as out of reach of theoretical methods owing to the lack of reproducibility of the available methods, not to mention their complexity, computational cost and time-consuming procedures. The lack of reproducibility stems primarily from the chaotic nature of classical molecular dynamics (MD) and the associated extreme sensitivity of trajectories to their initial conditions. Here, we review computational approaches for both relative and absolute binding free energy calculations, and illustrate their application to a diverse set of ligands bound to a range of proteins with immediate relevance in a number of medical domains. We focus on ensemble-based methods which are essential in order to compute statistically robust results, including two we have recently developed, namely thermodynamic integration with enhanced sampling and enhanced sampling of MD with an approximation of continuum solvent. Together, these form a set of rapid, accurate, precise and reproducible free energy methods. They can be used in real-world problems such as hit-to-lead and lead optimization stages in drug discovery, and in personalized medicine. These applications show that individual binding affinities equipped with uncertainty quantification may be computed in a few hours on a massive scale given access to suitable high-end computing resources and workflow automation. A high level of accuracy can be achieved using these approaches.
Micro-fusion inhibition tests: quantifying antibody neutralization of virus-mediated cell–cell fusion
Authors: Thakur Nazia , Conceicao Carina , Isaacs Ariel , Human Stacey , Modhiran Naphak , McLean Rebecca K. , Pedrera Miriam , Tan Tiong Kit , Rijal Pramila , Townsend Alain , Taylor Geraldine , Young Paul R. , Watterson Daniel , Chappell Keith J. , Graham Simon P. , Bailey Dalan
Published: October 2020

Although enveloped viruses canonically mediate particle entry through virus–cell fusion, certain viruses can spread by cell–cell fusion, brought about by receptor engagement and triggering of membrane-bound, viral-encoded fusion proteins on the surface of cells. The formation of pathogenic syncytia or multinucleated cells is seen in vivo, but their contribution to viral pathogenesis is poorly understood. For the negative-strand paramyxoviruses respiratory syncytial virus (RSV) and Nipah virus (NiV), cell–cell spread is highly efficient because their oligomeric fusion protein complexes are active at neutral pH. The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has also been reported to induce syncytia formation in infected cells, with the spike protein initiating cell–cell fusion. Whilst it is well established that fusion protein-specific antibodies can block particle attachment and/or entry into the cell (canonical virus neutralization), their capacity to inhibit cell–cell fusion and the consequences of this neutralization for the control of infection are not well characterized, in part because of the lack of specific tools to assay and quantify this activity. Using an adapted bimolecular fluorescence complementation assay, based on a split GFP–Renilla luciferase reporter, we have established a micro-fusion inhibition test (mFIT) that allows the identification and quantification of these neutralizing antibodies. This assay has been optimized for high-throughput use and its applicability has been demonstrated by screening monoclonal antibody (mAb)-mediated inhibition of RSV and NiV fusion and, separately, the development of fusion-inhibitory antibodies following NiV vaccine immunization in pigs. In light of the recent emergence of coronavirus disease 2019 (COVID-19), a similar assay was developed for SARS-CoV-2 and used to screen mAbs and convalescent patient plasma for fusion-inhibitory antibodies. Using mFITs to assess antibody responses following natural infection or vaccination is favourable, as this assay can be performed entirely at low biocontainment, without the need for live virus. In addition, the repertoire of antibodies that inhibit cell–cell fusion may be different to those that inhibit particle entry, shedding light on the mechanisms underpinning antibody-mediated neutralization of viral spread.
Evaluation of the antiviral effect of chlorine dioxide (ClO2) using a vertebrate model inoculated with avian coronavirus
Authors: Zambrano-Estrada Xóchitl , Domínguez-Sánchez Carlos , Banuet-Martínez Marina , Guerrero de la Rosa Fabiola , García-Gasca Teresa , Prieto-Valiente Luis , Acevedo-Whitehouse Karina
Published: October 2020

Background

The need for safe and effective antiviral treatments is pressing given the number of viral infections that are prevalent in animal and human populations, often causing devastating economic losses and mortality. Informal accounts of anecdotal use of chlorine dioxide (ClO2), a well-known disinfectant and antiseptic, in COVID-19 patients has raised concern about potential toxicity, but also raises the question that ClO2might elicit antiviral effects, a possibility that has never been examinedin vivoin any animal model. Here, we challenged the hypothesis that ClO2decreases the viral load and virus-induced mortality in a vertebrate model. For this, we determined viral load, virus-induced lesions and mortality in 10-day old chick embryos inoculated with 104mean EID50/mL of attenuated Massachusetts and Connecticut avian coronavirus (IBV) strains.

Results

The ClO2treatment had a marked impact on IBV infection. Namely, viral titres were 2.4-fold lower and mortality was reduced by half in infected embryos that were treated with ClO2. Infection led to developmental abnormalities regardless of treatment. Lesions typical of IBV infections were observed in all inoculated embryos, but severity tended to be significantly lower in ClO2-treated embryos. We found no gross or microscopic evidence of toxicity caused by ClO2at the doses used herein.

Conclusions

Our study shows that ClO2could be a safe and viable way of treating and mitigating the effects of avian coronavirus infections, and raises the possibility that similar effects could be observed in other organisms.

Graphical abstract
In-silico development of a method for the selection of optimal enzymes using L-asparaginase II against Acute Lymphoblastic Leukemia as an example
Authors: Baral Adesh , Gorkhali Ritesh , Basnet Amit , Koirala Shubham , Bhattarai Hitesh K.
Published: October 2020

L-Asparaginase II (asnB), a periplasmic protein, commercially extracted fromE. coliandErwinia, is often used to treat Acute Lymphoblastic Leukemia. L-Asparaginase is an enzyme that converts L-asparagine to aspartic acid and ammonia. Cancer cells are dependent on asparagine from other sources for growth and when these cells are deprived of asparagine by the action of the enzyme the cancer cells selectively die. Questions remain as to whether asnB fromE. coliandErwiniais the best asparaginase as they have many side-effects. asnB with the lowest Michaelis constant (Km) (most potent), and with the lowest immunogenicity is considered the most optimal enzyme. In this paper asnB sequence ofE. coliwas used to search for homologous proteins in different bacterial and archaeal phyla and a maximum likelihood phylogenetic tree was constructed. The sequences that are most distant fromE. coliandErwiniawere considered best candidates in terms of immunogenicity and were chosen for further processing. The structures of these proteins were built by homology modeling and asparagine was docked with these proteins to calculate the binding energy. asnBs fromStreptomyces griseus,Streptomyces venezuelaeandStreptomyces collinuswere found to have the highest binding energy i.e. −5.3 kcal/mol, −5.2 kcal/mol, and −5.3 kcal/mol respectively (Higher than theE.coliandErwiniaasnBs) and were predicted to have the lowest Kms as we found that there is an inverse relationship between binding energy and Km. Besides predicting the most optimal asparaginase, this technique can also be used to predict the most optimal enzymes where the substrate is known and the structure of one of the homologs is solved.
Scale-invariant time registration of 24-hour accelerometric rest-activity profiles and its application to human chronotypes
Authors: McDonnell Erin I. , Zipunnikov Vadim , Schrack Jennifer A. , Goldsmith Jeff , Wrobel Julia
Published: October 2020

By collecting data continuously over 24 hours, accelerometers and other wearable devices can provide novel insights into circadian rhythms and their relationship to human health. Existing approaches for analyzing diurnal patterns using these data, including the cosinor model and functional principal components analysis, have revealed and quantified population-level diurnal patterns, but considerable subject-level variability remained uncaptured in features such as wake/sleep times and activity intensity. This remaining informative variability could provide a better understanding of chronotypes, or behavioral manifestations of one’s underlying 24-hour rhythm. Curve registration, or alignment, is a technique in functional data analysis that separates “vertical” variability in activity intensity from “horizontal” variability in time-dependent markers like wake and sleep times; this data-driven approach is well-suited to studying chronotypes using accelerometer data. We develop a parametric registration framework for 24-hour accelerometric rest-activity profiles represented as dichotomized into epoch-level states of activity or rest. Specifically, we estimate subject-specific piecewise linear time-warping functions parametrized with a small set of parameters. We apply this method to data from the Baltimore Longitudinal Study of Aging and illustrate how estimated parameters give a more flexible quantification of chronotypes compared to traditional approaches.
Calcium- and Phosphorus-Supplemented Diet Increases Bone Volume After Four Weeks of High-Speed Treadmill Exercise in Adult Mice
Authors: Friedman Michael A. , Kohn David H.
Published: October 2020

Exercise has long-lasting benefits to bone health. Bone mass and the ability to exercise both decline with age, making it ideal to exercise earlier in life and to maximize gains in bone mass. Increasing strain on bone and frequency of loading during exercise can increase bone formation rate and cross-sectional area. Combining a short-term exercise program with a calcium- and phosphorus-supplemented diet increases cortical bone tissue mineral content (TMC) and area more than exercise alone in adult mice. It was hypothesized that combining high-speed running with a mineral-supplemented diet would lead to greater cortical TMC and area than high-speed running on a standard diet and low-speed running on a supplemented diet after 4 weeks. Male, 15-week old mice were assigned to 7 groups – a baseline group, non-exercised groups fed a control or supplemented diet, low-speed exercised groups fed a control or supplemented diet, and high-speed exercised groups fed a control or supplemented diet. Exercise consisted of 4 weeks of daily treadmill running for 20 min/day at 12 m/min or 20 m/min for low- and high-speed exercise, respectively. High-speed exercised mice had significantly lower body weight and lower tibial length after 4 weeks. Cortical TMC and area were significantly higher in high-speed exercised mice on the supplemented diet than high-speed exercised mice on the control diet. Trabecular bone volume (BV) and bone density were significantly higher in all groups on the supplemented diet than groups on the control diet, regardless of exercise. For mice on the control diet, non-exercised mice had significantly lower trabecular BV than baseline, while both speeds of exercise prevented this decline. There were few effects of exercise or diet on mechanical properties. For mice on the control diet, exercise significantly decreased serum PINP/CTX ratio on day 9 which may be preventing exercise from increasing bone mass or strength after only 4 weeks. For non-exercised mice on the supplemented diet, the serum PINP/CTX ratio on day 30 was significantly greater than for exercised mice, suggesting the supplemented diet may also lead to significantly greater bone mass in non-exercised mice if these interventions were extended beyond 4 weeks. Increasing treadmill speed can lower body weight while maintaining cortical and trabecular bone mass. A mineral-supplemented diet increases cortical and trabecular bone mass with high-speed exercise.
Framework for Rapid Comparison of Extracellular Vesicle Isolation Methods
Authors: Ter-Ovanesyan Dmitry , Norman Maia , Lazarovits Roey , Trieu Wendy , Lee Ju-Hyun , Church George M. , Walt David R.
Published: October 2020

Extracellular vesicles (EVs) are released by all cells into biofluids and hold great promise as reservoirs of disease biomarkers. One of the main challenges in studying EVs is a lack of methods to quantify EVs that are sensitive enough and can differentiate EVs from similarly sized lipoproteins and protein aggregates. We demonstrate the use of ultrasensitive, single molecule array (Simoa) assays for the quantification of EVs using three widely expressed transmembrane proteins: the tetraspanins CD9, CD63, and CD81. Using Simoa to measure these three EV markers, as well as albumin to measure protein contamination, we were able to compare the relative efficiency and purity of several commonly used EV isolation methods in plasma and cerebrospinal fluid (CSF): ultracentrifugation, precipitation, and size exclusion chromatography (SEC). We further used these assays, all on one platform, to improve SEC isolation from plasma and CSF. Our results highlight the utility of quantifying EV proteins using Simoa and provide a rapid framework for comparing and improving EV isolation methods from biofluids.
SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions
Authors: Srinivasan S. , Yee N. A. , Wu K. , Zakharian M. , Mahmoodi A. , Royzen M. , Oneto J.M. Mejia
Published: October 2020

While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic antitumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.
Obesity alters Ace2 and Tmprss2 expression in lung, trachea, and esophagus in a sex-dependent manner: Implications for COVID-19
Authors: Sarver Dylan C. , Wong G. William
Published: October 2020

Obesity is a major risk factor for SARS-CoV-2 infection and COVID-19 severity. The underlying basis of this association is likely complex in nature. The host-cell receptor angiotensin converting enzyme 2 (ACE2) and the type II transmembrane serine protease (TMPRSS2) are important for viral cell entry. It is unclear whether obesity alters expression of Ace2 and Tmprss2 in the lower respiratory tract. Here, we show that: 1) Ace2 expression is elevated in the lung and trachea of diet-induced obese male mice and reduced in the esophagus of obese female mice relative to lean controls; 2) Tmprss2 expression is increased in the trachea of obese male mice but reduced in the lung and elevated in the trachea of obese female mice relative to lean controls; 3) in chow-fed lean mice, females have higher expression of Ace2 in the lung and esophagus as well as higher Tmprss2 expression in the lung but lower expression in the trachea compared to males; and 4) in diet-induced obese mice, males have higher expression of Ace2 in the trachea and higher expression of Tmprss2 in the lung compared to females, whereas females have higher expression of Tmprss2 in the trachea relative to males. Our data indicate diet- and sex-dependent modulation of Ace2 and Tmprss2 expression in the lower respiratory tract and esophagus. Given the high prevalence of obesity worldwide and a sex-biased mortality rate, we discuss the implications and relevance of our results for COVID-19.
Inference of deformation mechanisms and constitutive response of soft material surrogates of biological tissue by full-field characterization and data-driven variational system identification
Authors: Wang Z. , Estrada J.B. , Arruda E.M. , Garikipati K.
Published: October 2020

We present a novel, fully three-dimensional approach to soft material characterization and constitutive modeling with relevance to soft biological tissue. Our approach leverages recent advances in experimental techniques and data-driven computation. The experimental component of this approach involvesin situmechanical loading in a magnetic field (using MRI), yielding the entire deformation tensor field throughout the specimen regardless of the possible irregularities in its three-dimensional shape. Characterization can therefore be accomplished with data at a reduced number of deformation states. We refer to this experimental technique as MR-u. Its combination with powerful approaches to inverse modelling, specifically methods of model inference, would open the door to insightful mechanical characterization for soft materials. In recent computational advances that answer this need, we have developed new, data-driven inverse techniques to infer the model that best explains the physics governing observed phenomena from a spectrum of admissible ones, while maintaining parsimony of representation. This approach is referred to as Variational System Identification (VSI). In this communication, we apply the MR–uapproach to characterize soft polymers regarding them as surrogates of soft biological tissue, and using VSI, we infer the physically best-suited and parsimonious mathematical models of their mechanical response. We demonstrate the performance of our methods in the face of noisy data with physical constraints that challenge the identification of mathematical models, while attaining high accuracy in the predicted response of the inferred models.
SWOTein: A structure-based approach to predict stability Strengths and Weaknesses of prOTEINs
Authors: Hou Q. , Pucci F. , Ancien F. , Kwasigroch J.M. , Bourgeas R. , Rooman M.
Published: October 2020

Motivation

Although structured proteins adopt their lowest free energy conformation in physiological conditions, the individual residues are generally not in their lowest free energy conformation. Residues that are stability weaknesses are often involved in functional regions, whereas stability strengths ensure local structural stability. The detection of strengths and weaknesses provides key information to guide protein engineering experiments aiming to modulate folding and various functional processes.

Results

We developed the SWOTein predictor which identifies strong and weak residues in proteins on the basis of three types of statistical energy functions describing local interactions along the chain, hydrophobic forces and tertiary interactions. The large-scale comparison of the different types of strengths and weaknesses showed their complementarity and the enhancement of the information they provide. We applied SWOTein to apocytochrome b562and found good agreement between predicted strengths and weaknesses and native hydrogen exchange data. Its application to an amino acid-binding protein identified the hinge at the basis of the conformational change. SWOTein is both fast and accurate and can be applied at small and large scale to analyze and modulate folding and molecular recognition processes.

Availability

The SWOTein webserver provides the list of predicted strengths and weaknesses and a protein structure visualization tool that facilitates the interpretation of the predictions. It is freely available for academic use athttp://babylone.ulb.ac.be/SWOTein.
Tasting Pictures: Viewing Images of Foods Evokes Taste-Quality-Specific Activity in Gustatory Insular Cortex
Authors: Avery Jason A. , Liu Alexander G. , Ingeholm John E. , Gotts Stephen J. , Martin Alex
Published: October 2020

Previous studies have shown that the conceptual representation of food involves brain regions associated with taste perception. The specificity of this response, however, is unknown. Does viewing pictures of food produce a general, non-specific response in taste-sensitive regions of the brain? Or, is the response specific for how a particular food tastes? Building on recent findings that specific tastes can be decoded from taste-sensitive regions of insular cortex, we asked whether viewing pictures of foods associated with a specific taste (e.g., sweet, salty, sour) can also be decoded from these same regions and if so, are the patterns of neural activity elicited by the pictures and their associated tastes similar? Using ultra-high resolution functional magnetic resonance imaging at high magnetic field strength (7-Tesla), we were able to decode specific tastes delivered during scanning, as well as the specific taste category associated with food pictures within the dorsal mid-insula, a primary taste responsive region of brain. Thus, merely viewing food pictures triggers an automatic retrieval of specific taste quality information associated with the depicted foods, within gustatory cortex. However, the patterns of activity elicited by pictures and their associated tastes were unrelated, thus suggesting a clear neural distinction between inferred and directly experienced sensory events. These data show how higher-order inferences derived from stimuli in one modality (i.e. vision) can be represented in brain regions typically thought to represent only low-level information about a different modality (i.e. taste).

Significance Statement

Does a picture of an apple taste sweet? Previous studies have shown that viewing food pictures activates brain regions involved in taste perception. However, it’s unclear if this response is actually specific to the taste of depicted foods. Using ultra-high resolution functional magnetic resonance imaging and multi-voxel pattern analysis, we decoded specific tastes delivered during scanning, as well as the dominant tastes associated with food pictures within primary taste cortex. Thus, merely viewing pictures of food evokes an automatic retrieval of information about the taste of those foods. These results show how higher-order information from one sensory modality (i.e. vision) can be represented in brain regions thought to represent only low-level information from a different modality (i.e. taste).
Asymmetrical pegs in square holes? Functional and phylogenetic determinants of plant community assembly in temperate forest understories
Authors: Beck Jared J. , Li Daijiang , Johnson Sarah E. , Rogers David , Cameron Kenneth M. , Sytsma Kenneth J. , Givnish Thomas J. , Waller Donald M.
Published: October 2020

Despite advances in community assembly theory, uncertainties remain regarding how ecological and evolutionary processes shape species distributions and communities. We analyzed patterns of occurrence for 139 herbaceous plant species across 257 forest stands in Wisconsin (USA) to test predictions from community assembly theory. Specifically, we applied Bayesian phylogenetic linear mixed effects models (PGLMMs) to examine how functional traits and phylogenetic relationships influence plant distributions along environmental gradients and how functional similarity and phylogenetic relatedness affect local species co-occurrence. Leaf height, specific leaf area, and seed mass mediate species distributions along edaphic, climatic, and light gradients. In contrast, functional trait similarity and phylogenetic relationships only weakly affect patterns of local co-occurrence. These results confirm that broad-scale plant distributions are largely shaped by ecological sorting along environmental gradients but suggest deterministic assembly rules based on niche differentiation and complementary resource use may not govern local species co-occurrence in homogeneous environments.

Statement of authorship

JB conceived the idea for the study. DL, SJ, and DR collected the vegetation and functional trait data. JB analyzed the data with assistance from DL. KC, KS, TG, and DW secured funding for research and oversaw data collection. JB wrote the first draft of the manuscript, all authors contributed to manuscript revisions.

Data accessibility statement

Upon acceptance, data will be archived at Figshare (https://figshare.com/) and scripts used to analyze the data will be shared on Github (https://github.com/jaredjbeck/).
Toxoplasma gondii GRA28is required for placenta-specific induction of the regulatory chemokine CCL22 in human and mouse
Authors: Rudzki Elizabeth N. , Ander Stephanie E. , Coombs Rachel S. , Alrubaye Hisham S. , Cabo Leah F. , Blank Matthew L. , Gutierrez-Melo Nicolas , Dubey JP , Coyne Carolyn B. , Boyle Jon P.
Published: October 2020

Toxoplasma gondiiis an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanism used byT. gondiito cross the placenta are unknown but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed thatT. gondiiinfection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection.. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specificT. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identifiedT. gondiiGRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell where it localizes to the nucleus, and deletion of this gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells bothin vitroandin vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells, and show a clear impact of this immunomodulation on infection outcome.

AUTHOR SUMMARY

Toxoplasma gondiiis a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected withT. gondiisecrete significant amounts of a chemokine (called “CCL22”) that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified aT. gondiigene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found thatT. gondiiparasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector, and provide an interesting example of howT. gondiican directly modulate host signaling pathways in order to facilitate its growth and dissemination.