bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNAs of bone marrow mesenchymal stem cell-derived exosomes regulate acute myeloid leukemia cell proliferation and apoptosis
Authors: Xu Yi-Chuan , Lin Yan-Si , Zhang Ling , Lu Ying , Sun Yan-Ling , Fang Zhi-Gang , Li Zi-Yu , Fan Rui-Fang
Published: October 2020

Background:

Acute myeloid leukemia (AML) is a malignant hematological disease, originating from hematopoiesis stem cell differentiation obstruction and clonal proliferation. New reagents or biologicals for the treatment of AML are urgently needed, and exosomes have been identified as candidate biomarkers for disease diagnosis and prognosis. This study aimed to investigate the effects of exosomes from bone marrow mesenchymal stem cells (BMSCs) on AML cells as well as the underlying microRNA (miRNA)-mediated mechanisms.

Methods:

Exosomes were isolated using a precipitation method, followed by validation using marker protein expression and nanoparticle tracking analysis. Differentially expressed miRNAs were identified by deep RNA sequencing and confirmed by quantitative real-time polymerase chain reaction (qPCR). Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt method, and cell cycle progression and apoptosis were detected by flow cytometry. Functional gene expression was analyzed by qPCR and Western blotting (WB). Significant differences were determined using Student's t test or analysis of variance.

Results:

BMSCs-derived exosomes effectively suppressed cell proliferation (both P < 0.0001 at 10 and 20 μg/mL) and cell cycle progression (P < 0.01 at G0–G1 stage), and also significantly enhanced cell apoptosis (P < 0.001) in KG-1a cells. There were 1167 differentially expressed miRNAs obtained from BMSCs-derived exosomes compared with KG-1a cell-derived exosomes (P < 0.05). Knockdown of hsa-miR-124-5p in BMSCs abrogated the effects of BMSCs-derived exosomes in regulating KG-1a such as the change in cell proliferation (both P < 0.0001 vs. normal KG-1a cell [NC] at 48 and 72 h). KG-1a cells treated with BMSCs-derived exosomes suppressed expression of structural maintenance of chromosomes 4 (P < 0.001 vs. NC by qPCR and P < 0.0001 vs. NC by WB), which is associated with the progression of various cancers. This BMSCs-derived exosomes effect was significantly reversed with knockdown of hsa-miR-124-5p (P < 0.0001 vs. NC by WB).

Conclusions:

BMSCs-derived exosomes suppress cell proliferation and cycle progression and promote cell apoptosis in KG-1a cells, likely acting through hsa-miR-124-5p. Our study establishes a basis for a BMSCs-derived exosomes-based AML treatment.
Artificial intelligence in cardiovascular medicine
Authors: Ranka Sagar , Reddy Madhu , Noheria Amit
Published: October 2020

Purpose of review

Artificial intelligence is a broad set of sophisticated computer-based statistical tools that have become widely available. Cardiovascular medicine with its large data repositories, need for operational efficiency and growing focus on precision care is set to be transformed by artificial intelligence. Applications range from new pathophysiologic discoveries to decision support for individual patient care to optimization of system-wide logistical processes.

Recent findings

Machine learning is the dominant form of artificial intelligence wherein complex statistical algorithms ‘learn’ by deducing patterns in datasets. Supervised machine learning uses classified large data to train an algorithm to accurately predict the outcome, whereas in unsupervised machine learning, the algorithm uncovers mathematical relationships within unclassified data. Artificial multilayered neural networks or deep learning is one of the most successful tools. Artificial intelligence has demonstrated superior efficacy in disease phenomapping, early warning systems, risk prediction, automated processing and interpretation of imaging, and increasing operational efficiency.

Artificial intelligence demonstrates the ability to learn through assimilation of large datasets to unravel complex relationships, discover prior unfound pathophysiological states and develop predictive models. Artificial intelligence needs widespread exploration and adoption for large-scale implementation in cardiovascular practice.
Effects of a Mediterranean diet on blood pressure: a systematic review and meta-analysis of randomized controlled trials and observational studies
Authors: Cowell Owen R. , Mistry Nathan , Deighton Kevin , Matu Jamie , Griffiths Alex , Minihane Anne Marie , Mathers John C. , Shannon Oliver M. , Siervo Mario
Published: October 2020

Objective:

To conduct a systematic review and meta-analysis investigating effects of MedDiet on blood pressure in randomized controlled trials (RCTs) and associations of MedDiet with risk of hypertension in observational studies.

Methods:

PubMed, The Cochrane Library and EBSCOhost were searched from inception until January 2020 for studies that met the following criteria: participants aged at least 18 years, RCTs investigating effects of a MedDiet versus control on BP, observational studies exploring associations between MedDiet adherence and risk of hypertension. Random-effects meta-analyses were conducted. Meta-regression and subgroup analyses were performed for RCTs to identify potential effect moderators.

Results:

Nineteen RCTs reporting data on 4137 participants and 16 observational studies reporting data on 59 001 participants were included in the meta-analysis. MedDiet interventions reduced SBP and DBP by a mean −1.4 mmHg (95% CI: −2.40 to −0.39 mmHg, P = 0.007, I
2 = 53.5%, Q = 44.7, τ
2 = 1.65, df = 19) and −1.5 mmHg (95% CI: −2.74 to −0.32 mmHg, P = 0.013, I
2 = 71.5%, Q = 51.6, τ
2 = 4.72, df = 19) versus control, respectively. Meta-regression revealed that longer study duration and higher baseline SBP was associated with a greater decrease in BP, in response to a MedDiet (P < 0.05). In observational studies, odds of developing hypertension were 13% lower with higher versus lower MedDiet adherence (95% CI: 0.78--0.98, P = 0.017, I
2 = 69.6%, Q = 41.1, τ
2 = 0.03, df = 17).

Conclusion:

Data suggest that MedDiet is an effective dietary strategy to aid BP control, which may contribute towards the lower risk of CVD reported with this dietary pattern. This study was registered with PROSPERO: CRD42019125073.
On or Off: Life-Changing Decisions Made by Vibrio cholerae Under Stress
Authors: Zhou Yitian , Lee Zachariah L. , Zhu Jun
Published: October 2020

Vibrio cholerae, the causative agent of the infectious disease, cholera, is commonly found in brackish waters and infects human hosts via the fecal-oral route. V. cholerae is a master of stress resistance as V. cholerae's dynamic lifestyle across different physical environments constantly exposes it to diverse stressful circumstances. Specifically, V. cholerae has dedicated genetic regulatory networks to sense different environmental cues and respond to these signals. With frequent outbreaks costing a tremendous amount of lives and increased global water temperatures providing more suitable aquatic habitats for V. cholerae, cholera pandemics remain a probable catastrophic threat to humanity. Understanding how V. cholerae copes with different environmental stresses broadens our repertoire of measures against infectious diseases and expands our general knowledge of prokaryotic stress responses. In this review, we summarize the regulatory mechanisms of how V. cholerae fights against stresses in vivo and in vitro.
Cost Study of a Cluster Randomized Trial on a Clinical Decision Rule Guiding Antibiotic Treatment in Children With Suspected Lower Respiratory Tract Infections in the Emergency Department
Authors: van de Maat Josephine , van der Ven Michaël , Driessen Gertjan , van Wermeskerken Anne-Marie , Smit Frank , Noordzij Jeroen , Tramper-Stranders Gerdien , Obihara Charlie , Punt Jeanine , Moll Henriette , Polinder Suzanne , Oostenbrink Rianne
Published: October 2020

Background:

Children with fever and respiratory symptoms represent a large patient group at the emergency department (ED). A decision rule-based treatment strategy improved targeting of antibiotics in these children in a recent clinical trial. This study aims to evaluate the impact of the decision rule on healthcare and societal costs, and to describe costs of children with suspected lower respiratory tract infections (RTIs) in the ED in general.

Methods:

In a stepped-wedge, cluster randomized trial, we collected cost data of children 1 month to 5 years of age with fever and cough/dyspnea in 8 EDs in The Netherlands (2016–2018). We calculated medical costs and societal costs per patient, during usual care (n = 597), and when antibiotic prescription was guided by the decision rule (n = 402). We calculated cost-of-illness of this patient group and estimated their annual costs at national level.

Results:

The cost-of-illness of children under 5 years with suspected lower RTIs in the ED was on average €2130 per patient. At population level this is €15 million per year in The Netherlands (€1.7 million/100,000 children under 5). Mean costs per patient in usual care (€2300) were reduced to €1870 in the intervention phase (P = 0.01). Main cost drivers were hospitalization and lost parental workdays.

Conclusions:

Implementation of a decision rule-based treatment strategy in children with suspected lower RTI was cost-saving, due to a reduction in hospitalization and parental absenteeism. Given the high frequency of this disease in children, the decision rule has the potential to result in a considerable cost reduction at population level.
Four-component Meningococcal Serogroup B Vaccine Induces Antibodies With Bactericidal Activity Against Diverse Outbreak Strains in Adolescents
Authors: Biolchi Alessia , Tomei Sara , Santini Laura , La Gaetana Rita , Mori Elena , Novy Patricia , Rappuoli Rino , Bekkat-Berkani Rafik , Giuliani Marzia Monica , Pizza Mariagrazia
Published: October 2020

Background:

Neisseria meningitidis serogroup B (MenB) causes most meningitis outbreaks worldwide. We evaluated the ability of the 4-component MenB vaccine (4CMenB) to induce bactericidal activity against outbreak strains in adolescents.

Methods:

Individual sera from 20 United States and 23 Chilean adolescents who received 2 doses of 4CMenB 2 months apart were assayed at prevaccination and 1 month after second dose using a human complement serum bactericidal antibody assay (hSBA) against a full or subset strain panel consisting of 14 MenB outbreak strains and 1 MenW hyperendemic strain collected between 2001 and 2017 in the United States, United Kingdom, and France. Bactericidal activity was determined as the percentage of adolescents with hSBA titer ≥1:4 or ≥1:8.

Results:

One month after the second 4CMenB dose, antibodies from 65% to 100% of the US adolescents were able to kill 12 of 15 strains at 1:4 dilution. The remaining 3 strains were killed by 45%, 25%, and 15% of US adolescent sera. Similar percentages exhibited hSBA titers of ≥1:8. Across a subset of 4 strains, point estimates for the percentages of Chilean and US adolescents with hSBA titers of ≥1:4 after the second 4CMenB dose were similar (100% for strain M27703, 74% vs. 80% for M26312, 52% vs. 45% for M08 0240745), except for strain M39090 (91% vs. 65%).

Conclusions:

This study was the first to evaluate bactericidal activity elicited by a MenB vaccine against 15 outbreak strains. Two doses of 4CMenB elicited bactericidal activity against MenB outbreak strains and a hyperendemic MenW strain.
Additional roles of diastolic parameters in the diagnosis of obstructive coronary artery disease
Authors: Kim Hyue Mee , Kim Hack-Lyoung , Kim Myung-A , Oh Sohee , Kim Mina , Park Sang Min , Yoon Hyun Ju , Byun Young Sup , Park Seong Mi , Shin Mi Seung , Hong Kyung-Soon , Shim Wan-Joo
Published: October 2020

Background

A recent guideline emphasizes the role of four indicators, including annular e´ velocity, E/e´, left atrial (LA) size, and peak tricuspid regurgitation (TR) velocity, in the assessment of left ventricular (LV) diastolic dysfunction. This study was performed to determine the relationships among these four parameters and obstructive coronary artery disease (CAD).

Methods

The study data were obtained from a nation-wide registry, composed of 1307 patients (age, 60.4 ± 10.8 years; 964 women) with normal LV ejection fraction (LVEF) who underwent invasive coronary angiography in the suspicion of CAD. Septal e´, E/e´, LA dimension (LAd), and TR velocity were assessed by transthoracic echocardiography.

Results

Compared with patients without obstructive CAD, those with obstructive CAD showed changes in diastolic parameters indicating more progressed LV diastolic dysfunction in univariate analyses. In multiple logistic regression analysis, low septal e´ velocity (<7 cm/s) was identified as an independent risk factor associated with obstructive CAD (odd ratio, 1.91; 95% confidence interval, 1.08–3.36; P = 0.026). Receiver-operating characteristic curve analysis showed that septal e´ velocity had the most powerful value in the detection of obstructive CAD than the other three diastolic parameters (P < 0.01 for each comparison). Septal e´ velocity significantly increased diagnostic value of treadmill exercise test (TET) in the detection of obstructive CAD (P < 0.001 for integrated discrimination improvement index).

Conclusions

Among the four diastolic parameters, septal e´ velocity had the most powerful relationship with obstructive CAD in stable patients with normal LVEF. The addition of septal e´ velocity could improve the diagnostic value of TET.
Role of Diet in Diarrhea-predominant Irritable Bowel Syndrome
Authors: Singh Prashant , Nee Judy
Published: October 2020

Irritable bowel syndrome (IBS) is a chronic condition characterized by abdominal pain associated with altered bowel habits. Patients with IBS often complain of food-related gastrointestinal symptoms. Specifically, those with diarrhea-predominant IBS report a significantly higher effect on quality on life because of food avoidance compared with those with other IBS subtypes. Physicians and patients often use dietary therapies to mitigate IBS symptoms. In the last 10 years, several dietary interventions such as a gluten-free diet, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diets have been studied in several studies. This review summarizes the current literature on the role of diets such as gluten-free diet, low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet, and other carbohydrate malabsorption in the pathophysiology and symptom management in patients with diarrhea-predominant IBS.
Low Risk of Neoplasia and Intraprocedural Adverse Events in Gastric Hyperplastic Polypectomy
Authors: Bar Nir , Kinaani Fadi , Sperber Ami D. , Amir-Barak Hadar , Dekel Roy
Published: October 2020

Goals:

Assess neoplasia and polypectomy-related adverse event (AE) rates in gastric hyperplastic polyps (GHPs).

Background:

GHPs carry a risk of neoplastic transformation. The rate of neoplastic transformation and the risk of polypectomy-related bleeding are unclear in the West, as data are derived from Asian or small studies. The authors aimed to determine the rate of dysplasia and intraprocedural AEs in GHP polypectomies in a western cohort.

Study:

A retrospective study of 591 GHPs >1 cm resected in 491 patients in a single referral center on the occurrence of neoplasia and intraprocedural AEs.

Results:

The mean age was 74.9±11.1 years, 57% female individuals. The mean polyp size was 2±0.8 cm. There were 11 neoplastic polyps (1.9%) with low-grade dysplasia, high-grade dysplasia, and cancer in 7 (1.3%), 2 (0.3%), and 2 (0.3%), respectively. Neoplasia was associated with age [9 (3.2%) for more than 75 years vs. 2 (0.7%) for less than 75 years; P=0.035], but not with polyp size or gender. Fifty patients (8.5%) had intraprocedural bleeding (IPB) requiring endoscopic intervention, with 3 hospitalizations. There were no perforations or procedure-related deaths. IPB was associated with polyp size and neoplasia. The adjusted odds ratio (95% confidence interval) for IPB was 1.63 (1.2-2.2) for a 1 cm increase in polyp size, and 7.4 (1.9-29.6) for the presence of neoplasia.

Conclusions:

The neoplasia rate in GHPs was 1.9%, lower than most previous reports, with no major intraprocedural AEs. Physicians may consider biopsy and follow-up in frail elderly patients, but the safety of this strategy needs further confirmation.
Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure
Authors: Ahmed Syed , Premkumar Madhumita , Dhiman Radha K. , Kulkarni Anand V. , Imran Rather , Duseja Ajay , Kaur Prabhdeep , Taneja Sunil , Singh Virendra , Mishra Saurabh , Roy Akash , Mehtani Rohit
Published: October 2020

Background and Aims:

Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label–randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome.

Patients and Methods:

Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit.

Results:

Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%);P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d;P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13);P=0.03], HESA score [HR, 6.01 (1.27 to 28.5);P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53);P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm.

Conclusions:

PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.
Improving pediatric problem-based learning sessions in undergraduate and graduate medical education
Authors: Harriel Katherine L. , Parboosingh John T.
Published: October 2020

Purpose of review

Problem-based learning (PBL) sessions have become common alternatives to traditional didactic-style sessions in medical education, including within pediatric education. The creation and execution of PBL sessions, however, can vary among institutions and even between educators at a given institution. Coupling the personal experiences of a recently-graduated medical student with that of a knowledgeable medical educator, the authors sought to analyze two PBL session experiences of the medical student during her second year with the goal of pinpointing specific elements that add value for both learners and facilitators.

Recent findings

Through this analysis, the authors propose enhancements to PBL sessions that may make them more optimal for developing knowledge in pediatric medicine. These include utilizing an interactive video of the clinical problem to more uniformly assess the learner's knowledge gaps, supporting the creation and evolution of peer-to-peer learning communities, and helping to educate facilitators in how to guide dialogue in this type of educational setting.

The PBL enhancements identified by the authors provide educators with innovative suggestions to better engage pediatric trainees in building social capital, acquiring knowledge, and helping learners retain that knowledge beyond their assessments.
Predicting Infection in Very Preterm Infants
Authors: Dail Robin B. , Everhart Kayla C. , Hardin James W. , Chang Weili , Kuehn Devon , Iskersky Victor , Fisher Kimberley , Murphy Heidi J.
Published: October 2020

Background

Neonatal sepsis causes morbidity and mortality in preterm infants. Clinicians need a predictive tool for the onset of neonatal infection to expedite treatment and prevent morbidity. Abnormal thermal gradients, a central–peripheral temperature difference (CPtd) of >2°C or <0°C, and elevated heart rate characteristic (HRC) scores are associated with infection.

Objective

This article presents the protocol for the Predictive Analysis Using Temperature and Heart Rate Study.

Methods

This observational trial will enroll 440 very preterm infants to measure abdominal temperature and foot temperature every minute and HRC scores hourly for 28 days to compare infection data. Time with abnormal thermal gradients (Model 1) and elevated HRC scores (Model 2) will be compared to the onset of infections. For data analysis, CPtd (abdominal temperature − foot temperature) will be investigated as two derived variables, high CPtd (number/percentage of minutes with CPtd of >2°C) and low CPtd (number/percentage of minutes with CPtd of <0°C). In the infant-level model, the outcome yi
will be an indicator of whether the infant was diagnosed with an infection in the first 28 days of life, and the high CPtd and low CPtd variables will be the average over the entire observation period, logit(yi
) = β
0 + xiβ
1 + ziγ. For the day-level model, the outcome yit
will be an indicator of whether the ith infant was diagnosed with an infection on the tth day from t = 4 through t = 28 or the day that infection is diagnosed (25 possible repeated measures), logit(yit
) = β
0 + xitβ
1 + zitγ. It will be determined whether a model with only high CPtd or only low CPtd is superior in predicting infection. Also, the correlation of abnormal HRC scores with high CPtd and low CPtd values will be assessed.

Discussion

Study results will inform the design of an interventional study using temperatures and/or heart rate as a predictive tool to alert clinicians of cardiac and autonomic instability present with infection.
Assessing the Necessity for the “Joint Above and Below” Radiography Approach for Lower-extremity Long Bone Fractures in Children
Authors: Koetter Paige , Gallo Robert , Kasmire Kathryn E.
Published: October 2020

Objectives

A common strategy for evaluation of extremity fractures is the “joint above and below” (JAB) radiograph approach, which includes dedicated imaging of the joint proximal and distal to a fracture independent of clinical suspicion for an injury involving the joint. The incidence of concomitant ipsilateral lower-extremity fractures or dislocations associated with lower-extremity long bone fractures in children has not been commonly reported and represents an evidential gap for determining a radiograph approach. Our purpose was to determine the frequency of and risk factors for concomitant ipsilateral lower-extremity fractures or dislocations.

Methods

A retrospective study of children aged 1 to 17 years treated at an academic medical center emergency department from 2015 to 2018 with any fracture involving the tibia, fibula, or femur. Children with pathologic fractures, transferred from another facility, and/or designated as a level I trauma were excluded. The primary outcome was the prevalence of a concomitant bony injury (fracture or dislocation) at a distinct site in the same extremity. Differences between the concomitant bony injury group and single injury group were characterized using Fisher exact tests. Regression analysis was used to determine predictors of concomitant bony injuries, including age, sex, and mechanism of injury (with injuries requiring level II or III trauma activation classified as high risk).

Results

During the study period, 241 patients with lower-extremity long bone fractures were included. Complete JAB radiographs, defined as dedicated orthogonal radiographs of the joint proximal to and distal to the fracture site, were taken in 85 (35.3%) of 241 patients. Concomitant bony injuries were found in 9 (3.73%) of 241 patients (95% confidence interval, 1.7–7.0%). No additional concomitant bony injuries were identified at follow-up. When comparing patients with and without concomitant bony injuries, there was no significant difference in age (P = 0.34) and sex (P = 0.73). However, patients with a high-risk injury were more likely to have a concomitant bony injury (P < 0.01; odds ratio, 21.9; 95% confidence interval, 3.6–131.5).

Conclusions

Concomitant ipsilateral lower-extremity fractures or dislocations are uncommon in children sustaining tibia, fibula, and/or femur fractures. Although the JAB approach to radiographs may be useful in identifying additional injuries in children with lower-extremity injuries resulting from a “high-risk” mechanisms, its overall yield is low. To provide safe, cost-effective care, providers should continue to value clinical suspicion, history, and physical examination findings to guide selection of radiographs in those with lower-extremity long bone fractures as significant fractures can typically be identified with limited imaging in patients with low-risk injury mechanisms.
Freeze-dried platelets promote clot formation, attenuate endothelial cell permeability, and decrease pulmonary vascular leak in a murine model of hemorrhagic shock
Authors: Trivedi Alpa , Potter Daniel R. , Miyazawa Byron Y. , Lin Maximillian , Vivona Lindsay R. , Khakoo Manisha A. , Antebi Ben , Lee Amber , Ishler Braden , Dickerson Matthew , Kozar Rosemary , Schreiber Martin A. , Holcomb John B. , Fitzpatrick Glen M. , Pati Shibani
Published: October 2020

BACKGROUND

Hemorrhagic shock (HS) and trauma induce endothelial barrier compromise, inflammation, and aberrant clotting. We have shown that fresh human platelets (Plts) and Plt extracellular vesicles mitigate vascular leak in murine models of injury. Here, we investigate the potential of freeze-dried platelets (FDPlts) to attenuate pulmonary vascular permeability, decrease inflammation, and promote clotting in a murine model of HS.

METHODS

Human FDPlts were characterized using in vitro assays of Plt marker expression, aggregation, coagulation, and endothelial cell permeability. An intravital model of vascular injury in the mouse cremaster muscle was used to assess the ability of FDPlts to incorporate into clots. Mouse groups subjected to controlled hemorrhage for 90 minutes were (1) lactated Ringer solution (LR), (2) FDPlts, (3) fresh human Plts, (4) murine whole blood (WB), and (5) shams (only instrumented). Hemorrhagic shock mouse endpoints included coagulation, pulmonary vascular permeability, and lung injury.

RESULTS

Freeze-dried Plts expressed Plt-specific markers and retained functionality similar to fresh Plts. In in vitro assays of Plt aggregation, differences were noted. In vivo, FDPlts and Plts were found to incorporate into clots in postcapillary venules in the mouse cremaster muscle. Hemorrhagic shock mice resuscitated with LR displayed increased pulmonary vascular permeability compared with sham (sham, 686.6 ± 359.7; shock-LR, 2,637 ± 954.7; p = 0.001), and treatment with FDPlts or WB attenuated permeability compared with shock: shock-FDPlts, 1,328 ± 462.6 (p = 0.05), and shock-WB, 1,024 ± 370.5 (p = 0.0108). However, human Plts (Days 1–3) did not attenuate vascular leak in HS mice compared with shock-LR (shock-Plts, 3,601 ± 1,581; p = 0.33).

CONCLUSION

FDPlts contribute to clot formation similar to fresh human Plts. FDPlts also attenuated vascular permeability in vitro and in vivo. Mouse WB resuscitation but not fresh human Plts attenuated vascular permeability after HS. These data suggest that the effect of FDPlts may be a suitable alternative to fresh Plts in modulating hemostasis and the endotheliopathy associated with injury.
The influence of base pair tautomerism on single point mutations in aqueous DNA
Authors: Gheorghiu A. , Coveney P. V. , Arabi A. A.
Published: October 2020

The relationship between base pair hydrogen bond proton transfer and the rate of spontaneous single point mutations at ambient temperatures and pressures in aqueous DNA is investigated. By using an ensemble-based multiscale computational modelling method, statistically robust rates of proton transfer for the A:T and G:C base pairs within a solvated DNA dodecamer are calculated. Several different proton transfer pathways are observed within the same base pair. It is shown that, in G:C, the double proton transfer tautomer is preferred, while the single proton transfer process is favoured in A:T. The reported range of rate coefficients for double proton transfer is consistent with recent experimental data. Notwithstanding the approximately 1000 times more common presence of single proton transfer products from A:T, observationally there is bias towards G:C to A:T mutations in a wide range of living organisms. We infer that the double proton transfer reactions between G:C base pairs have a negligible contribution towards this bias for the following reasons: (i) the maximum half-life of the G*:C* tautomer is in the range of picoseconds, which is significantly smaller than the milliseconds it takes for DNA to unwind during replication, (ii) statistically, the majority of G*:C* tautomers revert back to their canonical forms through a barrierless process, and (iii) the thermodynamic instability of the tautomers with respect to the canonical base pairs. Through similar reasoning, we also deduce that proton transfer in the A:T base pair does not contribute to single point mutations in DNA.
Thermal Effect On The Persistence Of SARS-CoV2 Egyptian Isolates As Measured By Quantitative RT-PCR
Authors: Seadawy M.G. , Gad A.F. , Elhoseny M.F. , ELharty B. , EL Desoky M.S. , Soliman Y.A.
Published: October 2020

Coronavirus pandemic that caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) appeared in China in 2019 then spread all over the world .COVID-19 firstly appeared in Egypt in Feb 2020. Studies on the thermal stability of the virus is crucial proper specimens’ transportation for molecular study. Oropharyngeal swabs were taken from recently infected military people with COVID-19 from Egypt during April 2020. Samples were aliquoted and the thermal stability of the virus was measured using quantitative real Time RT-PCR for samples treated at different temperature ranges from 20 °C to 70 °C for 2,4and 6 hours. Results shown that inactivation of the virus and significant reduction in the ΔCq values begin at 40 °C/4h. Complete virus inactivation and loss of ΔCq values were seen at 50 °C/6h and 60 °C. Tested samples showed no significant difference in thermal stability at any temp/time combinations tested.
The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation
Authors: Tidu Antonin , Janvier Aurélie , Schaeffer Laure , Sosnowski Piotr , Kuhn Lauriane , Hammann Philippe , Westhof Eric , Eriani Gilbert , Martin Franck
Published: October 2020

SARS-CoV-2 coronavirus is responsible for Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into non-structural proteins (NSP). One of the first proteins produced during viral infection, NSP1, binds to the host ribosome and blocks the mRNA entry channel. This triggers translation inhibition of cellular translation. In spite of the presence of NSP1 on the ribosome, viral translation proceeds however. The molecular mechanism of the so-called viral evasion to NSP1 inhibition remains elusive. Here, we confirm that viral translation is maintained in the presence of NSP1. The evasion to NSP1-inhibition is mediated by thecis-acting RNA hairpin SL1 in the 5’UTR of SARS-CoV-2. NSP1-evasion can be transferred on a reporter transcript by SL1 transplantation. The apical part of SL1 is only required for viral translation. We show that NSP1 remains bound on the ribosome during viral translation. We suggest that the interaction between NSP1 and SL1 frees the mRNA accommodation channel while maintaining NSP1 bound to the ribosome. Thus, NSP1 acts as a ribosome gatekeeper, shutting down host translation or fostering SARS-CoV-2 translation depending on the presence of the SL1 5’UTR hairpin. SL1 is also present and necessary for translation of sub-genomic RNAs in the late phase of the infectious program. Consequently, therapeutic strategies targeting SL1 should affect viral translation at early and late stages of infection. Therefore, SL1 might be seen as a genuine ‘Achille heel’ of the virus.
Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription
Authors: Rimel Jenna K. , Poss Zachary C. , Erickson Benjamin , Maas Zachary L. , Ebmeier Christopher C. , Johnson Jared L. , Decker Tim-Michael , Yaron Tomer M. , Bradley Michael J. , Hamman Kristin B. , Hu Shanhu , Malojcic Goran , Marineau Jason J. , White Peter W. , Brault Martine , Tao Limei , DeRoy Patrick , Clavette Christian , Nayak Shraddha , Damon Leah J. , Kaltheuner Ines H. , Bunch Heeyoun , Cantley Lewis C. , Geyer Matthias , Iwasa Janet , Dowell Robin D. , Bentley David L. , Old William M. , Taatjes Dylan J.
Published: October 2020

CDK7 associates with the 10-subunit TFIIH complex and regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Few additional CDK7 substrates are known. Here, using the covalent inhibitor SY-351 and quantitative phosphoproteomics, we identified CDK7 kinase substrates in human cells. Among hundreds of high-confidence targets, the vast majority are unique to CDK7 (i.e., distinct from other transcription-associated kinases), with a subset that suggest novel cellular functions. Transcription-associated factors were predominant CDK7 substrates, including SF3B1, U2AF2, and other splicing components. Accordingly, widespread and diverse splicing defects, such as alternative exon inclusion and intron retention, were characterized in CDK7-inhibited cells. Combined with biochemical assays, we establish that CDK7 directly activates other transcription-associated kinases CDK9, CDK12, and CDK13, invoking a “master regulator” role in transcription. We further demonstrate that TFIIH restricts CDK7 kinase function to the RNAPII CTD, whereas other substrates (e.g., SPT5 and SF3B1) are phosphorylated by the three-subunit CDK-activating kinase (CAK; CCNH, MAT1, and CDK7). These results suggest new models for CDK7 function in transcription and implicate CAK dissociation from TFIIH as essential for kinase activation. This straightforward regulatory strategy ensures CDK7 activation is spatially and temporally linked to transcription, and may apply toward other transcription-associated kinases.
Active retrotransposons help maintain pericentromeric heterochromatin required for faithful cell division
Authors: Hao Yajing , Wang Dongpeng , Wu Shuheng , Li Xiao , Shao Changwei , Zhang Peng , Chen Jia-Yu , Lim Do-Hwan , Fu Xiang-Dong , Chen Runsheng , He Shunmin
Published: October 2020

Retrotransposons are populated in vertebrate genomes, and when active, are thought to cause genome instability with potential benefit to genome evolution. Retrotransposon-derived RNAs are also known to give rise to small endo-siRNAs to help maintain heterochromatin at their sites of transcription; however, as not all heterochromatic regions are equally active in transcription, it remains unclear how heterochromatin is maintained across the genome. Here, we address these problems by defining the origins of repeat-derived RNAs and their specific chromatin locations in Drosophila S2 cells. We demonstrate that repeat RNAs are predominantly derived from active gypsy elements and processed by Dcr-2 into small RNAs to help maintain pericentromeric heterochromatin. We also show in cultured S2 cells that synthetic repeat-derived endo-siRNA mimics are sufficient to rescue Dcr-2-deficiency-induced defects in heterochromatin formation in interphase and chromosome segregation during mitosis, demonstrating that active retrotransposons are required for stable genetic inheritance.
Ultrafast and scalable variant annotation and prioritization with big functional genomics data
Authors: Huang Dandan , Yi Xianfu , Zhou Yao , Yao Hongcheng , Xu Hang , Wang Jianhua , Zhang Shijie , Nong Wenyan , Wang Panwen , Shi Lei , Xuan Chenghao , Li Miaoxin , Wang Junwen , Li Weidong , Kwan Hoi Shan , Sham Pak Chung , Wang Kai , Li Mulin Jun
Published: October 2020

The advances of large-scale genomics studies have enabled compilation of cell type–specific, genome-wide DNA functional elements at high resolution. With the growing volume of functional annotation data and sequencing variants, existing variant annotation algorithms lack the efficiency and scalability to process big genomic data, particularly when annotating whole-genome sequencing variants against a huge database with billions of genomic features. Here, we develop VarNote to rapidly annotate genome-scale variants in large and complex functional annotation resources. Equipped with a novel index system and a parallel random-sweep searching algorithm, VarNote shows substantial performance improvements (two to three orders of magnitude) over existing algorithms at different scales. It supports both region-based and allele-specific annotations and introduces advanced functions for the flexible extraction of annotations. By integrating massive base-wise and context-dependent annotations in the VarNote framework, we introduce three efficient and accurate pipelines to prioritize the causal regulatory variants for common diseases, Mendelian disorders, and cancers.
Motivational factors underlying aversive Pavlovian-instrumental transfer
Authors: Campese Vinn D. , Kim Ian T. , Kurpas Botagoz , Branigan Lauren , Draus Cassandra , LeDoux Joseph E.
Published: October 2020

While interest in active avoidance has recently been resurgent, many concerns relating to the nature of this form of learning remain unresolved. By separating stimulus and response acquisition, aversive Pavlovian-instrumental transfer can be used to measure the effect of avoidance learning on threat processing with more control than typical avoidance procedures. However, the motivational substrates that contribute to the aversive transfer effect have not been thoroughly examined. In three studies using rodents, the impact of a variety of aversive signals on shock-avoidance responding (i.e., two-way shuttling) was evaluated. Fox urine, as well as a tone paired with the delivery of the predator odor were insufficient modulatory stimuli for the avoidance response. Similarly, a signal for the absence of food did not generate appropriate aversive motivation to enhance shuttling. Only conditioned Pavlovian stimuli that had been paired with unconditioned threats were capable of augmenting shock-avoidance responding. This was true whether the signaled outcome was the same (e.g., shock) or different (e.g., klaxon) from the avoidance outcome (i.e., shock). These findings help to characterize the aversive transfer effect and provide a more thorough analysis of its generalization to warning signals for different kinds of threats. This feature of aversive motivation has not been demonstrated using conventional avoidance procedures and could be potentially useful for applying avoidance in treatment settings.
The impact of brand and social cause prominence dimensions of fit on consumer intentions to buy cause-related products
Authors: Dagyte-Kavoliune Gintare , Adomaviciute Karina , Urbonavicius Sigitas
Published: October 2020

Purpose

The aim of this study is to assess the direct and indirect impact of the prominence dimensions of fit between a brand and a cause on consumer intentions to purchase cause-related products by considering cases with more versus less positive attitudes towards a brand and a higher versus lower social cause affinity.

Design/methodology/approach

The study is based on data obtained via a survey of 403 respondents in Lithuania. A between-subjects study design with different brands and causes was used to identify the role of the differences in brand attitude and cause affinity on the message strength.

Findings

The data analysis has revealed that the specific prominence dimensions of fit (relationship visibility, relationship explicitness, visuals/colours, local attributes) have a direct and indirect impact, via the message strength, on consumer intentions to purchase cause-related products. Additionally, the mediation of the message strength was dependent on attitudes towards a brand but not on cause affinity.

Originality/value

This is the first attempt to contribute to filling the research gap regarding the impact of the prominence dimensions of fit on the intention to purchase a cause-related product. Paying special attention to message strength mediation allowed for the assessment of both the direct and indirect effects of the individual dimensions of fit.
Exploitation of the advanced manufacturing machine tool evaluation model under objective-grey information: a knowledge-based cluster with the grey relational analysis approach
Authors: He Zitong , Ma Xiaolin , Luo Jie , Sahu Anoop Kumar , Sahu Atul kumar , Sahu Nitin Kumar
Published: October 2020

Purpose

Advanced manufacturing machines (AMMs) are searched as a momentous asset across the manufacturing societies for quenching and addressing the production units under economical circumstances, i.e. production of high-quality of goods under feasible cost. AMMs are significant in holding the managers against their rivals and competitors with high profit margins. The authors developed the decision support mechanism/portfolio (DSM-P) consist of knowledge-based cluster approach with a dynamic model. The purpose of research work is to measure overall economic worth of AMMs under objective and grey-imperfect (mixed) data by exploring the proposed DSM-P.

Design/methodology/approach

The authors developed the DSM-P that consist of knowledge-based cluster, three multi-criteria decision-making (MCDM) techniques-1-2-3 with complementary grey relational analysis-4(GRA), approach with a dynamic model (complied by technical plus cost and agility measures of AMMs). The proposed DSM-P enables the manager to map the overall economic worth of candidate AMMs under objective and grey-mixed data.

Findings

The presented DSM-P assist the managers for handling the selection problem of AMMs, i.e. CNCs, robots, automatic-guided vehicle, etc under mixed (objective cum grey) data. To enable the readers for intensely understand the work, the utility of proposed approach is displayed by illustrating a polar robot evaluation and selection problem. It is ascertained that the robot candidate-11 alternative is fulfilling the entire technical cum cost and agility measures.

Originality/value

The DSM-P provides more precise and reliable outcomes due to a usage of the dominance theory. Under the dominance theory, the ranks are obtained by MCDM techniques-1-2-3 are compared with ranks gathered by the GRA-4 under objective cum grey data, formed the novelties in presented research work. From a future perspective, the grey-based models in DSM-P can be built/extended/constructed more extensive and can be simulated by the same approach.
“Not in the business of indoctrination”: religious education in South Australian public schools, 1968–1980
Authors: Jackson Stephen James
Published: October 2020

Purpose

This paper explores religious education (RE) in South Australia from 1968–1980. It focuses especially on the collapse of the RE settlement from 1968–1972 and the controversial legislation and subsequent curricula emerging from changes to the Education Act in 1972.

Design/methodology/approach

This paper draws upon archival materials, published sources from the South Australian Institute of Teachers, the South Australian Education Department and the Religious Education Project Team, as well as an interview with Malcolm McArthur, one of the most influential figures in the controversy.

Findings

Following the collapse of religious instruction from 1968–1972, the Minister of Education quickly passed legislation regarding a new course of religious education. A major controversy subsequently broke out over the appropriateness and design of a new programme of religious education. Educators attempted to design an educationally sound programme of RE that would avoid the problem of indoctrination. Ultimately, a new programme was created that satisfied neither proponents nor opponents of religion in state schools, and General Religious Teaching gradually faded from South Australian classrooms by 1980.

Originality/value

The article engages with broader debates on the nature of secularity in Australian history. In particular, it complicates the political-institutional approach developed by Damon Mayrl by stressing the agency and significance of elite educational and religious actors in the creation of new secular settlements. It also provides a useful addition to an older South Australian historiography by utilising newly available sources on the topic.
Mindfulness, remote engagement and employee morale: conceptual analysis to address the “new normal”
Authors: Pattnaik Laxmiprada , Jena Lalatendu Kesari
Published: October 2020

Purpose

The purpose of this paper is to explore the inter-linkages of mindfulness, remote engagement and employee morale as a solution to new normal, during the turbulent times of the pandemic.

Design/methodology/approach

Remote engagement is the biggest challenge that is faced by many organisations with their employees working remotely. This paper examines the relevance of mindfulness amidst all distractions that obstruct the employees to stay focussed in their work assignments while performing remotely. Therefore, a thorough literature survey has been made to analyse the conceptual relationship among mindfulness, remote engagement and employee morale. Based on the conceptual analysis, a set of possible frameworks linking the three constructs has been stated for future research.

Findings

This conceptual paper has come up with few possible frameworks to model the assertions by investigating and corroborating it with quantitative or qualitative studies by the future researchers.

Research limitations/implications

This paper has tried to advocate the linkage of the three constructs, which is the need of the hour for setting the organisation to the new normal way of work.

Practical implications

The current paper suggests that the organisations can deal with the toughest challenge of engaging people remotely by practising mindfulness technique, and thereby, it would result in high morale leading to improved performance. This approach paves the way for leading a “new normal” even post-pandemic.

Originality/value

Due to the prevalence of the unforeseen situation of pandemic, organisations have no other way but to resort to remote work. Through the practice of mindfulness, the engagement of employees can be adhered to an extent, which results in enhanced employee morale, which can help the organisation to achieve its business objectives amidst this turbulent time and gradually resorts to function in the new normal.