bluuebunny/crossref_metadata_2025 huggingface dataset:
Computer- and Telephone-Delivered Interventions on Patient Outcomes and Resource Utilization in Patients With Orthopaedic Conditions
Authors: Jansson Miia Marika , Hyvämäki Piia , Pikkarainen Minna
Published: September 2020

BACKGROUND:

As the number of patients with orthopaedic conditions has risen continuously, hospital-based healthcare resources have become limited. Delivery of additional services is needed to adapt to this trend.

PURPOSE:

The purpose of this study was to describe the current literature of computer- and telephone-delivered interventions on patient outcomes and resource utilization in patients with orthopaedic conditions.

METHODS:

The systematic review was conducted in January 2019. The standardized checklist for randomized controlled trials was used to assess the quality of the relevant studies. A meta-analysis was not possible due to heterogeneity in the included studies, and a narrative synthesis was conducted to draw informative conclusions relevant to current research, policy, and practice.

RESULTS:

A total of 1,173 articles were retrieved. Six randomized controlled trials met the inclusion criteria, providing evidence from 434 individuals across four countries. Two studies reported findings of computer-delivered interventions and four reported findings of telephone-delivered interventions. The patients who received both computer- and telephone-delivered interventions showed improvements in patient outcomes that were similar or better to those of patients receiving conventional care. This was without any increase in adverse events or costs.

CONCLUSION:

Computer- and telephone-delivered interventions are promising and safe alternatives to conventional care. This review, however, identifies a gap in evidence of high-quality studies exploring the effects of computer- and telephone-delivered interventions on patient outcomes and resource utilization. In future, these interventions should be evaluated from the perspective of intervention content, self-management, and patient empowerment. In addition, they should consider the whole care journey and the development of the newest technological innovations. Additionally, future surgery studies should take into account the personalized needs of special, high-risk patient groups and focus on patient-centric care to reduce postdischarge health problems and resource utilization in this population.
The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis
Authors: Sit Michelle T. , Schmidt Thomas W. , Edmonds Lance D. , Kelly Jason A. , Sky Karen M. , Thornton Jennifer A. , McNeary-Garvin Antoinette M. , Thom Stephen R. , Slade John B.
Published: September 2020

Background/Objective

This case series pilot study assessed the effects of hyperbaric oxygen therapy (HBO2) for treating rheumatoid arthritis (RA).

Methods

Ten RA subjects received 30 HBO2 treatments over 6 to 10 weeks. Serial rheumatologic evaluations (ie, the Disease Activity Scale [DAS28], the Routine Assessment of Patient Index Data 3, and the Pain and Sleep Quality Questionnaire) were completed at baseline, throughout the course of the study, and at the 6-month follow-up.

Results

There was a statistically significant effect of HBO2 therapy over time on the DAS28–Global Health (p = 0.01), the DAS28–C-reactive protein (p = 0.002), and the DAS28–erythrocyte sedimentation rate (p = 0.008) measures; these analyses excluded 2 patients who were in clinical remission at baseline. Selected post hoc comparisons showed significantly lower DAS28–Global Health, DAS28–C-reactive protein, and DAS28–erythrocyte sedimentation rate scores at 3 and 6 months relative to baseline. In addition, statistically significant decreases in pain as measured by the Routine Assessment of Patient Index Data 3 and Pain and Sleep Quality Questionnaire were observed at the end of HBO2 relative to baseline.

Conclusions

Hyperbaric oxygen therapy is effective for joint pain in patients with RA based on data from multiple, validated clinical measures. Further research with more subjects and the use of a control group is necessary.
Early Detection of Cartilage Degradation Among Heavy Manual Workers Using Serum Level of Collagen Type II Metabolite
Authors: Ramadan Mona , Amr Mahmoud M. , Elsaid Nora Yousry , Fouad Marwa M.
Published: September 2020

Background

Work-related musculoskeletal disorders are common health problems in brick manufacturers, where mechanical load leads to degenerative joint diseases. Collagen type II metabolite (C2C) is a small peptide excreted in urine, and its serum concentration can directly reflect articular cartilage decomposition.

Objective

Early detection of musculoskeletal disorders among brick workers, using serum C2C as a biomarker of cartilage damage.

Methods

This study involved 88 male brick workers in Arab Abu Saed matched to 88 age- and sex-matched controls. Full history taking, pain assessment using the Standardized Nordic Questionnaire, and complete clinical examination were done for both groups. Serum C2C was measured using a competitive immunoassay method.

Results

Brick workers involved in the study were of a mean age 30.66 ± 7.90 years and mean work duration 14.80 ± 7.89 years, matched to 88 controls. The majority of the participants (77.3%) were of normal body mass index. An increase in pain/discomfort was found among the exposed group. Serum C2C had an increased mean among the exposed group compared with the control. Pearson correlation between serum C2C level, body mass index, age, and years of employment showed no correlation.

Conclusions

Musculoskeletal disorders are prevalent among brick workers who adopt specific awkward postures, unhealthy working conditions, and nonexistent safety procedures, for prolonged periods. Detection of serum C2C level can be used as a predictive biomarker for the early detection of musculoskeletal disorders among brick workers.
Esthetic Repair of Facial Skin Defect After Resection of Malignant Tumor With Lateral Maxillocervical-Island Fasciocutaneous Flap
Authors: Lang Zhongliang , Zhao Liping , Chu Yanjun
Published: September 2020

The face is a high-incidence area for malignant skin tumors, which often need surgically extended resectioning, and the secondary defects generally need esthetic repair. This report introduces a type of flap (lateral maxillocervical-island fasciocutaneous flap)-repair method that can not only repair the defect accurately but also result in skin texture comparable with the surroundings. Moreover, the incision in the flap area is concealed, so as to not cause facial-organ deformity and to achieve an esthetic repair effect. The operation is straightforward and the flap survival rate is high.
Unification of Abyssicoccus albus Jiang et al. 2016 and Auricoccus indicus Prakash et al. 2017 and the status of the genus Auricoccus Prakash et al. 2017
Authors: Dobritsa Anatoly P. , Samadpour Mansour
Published: September 2020

Based on the high phylogenetic relatedness of

Auricoccus indicus

Prakash et al. 2017 and

Abyssicoccus albus

Jiang et al. 2016, it is proposed to unite them with retaining the latter name as having nomenclatural priority. As the result of the species unification, the genus

Auricoccus

name is proposed to consider as illegitimate in the boundaries determined by Rule 51a of the International Code of Nomenclature of Prokaryotes.
An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity
Authors: Teruel María , Barturen Guillermo , Martínez-Bueno Manuel , Barroso Miguel , Castelli Olivia , Povedano Elena , Kerick Martin , Català-Moll Francesc , Makowska Zuzanna , Buttgereit Anne ,   PRECISESADS Clinical Consortium,   PRECISESADS Flow Cytometry Study Group, Pers Jacques-Olivier , Marañón Concepción , Ballestar Esteban , Martin Javier , Carnero-Montoro Elena , Alarcón-Riquelme Marta E.
Published: September 2020

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.
Comparison of Local Influenza Vaccine Effectiveness Using Two Methods
Authors: Balasubramani GK , Zimmerman Richard K , Eng Heather , Lyons Jason , Clarke Lloyd , Nowalk Mary Patricia
Published: September 2020

Background

In some settings, research methods to determine influenza vaccine effectiveness (VE) may not be appropriate because of cost, time constraints, or other factors. Administrative database analysis of viral testing results and vaccination history may be a viable alternative. This study compared VE estimates from outpatient research and administrative databases.

Methods

Using the test-negative, case-control design, data for 2017-2018 and 2018-2019 influenza seasons, were collected using: 1) research methods including consent, specimen collection, RT-PCR testing and vaccine verification using multiple methods; and 2) an administrative database of outpatients with a clinical respiratory viral panel combined with electronic immunization records. Odds ratios for likelihood of influenza infection by vaccination status were calculated using multivariable logistic regression. VE = (1 - OR) × 100.

Results

Research participants were significantly younger (P<0.001), more often white (69% vs. 59%; P<0.001) than non-white and less frequently enrolled through the emergency department (ED) (35% vs. 72%; P<0.001) than administrative database participants. VE was significant against all influenza and influenza A in each season and both seasons combined (37%-49%). Point estimate differences between methods were evident, with higher VE in the research database, but insignificant due to low sample sizes. When enrollment sites were separately analyzed, there were significant differences in VE estimates for all influenza (66% research vs. 46% administrative P<0.001) and influenza A (67% research vs. 49% administrative; P<0.001) in the ED.

The selection of the appropriate method for determining influenza vaccine effectiveness depends on many factors, including sample size, subgroups of interest, etc., suggesting that research estimates may be more generalizable. Other advantages of research databases for VE estimates include lack of clinician-related selection bias for testing and less misclassification of vaccination status. The advantages of the administrative databases are potentially shorter time to VE results and lower cost.
Killip-Kimball Classification Validation, Outcomes and Demographics in an Octogenarian Cohort with Acute Coronary Syndrome in a Developing Country: A Third-Level Multicenter 11-Year Experience
Authors: Ramonfaur Diego , Hinojosa-González David Eugenio , Paredes-Vázquez José G.
Published: September 2020

Introduction

The Killip-Kimball Classification (KC) is used to group patients with acute coronary syndrome (ACS) based on their clinical profile. It has proven to be useful while predicting both short- and long-term mortality. Contemporary data in the elderly population is limited. We sought to analyze trends in outcomes of patients 80 years or older admitted for ACS, by Killip Class. In addition, we assess the validity of the KC in this population.

Methodology

A retrospective analysis of patients who underwent a catheterization procedure for ACS was performed. ACS was defined as per AHA guidelines, and included STEMI, non-STEMI and Unstable Angina. We determined factors influencing the KC in which patients present to the emergency room. Likewise, we compared inhospital mortality, length of stay, and other outcomes dividing the patients by KC.

Results

A total of 133 patients were analyzed. Included were: 86, 9, 23 and 15 patients in KC-I through IV respectively with a mean age of 83. The main comorbidities were hypertension (73%), and diabetes (43%). In-hospital mortality was 12%, which was different between KC groups (p < 0.01). In addition, we found higher KC groups to be associated with acute kidney injury during the hospitalization (p< 0.01).

Conclusion

Despite a strong reduction in mortality for elderly patients with ACS in recent decades, patients presenting with ACS and higher Killip class have a high mortality rate, as described in younger cohorts. The Killip-Kimball classification remains a reliable prognostic tool, with applicability in octogenarian patients.
Limited specificity of commercially available SARS-CoV-2 IgG ELISAs in serum samples of African origin
Authors: Emmerich Petra , Murawski Carolin , Possel Ronald von , Oestereich Lisa , Duraffour Sophie , Pahlmann Meike , Struck Nicole , Eibach Daniel , Krumkamp Ralf , Amuasi John , Maiga-Ascofare Oumou , Rakotozandrindrainy Raphael , Asogun Danny , Ighodalo Yemisi , May Jürgen , Tannich Egbert , Deschermeier Christina
Published: September 2020

Specific serological tests are mandatory for reliable SARS-CoV-2 seroprevalence studies but assay specificity may vary considerably between populations due to interference of immune responses to other pathogens. Here, we assess the false positive rates obtained with four commercially available IgG ELISAs in serum panels originating from three different African countries.

Article summary line

Several commercially available SARS-CoV-2 ELISAs show limited specificity when applied to serum panels of African origin
Distribution equality as an optimal epidemic mitigation strategy
Authors: Hacohen Adar , Cohen Reuven , Efroni Sol , Bachelet Ido , Barzel Baruch
Published: September 2020

Upon the development of a drug or vaccine, a successful response to a global pandemic, such as COVID-19, requires the capacity for efficient distribution at a global scale. Considering constraints on production and shipping, most existing strategies seek to maximize the outflow of therapeutics, hence optimizing for rapid dissemination. Surprisingly, we find that this intuitive approach is counterproductive. The reason is that focusing strictly on the quantity of disseminated therapeutics, such strategies disregard their specific spreading patterns, most crucially – they overlook the interplay of these spreading patterns with those of the pathogens. This results in a discrepancy between supply and demand, that prohibits efficient mitigation even under optimal conditions of superfluous drug/vaccine flow. Therefore, here, we design a dissemination strategy that naturally follows the predicted spreading patterns of the epidemic, optimizing not just for supply volume, but also for its congruency with the anticipated demand. Specifically, we show that epidemics spread relatively uniformly across all destinations, and hence we introduce an equality constraint into our dissemination that prioritizes supply homogeneity. This strategy may, at times, slow down the supply rate in certain locations, however, thanks to its egalitarian nature, which mimics the flow of the viral spread, it provides a dramatic leap in overall mitigation efficiency, saving more lives with orders of magnitude less resources.
Grand battement kinematics and aesthetics in adolescent recreational dancers: Short term effects of static and dynamic hamstrings stretching
Authors: Dierick Frédéric , Buisseret Fabien , Filiputti Loreda , Roussel Nathalie
Published: September 2020

We have studied the kinematics of ballet figures performed by adolescent recreational dancers and determined the most effective muscle stretching modality allowing to increase their physical performance while not harming the aesthetic perception of their motion. Sixteen participants aged between 10 and 19 years were recruited to perform a grand battement, before and after a static or dynamic stretching of hamstring muscles. The three-dimensional kinematics of the grand battement was measured by an optoelectronic system and the aesthetics was scored from a video watched by a jury of professional dancers. Our results show that stretching has a significant impact on grand battement kinematics, and that the most important modifications are induced by dynamic stretching rather than static stretching. Dynamic stretching significantly improves the explosive aspects of the movement (duration and maximal speed), but leads to a significant reduction of its smoothness (jerk). Significant correlations between kinematic parameters and aesthetic scores have been observed, one of them being a positive correlation between thigh’s range of motion and total aesthetic score. These correlations can serve as a reference for movement analysis experts, dancers and their teachers to improve physical performance required by the standards of today’s dance practice without altering the corresponding aesthetic judgment.
Demand for Self-Managed Online Telemedicine Abortion in Eight European Countries During the COVID-19 Pandemic: A Regression Discontinuity Analysis
Authors: Aiken Abigail R.A. , Starling Jennifer E , Gomperts Rebecca , Scott James G , Aiken Catherine
Published: September 2020

Objectives: In most European countries, patients seeking medication abortion during the COVID-19 pandemic are still expected to attend healthcare settings in person despite lockdown measures and infection risk. We assessed whether demand for self-managed medication abortion provided by a fully remote online telemedicine service increased following the emergence of COVID-19.
Design: We used regression discontinuity to compare the number of requests to online telemedicine service Women on Web in eight European countries before and after they implemented lockdown measures to slow COVID-19 transmission. We examined the number deaths due to COVID-19, the degree of government-provided economic support, the severity of lockdown travel restrictions, and the medication abortion service provision model in countries with and without significant changes in requests.
Setting: Eight European countries served by Women on Web.
Participants: 3,915 people who made requests for self-managed abortion to Women on Web between January 1st, 2019 and June 1st, 2020.
Main Outcome Measures: Percent change in requests to Women on Web before and after the emergence of COVID-19 and associated lockdown measures.
Results: Five countries showed significant increases in requests, ranging from 28% in Northern Ireland (p=0.001) to 139% in Portugal (p<0.001). Two countries showed no significant change in requests, and one country, Great Britain, showed an 88% decrease in requests (p<0.001). Countries with significant increases in requests were either countries where abortion services are mainly provided in hospitals or where no abortion services are available and international travel was prohibited during lockdown. By contrast, Great Britain authorized teleconsultation for medication abortion and provision of medications by mail during the pandemic.
Conclusion: These marked changes in requests for self-managed medication abortion during COVID-19 demonstrate demand for fully remote models of abortion care and an urgent need for policymakers to expand access to medication abortion by telemedicine.
Early-life environment programs reproductive strategies through epigenetic regulation ofSRD5A1
Authors: Bar-Sadeh Ben , Eden Or , Pnueli Lilach , Begum Kurshida , Leeman Gregory , Emes Richard D. , Stöger Reinhard , Bentley Gillian R. , Melamed Philippa
Published: September 2020

Reproductive function and duration of the reproductive life span are phenotypically plastic and programmed in response to the early-life environment. Such adaptive responses are described and rationalized in life history theory in the context of resource availability, but the molecular mechanisms responsible have remained enigmatic. In this study, we hypothesized that epigenetic modifications underlie adaptive reproductive strategies, and found distinct methylation patterns in buccal DNA of Bangladeshi women who grew up in Bangladesh or the UK. The later pubertal onset and lower ovarian reserve associated with Bangladeshi childhood was seen to correlate with more numerous childhood infections, so we adopted a mouse model of pre-pubertal colitis to mimic these conditions. These mice have a similarly-altered reproductive phenotype, which enabled us to determine its mechanistic basis. Several genes encoding proteins with known functions in follicle recruitment were differentially expressed in the mice ovaries, and were also differentially methylated in the women’s buccal DNA. One of these,SRD5A1which encodes the steroidogenic enzyme 5α reductase-1, was down-regulated in the mice ovaries and hyper methylated at the same putative transcriptional enhancer as in the women’s DNA; the levels of methylation correlating with gene expression levels.Srd5a1expression was down-regulated also in the hypothalamus where 5α reductase-1 catalyzes production of neurosteroids that regulate gonadotropin releasing hormone (GnRH). Chemical inhibition of this enzyme affected both GnRH synthesis and release, and resulted in delayed pubertal onsetin vivo. The activity of 5α reductase-1 in hypothalamus and ovary and the sensitivity ofSRD5A1to epigenetic regulation attest to its role in directing long-term physiological strategies in response to environmental conditions. In the reproductive axis, this includes timing of pubertal onset, adult reproductive function and duration of the reproductive lifespan.
A method to remove the influence of fixative concentration on post-mortem T2maps using a Kinetic Tensor model
Authors: Tendler Benjamin C. , Qi Feng , Foxley Sean , Pallebage-Gamarallage Menuka , Menke Ricarda A.L. , Ansorge Olaf , Hurley Samuel A. , Miller Karla L.
Published: September 2020

Formalin fixation has been shown to substantially reduce T2estimates when performing post-mortem imaging, primarily driven by the presence of bulk fixative in tissue. Prior to scanning, post-mortem tissue samples are often placed into a fluid that has more favourable imaging properties, such as matched magnetic susceptibility. This study investigates whether there is any evidence for a change in T2in regions close to the tissue surface in post-mortem T2maps due to fixative outflux into this surrounding fluid. Furthermore, we investigate whether a simulated spatial map of fixative concentration can be used as a confound regressor to reduce T2inhomogeneity. To achieve this, T2maps and diffusion tensor estimates were obtained in 14 whole, formalin fixed post-mortem brains placed in fluorinert approximately 48 hours prior to scanning. This consisted of 7 brains fixed with 10% formalin and 7 brains fixed with 10% neutral buffered formalin (NBF). Fixative outflux was modelled using a Kinetic Tensor (KT) model, which incorporates voxelwise diffusion tensor estimates to account for diffusion anisotropy and tissue-specific diffusion coefficients. Brains fixed with 10% NBF revealed a spatial T2pattern consistent with the modelled fixative outflux. Confound regression of fixative concentration reduced T2inhomogeneity across both white and grey matter, with the greatest reduction attributed to the KT model vs simpler models of fixative outflux. No such effect was observed in brains fixed with 10% formalin. Correlations with ferritin and myelin proteolipid protein (PLP) histology lead to an increased similarity for the relationship between T2and PLP for the two fixative types after KT correction. Only small correlations were identified between T2and ferritin before and after KT correction.
Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds
Authors: McKee Christina , Brown Christina , Bakshi Shreeya , Walker Keegan , Govind Chhabi K. , Chaudhry G. Rasul
Published: September 2020

Derivation of primed and naïve human embryonic stem cells (ESCs) have prompted an increased interest in devising culture conditions for maintaining their pluripotency and differential potential. Naïve ESCs are characterized by improved viability, proliferation, and differentiation capacity in comparison to primed ESCs. However, traditional two-dimensional (2-D) cell culture techniques fail to mimic the three-dimensional (3-D)in vivomicroenvironment, which results in altered morphological and molecular characteristics of ESCs. Here, we describe the use of 3-D self-assembling scaffolds that support growth and maintenance of the naïve state characteristics of human ESC line, Elf1. Scaffolds were formed via a Michael addition reaction upon combination of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups. 3-D scaffolds not only maintained the naïve state, but also supported long-term growth for up to 3 weeks without requiring routine passaging and manipulation. 3-D grown cells exhibited upregulation of core (OCT4,NANOG, andSOX2) and naïve (KLF17,KLF4,TFCP2L1,DPPA3, andDNMT3L) genes. These genes returned to normal levels when 3-D grown cells were propagated under 2-D culture conditions. Examination of RNA-sequencing demonstrated significant changes in gene expression profiles between 2-D and 3-D grown Elf1 cells. Gene Ontology analysis revealed upregulation of biological processes involved in the regulation of transcription and translation, as well as β-catenin-TCF complex assembly, extracellular matrix organization, and chromatin remodeling in 3-D grown Elf1 cells. 3-D culture conditions also induced upregulation of genes associated with several signaling pathways including Wnt signaling and focal adhesion. However, p53 signaling pathway associated genes were downregulated under these culture conditions. Our findings provide insight into the possible mechanisms of prolonged self-renewal as well as upregulation of pluripotent genes stimulated by the transduction of mechanical signals from the 3-D microenvironment.
Tuning of self-renewing capacity in theArabidopsisstomatal lineage by hormonal and nutrition regulation of asymmetric cell divisions
Authors: Gong Yan , Alassimone Julien , Varnau Rachel , Sharma Nidhi , Cheung Lily S. , Bergmann Dominique C.
Published: September 2020

Asymmetric and self-renewing divisions build and pattern tissues. In theArabidopsis thalianastomatal lineage, asymmetric cell divisions, guided by polarly localized cortical proteins, generate the majority of cells on the leaf surface. These divisions can be fine-tuned by systemic and environmental signals to modify tissue development, but the molecular mechanisms by which plants incorporate such cues to regulate asymmetric divisions are largely unknown. In a screen for modulators of cell polarity and asymmetric divisions, we identified a mutation inCONSTITIUTIVE TRIPLE RESPONSE 1, a negative regulator of ethylene signaling. We subsequently revealed antagonistic impacts of ethylene and glucose signaling on the self-renewing capacity of stomatal lineage stem cells. Quantitative analysis of the impacts of these signaling systems on cell polarity and fate dynamics showed that developmental information may be encoded in both the spatial and temporal asymmetries of polarity proteins. Taken together, our results provide a framework for a mechanistic understanding of how systemic information such as nutritional status and environmental factors tune stem cell behavior in the stomatal lineage, ultimately enabling optimization of leaf size and cell-type composition.
Expression of ERV3-1 in Leukocytes of Acute Myelogenous Leukemia Patients
Authors: Nakagawa So , Kawashima Masaharu , Miyatake Yuji , Kudo Kai , Kotaki Ryutaro , Ando Kiyoshi , Kotani Ai
Published: September 2020

Acute myelogenous leukemia (AML) is one of the major hematological malignancies. In the human genome, several have been found to originate from retroviruses, and some of which are involved in progression of various cancers. Hence, to investigate whether retroviral-like genes are associated with the development of AML, we conducted a transcriptome sequencing analysis of 12 retroviral-like genes of 150 AML patients using The Cancer Genome Atlas database. We found high expression of ERV3-1, an envelope gene of endogenous retrovirus group 3 member 1. In particular, blood and bone marrow cells of the myeloid lineage in AML patients, exhibited higher expression of ERV3-1 than those of the monocytic AML lineage. We also examined the protein expression of ERV3-1 by immunohistochemical analysis and found expression of ERV3-1 protein in 7 out of 12 AML patients, with a particular concentration observed at the membrane of some leukemic cells. Transcriptome analysis further suggested that upregulated ERV3-1 expression may be associated with chromosome 8 trisomy as anomaly was found to be more common among the high expression group compared to the low expression group. However, this finding was not corroborated by the immunohistochemical data. This discrepancy may have been caused, in part, by the small number of samples analyzed in this study. Although the precise associated molecular mechanisms remain unclear, our results suggest that ERV3-1 may be involved in AML development.

Highlights

Expression of 12 retroviral-like genes in the human genome were analyzed using transcriptome data of 150 acute myelogenous leukemia (AML) patients.

ERV3-1, an envelope gene of endogenous retrovirus group 3 member 1, was found to uniquely show high expression level.

Morphologic characteristics and chromosomal abnormalities are found to be related with the expression of ERV3-1.
Introduction of two prolines and removal of the polybasic cleavage site leads to optimal efficacy of a recombinant spike based SARS-CoV-2 vaccine in the mouse model
Authors: Amanat Fatima , Strohmeier Shirin , Rathnasinghe Raveen , Schotsaert Michael , Coughlan Lynda , García-Sastre Adolfo , Krammer Florian
Published: September 2020

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coronavirus spike proteins are large trimers that are relatively instable, a feature that might be enhanced by the presence of a polybasic cleavage site in the SARS-CoV-2 spike. Exchange of K986 and V987 to prolines has been shown to stabilize the trimers of SARS-CoV-1 and the Middle Eastern respiratory syndrome coronavirus spikes. Here, we test multiple versions of a soluble spike protein for their immunogenicity and protective effect against SARS-CoV-2 challenge in a mouse model that transiently expresses human angiotensin converting enzyme 2 via adenovirus transduction. Variants tested include spike protein with a deleted polybasic cleavage site, the proline mutations, a combination thereof, as well as the wild type protein. While all versions of the protein were able to induce neutralizing antibodies, only the antigen with both a deleted cleavage site and the PP mutations completely protected from challenge in this mouse model.

Importance

A vaccine for SARS-CoV-2 is urgently needed. A better understanding of antigen design and attributes that vaccine candidates need to have to induce protective immunity is of high importance. The data presented here validates the choice of antigens that contain the PP mutation and suggests that deletion of the polybasic cleavage site could lead to a further optimized design.
PAF1 facilitates RNA polymerase II ubiquitination by the Elongin A complex through phosphorylation by CDK12
Authors: Sanchez Gabriel , Barbier Jérôme , Elie Céline , Kiernan Rosemary , Rouquier Sylvie
Published: September 2020

The conserved Polymerase-Associated Factor 1 complex (PAF1C) regulates all stages of the RNA polymerase II (RNAPII) transcription cycle from the promoter to the 3’ end formation site of mRNA encoding genes and has been linked to numerous transcription related processes. Here, we show that PAF1 interacts with Elongin A, a transcription elongation factor as well as a component of a cullin-RING ligase that targets stalled RNAPII for ubiquitination and proteasome-dependent degradation in response to DNA damage or other stresses. We show that, in absence of any induced stress, PAF1 physically interacts with the E3 ubiquitin ligase form of the Elongin A complex and facilitates ubiquitination of RNAPII. We demonstrate that this ubiquitination is dependent of the Ser2 phosphorylation of the RNAPII carboxy-terminal domain (CTD) by CDK12. Our findings highlight a novel unexpected role of PAF1-CDK12 in RNAPII transcription cycle, raising the possibility that the Elongin A ubiquitin ligase plays a role in normal transcription process, and suggest a transcription surveillance mechanism ready to degrade RNAPII if needed.
Identification of novel antiviral drug combinations in vitro and tracking their development
Authors: Ianevski Aleksandr , Yao Rouan , Biza Svetlana , Zusinaite Eva , Männik Andres , Kivi Gaily , Planken Anu , Kurg Kristiina , Tombak Eva-Maria , Ustav Mart , Shtaida Nastassia , Kulesskiy Evgeny , Jo Eunji , Yang Jaewon , Lysvand Hilde , Løseth Kirsti , Oksenych Valentyn , Aas Per Arne , Tenson Tanel , Vitkauskiene Astra , Windisch Marc P. , Fenstad Mona Høysæter , Nordbø Svein Arne , Ustav Mart , Bjørås Magnar , Kainov Denis
Published: September 2020

Combination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.
The generation of persister cells is regulated at the initiation of translation by (p)ppGpp
Authors: Molina-Quiroz Roberto C. , Camilli Andrew
Published: September 2020

Bacterial persistence is a non-heritable phenotypic trait characterized by a dormant state that leads to tolerance to different antibiotics. Several mechanisms contributing to persister cells generation have been identified. Among these, is the signaling molecule (p)ppGpp, but knowledge of how this molecule regulates persister generation is incomplete. Here, we show an increase of the persister fraction of uropathogenicEscherichia coli(UPEC) that correlates with the time of protein synthesis inhibition and a decrease in the availability of antibiotic target. Specifically, the arrest of translation initiation induces bacterial survival to ampicillin and ciprofloxacin in a (p)ppGpp-dependent manner. These findings support a global mechanism of persister cell generation and establish a regulatory role of the (p)ppGpp molecule in this phenomenon.

Importance

The study of persister cell formation is relevant because this bacterial subpopulation is involved in the emergence of antibiotic resistance and the generation of chronic infections. A role of the (p)ppGpp molecule in the generation of the persister fraction has been described, but the identification of the regulatory mechanism mediated by this alarmone during protein translation and its contribution to persistence has not been described to date. In this work, we show that (p)ppGpp regulates the generation of persister cells at the initiation of the protein synthesis process in UPEC. Our results also suggest that a (p)ppGpp-dependent regulation of translation, might be a global mechanism for the generation of the persister fraction.
Molecular and functional characterization of buffalo nasal epithelial odorant binding proteins and their structural insights byin-silicoand biochemical approach
Authors: Manikkaraja Chidhambaram , Mam Bhavika , Singh Randhir , Nagarathnam Balasubramanian , George Geen , Gulyani Akash , Archunan Govindharaju , Sowdhamini Ramanathan
Published: September 2020

The olfactory system is capable of detecting and distinguishing thousands of environmental odorants that play a key role in reproduction, social behaviours including pheromones influenced classical events. Membrane secretary odorant binding proteins (OBPs) are soluble lipocalins, localized in the nasal membrane of mammals. They bind and carry odorants within the nasal epithelium to putative olfactory transmembrane receptors (ORs). While the existence of OBPs and their significant functions are very well known in insects and laboratory mammals, there is little information about the species-specific OBPs in buffaloes. In fact, the OBP of nasal epithelium has not yet been exploited to develop a suitable technique to detect estrus which is being reported as a difficult task in buffalo. In the present study, using molecular biology and protein engineering approaches, we have cloned six novel OBP isoforms from buffalo nasal epithelium (bnOBPs). Furthermore, 3D model was developed and molecular-docking, dynamics experiments were performed byIn-silicoapproach. In particular, we found four residues (Phe104, Phe134, Phe69 and Asn118) from OBP1a, which had strong binding affinities towards two sex pheromones, specifically oleic acid and p-cresol. We expressed this protein inEscherichia colito examine its involvement in the sex pheromone perception from female buffalo urine and validated through fluorescence quenching studies. Interestingly, fluorescence binding experiments also showed similar strong binding affinities of OBP1a to oleic acid and p-cresol. By using structural data, the binding specificity is also verified by site-directed mutagenesis of the four residues followed by in-vitro binding assays. Our results enable to better understand the functions of different nasal epithelium OBPs in buffaloes. They also lead to improved understanding of the interaction between olfactory proteins and odorants to develop highly selective biosensing devices for non-invasive detection of estrus in buffaloes.
Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer
Authors: Martinez Rafael S. , Salji Mark J. , Rushworth Linda , Ntala Chara , Blanco Giovanny Rodriguez , Hedley Ann , Clark William , Peixoto Paul , Hervouet Eric , Renaude Elodie , Kung Sonia H.Y. , Galbraith Laura C.A. , Nixon Colin , Lilla Sergio , MacKay Gillian M. , Fazli Ladan , Sumpton David , Gleave Martin E. , Zanivan Sara , Blomme Arnaud , Leung Hing Y.
Published: September 2020

Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of threein vivo,androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome.In vivo, SLFN5depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently,SLFN5depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
CRISPRi screens reveal genes modulating yeast growth in lignocellulose hydrolysate
Authors: Gutmann Friederike , Jann Cosimo , Pereira Filipa , Johansson Andreas , Steinmetz Lars M. , Patil Kiran R.
Published: September 2020

Background

Baker’s yeast is a widely used eukaryotic cell factory, producing a diverse range of compounds including biofuels and fine chemicals. The use of lignocellulose as feedstock offers the opportunity to run these processes in an environmentally sustainable way. However, the required hydrolysis pretreatment of lignocellulosic material releases toxic compounds that hamper yeast growth and consequently productivity.

Results

Here, we employ CRISPR interference inS. cerevisiaeto identify genes modulating fermentative growth in plant hydrolysate and in presence of lignocellulosic toxins. We find that at least one third of hydrolysate-associated gene functions are explained by effects of known toxic compounds, such as the decreased growth ofYAP1orHAA1, or increased growth ofDOT6knock-down strains in hydrolysate.

Conclusion

Our study confirms previously known genetic elements and uncovers new targets towards designing more robust yeast strains for the utilization of lignocellulose hydrolysate as sustainable feedstock, and, more broadly, paves the way for applying CRISPRi screens to improve industrial fermentation processes.
Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome
Authors: Heller H.C. , Freeburn A. , Finn D.P. , Munn R.G.K
Published: September 2020

Down Syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS have shown changes in spectral coherence in the field potentials of hippocampus and regions important for executive function such as prefrontal cortex. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from Medial Septum (MS) to regions such as hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus usingin vivoelectrophysiology in the Ts65Dn mouse model of DS in comparison to their non-trisomic 2N littermates. We find changes in hippocampal phenomenology that suggest that MS output, which drives theta rhythm in the hippocampus, is strongly altered. Moreover, we find that this change affects the phasic relationship of both CA1 place cells and gamma rhythms to theta. Since the phasic relationship of both of these aspects of hippocampal phenomenology to theta are thought to be critical for the segregation of encoding and retrieval epochs within hippocampus, it is likely that these changes are the neural substrates of the learning and memory deficits seen both in human DS and animal models such as Ts65Dn.
TIP family aquaporins play role in chloroplast osmoregulation and photosynthesis
Authors: Beebo Azeez , Zia Ahmad , Kinzel Christopher R. , Herdean Andrei , Bouhidel Karim , Kirchhoff Helmut , Schoefs Benoît , Spetea Cornelia
Published: September 2020

Photosynthetic oxygen evolution by photosystem II requires water supply into the chloroplast to reach the thylakoid lumen. A rapid water flow is also required into the chloroplast for optimal oxygen evolution and to overcome osmotic stress. The mechanisms governing water transport in chloroplasts are largely unexplored. Previous proteomics indicated the presence of three aquaporins from the tonoplast intrinsic protein (TIP) family, TIP1;1, TIP1;2 and TIP2;1, in chloroplast membranes ofArabidopsis thaliana. Here we revisited their location and studied their role in chloroplasts. Localization experiments indicated that TIP2;1 resides in the thylakoid, whereas TIP1;2 is present in both thylakoid and envelope membranes. Mutants lacking TIP1;2 and/or TIP2;1 did not display a macroscopic phenotype when grown under standard conditions. The mutant chloroplasts and thylakoids underwent less volume changes than the corresponding wild type preparations upon osmotic treatment and in the light. Significantly reduced rates of photosynthetic electron transport were obtained in the mutant leaves, with implications on the CO2fixation rates. However, electron transport rates did not significantly differ between mutants and wild type when isolated thylakoids were examined. Less acidification of the thylakoid lumen was measured in mutants thylakoids, resulting in a slower induction of delta pH-dependent photoprotective mechanisms. These results identify TIP1;2 and TIP2;1 as chloroplast proteins and highlight their importance for osmoregulation and optimal photosynthesis. A third aquaporin, TIP1;1, is present in the chloroplast envelope, and may play role in photosynthesis under excessive light conditions, as based on the weak photosynthetic phenotype of its mutant.
A flexible and standalone forward simulation model for laboratory X-ray diffraction contrast tomography
Authors: Fang H. , Juul Jensen D. , Zhang Y.
Published: September 2020

Laboratory X-ray diffraction contrast tomography (LabDCT) has recently been developed as a powerful technique for non-destructive mapping of grain microstructures in bulk materials. As the grain reconstruction relies on segmentation of diffraction spots, it is essential to understand the physics of the diffraction process and resolve all the spot features in detail. To this aim, a flexible and standalone forward simulation model has been developed to compute the diffraction projections from polycrystalline samples with any crystal structure. The accuracy of the forward simulation model is demonstrated by good agreements in grain orientations, boundary positions and shapes between a virtual input structure and that reconstructed based on the forward simulated diffraction projections of the input structure. Further experimental verification is made by comparisons of diffraction spots between simulations and experiments for a partially recrystallized Al sample, where a satisfactory agreement is found for the spot positions, sizes and intensities. Finally, applications of this model to analyze specific spot features are presented.