bluuebunny/crossref_metadata_2025 huggingface dataset:
Probiotics supplementation in patients with colorectal cancer: a systematic review of randomized controlled trials
Authors: Dikeocha Ifeoma Julieth , Al-Kabsi Abdelkodose Mohammed , Eid Eltayeb E M , Hussin Salasawati , Alshawsh Mohammed Abdullah
Published: January 2021

Context

Colorectal cancer (CRC) is a leading cause of cancer deaths. Recently, much attention has been given to the microbiome and probiotics as preventive and therapeutic approaches to CRC and the mechanisms involved.

Objectives

To interpret the findings of randomized controlled trials (RCTs) of probiotics relative to patients with CRC and to outline challenges of and future directions for using probiotics in the management and prevention of CRC.

Data sources

Web of Science, PubMed, ProQuest, Wile,y and Scopus databases were searched systematically from January 17–20, 2020, in accordance with PRISMA guidelines.

Study selection

Primacy RCTs that reported the effects of administration to patients with CRC of a probiotic vs a placebo were eligible to be included.

Data Extraction

The studies were screened and selected independently by 2 authors on the basis of prespecified inclusion and exclusion criteria. The data extraction and risk-of-bias assessment were also performed independently by 2 authors.

Results

A total of 23 RCTs were eligible for inclusion. Probiotics supplementation in patients with CRC improved their quality of life, enhanced gut microbiota diversity, reduced postoperative infection complications, and inhibited pro-inflammatory cytokine production. The use of certain probiotics in patients with CRC also reduced the side effects of chemotherapy, improved the outcomes of surgery, shortened hospital stays, and decreased the risk of death. Bifidobacteria and Lactobacillus were the common probiotics used across all studies.

Conclusion

Probiotics have beneficial effects in patients with CRC regardless of the stage of cancer. There is an opportunity for probiotics to be used in mainstream health care as a therapy in the fight against CRC, especially in early stages; however, larger clinical trialsof selected or a cocktail of probiotics are needed to confirm the efficacy, dosage, and interactions with chemotherapeutics agents.

Systematic Review Registration

PROSPERO registration no. CRD42020166865.
What Price Are We Willing to Pay for the Dream of Equal Justice?†
Authors: Higgins Andrew
Published: January 2021

The injustices wrought by unequal access to the legal system pose a direct threat to the rule of law, yet such injustices are widespread in England and elsewhere. Lawyers regularly criticise governments for a lack of funding for the legal system, but the private market for delivering legal services receives much less scrutiny. A private market for legal resources is antithetical to equal justice because it makes the outcome of cases turn on arbitrary factors such as wealth. The solution, according to Wilmot-Smith in his book Equal Justice, is to socialise the allocation of legal services so that the rich cannot buy the best lawyers, and to prevent them from contracting out of this public system by making private arbitrations unenforceable. This review article argues that Wilmot-Smith’s thesis is persuasive, but there might also be second-best solutions that could deliver greater legal equality at lower cost.
Rebuilding public trust: a clarified response to COVID-19 vaccine hesitancy predicament
Authors: Cordero Dalmacito A
Published: January 2021

As the world welcomes the availability and distribution of COVID-19 vaccines, coupled with it is the ‘hesitant’ predicament of some Filipinos to get vaccinated because of the confusing information regarding its efficacy. With this, the government needs to build up public trust to assure a successful vaccination program. A recent study suggested that a more ‘localized’ public education and role-modeling from public officials and health authorities can help in building public trust. However, this needs a lot of clarification if applied in the current situation where education is fully executed online. The problem now lies in the country’s poor internet connectivity which greatly affects the online setup. This study then proposes that a house-to-house massive information campaign by local health care personnel which is led by a medical doctor to ensure a credible explanation of the entire procedure. In the same way, the idea of public officials as role-models seemed to be ineffective since there were already casualties linked to the vaccine. A consistent transparent approach is suggested in lieu of this which can prepare the country for a more defensive strategy to fight the pandemic.
Land Rezoning and Structural Transformation in Rural India: Evidence from the Industrial Areas Program
Authors: Blakeslee David , Chaurey Ritam , Fishman Ram , Malik Samreen
Published: January 2021

Zoning laws that restrict rural land to agricultural production pose an important institutional barrier to industrial development. We study the effects of the Industrial Areas (IA) program in Karnataka, India, which rezoned agricultural land for industrial use, but without the economic incentives common with other place-based policies. We find that the program caused a large increase in firm creation and employment in villages overlapping the IAs. Moreover, the surrounding areas experienced spillover effects, with workers shifting from agricultural to non-agricultural employment, and entrepreneurs establishing numerous small-scale service sector and agricultural firms.
Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection
Authors: Kellum John A. , Artigas Antonio , Gunnerson Kyle J. , Honore Patrick M. , Kampf J. Patrick , Kwan Thomas , McPherson Paul , Nguyen H. Bryant , Rimmelé Thomas , Shapiro Nathan I. , Shi Jing , Vincent Jean-Louis , Chawla Lakhmir S.
Published: January 2021

OBJECTIVES:

Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care.

DESIGN:

Retrospective, international, Sapphire study.

SETTING:

Academic Medical Center.

PATIENTS:

Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We stratified patients enrolled in the Sapphire study into three groups—those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2–3 acute kidney injury within the first 3 days compared with 14% without stage 2–3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53–11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2–3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8–34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury.

CONCLUSIONS:

Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.
Primary Cutaneous B-Cell Lymphoma Complicated by Clonal T-Cell Populations: A Diagnostic Dilemma
Authors: Symes Emily , Dominiak Nicole
Published: January 2021

Cutaneous lymphomas, both B-cell and T-cell, are not uncommonly seen in the skin, but those lymphomas exhibiting clonality for both B-cell and T-cell populations are scarce. Characterization of dual receptor rearrangement as primary composite lymphoma versus primary lymphoma with reactionary response is complex and often a challenge that goes unrecognized. In this study, we report a unique case of T-cell gene rearrangement positivity complicating the diagnosis of primary cutaneous low-grade B-cell lymphoma along with a review of reported cases containing dual receptor rearrangement to identify trends among final diagnostic decisions. As one might guess, for cutaneous lymphomas presenting with clonality for both T-cell and B-cell receptors, diagnosis can be difficult and confusing because the differential is broad. The literature suggests the majority of these cases may be cutaneous composite lymphomas. However, immunohistochemical, clinical, and histomorphologic features must all be assessed for an accurate diagnosis, which is critical for proper prognosis and therapy.
Acupoint Catgut Embedding as Adjunctive Therapy for Patients With Gallstones
Authors: Duan Junyi , Chen Xin , Wang Yixing , Zhao Gang , Li Jing , Gao Yi , Zhang Jinyuan , Wang Xiangrui , Liao Lijun , Chen Yuelai
Published: January 2021

Aims of This Study:

A randomized clinical trial was undertaken to investigate the efficacy of acupoint catgut embedding (ACE) as adjunctive therapy to tauroursodeoxycholic acid (TUDCA) therapy on gallbladder emptying and clinical symptoms in patients with gallstone disease.

Materials and Methods:

Between August 2018 and January 2019, 70 patients with gallstones in our hospital were enrolled in this prospective clinical trial. All the patients were randomly divided into the ACE group (ACE+TUDCA treatment for 8 wk) and the Sham group (Sham ACE+TUDCA treatment for 8 wk). In the ACE group, all the patients were nightly given ACE every 2 weeks, and in 2 groups, every patient took TUDCA 500 mg at bedtime. The parameters about gallbladder emptying were detected by ultrasound before and after the treatment, and the clinical symptom scores were recorded at the same time points.

Results:

A total of 63 patients with gallstone disease were included in our study, with 33 patients in the ACE group and 30 patients in the Sham group. In the ACE group, the empty volume (EV) and gallbladder ejection fraction (GBEF) were improved after treatment (P<0.05). Almost every symptom score (except symptom 7, P=0.15) and total score were decreased (P<0.05). In the Sham group, the symptom 1, 2, 4, 5 scores, and total score were significantly decreased (P<0.05). Moreover, the residual volume in the ACE group was significantly lower than in the Sham group (P=0.008). The EV and GBEF in the ACE group were higher than that in the Sham group (P<0.05). The score of symptom 6 in the ACE group was lower than that in the Sham group (P=0.008).

Conclusion:

ACE therapy could more effectively improve the gallbladder emptying with a shorter treatment course. Therefore, ACE+TUDCA therapy might be a time-saving treatment for gallstones.
“There Should Have Been a More Holistic Approach”—A Qualitative Study of Young Adult Cancer Survivors’ Experiences of Follow-up After Cancer Treatment
Authors: Aase Andrea S. , Ingebretsen Thea K. , Hauken May Aa.
Published: January 2021

Background

Young adult cancer survivors (YACSs) are in a vulnerable period of life with increased risk of severe physical and psychosocial late effects. However, limited research exists on follow-up of YACSs after cancer treatment.

Objective

The aim of this study was to explore how YACSs experience follow-up from the healthcare system after finishing cancer treatment.

Methods

Using a qualitative method with an interpretive descriptive design, 20 YACSs were interviewed 4 times over a period of 6 months. The transcribed interviews were analyzed using Systematic Text Condensation.

Results

Four main themes were identified: “They should have prepared me better,” “The GP (general practitioner) does not understand my challenges,” “My check-ups are all about cancer relapse,” and “I do not know who’s in charge.”

Conclusion

The findings indicate deficiency in the healthcare system’s follow-up of YACSs in terms of preparation for the survival phase, interdisciplinary cooperation, and acknowledgement of late effects, as well as organization of follow-up care within the healthcare system.

Implications for Practice

A more holistic perspective on follow-up care that addresses YACSs’ multidimensional challenges is suggested, including a multidisciplinary approach where cancer nurses should play an active role.
Lymphocytic Esophagitis
Authors: Pittman Meredith E.
Published: January 2021

This review summarizes our current understanding of lymphocytic esophagitis (LE), a novel form of chronic esophagitis that incorporates distinctive histologic, clinical, and endoscopic features. First described as a histologic entity, a diagnosis of LE requires intraepithelial lymphocytosis without significant granulocytic inflammation and some evidence of epithelial damage; the rationale for and studies supportive of these histologic criteria are discussed within. Clinically, the majority of patients who present with histologically confirmed LE are older women or patients with underlying immunologic abnormalities, such as Crohn disease, rheumatologic disorders, or common variable immunodeficiency. The most common presenting symptom of LE is dysphagia, and the endoscopic findings can vary from normal mucosa to mucosal changes that resemble eosinophilic esophagitis: edema, rings, furrows, and plaques. The incidence of luminal strictures and the persistent dysphagia and/or lymphocytosis present in some patients provide evidence that LE is a chronic inflammatory disorder, at least within a subset of individuals. Several histologic mimics of LE are examined, as are disagreements surrounding the LE diagnosis.
Microbacterium karelineae sp. nov. isolated from a halophyte plant in the Taklamakan desert
Authors: Zhu Qi-hui , Yang Cai-ling , Luo Xiao-xia , Zhang Li-li , Xia Zhan-feng
Published: January 2021

A bacterial strain, designated TRM 80801T, was isolated from the Karelinea in Taklamakan desert, Xinjiang Uygur Autonomous Region, north-west China. Cells were Gram-stain-positive, aerobic, non-motile, short rods. Strain TRM 80801T grew at 4–50 °C, with optimum growth at 28 °C, and grew at pH 6.0–11.0 and 1–15 % (w/v) NaCl. Phylogenetic analyses of the 16S rRNA gene sequences placed strain TRM 80801T within the genus

Microbacterium

with the highest similarities to

Microbacterium suaedae

YZYP 306T (98.97 %) and

Microbacterium indicum

BBH6T (98.17 %), respectively. The DNA G+C content of TRM 80801T is 69.38 mol%. The cell-wall peptidoglycan contained the amino acids ornithine, glutamic acid, glycine and alanine, the diagnostic diamino acid was ornithine. The acyl type of the peptidoglycan was glycolyl. Whole-cell sugars were ribose, mannose, glucose, rhamnose and galactose. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The predominant menaquinones were MK-10, MK-11 and MK-12. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol. The whole-genome average nucleotide identity (ANI) value between strain TRM 80801T and

Microbacterium suaedae

YZYP 306T is 70.2 %. On the basis of the evidence presented in this study, strain TRM 80801T is representative of a novel species in the genus

Microbacterium

, for which the name Microbacterium karelineae sp. nov. is proposed. The type strain is TRM 80801T (=CCTCC AB 2019248T=KCTC 49357T).
Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle
Authors: Theret Marine , Low Marcela , Rempel Lucas , Li Fang Fang , Tung Lin Wei , Contreras Osvaldo , Chang Chih-Kai , Wu Andrew , Soliman Hesham , Rossi Fabio M.V.
Published: January 2021

Aim

Fibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors.

Method

We performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under theCollagen1a1promotor. We first confirmed that the EGFP was expressed in response to TGFβ1 stimulationin vitro. Then we treated cells with TGFβ1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were testedin vivoin the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size).

Key findings

From the in vitro drug screening, we identified 21 drugs and tested 3in vivoon the mdx mice. None of the three drugs significantly improved muscle histopathology.

Significance

Thein vitrodrug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.
In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response
Authors: Schaller Matthew A. , Sharma Yamini , Dupee Zadia , Nguyen Duy , Uruena Juan , Smolchek Ryan , Loeb Julia C. , Machuca Tiago N. , Lednicky John A. , Odde David J. , Campbell Robert F. , Sawyer W. Gregory , Mehrad Borna
Published: January 2021

Cell lines are the mainstay in understanding the biology of COVID-19 infection, but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue allows for thein vitrostudy of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 16 donors, most of whom had risk factors for severe illness from COVID-19. Cryopreserved tissues preserved 90% of cell viability and contained heterogeneous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infectible with HCoV-OC43 and SARS-CoV-2 coronavirus strains, and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL-6, CXCL8 and IFNβ in response to SARS-CoV-2 infection. Treatment of tissues with dexamethasone and the experimental drug, N-hydroxycytidine, suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted antiviral activity, suppressed viral replication in tissues from a subset of donors. In summary, we developed a novel system for thein vitrostudy of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.

Importance

The current biological systems for the study of COVID-19 arein vitrosystems that differ from the human lung in many respects, and animal hosts to which the virus is not adapted. We developed another alternative for studying pathogenesis and drug susceptibility of SARS-CoV-2 in a cryopreserved bank of human lung tissues. We consider the importance of this work to relate to the practical use of this culture system as a repeatable and scalable approach that allows for the study of an important infection in relevant tissues.

The tissue bank highlights the heterogeneous response to SARS-CoV-2 infection and treatment, which allows researchers to investigate why treatments work in some donors but not others.
Symptoms of anxiety and depression in relation to work patterns during the first wave of the COVID-19 epidemic in Philadelphia PA: a cross-sectional survey
Authors: Burstyn Igor , Huynh Tran
Published: January 2021

Objective

We investigated whether patterns of work during COVID-19 pandemic altered by effort to contain the outbreak affected anxiety and depression.

Methods

We conducted a cross-sectional online survey of 911 residents of Philadelphia, inquiring about their working lives during early months of the epidemic, symptoms of anxiety and depression, plus demographics, perceived sources of support, and general health.

Results

Occupational contact with suspected COVID-19 cases was associated with anxiety. Concerns about return to work, childcare, lack of sick leave, and loss/reduction in work correlated with anxiety and depression, even when there was no evidence of occupational contact with infected persons; patterns differed by gender.

Conclusions

Heightened anxiety and depression during COVID-19 pandemic can be due to widespread disruption of working lives, especially in “non-essential” low-income industries, on par with experience in healthcare.

The significance to clinical practice of the information being presented:Anxiety and depression symptoms that emerged during COVID-19 pandemic may be related to disruption of working lives even among people who are not the “essential” workers with one-one-one contact with infected persons. Clinicians may find this evidence of occupational correlates and articulated specific worries useful in treating such patients.
Age-dependent heterogeneity of lymph node metastases and survival identified by analysis of a national breast cancer registry
Authors: Behring Michael , Bajpai Prachi , Afaq Farrukh , Elkholy Amr , Kim Hyung-Gyoon , Diffalha Sameer Al , Shrestha Sadeep , Manne Upender
Published: January 2021

Background

For several cancers, including those of the breast, young age at diagnosis is associated with an adverse prognosis. Although this effect is often attributed to heritable mutations such as BRCA1/2, the relationship between pathologic features, young age of onset, and prognosis for breast cancer remains unclear. In the present study, we highlight links between age of onset and lymph node metastasis (NM) in US women with breast cancer.

Methods

Case listings from Surveillance, Epidemiology, and End Result (SEER) 18 registry data for women with breast cancer, which include information on race, were used. NM and its associated outcomes were evaluated for a subset of women with receptor subtype information and then compared against a larger, pre-subtype validation set of data from the same registry. Age of diagnosis was a 5-category variable; under 40 years, 40-49 years, 50-59 years, 60-69 years and 70+ years. Univariate and adjusted multivariate survival models were applied to both sets of data.

Results

As determined with adjusted logistic regression models, women under 40 years old at diagnosis had 1.55 times the odds of NM as women 60-69 years of age. The odds of NM for (HR = hormone receptor) HR+/HER2+, HR-/HER2+, and triple-negative breast cancer subtypes were significantly lower than those for HR+/HER2-. In subtype-stratified adjusted models, age of diagnosis had a consistent trend of decreasing odds of NM by age category, most noticeable for HR+ subtypes of luminal A and B. Univariate 5-year survival by age was worst for women under 40 years, with NM attributable for 49% of the hazard of death from cancer in adjusted multivariate models.

Conclusions

Lymph node metastasis is age-dependent, yet not all molecular subtypes are clearly affected by this relationship. For <40-yr-old women, NM is a major cause for shorter survival. When stratified by subtype, the strongest associations were in HR+ groups, suggesting a possible hormonal connection between young age of breast cancer onset and NM.
Theoretical framework for retrospective studies of the effectiveness of SARS-CoV-2 vaccines
Authors: Lewnard Joseph A. , Patel Manish M. , Jewell Nicholas P. , Verani Jennifer R. , Kobayashi Miwako , Tenforde Mark , Dean Natalie E. , Cowling Benjamin J. , Lopman Benjamin A.
Published: January 2021

Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. These are now in planning amid the ongoing rollout of SARS-CoV-2 vaccines globally. While traditional case-control (TCC) and test-negative design (TND) studies feature prominently among strategies used to assess vaccine effectiveness, such studies may encounter important threats to validity. Here we review the theoretical basis for estimation of vaccine direct effects under TCC and TND frameworks, addressing specific natural history parameters of SARS-CoV-2 infection and COVID-19 relevant to these designs. Bias may be introduced by misclassification of cases and controls, particularly when clinical case criteria include common, non-specific indicators of COVID-19. When using diagnostic assays with high analytical sensitivity for SARS-CoV-2 detection, individuals testing positive may be counted as cases even if their symptoms are due to other causes. The TCC may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The TND reduces but may not eliminate this confounding, for instance if individuals who receive vaccination seek care or testing for less-severe infection. These circumstances indicate the two study designs cannot be applied naively to datasets gathered through public health surveillance or administrative sources. We suggest practical strategies to reduce bias in vaccine effectiveness estimates at the study design and analysis stages.
Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells
Authors: Vilaplana-Lopera Nuria , Almaghrabi Ruba , Papatzikas Grigorios , Cuminetti Vincent , Jeeves Mark , González Elena , Cunningham Alan , Erdem Ayşegül , Schnuetgen Frank , Raghavan Manoj , Potluri Sandeep , Cazier Jean-Baptiste , Schuringa Jan Jacob , Reed Michelle AC , Arranz Lorena , Günther Ulrich L , Garcia Paloma
Published: January 2021

Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, it is unclear whether AML cells could establish beneficial metabolic interactions with stromal cells. Here, we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA). By performing transcriptome analysis, tracer-based metabolic NMR analysis and ROS measurements, we observe that stromal cells present a higher rate of glycolysis. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells that could potentially be exploited for adjuvant therapy.
SARS-CoV-2 Can Infect Human Embryos
Authors: Montano Mauricio , Victor Andrea R. , Griffin Darren K. , Duong Tommy , Bolduc Nathalie , Farmer Andrew , Garg Vidur , Hadjantonakis Anna-Katerina , Coates Alison , Barnes Frank L. , Zouves Christo G. , Greene Warner C. , Viotti Manuel
Published: January 2021

The spread of SARS-CoV-2 has led to a devastating pandemic, with infections resulting in a range of symptoms collectively known as COVID-19. The full repertoire of human tissues and organs susceptible to infection is an area of active investigation, and some studies have implicated the reproductive system. The effects of COVID-19 on human reproduction remain poorly understood, and particularly the impact on early embryogenesis and establishment of a pregnancy are not known. In this work, we explore the susceptibility of early human embryos to SARS-CoV-2 infection. We note that ACE2 and TMPRSS2, two canonical cell entry factors for SARS-CoV-2, are co-expressed in cells of the trophectoderm in blastocyst-stage preimplantation embryos. Using fluorescent reporter virions pseudotyped with Spike (S) glycoprotein from SARS-CoV-2, we observe robust infection of trophectoderm cells, and this permissiveness could be attenuated with blocking antibodies targeting S or ACE2. When exposing human blastocysts to the live, fully infectious SARS-CoV-2, we detected cases of infection that compromised embryo health. Therefore, we identify a new human target tissue for SARS-CoV-2 with potential medical implications for reproductive health during the COVID-19 pandemic and its aftermath.
Efficacy of bacteriophage therapy against vancomycin-resistantEnterococcus feacalisin induced and non-induced diabetic mice
Authors: Oli Ajay Kumar , Shivshetty Nagveni , Ahmed Likyat , Chavadi Manjunath , Kambar Rahul N , Kelmani Chandrakanth R
Published: January 2021

The antibiotic resistance of an organism has become an endeavor worldwide. The resistance of bacteria is impacting the immunocompromised patient, especially with diabetic. The bacteriophages are more specific in the elimination of the infections caused by the organism. One of the significant bacteria is Vancomycin-resistantEnterococcus faecalis(VREF), emerging as bioburden rendering infectious diseases in developing countries. We attempted to treat infection of VREF in the induced and non-induced diabetic mice model along with antibiotic and phage treatment. The phage has shown more efficiency than vancomycin antibiotic alone and combined therapy with antibiotic phage treated. The considering phage therapy an alternative source for the treatment in the insulin-dependent diabetic with an infection of bacteria.
4D imaging of soft matter in liquid water
Authors: Marchello Gabriele , De Pace Cesare , Acosta-Gutierrez Silvia , Lopez-Vazquez Ciro , Wilkinson Neil , Gervasio Francesco L. , Ruiz-Perez Lorena , Battaglia Giuseppe
Published: January 2021

Water is a critical component for both function and structure of soft matter and it is what bestows the adjective soft. Imaging samples in liquid state is thus paramount to gathering structural and dynamical information of any soft materials. Herein we propose the use of liquid phase electron microscopy to expand ultrastructural analysis into dynamical investigations. We imaged two soft matter examples: a polymer micelle and a protein in liquid phase using transmission electron microscopy and demonstrate that the inherent Brownian motion associated with the liquid state can be exploited to gather three-dimensional information of the materials in their natural state. We call such an approach brownian tomography (BT). We combine BT with single particle analysis (Brownian particle analysis BPA) to image protein structures with a spatial resolution close that achievable using cryogenic TEM. We show that BPA allows sub-nanometer resolution of soft materials and enables to gather information on conformational changes, hydration dynamics, and the effect of thermal fluctuations.

Abstract Figure
Genetic analysis of the septal peptidoglycan synthase FtsWI complex supports a conserved activation mechanism for SEDS-bPBP complexes
Authors: Li Ying , Gong Han , Zhan Rui , Ouyang Shushan , Park Kung-tae , Lutkenhaus Joe , Du Shishen
Published: January 2021

SEDS family peptidoglycan (PG) glycosyltransferases RodA and FtsW require their cognate transpeptidases PBP2 and FtsI (class B penicillin binding proteins) to synthesize PG along the cell cylinder and at the septum, respectively. The activities of these SEDS-bPBPs complexes are tightly regulated to ensure proper cell elongation and division. InEscherichia coliFtsN switches FtsA and FtsQLB to the active forms that synergize to stimulate FtsWI, but the exact mechanism is not well understood. Previously, we isolated an activation mutation inftsW(M269I) that allows cell division with reduced FtsN function. To try and understand the basis for activation we isolated additional substitutions at this position and found that only the original substitution produced an active mutant whereas drastic changes resulted in an inactive mutant. In another approach we isolated suppressors of an inactive FtsL mutant and obtained FtsWE289Gand FtsIK211Iand found they bypassed FtsN. Epistatic analysis of these mutations and others confirmed that the FtsN-triggered activation signal goes from FtsQLB to FtsI to FtsW. Mapping these mutations and others affecting the activities of FtsWI on the RodA-PBP2 structure revealed they are located at the interaction interface between the extracellular loop 4 (ECL4) of FtsW and the pedestal domain of FtsI (PBP3). This supports a model in which the interaction between the ECL4 of SEDS proteins and the pedestal domain of their cognate bPBPs plays a critical role in the activation mechanism.

Author summary

Bacterial cell division requires the synthesis of septal peptidoglycan by the widely conserved SEDS-bPBP protein complex FtsWI, but how the complex is activated during cell division is still poorly understood. Previous studies suggest that FtsN initiates a signaling cascade in the periplasm to activate FtsW. Here we isolated and characterized activated FtsW and FtsI mutants and confirmed that the signaling cascade for FtsW activation goes from FtsN to FtsQLB to FtsI and then to FtsW. The residues corresponding to mutations affecting FtsWI activation are clustered to a small region of the interaction interface between the pedestal domain of FtsI and the extracellular loop 4 of FtsW, suggesting that this interaction mediates activation of FtsW. This is strikingly similar to the proposed activation mechanism for the RodA-PBP2 complex, another SEDS-bPBP complex required for cell elongation. Thus, the two homologous SEDS-bPBP complexes are activated similarly by completely unrelated activators that modulate the interaction interface between the SEDS proteins and the bPBPs.
Pannexin 1 influences lineage specification of human iPSCs
Authors: Noort Rebecca J. , Christopher Grace A. , Esseltine Jessica L.
Published: January 2021

Every single cell in the body communicates with nearby cells to locally organize activities with their neighbors and dysfunctional cell-cell communication can be detrimental during cell lineage commitment, tissue patterning and organ development.Pannexin channels (PANX1, PANX2, PANX3)facilitate purinergic paracrine signaling through the passage of messenger molecules out of cells. PANX1 is widely expressed throughout the body and has recently been identified in human oocytes as well as 2 and 4-cell stage human embryos. Given its abundance across multiple adult tissues and its expression at the earliest stages of human development, we sought to understand whether PANX1 impacts human induced pluripotent stem cells (iPSCs) or plays a role in cell fate decisions. Western blot, immunofluorescence and flow cytometry reveal that PANX1 is expressed in iPSCs as well as all three germ lineages derived from these cells: ectoderm, endoderm, and mesoderm. PANX1 demonstrates differential glycosylation patterns and subcellular localization across the germ lineages. Using CRISPR-Cas9 gene ablation, we find that loss of PANX1 has no obvious impact on iPSC morphology, survival, or pluripotency gene expression. However,PANX1knockout iPSCs exhibit apparent lineage specification bias during 2-dimensional and 3-dimensional spontaneous differentiation into the three germ lineages. Indeed, loss of PANX1 significantly decreases the proportion of ectodermal cells within spontaneously differentiated cultures, while endodermal and mesodermal representation is increased in PANX1 knockout cells. Importantly,PANX1knockout iPSCs are fully capable of differentiating toward each specific lineage when exposed to the appropriate external signaling pressures, suggesting that although PANX1 influences germ lineage specification, it is not essential to this process.

Graphical abstract
Restoring fertility in yeast hybrids: breeding and quantitative genetics of beneficial traits
Authors: Naseeb S. , Visinoni F. , Hu Y. , Hinks Roberts A. J. , Maslowska A. , Walsh T. , Smart K. A. , Louis E. J. , Delneri D.
Published: January 2021

Hybrids species can harbour a combination of beneficial traits from each parent and may exhibit hybrid vigour, more readily adapting to new harsher environments. Inter-species hybrids are also sterile and therefore an evolutionary dead-end unless fertility is restored, usually via auto-polyploidisation events. In theSaccharomycesgenus, hybrids are readily found in nature and in industrial settings, where they have adapted to severe fermentative conditions. Due to their hybrid sterility, the development of new commercial yeast strains has so far been primarily conducted via selection methods rather than breeding. In this study, we overcame infertility by creating tetraploid intermediates ofSaccharomycesinter-species hybrids, to allow continuous multigenerational breeding. We incorporated nuclear and mitochondrial genetic diversity within each parental species, allowing for quantitative genetic analysis of traits exhibited by the hybrids, and for nuclear-mitochondrial interactions to be assessed. Using pooled F12 generation segregants of different hybrids with extreme phenotype distributions, we identified QTLs for tolerance to high and low temperatures, high sugar concentration, high ethanol concentration, and acetic acid levels. We identified QTLs that are species specific, that are shared between species, as well as hybrid specific, where the variants do not exhibit phenotypic differences in the original parental species. Moreover, we could distinguish between mitochondria-type dependent and independent traits. This study tackles the complexity of the genetic interactions and traits in hybrid species, bringing hybrids into the realm of full genetic analysis of diploid species, and paves the road for the biotechnological exploitation of yeast biodiversity.
T cell circuits that sense antigen density with an ultrasensitive threshold
Authors: Hernandez-Lopez Rogelio A. , Yu Wei , Cabral Katie , Creasey Olivia , del Pilar Lopez Pazmino Maria , Tonai Yurie , De Guzman Arsenia , Mäkelä Anna , Saksela Kalle , Gartner Zev J. , Lim Wendell A.
Published: January 2021

Overexpressed tumor associated antigens (e.g. HER2 and EGFR) are attractive targets for therapeutic T cells, but toxic cross-reaction with normal tissues expressing low antigen levels has been observed with Chimeric Antigen Receptor (CAR) T cells targeting such antigens. Inspired by natural ultrasensitive response circuits, we engineer a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity SynNotch receptor for HER2 controls the expression of a high affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells ╌ it both increases CAR expression and activation ╌ leading to a sigmoidal response. T Cells with this circuit show sharp discrimination between target cells expressing normal and disease levels of HER2, bothin vitroandin vivo.

One Sentence Summary

A two-step positive feedback circuit generates engineered T cells capable of killing target cells with an ultrasensitive antigen density threshold.
Ready-to-drink beverage (RTD) consumption in Thai population: trend and associated factors
Authors: Saengow Udomsak , Asksonthong Ruttiya , Laohaprapanon Apinya
Published: January 2021

Objectives

To examine ready-to-drink beverage (RTD) consumption and to investigate the effects of gender and age on RTD consumption by using data 2011 and 2014 waves of a national alcohol survey.

Design

Analysis of data from Smoking and Drinking Behavior Survey (SADBeS) 2011 and 2014, a nationally representative survey.

Setting

Thailand

Participants

177,350 (2011 survey) and 25,758 (2014 survey) samples of Thais aged 15 years or older who were randomly selected using multistage-sampling technique.

Primary outcome

RTD consumption in past 12 months (yes/no) as stated by survey participants

Results

The prevalence of RTD drinkers increased from 0.5% (95% CI, 0.5-0.5%) in 2011 to 2.4% (95% CI, 2.1-2.6%) in 2014. Female drinkers were 5.1 (95% CI, 4.1-6.4) times more likely to consume RTDs than male drinkers. The likelihood of drinking RTDs decreased with age. Drinking initiation before the legal purchasing age (20 years old) was associated with 1.5 (95% CI, 1.1-1.9) times likelihood of RTDs consumption.

Conclusions

A substantial increase in RTD consumption was observed in Thailand, a middle-income country, during 2011-2014. The consumption was notable in youths and females. Given that RTDs have been introduced into the Thai market relatively recently, this may be a part of the alcohol industry strategies to boost their sales in middle-income countries. Growth in RTD consumption could pose a challenge for health authorities to control alcohol-related harms in the future especially among youths and females.

Article Summary

Strengths and limitations of this study

A reliable estimate of prevalence of RTD consumption was obtained by using data from two waves of a large national representative survey.

The lack of information about pattern of RTD consumption including quantity and drinking frequency limited further analysis.

Funding

This work was supported by the Center for Alcohol Studies, Thailand, grant number 62-02029-0043.

Competing interests statement

None declared.
Implementation of a self-consistent slab model of bilayer structure in the SasView suite
Authors: Tan Luoxi , Elkins James G. , Davison Brian H. , Kelley Elizabeth G. , Nickels Jonathan
Published: January 2021

Slab models are simple and useful structural descriptions which have long been used to describe lyotropic lamellar phases, such as lipid bilayers. Typically, slab models assume a midline symmetry and break a bilayer structure into three pieces, a central solvent-free core and two symmetric outer layers composed of the soluble portion of the amphiphile and associated solvent. This breakdown matches reasonably well to the distribution of neutron scattering length density and therefore is a convenient and common approach for the treatment of small-angle scattering data. Here, an implementation of this model within the SasView software suite is reported. The implementation is intended to provide physical consistency through the area per amphiphile molecule and number of solvent molecules included within the solvent-exposed outer layer. The proper use of this model requires knowledge of (or good estimates for) the amphiphile and solvent molecule volume and atomic composition, ultimately providing a self-consistent data treatment with only two free parameters: the lateral area per amphiphile molecule and the number of solvent molecules included in the outer region per amphiphile molecule. The use of this code is demonstrated in the fitting of standard lipid bilayer data sets, obtaining structural parameters consistent with prior literature and illustrating the typical and ideal cases of fitting for neutron scattering data obtained using single or multiple contrast conditions. While demonstrated here for lipid bilayers, this model is intended for general application to block copolymers, surfactants, and other lyotropic lamellar phase structures for which a slab model is able to reasonably estimate the neutron scattering length density/electron-density profile of inner and outer layers of the lamellae.
Illustrated formalisms for total scattering data: a guide for new practitioners
Authors: Peterson Peter F. , Olds Daniel , McDonnell Marshall T. , Page Katharine
Published: January 2021

The total scattering method is the simultaneous study of both the real- and reciprocal-space representations of diffraction data. While conventional Bragg-scattering analysis (employing methods such as Rietveld refinement) provides insight into the average structure of the material, pair distribution function (PDF) analysis allows for a more focused study of the local atomic arrangement of a material. Generically speaking, a PDF is generated by Fourier transforming the total measured reciprocal-space diffraction data (Bragg and diffuse) into a real-space representation. However, the details of the transformation employed and, by consequence, the resultant appearance and weighting of the real-space representation of the system can vary between different research communities. As the worldwide total scattering community continues to grow, these subtle differences in nomenclature and data representation have led to conflicting and confusing descriptions of how the PDF is defined and calculated. This paper provides a consistent derivation of many of these different forms of the PDF and the transformations required to bridge between them. Some general considerations and advice for total scattering practitioners in selecting and defining the appropriate choice of PDF in their own research are presented. This contribution aims to benefit people starting in the field or trying to compare their results with those of other researchers.
Incomplete proline catabolism drives premature sperm aging
Authors: Yen Chia‐An , Curran Sean P.
Published: January 2021

Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on reproductive health, however, the impact of altering cellular metabolism and its endogenous reactive oxygen species (ROS) on fertility remains unclear. Here, we demonstrate the loss of proline dehydrogenase, the first committed step in proline catabolism, is relatively benign. In contrast, disruption of alh‐6, which facilitates the second step of proline catabolism by converting 1‐pyrroline‐5‐carboxylate (P5C) to glutamate, results in premature reproductive senescence, specifically in males. The premature reproductive senescence in alh‐6 mutant males is caused by aberrant ROS homeostasis, which can be countered by genetically limiting the first committed step of proline catabolism that functions upstream of ALH‐6 or by pharmacological treatment with antioxidants. Taken together, our work uncovers proline metabolism as a critical component of normal sperm function that can alter the rate of aging in the male reproductive system.
Everyday Madness
Authors: Appignanesi Lisa , Scott Ann
Published: January 2021

In this conference conversation, Lisa Appignanesi reads from her recently published memoir Everyday Madness: On Grief, Anger, Loss and Love, written after the death of her husband, the historian John Forrester. In the memoir she attempts to understand the grieving process and the rage that overtook her after his death. In conversation with the editor of the BJP, she comments on the symbolic import of ‘last words', illness and death as forms of contagion, the nature of the caring relationship, and the way in which the dead inhabit us. The conversation moves on to the way in which her grandson's presence enables her gradually to move away from her rage, along with the birth of a second grandson – the arrival of new life. Comments from the floor, focusing on the nature of care, follow.