bluuebunny/crossref_metadata_2025 huggingface dataset:
Degradation of epigallocatechin and epicatechin gallates by a novel tannase TanHcw from Herbaspirillum camelliae
Authors: Lei Jia , Zhang Yong , Ni Xuechen , Yu Xuejing , Wang Xingguo
Published: October 2021

Background

Herbaspirillum camelliae is a gram-negative endophyte isolated from the tea plant. Both strains WT00C and WT00F were found to hydrolyze epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) to release gallic acid (GA) and display tannase activity. However, no tannase gene was annotated in the genome of H. camelliae WT00C.

Results

The 39 kDa protein, annotated as the prolyl oligopeptidase in the NCBI database, was finally identified as a novel tannase. Its gene was cloned, and the enzyme was expressed in E. coli and purified to homogeneity. Moreover, enzymatic characterizations of this novel tannase named TanHcw were studied. TanHcw was a secretary enzyme with a Sec/SPI signal peptide of 48 amino acids at the N-terminus, and it catalyzed the degradation of tannin, methyl gallate (MG), epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG). The optimal temperature and pH of TanHcw activities were 30 °C, pH 6.0 for MG and 40 °C, pH 7.0 for both EGCG and ECG. Na+, K+ Mn2+ and Triton-X100, Tween80 increased the enzyme activity of TanHcw, whereas Zn2+, Mg2+, Hg2+, EMSO, EDTA and β-mercaptoethanol inhibited enzyme activity. Km, kcat and kcat /Km of TanHcw were 0.30 mM, 37.84 s−1, 130.67 mM−1 s−1 for EGCG, 0.33 mM, 34.59 s−1, 105.01 mM−1 s−1 for ECG and 0.82 mM, 14.64 s−1, 18.17 mM−1 s−1 for MG, respectively.

Conclusion

A novel tannase TanHcw from H. camelliae has been identified and characterized. The biological properties of TanHcw suggest that it plays a crucial role in the specific colonization of H. camelliae in tea plants. Discovery of the tannase TanHcw in this study gives us a reasonable explanation for the host specificity of H. camelliae. In addition, studying the characteristics of this enzyme offers the possibility of further defining its potential in industrial application.
Licorice extract inhibits growth of non-small cell lung cancer by down-regulating CDK4-Cyclin D1 complex and increasing CD8+ T cell infiltration
Authors: Zhu Jinglin , Huang Ruifei , Yang Ruijie , Xiao Yue , Yan Jiangna , Zheng Chunli , Xiao Wei , Huang Chao , Wang Yonghua
Published: October 2021

Background

Targeting tumor microenvironment (TME) may provide therapeutic activity and selectivity in treating cancers. Therefore, an improved understanding of the mechanism by which drug targeting TME would enable more informed and effective treatment measures. Glycyrrhiza uralensis Fisch (GUF, licorice), a widely used herb medicine, has shown promising immunomodulatory activity and anti-tumor activity. However, the molecular mechanism of this biological activity has not been fully elaborated.

Methods

Here, potential active compounds and specific targets of licorice that trigger the antitumor immunity were predicted with a systems pharmacology strategy. Flow cytometry technique was used to detect cell cycle profile and CD8+ T cell infiltration of licorice treatment. And anti-tumor activity of licorice was evaluated in the C57BL/6 mice.

Results

We reported the G0/G1 growth phase cycle arrest of tumor cells induced by licorice is related to the down-regulation of CDK4-Cyclin D1 complex, which subsequently led to an increased protein abundance of PD-L1. Further, in vivo studies demonstrated that mitigating the outgrowth of NSCLC tumor induced by licorice was reliant on increased antigen presentation and improved CD8+ T cell infiltration.

Conclusions

Briefly, our findings improved the understanding of the anti-tumor effects of licorice with the systems pharmacology strategy, thereby promoting the development of natural products in prevention or treatment of cancers.
Analysing malaria events from 1840 to 2020: the narrative told through postage stamps
Authors: Brabin Bernard
Published: October 2021

The role played by postage stamps in the history of malaria control and eradication has largely gone unrecognized. Scientific investigators of malaria, especially Nobel laureates, were commemorated with special issues, but the work of the World Health Organization (WHO), which promoted an ambitious and global philatelic initiative in 1962 to support global eradication, is generally overlooked. This review examines the philatelic programme that helped to generate international commitment to the goal of malaria eradication in 1962 and established philatelic malaria icons that had worldwide recognition. Malaria-related postage stamps have continued to be issued since then, but the initial failure of malaria eradication and the changing goals of each new malaria programme, inevitably diluted their role. After the first Global Malaria Eradication Campaign was discontinued in 1969, few Nations released philatelic issues. Since the Spirit of Dakar Call for Action in 1996 a resurgence of postage stamp releases has occurred, largely tracking global malaria control initiatives introduced between 1996 and 2020. These releases were not co-ordinated by the WHO as before, were more commercialized and targeted stamp collectors, especially with attractive miniature sheets, often produced by photomontage. Having a different purpose, they demonstrated a much wider diversity in symbolism than the earlier stylized issues and at times, have been scientifically inaccurate. Nonetheless postage stamps greatly helped to communicate the importance of malaria control programmes to a wide audience and to some extent, have supported preventive health messages.
Assessing demographic access to hip replacement surgery in the United Kingdom: a systematic review
Authors: Ryan-Ndegwa Sebastian , Zamani Reza , Akrami Mohammad
Published: October 2021

Persisting evidence suggests significant socioeconomic and sociodemographic inequalities in access to medical treatment in the UK. Consequently, a systematic review was undertaken to examine these access inequalities in relation to hip replacement surgery. Database searches were performed using MEDLINE, PubMed and Web of Science. Studies with a focus on surgical need, access, provision and outcome were of interest. Inequalities were explored in the context of sociodemographic characteristics, socioeconomic status (SES), geographical location and hospital-related variables. Only studies in the context of the UK were included. Screening of search and extraction of data were performed and 482 articles were identified in the database search, of which 16 were eligible. Eligible studies consisted of eight cross-sectional studies, seven ecological studies and one longitudinal study. Although socioeconomic inequality has somewhat decreased, lower SES patients and ethnic minority patients demonstrate increased surgical needs, reduced access and poor outcomes. Lower SES and Black minority patients were younger and had more comorbidities. Surgical need increased with age. Women had greater surgical need and provision than men. Geographical inequality had reduced in Scotland, but a north-south divide persists in England. Rural areas received greater provision relative to need, despite increased travel for care. In all, access inequalities remain widespread and policy change driven by research is needed.
AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway
Authors: Pokhrel Ram Hari , Acharya Suman , Ahn Jae-Hee , Gu Ye , Pandit Mahesh , Kim Jong-Oh , Park Yun-Yong , Kang Ben , Ko Hyun-Jeong , Chang Jae-Hoon
Published: October 2021

Background

AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined.

Methods

AMPKα1fl/flFoxp3YFP-Cre, Foxp3YFP-Cre, Rag1−/−, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation.

Results

The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3β (GSK-3β), inhibiting the expression of PD-1 in Tregs.

Conclusion

Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3β signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.
Community health workers at the dawn of a new era: 8. Incentives and remuneration
Authors: Colvin Christopher J. , Hodgins Steve , Perry Henry B.
Published: October 2021

Background

This is the eighth in our series of 11 papers on “CHWs at the Dawn of a New Era”. Community health worker (CHW) incentives and remuneration are core issues that affect the performance of individual CHWs and the performance of the overall CHW programme. A better understanding of what motivates CHWs and a stronger awareness of the social justice dimensions of remuneration are essential in order to build stronger CHW programmes and to support the professionalization of the CHW workforce.

Methods

We provide examples of incentives that have been provided to CHWs and identify factors that motivate and demotivate CHWs. We developed our findings in this paper by synthesizing the findings of a recent review of CHW motivation and incentives in a wide variety of CHW programmes with detailed case study data about CHW compensation and incentives in 29 national CHW programmes.

Results

Incentives can be direct or indirect, and they can be complementary/demand-side incentives. Direct incentives can be financial or nonfinancial. Indirect incentives can be available through the health system or from the community, as can complementary, demand-side incentives. Motivation is sustained when CHWs feel they are a valued member of the health system and have a clear role and set of responsibilities within it. A sense of the “do-ability” of the CHW role is critical in maintaining CHW motivation. CHWs are best motivated by work that provides opportunities for personal growth and professional development, irrespective of the direct remuneration and technical skills obtained. Working and social relationships among CHWs themselves and between CHWs and other healthcare professionals and community members strongly shape CHW motivation.

Conclusion

Our findings support the recent guidelines for CHWs released by WHO in 2018 that call for CHWs to receive a financial package that corresponds to their job demands, complexity, number of hours worked, training, and the roles they undertake. The guidelines also call for written agreements that specify the CHW’s role and responsibilities, working conditions, remuneration, and workers’ rights.
Community health workers at the dawn of a new era: 1. Introduction: tensions confronting large-scale CHW programmes
Authors: Hodgins Stephen , Kok Maryse , Musoke David , Lewin Simon , Crigler Lauren , LeBan Karen , Perry Henry B.
Published: October 2021

Background

Community health worker (CHW) programmes are again receiving more attention in global health, as reflected in important recent WHO guidance. However, there is a risk that current CHW programme efforts may result in disappointing performance if those promoting and delivering them fail to learn from past efforts. This is the first of a series of 11 articles for a supplement entitled “Community Health Workers at the Dawn of a New Era”.

Methods

Drawing on lessons from case studies of large well-established CHW programmes, published literature, and the authors’ experience, the paper highlights major issues that need to be acknowledged to design and deliver effective CHW programmes at large scale. The paper also serves as an introduction to a set of articles addressing these issues in detail.

Results

The article highlights the diversity and complexity of CHW programmes, and offers insights to programme planners, policymakers, donors, and others to inform development of more effective programmes. The article proposes that be understood as actors within community health system(s) and examines five tensions confronting large-scale CHW programmes; the first two tensions concern the role of the CHW, and the remaining three, broader strategic issues:

What kind of an actor is the CHW? A lackey or a liberator? Provider of clinical services or health promoter?

Lay versus professional?

Government programme at scale or nongovernmental organization-led demonstration project?

Standardized versus tailored to context?

Vertical versus horizontal?

Conclusion

CHWs can play a vital role in primary healthcare, but multiple conditions need to be met for them to reach their full potential.
Community health workers at the dawn of a new era: 7. Recent advances in supervision
Authors: Westgate Carey , Musoke David , Crigler Lauren , Perry Henry B.
Published: October 2021

Background

Supervision is essential for optimizing performance and motivation of community health workers (CHWs). This paper, the seventh in our series, “Community health workers at the dawn of a new era”, supplements the existing evidence on CHW supervision in low- and middle-income countries by reviewing what supervision approaches are employed in specific contexts, identifying potential facilitators of CHW supervision including mobile health (mHealth) interventions, and noting challenges of supervision including the relationship between supervision and other CHW programme elements.

Methods

For this exploratory research study on CHW supervision, we reviewed the supervisory interventions described in a compendium of 29 case studies of large-scale CHW programmes, performed an electronic search of multiple databases to identify articles related to CHW supervision published between 15 June 2017 and 1 December 2020, and from those articles followed additional references that appeared to be relevant for our results.

Results

We reviewed 55 case studies, academic articles, and grey literature resources as part of this exploratory research. A variety of supervision approaches have been adapted over time, which we grouped into five categories: external supervision, community supervision, group supervision, peer supervision, and dedicated supervision. These approaches are frequently used in combination. Digital (mHealth) technologies are being explored as potential facilitators of CHW supervision in both small- and large-scale programmes; however, evidence of their effectiveness remains limited to date. Inadequate support for supervisors is a major challenge, particularly given the numerous and varied roles they are expected to fulfil, spanning administrative, clinical, and supportive activities. Supervisors can help CHWs acquire other critical elements needed from the health system for them to perform more effectively: incentives to foster motivation, clarity of roles and tasks, adequate tools and supplies, appropriate knowledge and skills, and a safe work environment.

Conclusion

In the absence of a universal “best approach” for CHW supervision, our recommendation is that countries and programmes prioritize homegrown evolution over time to suit the local context. In some cases, this may involve scaling up novel approaches that have proven effective at small scale or testing approaches that have worked in other countries.
Exploring safety culture in the Finnish ambulance service with Emergency Medical Services Safety Attitudes Questionnaire
Authors: Venesoja Anu , Lindström Veronica , Aronen Pasi , Castrén Maaret , Tella Susanna
Published: October 2021

Background

Emergency Medical Services (EMS) is, by its nature, a challenging context that may create risks for both patients and employees. It is also known that an organisation’s safety culture has an influence on both patient and employee safety. Finnish EMS organisations lack knowledge of how their safety culture is perceived by their employees.

Aim

This study aims to test the psychometric properties of the Emergency Medical Services Safety Attitudes Questionnaire (EMS-SAQ) in a Finnish EMS setting. We also explore the connections between individual- and organisation-based characteristics and safety attitudes in the Finnish EMS.

Methods

A cross-sectional survey study design was used. The EMS-SAQ was used to collect data via social media. The instrument measures six domains of workplace safety culture: safety climate, teamwork climate, perceptions of management, job satisfaction, working conditions and stress recognition. The 5-point Likert scale was converted to a 100-point scale and mean ≥ 75 was dichotomized as a positive. Confirmatory factor analysis (CFA) was carried out to validate the EMS-SAQ in a Finnish setting. Other results were analysed by using non-parametric tests.

Results

327 responses were included in the analysis. CFA showed that the total EMS-SAQ model had acceptable goodness-of-fit values in the Finnish EMS setting. Total mean scores for each safety culture domain were identified non-positively (mean score < 75); safety climate 60.12, teamwork climate 60.92, perceptions of management 56.31, stress recognition 64.55, working conditions 53.43 and job satisfaction 70.36. Higher education was connected to lower job satisfaction and the teamwork climate within the individual characteristics. All organisation-based characteristics caused at least one significant variation in the safety culture domain scores. Working area significantly affected (p < 0.05) five out of the six safety culture domain scores.

Conclusions

The EMS-SAQ is a valid tool to evaluate safety culture among the Finnish EMS organisations; it offers a novel method to evaluate safety and patient safety within the Finnish EMS organisations. According to the findings, the organisation-based characteristics more likely had an impact on safety attitudes than did the individual-based characteristics. Therefore, it is suggested that the Finnish EMS organisations undertake safety culture development at the organisational level.
Germline mutations among Polish patients with acute myeloid leukemia
Authors: Bąk Aneta , Skonieczka Katarzyna , Jaśkowiec Anna , Junkiert-Czarnecka Anna , Heise Marta , Pilarska-Deltow Maria , Potoczek Stanisław , Czyżewska Maria , Haus Olga
Published: October 2021

Background

A small but important proportion of patients (4–10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT).

Methods

103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations.

Results

In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028).

Conclusions

We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.
Fluid flow exposure promotes epithelial-to-mesenchymal transition and adhesion of breast cancer cells to endothelial cells
Authors: Fuh Kenneth F. , Shepherd Robert D. , Withell Jessica S. , Kooistra Brayden K. , Rinker Kristina D.
Published: October 2021

Background

Mechanical interactions between tumor cells and microenvironments are frequent phenomena during breast cancer progression, however, it is not well understood how these interactions affect Epithelial-to-Mesenchymal Transition (EMT). EMT is associated with the progression of most carcinomas through induction of new transcriptional programs within affected epithelial cells, resulting in cells becoming more motile and adhesive to endothelial cells.

Methods

MDA-MB-231, SK-BR-3, BT-474, and MCF-7 cells and normal Human Mammary Epithelial Cells (HMECs) were exposed to fluid flow in a parallel-plate bioreactor system. Changes in expression were quantified using microarrays, qPCR, immunocytochemistry, and western blots. Gene–gene interactions were elucidated using network analysis, and key modified genes were examined in clinical datasets. Potential involvement of Smads was investigated using siRNA knockdown studies. Finally, the ability of flow-stimulated and unstimulated cancer cells to adhere to an endothelial monolayer, migrate and invade membrane pores was evaluated in flow and static adhesion experiments.

Results

Fluid flow stimulation resulted in upregulation of EMT inducers and downregulation of repressors. Specifically, Vimentin and Snail were upregulated both at the gene and protein expression levels in flow stimulated HMECs and MDA-MB-231 cells, suggesting progression towards an EMT phenotype. Flow-stimulated SNAI2 was abrogated with Smad3 siRNA. Flow-induced overexpression of a panel of cell adhesion genes was also observed. Network analysis revealed genes involved in cell flow responses including FN1, PLAU, and ALCAM. When evaluated in clinical datasets, overexpression of FN1, PLAU, and ALCAM was observed in patients with different subtypes of breast cancer. We also observed increased adhesion, migration and invasion of flow-stimulated breast cancer cells compared to unstimulated controls.

Conclusions

This study shows that fluid forces on the order of 1 Pa promote EMT and adhesion of breast cancer cells to an endothelial monolayer and identified biomarkers were distinctly expressed in patient populations. A better understanding of how biophysical forces such as shear stress affect cellular processes involved in metastatic progression of breast cancer is important for identifying new molecular markers for disease progression, and for predicting metastatic risk.
A transcription factor DAF-5 functions in Haemonchus contortus development
Authors: Di Wenda , Li Fangfang , He Li , Wang Chunqun , Zhou Caixian , Liu Lu , Ye Lisa , Chen Jian , Hu Min
Published: October 2021

Background

Abnormal dauer formation gene (daf-5), located downstream of the DAF-7 signalling pathway, mainly functions in dauer formation and reproductive processes in the free-living nematode Caenorhabditis elegans. Although the structure and function of daf-5 have been clarified in C. elegans, they still remain totally unknown in Haemonchus contortus, a socio-economically important parasitic nematode of gastric ruminants.

Methods

A homologue of daf-5, Hc-daf-5, and its inferred product (Hc-DAF-5) in H. contortus were identified and characterized in this study. Then the transcriptional profiles of Hc-daf-5 and the anatomical expression of Hc-DAF-5 in H. contortus were studied using an integrated molecular approach. RNA interference (RNAi) was performed to explore its function in transition from the exsheathed third-stage larvae (xL3s) to the fourth-stage larvae (L4s) in vitro. Finally, the interaction between Hc-DAF-5 and Hc-DAF-3 (a co-Smad) was detected by bimolecular fluorescence complementation (BiFc) in vitro.

Results

It was shown that Hc-DAF-5 was a member of the Sno/Ski superfamily. Hc-daf-5 was transcribed in all developmental stages of H. contortus, with significant upregulation in L3s. Native Hc-DAF-5 was localized in the reproductive organs, cuticle, and intestine via immunohistochemistry. RNAi revealed that specific small interfering RNAs (siRNAs) could retard xL3 development. In addition, the interaction between Hc-DAF-5 and Hc-DAF-3 indicated that the SDS box of Hc-DAF-5 was dispensable for the binding of Hc-DAF-5 to Hc-DAF-3, and the MH2 domain was the binding region between Hc-DAF-3 and Hc-DAF-5.

Conclusions

In summary, these findings show that Hc-daf-5 functions in the developmental processes of H. contortus, and this study is the first attempt to characterize the daf-5 gene in parasitic nematodes.

Graphical abstract
Correlation of peripheral CD4+GranzB+CTLs with disease severity in patients with primary Sjögren’s syndrome
Authors: Wang Qi , Che Nan , Lu Chengyin , Sun Xiaoxuan , Wang Yanyan , Wang Qiang , Tan Wenfeng , Zhou Lanlan , Zhang Xiaojun , Xu Dong , Gu Lei , Zhang Miaojia
Published: October 2021

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease which has focal lymphocytic infiltration including a majority of CD4+ T cells. This study was to investigate the correlation of peripheral granzyme B (GranzB)-expressing CD4+ T cells with disease severity and histological lesion in patients with pSS.

Methods

We recruited 116 pSS and 46 health control (HC) using flow cytometry to examine the percentage of CD4+GranzB+CTLs in the peripheral blood, and immunofluorescence to test their expression in the labial gland.

Results

The percentage of CD4+GranzB+CTLs was significantly upregulated in pSS than in HC (7.1 ± 4.9% vs 3.1 ± 1.9%, p < 0.0001) and positive correlation with ESSDAI. The frequency of them was markedly higher in pSS with extraglandular manifestations. After excluding the other risk factors associated with pSS, they were still related to ESSDIA and extraglandular manifestations independently (p < 0.05), and they are the risk factor of extraglandular involvement (odds ratio = 1.928). Moreover, they could be observed in the LSGs. ROC curve analysis indicated that the area under the curve (AUC) of CD4+GranzB+CTLs was 0.796 to predict the activity of pSS and 0.851 to presume extraglandular manifestations. The best diagnostic cutoff point was 4.865 for pSS patients.

Conclusion

In this study, we provide new evidence indicating the involvement of CD4+GranzB+CTLs over activation in the pathophysiology of pSS, which may serve as a new biomarker to evaluate the activity and severity of pSS.
Assessing the joint adoption and complementarity between in-field conservation practices of Kansas farmers
Authors: Gong Sheng , Bergtold Jason.S. , Yeager Elizabeth
Published: October 2021

Agricultural conservation systems consist of a myriad of conservation practices. The mix and intensity of conservation practices adopted can benefit farmers and affect the entire production system in addition to soil and water conservation. The purpose of this study is to examine and analyze farmer adoption of and complementarity between conservation practices from a joint and conditional probabilistic perspective using Kansas as a case study. We develop a modeling framework that can analyze and examine farmers’ joint and conditional adoption decisions using a multinomial logistic regression model. This framework is used to estimate conditional probabilities of adopting conservation practices given adoption of other practices to better capture the complementarity between different conservation practices. These estimates allow for an assessment of linkages between adoption of different conservation practices and the socioeconomic factors that affect the likelihood of adopting conservation practices given other conservation practices have already been adopted on-farm. The results can help guide policy and outreach efforts to promote further intensification of adoption by farmers.
Altered saturation pulse with a high flip angle for venous saturation on 7 T time-of-flight magnetic resonance angiography
Authors: Kim Sangwoo , Lee Chulhyun
Published: October 2021

This study aimed to apply minimum-time variable-rate selective excitation (MinVER) to a presaturation pulse (PSP) with a high flip angle on 7 T time-of-flight magnetic resonance angiography (7T TOF-MRA), to attain a superior vessel-to-tissue contrast (VTCR), short acquisition time, and minor off-resonance effect. An altered PSP modified by using the 90° flip angle (FA)-MinVER was implemented in the 7 T TOF-MRA, and its performance was evaluated with a signal profile and vessel-tissue contrast ratios and compared to the conventional PSP and 45 FA-TOF. The 90 FA-MinVER showed a similar signal profile to that of the conventional PSP and improved the vessel-tissue contrast ratios (0.313 ± 0.80) compared to all conventional types (45 FA-TOF: 0.088 ± 0.84, 90 FA-TOF: 0.203 ± 0.72). Moreover, this noteworthy approach achieved substantially reduced total acquisition time (5 min and 55 s) with a short repeat-to-time (28 ms), indicating that at the 7 T TOF-MRA, the 90 FA-MinVER could be applied by default to suppress the venous signals regardless of individual human status and the specific absorption ratio constraint and with rapid imaging. Ultimately, its application could also help to observe subtle microvascular changes in the early stages and serve as key biomarkers in various vascular diseases.
Recent progress and perspectives on the mechanisms underlying Asbestos toxicity
Authors: Kuroda Akio
Published: October 2021

Most cases of mesothelioma are known to result from exposure to asbestos fibers in the environment or occupational ambient air. The following questions regarding asbestos toxicity remain partially unanswered: (i) why asbestos entering the alveoli during respiration exerts toxicity in the pleura; and (ii) how asbestos causes mesothelioma, even though human mesothelial cells are easily killed upon exposure to asbestos. As for the latter question, it is now thought that the frustrated phagocytosis of asbestos fibers by macrophages prolongs inflammatory responses and gives rise to a “mutagenic microenvironment” around mesothelial cells, resulting in their malignant transformation. Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment. This leads to additional mutations, such as CDKN2A [p16], NF2, TP53, LATS2, and SETD2, which are associated with mesothelioma carcinogenesis. Regarding the former question, the receptors involved in the intracellular uptake of asbestos and the mechanism of transfer of inhaled asbestos from the alveoli to the pleura are yet to be elucidated. Further studies using live-cell imaging techniques will be critical to fully understanding the mechanisms underlying asbestos toxicity.
The TRUTH confirmed: validation of an intraindividual comparison of gadobutrol and gadoteridol for imaging of glioblastoma using quantitative enhancement analysis
Authors: Kuhn Matthew J. , Patriarche Julia W. , Patriarche Douglas , Kirchin Miles A. , Bona Massimo , Pirovano Gianpaolo
Published: October 2021

Background

Previous intraindividual comparative studies evaluating gadobutrol and gadoteridol for contrast-enhanced magnetic resonance imaging (MRI) of brain tumours have relied on subjective image assessment, potentially leading to misleading conclusions. We used artificial intelligence algorithms to objectively compare the enhancement achieved with these contrast agents in glioblastoma patients.

Methods

Twenty-seven patients from a prior study who received identical doses of 0.1 mmol/kg gadobutrol and gadoteridol (with appropriate washout in between) were evaluated. Quantitative enhancement (QE) maps of the normalised enhancement of voxels, derived from computations based on the comparison of contrast-enhanced T1-weighted images relative to the harmonised intensity on unenhanced T1-weighted images, were compared. Bland-Altman analysis, linear regression analysis and Pearson correlation coefficient (r) determination were performed to compare net QE and per-region of interest (per-ROI) average QE (net QE divided by the number of voxels).

Results

No significant differences were observed for comparisons performed on net QE (mean difference -24.37 ± 620.8, p = 0.840, r = 0.989) or per-ROI average QE (0.0043 ± 0.0218, p = 0.313, r = 0.958). Bland-Altman analysis revealed better per-ROI average QE for gadoteridol-enhanced MRI in 19/27 (70.4%) patients although the mean difference (0.0043) was close to zero indicating high concordance and the absence of fixed bias.

Conclusions

The enhancement of glioblastoma achieved with gadoteridol and gadobutrol at 0.1 mmol/kg bodyweight is similar indicating that these agents have similar contrast efficacy and can be used interchangeably, confirming the results of a prior double-blind, randomised, intraindividual, crossover study.
Perception of Iraqi youth towards social and psychological impact of COVID-19
Authors: Al Shawi Ameel F. , Lafta Riyadh
Published: October 2021

Background

COVID-19 pandemic is recently considered as the most public health challenge with global dramatic changes on different aspects of life and health, including the psychological burden on individuals and communities. A convenience sample of youth (university students) aged 18–24 years was chosen in this cross-sectional study that was conducted during the period from October through December 2020. The questionnaire included questions about COVID-19 and its effect on mental and social wellbeing.

Results

Out of the total 762 young adults who responded, 62% were females, with a mean age of 20.75+2.33; 40.4% of them reported severely impaired social leisure activities; 14.7% expressed severely impaired private leisure activities; and 15.5% had severely impaired ability to form and maintain close relationships. Continuous feeling of nervousness, anxiety, stress, or exaggerated worries about the coronavirus was reported by 18%, while 24.9% felt sad or depressed all the time, and 26.4% of the female respondents had depressive symptoms versus 22.5% males.

Conclusion

The findings of this study indicate that the COVID-19 pandemic had created severe limitations on people’s social activities that may be associated with negative changes in mental condition.
Evidence-based guidelines for protective actions and earthquake early warning systems
Authors: McBride Sara K. , Smith Hollie , Morgoch Meredith , Sumy Danielle , Jenkins Mariah , Peek Lori , Bostrom Ann , Baldwin Dare , Reddy Elizabeth , de Groot Robert , Becker Julia , Johnston David , Wood Michele
Published: October 2021

Earthquake early warning (EEW) systems are becoming increasingly available or are in development throughout the world. As these systems develop, it is important to provide evidence-based recommendations for protective action so people know how to protect themselves when they receive an alert. However, many factors need to be considered when developing contextually relevant and appropriate recommendations. We have reviewed earthquake injury reports, protective action and communication theories, and behavioral research to determine what factors can guide inquiry and decision making when developing protective action guidelines. Factors that emerge from relevant literature include: (1) social, cultural, and environmental context, such as which people are present, what their social roles are, and in what type of building they are located when an earthquake happens, (2) demographic and experiential variables, such as gender and age as well as previous history with earthquakes; and (3) magnitude and intensity that influence the duration and impacts of the earthquake itself. Although we examine data from around the world, we focus largely on evidence-based recommendations for the U.S. system, ShakeAlert, because it provides a timely case study for understanding how people receive and respond to EEW messages. In addition to synthesizing relevant literature, we recommend pathways forward for this interdisciplinary research community that explores EEW and its application around the world. Consistency in collecting and reporting injury data globally may assist in aligning this fragmented literature to develop a richer understanding of how demographic, cultural, seismic, engineering, and technological issues can be addressed to reduce human suffering due to earthquakes.
Mental health law in Nepal
Authors: Singh Rakesh , Khadka Seema
Published: October 2021

During the past three decades Nepal has gone through series of reforms to address the mental health needs of the Nepalese population by promulgation of an exclusive National Mental Health Policy and related Strategic Action Plan. Small but significant improvements have been achieved in Nepal with regard to mental health policies and plans. This article discusses the evolution of mental health policies in Nepal and analyses the challenges to be overcome for their effective implementation.
First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study
Authors: Lenz Heinz-Josef , Van Cutsem Eric , Luisa Limon Maria , Wong Ka Yeung Mark , Hendlisz Alain , Aglietta Massimo , García-Alfonso Pilar , Neyns Bart , Luppi Gabriele , Cardin Dana B. , Dragovich Tomislav , Shah Usman , Abdullaev Sandzhar , Gricar Joseph , Ledeine Jean-Marie , Overman Michael James , Lonardi Sara
Published: October 2021

PURPOSE

Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study.

PATIENTS AND METHODS

Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1).

RESULTS

Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events.

CONCLUSION

Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.
The Dual Biopolitics in the Cuban Postplantation of Gloria Rolando’s Raíces de mi corazón
Authors: Quesada Sarah Margarita
Published: October 2021

This essay focuses on the “dual” biopolitics of Cuban filmmaker Gloria Rolando’s Raíces de mi corazón (Roots of My Heart, 2001). In her film about an antiblack genocide in early-twentieth-century Cuba, Rolando seeks to recover the suppressed 1912 massacre of members of the black Cuban Partido Independiente de Color (the Independent Party of Color) and thousands of other Afro-Cubans through the plane of the intimate. The author argues that Rolando’s film challenges the myth of racial equality throughout Cuba’s modern history by celebrating Afro-Cuban traditions, from orisha rituals to patakíes (Afro-Cuban oral tradition), over a reappropriated plantational space in which black sensuality contests negative biopolitical forms. Rolando not only draws from transnational critical race theory to address the myth of Latin American exceptionalism, she also challenges Michel Foucault’s conceptualization of biopolitics casting black sensuality over racial violence.
Aurora kinase B inhibits aurora kinase A to control maternal mRNA translation in mouse oocytes
Authors: Aboelenain Mansour , Schindler Karen
Published: October 2021

Mammalian oocytes are transcriptionally quiescent, and meiosis and early embryonic divisions rely on translation of stored maternal mRNAs. Activation of these mRNAs is mediated by polyadenylation. Cytoplasmic polyadenylation binding element 1 (CPEB1) regulates mRNA polyadenylation. One message is aurora kinase C (Aurkc), encoding a protein that regulates chromosome segregation. We previously demonstrated that AURKC levels are upregulated in oocytes lacking aurora kinase B (AURKB), and this upregulation caused increased aneuploidy rates, a role we investigate here. Using genetic and pharmacologic approaches, we found that AURKB negatively regulates CPEB1-dependent translation of many messages. To determine why translation is increased, we evaluated aurora kinase A (AURKA), a kinase that activates CPEB1 in other organisms. We find that AURKA activity is increased in Aurkb knockout mouse oocytes and demonstrate that this increase drives the excess translation. Importantly, removal of one copy of Aurka from the Aurkb knockout strain background reduces aneuploidy rates. This study demonstrates that AURKA is required for CPEB1-dependent translation, and it describes a new AURKB requirement to maintain translation levels through AURKA, a function crucial to generating euploid eggs.
Desmosome dualism – most of the junction is stable, but a plakophilin moiety is persistently dynamic
Authors: Fülle Judith B. , Huppert Henri , Liebl David , Liu Jaron , Alves de Almeida Rogerio , Yanes Bian , Wright Graham D. , Lane E. Birgitte , Garrod David R. , Ballestrem Christoph
Published: October 2021

Desmosomes, strong cell–cell junctions of epithelia and cardiac muscle, link intermediate filaments to cell membranes and mechanically integrate cells across tissues, dissipating mechanical stress. They comprise five major protein classes – desmocollins and desmogleins (the desmosomal cadherins), plakoglobin, plakophilins and desmoplakin – whose individual contribution to the structure and turnover of desmosomes is poorly understood. Using live-cell imaging together with fluorescence recovery after photobleaching (FRAP) and fluorescence loss and localisation after photobleaching (FLAP), we show that desmosomes consist of two contrasting protein moieties or modules: a very stable moiety of desmosomal cadherins, desmoplakin and plakoglobin, and a highly mobile plakophilin (Pkp2a). As desmosomes mature from Ca2+ dependence to Ca2+-independent hyper-adhesion, their stability increases, but Pkp2a remains highly mobile. We show that desmosome downregulation during growth-factor-induced cell scattering proceeds by internalisation of whole desmosomes, which still retain a stable moiety and highly mobile Pkp2a. This molecular mobility of Pkp2a suggests a transient and probably regulatory role for Pkp2a in desmosomes.

This article has an associated First Person interview with the first author of the paper.
Neuroligin 1 expression is linked to plasticity of behavioral and neuronal responses to sex pheromone in the male moth Agrotis ipsilon
Authors: Durand Nicolas , Aguilar Paleo , Demondion Elodie , Bourgeois Thomas , Bozzolan Françoise , Debernard Stéphane
Published: October 2021

In the moth Agrotis ipsilon, the behavioral response of males to the female-emitted sex pheromone increases throughout adult life and following a prior exposure to sex pheromone, whereas it is temporally inhibited after the onset of mating. This behavioral flexibility is paralleled with changes in neuronal sensitivity to pheromone signal within the primary olfactory centers, the antennal lobes. In the present study, we tested the hypothesis that neuroligins, post-synaptic transmembrane proteins known to act as mediators of neuronal remodeling, are involved in the olfactory modulation in A. ipsilon males. We cloned a full-length cDNA encoding neuroligin 1, which is expressed predominantly in brain and especially in antennal lobes. The level of neuroligin 1 expression in antennal lobes gradually raised from day-2 until day-4 of adult life, as well as at 24 h, 48 h and 72 h following pre-exposure to sex pheromone, and the temporal dynamic of these changes correlated with increased sex pheromone responsiveness. By contrast, there was no significant variation in antennal lobe neuroligin 1 expression during the post-mating refractory period. Taken together, these results highlight that age- and odor experience-related increase in sex pheromone responsiveness is linked to the overexpression of neuroligin 1 in antennal lobes, thus suggesting a potential role played by this post-synaptic cell-adhesion molecule in mediating the plasticity of the central olfactory system in A. ipsilon.
Regiodivergent Carbene/Alkyne Metathesis in Chromium-Mediated Coupling and Cyclization with 1,6-Enynes
Authors: Murai Masahito , Taniguchi Ryuji , Takai Kazuhiko
Published: October 2021

Regiodivergent carbene/alkyne metathesis for the selective synthesis of 2-alkylidenebicyclo[4.1.0]heptanes and 1-alkenylbicyclo[3.1.0]hexanes from common 1,6-enynes precursors was demonstrated. The cyclization mode could be switched by simple addition of diamine ligands to control the relative orientation of the approaching chromium Schrock carbene equivalents generated in situ from gem-dichromiomethanes toward triple bonds.
Learning from each other in the COVID-19 pandemic
Authors: Seale Anna C. , Ibeto Maryirene , Gallo Josie , le Polain de Waroux Olivier , Glynn Judith R. , Fogarty Jenny
Published: October 2021

The increase in cases of coronavirus disease 2019 (COVID-19) worldwide has been paralleled by increasing information, and misinformation. Accurate public health messaging is essential to counter this, but education may also have a role. Early in the outbreak, The London School of Hygiene & Tropical Medicine partnered with FutureLearn to develop a massive open online course (MOOC) on COVID-19. Our approach was grounded in social constructivism, supporting participation, sharing uncertainties, and encouraging discussion. The first run of the course included over 200,000 participants from 184 countries, with over 88,000 comments at the end of the three-week run. Many participants supported each other’s learning in their responses and further questions. Our experience suggests that open education can complement traditional messaging, potentially providing a sustainable approach to countering the spread of misinformation in public health.