bluuebunny/crossref_metadata_2025 huggingface dataset:
Cohort Profile: Norwegian Survey of Health and Ageing (NORSE)
Authors: Strand Bjørn Heine , Skirbekk Vegard , Langballe Ellen Melbye , Bergh Sverre , Landmark Brynjar , Wangensteen Sigrid , Selbæk Geir , Kirkevold Øyvind
Published: September 2021

Purpose: The Norwegian Survey of Health and Ageing (NORSE) was set up to provide internationally comparable data on ageing in Norway, which includes measured intrinsic capacity and cognitive function.Participants: NORSE is a population-based health examination study of seniors aged 60+ from the 1929-1959 birth cohorts in the former Norwegian county of Oppland, interviewed and examined in three study waves 2017-19 (N=957, 16% response rate). NORSE is based on the SHARE (share-project.org) questionnaire, which includes work-related information, self-assessed and retrospective health, and expectations on longevity, quality of life, volunteering activities, consumption, and financial arrangements. In addition, several objective measures of intrinsic and cognitive capacity are included.Findings to date: A shorter preferred life expectancy (PLE)was found to be associated with the prospects of a life with dementia and chronic pain.Motivation for retirementwas found to be related towork-life experience and health.Social media was mostly used in the younger age groups and there was a tendency towards more use in the higher educational groups. NORSE incorporates questions on religion, and older women tend to have a higher degree of religiosity (proxied as self-assessed religiosity) than men in their 80s, but more similar (and lower levels) among those in their 60s.Future plans: NORSE participants have allowed their data to be linked to National registry data and midlife health examination studies and thereby provide a longitudinal design as well as information on disability status, socioeconomic status, household and marital status, support to/from children and parents, and pension status.
The Efficacy and Tolerability of Sitagliptin, Saxagliptin, Vildagliptin, Lindagliptin, Alogliptin, Omarigliptin and Trelagliptin in Patients with Type 2 Diabetes: Protocol for a Network Meta-Analysis of Randomized Control Trials
Authors: chen guoquan , Chen Jiale , Hu Xiaoxia , Chen Jianqing , He Yiling
Published: September 2021

Backgound: Type 2 diabetes mellitus remains a major public health challenge in the worldwide. The control of blood glucose is essential in the metabolic management of diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new hypoglycemic agents with good hypoglycemic effect. However, the difference of efficacy and tolerability among different kinds of DPP-4 inhibitors remains unclear and no network meta-analysis(NMA) has been performed yet to compare different kinds of DPP-4 inhibitors comprehensively. Our research aims to investigate and rank different kinds of DPP-4 inhibitors on efficacy and tolerability.Methods/design: English language studies will be searched in the electronic databases(PubMed, the Cochrane Library and EMBASE), without time restriction. Parallel-group randomized controlled trials (RCTs) meeting the following criteria will be included, regardless of the blinding design: (1) T2DM patients aged over 18, pregnant or breastfeeding female patients and patients with T2DM on Maintenance Hemodialysis will be excluded, (2) interventions with DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, lindagliptin, alogliptin, omarigliptin and trelagliptin), traditional antidiabetic agents includes α-glucosidase inhibitors, sulphonylureas, non-sulfonylureas and thiazolidinediones, or placebo and (3) change in HbA1c concentration, weight and FPG from baseline to the end of treatment and proportions of patients in achieving HbA1c < 7.0%, patients with treatment-emergent adverse events leading to treatment discontinuation and patients with hypoglycaemia. Random effects pairwise and Bayesian NMA will be performed for these outcomes. Subgroup analyses are carried out for race and dosing frequency.Discussion: Our NMA will be the first to systematically summarize, compare and rank the efficacy and tolerability of different kinds of DPP-4 inhibitors in T2DM patients. We are confident that our research project will significantly contribute to optimizing hypoglycemic therapy.Systematic review registration:PROSPERO:CRD42021253822
Preparation for Animal Models of Osteoporosis: a Systematic Review
Authors: Mu Panyun , Qu Peihua , Li Yulin , Feng Jie , Ma Xu , Xiong Feng , Hu Yimei
Published: September 2021

Background: it is of great significance for clinical diagnosis, prevention and treatment of osteoporosis to deeply understand the pathogenesis and development process of osteoporosis through animal models of osteoporosis. This systematic review aim to summarize the modeling methods of osteoporosis, reveal the current situation and progress of animal models of osteoporosis, and compare the advantages and disadvantages of various modeling methods, so as to provide reference for clinical research.Methods: CNKI, CBM database, VIP database, Wanfang database, PubMed database and EMBASE database were searched by computer from the database establishment to December 2020 with the key words of "animal model; osteoporosis" in Chinese and English respectively. The literatures were screened according to inclusion and exclusion criteria. The methods of osteoporosis modeling, the improvement of the methods and the advantages and disadvantages of each method are summarized.Discussion: a total of 9303 related literatures were collected, and 112 eligible literatures were included. The establishment of an appropriate animal model is the key to the etiology, pathophysiology and drug therapy of osteoporosis. As the causes and pathophysiological changes of different types of OP have their own characteristics, the modeling methods are also different. Therefore, different modeling methods and experimental animals should be selected according to different experimental requirements.Systematic review registration: No
Colon Cancer Classification and Prognosis Prediction Based on Genomics Multi-features
Authors: Xu Jiasheng , Liao Kaili , Wu Chengfeng , Yang Qijun , Wan Hongping , Wang Xiaozhong
Published: September 2021

Background: To classify colon cancer and predict the prognosis of patients with multiple characteristics of the genome.Methods: We used the mRNA expression profile data and mutation maf files of colon cancer patients in the TCGA database to calculate the TMB value of patients. Combined with CNV, MSI, and corresponding clinical information, the patients were clustered by the "K-means" method to identify different molecular subtypes of colon cancer. Comparing the differences of prognosis, and immune cell infiltration, and other indicators among patients in each subgroup, we used COX and lasso regression analysis to screen out the prognosis difference genes among subgroups and construct the prognosis prediction model. We used the external data set to verify the model, and carried out the hierarchical analysis of the model to compare the immune infiltration of patients in the high and low-risk groups. And detected the expression differences of core genes in tumor tissues of patients with different clinical stages by qPCR and immunohistochemistry.Results: We successfully calculated the TMB value and divided the patients into three subgroups. The prognosis of the second subgroup was significantly different from the other two groups. The mmunoinfiltration analysis showed that the expression of NK.cells.resting increased in cluster1 and cluster 3, and the expression of T.cells.CD4.memory.resting increased in cluster3. By analyzing the differences among subgroups, we screened out eight core genes related to prognoses, such as HYAL1, SPINK4, EREG, and successfully constructed a patient prognosis evaluation model. The test results of the external data set shows that the model can accurately predict the prognosis of patients; Compared with risk factors such as TNM stage and age, the risk score of the model has higher evaluation efficiency. The experimental results confirmed that the differential expression of eight core genes was basically consistent with the model evaluation results.Conclusion: Colon cancer patients were further divided into three subtypes by using genomic multi-features, and eight-core genes related to prognosis were screened out and the prognosis evaluation model was successfully constructed. With external data and experiments, it verified that the model had good evaluation efficiency.
Plant–Soil Feedback In Camellia Oleifera And Mixed Gardenia Jasminoides Ellis–Camellia Oleifera Stands Determined By Soil Bacterial Community Analysis
Authors: Wang Yun , Xie Peng , She Jiyun , Deng Aihua , Fan Shaogang
Published: September 2021

Purpose: Little is known regarding the combined impact of plant and soil traits on the soil bacterial community. Herein, we assessed physical and chemical properties along with bacterial community structure in soils sampled at different depths (0–20 cm, 20–40 cm, and 40–60 cm) and slope positions (peak, hillside, and bottom), in Camellia oleifera monoculture and mixed Gardenia jasminoides–Camellia oleifera stands. Methods: Soil physicochemical characteristics were determined using standard methods. The composition of soil bacterial communities was evaluated using high-throughput sequencing of the 16S rRNA gene. Results: Soil organic carbon, humus, and total organic contents were higher in G. jasminoides + C. oleifera low-yielding forest than in other stands, however, the NH4+-N levels were significantly lower than that in monoculture. The slope position did not greatly influence soil physical and chemical properties. The dominant bacteria were Proteobacteria, Chloroflexi, Acidobacteria, and Actinobacteria. The alpha and beta diversity and abundance of soil bacterial community were higher in intercropping systems than in monoculture systems. Potassium and nitrogen levels and pH significantly affected the soil microbial community composition. Correlation analysis revealed that alkaline hydrolysable nitrogen and pH were significantly correlated with the input of plant-associated organic matter and dynamic changes of keystone taxa.Conclusion: G. jasminoides improved the physicochemical characteristics of C. oleifera low-yielding soil and greatly affected the soil bacterial community, further improving the soil microecological environment. Therefore, this specific intercropping system is an effective strategy for improving soil health.
Bacteriophage EK99P-1 Alleviates Enterotoxigenic Escherichia Coli K99-Induced Barrier Dysfunction and Inflammation
Authors: Kim Narae , Gu Min jeong , Kye Yoon-Chul , Ju Young-Jun , Hong Rira , Ju Do Bin , Pyung Young Jin , Han Seung Hyun , Park Byung-Chul , Yun Cheol-Heui
Published: September 2021

Background
Bacteriophages have long been used as a potential alternative to antibiotics for livestock due to their ability to specifically kill enterotoxigenic Escherichia coli (ETEC), which are a major cause of diarrhea in piglets. However, the control of ETEC infection by phages within intestinal epithelial cells, and their relationship with host immune responses, remain poorly understood.
Results
In this study, we evaluated the effect of phage EK99P-1 against ETEC K99-infected porcine intestinal epithelial cell line (IPEC-J2). Phage EK99P-1 prevented ETEC K99-induced barrier disruption by attenuating the increased permeability mediated by the loss of tight junction proteins such as zonula occludens-1 (ZO-1), occludin, and claudin-3. ETEC K99-induced inflammatory responses, such as IL-8 secretion, were decreased by treatment with phage EK99P-1. We used a IPEC-J2/peripheral blood mononuclear cell (PBMC) Transwell co-culture system to investigate whether the modulation of barrier disruption and chemokine secretion by phage EK99P-1 in ETEC K99-infected IPEC-J2 would influence basolateral immune cells. The results showed that phage EK99P-1 reduced the mRNA expression of ETEC K99-induced pro-inflammatory cytokines, interleukin (IL)-1β and IL-8, from pPBMC collected on the basolateral side.
Conclusion
Together, these results suggest that phage EK99P-1 prevented ETEC K99-induced barrier dysfunction in IPEC-J2 and alleviated inflammation caused by ETEC K99 infection. Reinforcement of the intestinal barrier by phage EK99P-1 also modulates the immune cell inflammatory response.
Cognitive Strengths Assessment and Intervention in First Episode Psychosis: A Thematic Analysis of Clinicians’ Perspectives
Authors: Steele Peter , Cheng Nicholas , Phillips Lisa J. , Bryce Shayden , Alvarez-Jimenez Mario , Allott Kelly
Published: September 2021

Background

Cognitive deficits are associated with poor functional outcomes in individuals recovering from a first episode of psychosis (FEP). Existing treatments that target cognitive deficits in FEP may enhance cognitive function, but improvements to real-world functioning are less consistent. Furthermore, these treatments may not adequately address the personal recovery goals of young people attending FEP services. A novel cognitive strengths-based approach may overcome these shortcomings.
Methods

This qualitative study used semi-structured interviews to explore clinicians' (N = 12) perspectives toward the potential development of a cognitive strengths-based assessment or intervention in FEP. The interviews were analysed using thematic analysis.
Results

Five higher-order themes emerged: (1) pro-strengths attitude despite unfamiliarity and minimal use, (2) default to a cognitive deficit lens, (3) potential benefits of a cognitive strengths approach, (4) potential risks and barriers, and (5) considerations for successful implementation. While clinicians acknowledged their current deficit approach, they supported implementing a cognitive strengths assessment or intervention and highlighted their potential benefits for the personal recovery needs of young people with FEP.
Conclusions

These findings suggest that a deficit-focused approach to cognitive function amongst clinicians may be common practice in FEP services. Nevertheless, a cognitive strengths approach to assessment and intervention was viewed favourably by clinicians and may represent a novel method of supporting personal recovery. Thus, the design and implementation of a cognitive strengths approach may be worthwhile. Future exploration of other stakeholder perspectives, such as young people with FEP, is essential.
Distribution and Molecular Analysis of Subtilase Cytotoxin Gene (subAB) Variants in Shiga Toxin-Producing Escherichia Coli (STEC) Isolated From Different Sources in Iran
Authors: Badouei Mahdi Askari , Jajarmi Maziar , Narimani Aria , Salehi Taghi Zahraei , Ghanbarpour Reza , Morabito Stefano , Koochakzadeh Alireza
Published: September 2021

Background

Subtilase is a potent cytotoxin that was first described in O113:H21 strain in Australia as a plasmid- encoded cytotoxin (subAB1). Subsequently, chromosomal variants including subAB2-1, subAB2-2, and subAB2-3 were described.
Results

In the present study a collection of 101 archived STEC strains isolated from various sources in Iran (2009–2016) were analyzed for the detection of different genes encoding the subtilase variants, plasmidic and chromosomal virulence genes, together with the phylogroup and serogroups. Overall, 57 isolates (56.4%) carried at least one variant of subAB. Most strains from small ruminants including 93% of sheep and 96% of caprine isolates carried at least one chromosomally encoded variant (subAB-2-1 and/or subAb2-2). In contrast, 12 cattle isolates (24%) only harbored the plasmid encoded variant (subAB1). STEC strains from other sources including deer, pony and humans were positive for subAB-2-1 and/or subAb2-2. Concerning the virulence markers, some strains showed an association with hosts the bacteria were isolated from. In particular, tia was associated with sheep, goats and pony isolates and astA gene was present in deer, pony and goats and terD was only found in deer and pony isolates. Only cattle STEC carried espP and epeA, the important markers of pO113 plasmid. Some genes were widespread among strain of various sources like ehly, iha and lpfO113 and some genes were not detected such as efa1, toxB and katP. Most strains belonged to phylogenetic group B1 (89.47%), but five strains from cattle, deer, pony and a goat were assigned to A phylogroup. Most cattle strains belonged to O113, while O5 was just detected in ovine isolates, and O128 and O113 were present in caprine strains.
Conclusions

the present study reveals the presence of potentially pathogenic genotypes among LEE-negative isolates and some host specificity related to subtilase variants and other virulence markers that may aid in source tracking of STEC during outbreak investigations.
Transformer 2β Regulates the Alternative Splicing of Cell Cycle Regulator Genes to Promote Ovarian Cancer Cell Progression
Authors: Fu Peiying , Zhou Ting , Chen Dong , Wang ShiXuan , Liu Ronghua
Published: September 2021

Background: Late-stage ovarian cancer (OV) has a poor prognosis and a high metastasis rate, but the underlying molecular mechanism is ambiguous. RNA binding proteins (RBPs) play important roles in posttranscriptional regulation in the contexts of neoplasia and tumor metastasis. Results: In this study, we explored the molecular functions of a canonical RBP, TRA2B, in cancer cells. TRA2B knockdown in HeLa cells and whole-transcriptome sequencing (RNA-seq) experiments revealed that the TRA2B-regulated alternative splicing (AS) profile was tightly associated with the mitotic cell cycle, apoptosis, and several cancer pathways. Moreover, hundreds of genes were regulated by TRA2B at the expression level, and their functions were enriched in cell proliferation, cell adhesion and angiogenesis, which are related to cancer progression. We also observed that AS regulation and expression regulation occurred independently by integrating the alternatively spliced and differentially expressed genes. We then explored and validated the carcinogenic functions of TRA2B by knocking down its expression in OV cells. In vivo, a high expression level of TRA2B was associated with a poor prognosis in OV patients. Conclusions: We demonstrated the important roles of TRA2B in ovarian neoplasia and OV progression and identified the underlying molecular mechanisms, facilitating the targeted treatment of OV in the future.
As a Novel Tumor Suppressor, LHPP Promotes Apoptosis by Inhibiting the PI3K/AKT Signaling Pathway in Oral Squamous Cell Carcinoma
Authors: Liu Shanshan , Gao Wenzhen , Lu Yupu , Zhou Qin , Su Rongjian , Hasegawa Tomoka , Du Juan , Li Minqi
Published: September 2021

Background: Oral squamous cell carcinoma (OSCC) refers to the malignant tumor of the head and neck with a highest morbidity. It exhibits a poor prognosis and unsatisfactory treatment, which is partially attributed to delayed diagnosis. As indicated from existing reports, the protein histidine phosphatase LHPP acts as a vital factor in tumorigenesis in liver, lung, bladder, breast and pancreatic tumor tissues. Thus far, the expression level of LHPP in OSCC has been rarely studied, and its functional mechanism remains unclear. Methods: DEG analysis, OSCC cell lines and OSCC samples were used to detect the expression of LHPP in adjacent normal and cancerous tissues and its relationship with OSCC differentiation. Immunofluorescence staining was used to detect the over-expressed LHPP in OSCC cell lines. The cell counting kit 8 test, EdU proliferation test, scratch test, invasion test, single clone formation test, mouse xenograft tumor model HE staining and immunohistochemistry were used to estimate the biological characteristics of LHPP in OSCC in vivo and in vitro. GO and KEGG enrichment analysis and LHPP transcription factor analysis were used to further predict the role of LHPP and its related genes. The Western blotting assay, real-time PCR analysis and flow cytometry determined the inhibitory mechanism of LHPP in OSCC cells.Results: LHPP was down-regulated in OSCC tissues and cells than that in normal oral mucosa tissues and cells, LHPP expressing also displays a close association with the degree differentiation of OSCC. LHPP is capable of significantly inhibiting OSCC cells from proliferating, migrating and invading. The increase in LHPP expression facilitated OSCC cell apoptosis through PI3K/AKT signaling pathway.Conclusion: LHPP is a novel tumor suppressor which promotes apoptosis by inhibiting the PI3K/AKT signaling pathway in OSCC, indicating that LHPP is a new diagnostic marker and therapeutic target for OSCC.
Phenylboronic Acid Conjugated to Doxorubicin for the Treatment of Hepatocellular Carcinoma Through Transcatheter Arterial Chemoembolization
Authors: Kang Byung-Yoon , Kim Sung Min , Hur Wonhee , Roh Pu Reun , Han Ji Won , Sung Pil Soo , Tak Eunyoung , Kim Won Jong , Jin Long , Chun Ho Jong , Yoon Seung Kew
Published: September 2021

Background: Anticancer strategies using nanocarrier systems via the enhanced permeability and retention (EPR) effect and tumor targeting have been explored in various cancers. In previous studies, the anticancer effect of polymerized phenylboronic acid-conjugated doxorubicin (pPBA-Dox) nanocomplexes was confirmed in various cancers, and their anticancer effect and tumor targeting ability was confirmed in hepatocellular carcinoma (HCC).This study aimed to determine the anticancer effect and changes in the liver immune cell population and function after pPBA-Dox nanocomplex infusion through transcatheter arterial chemoembolization (TACE), which is a locoregional therapy (LRT), in HCC. TACE was performed in a rat liver cancer model, and the anticancer effects, immune cell populations and functional changes were confirmed after 1 week. Magnetic resonance imaging (MRI) and flow cytometry (FACS) were performed to analyze the anticancer effect and immune cell population and function. Results: In HCC, the infusion of pPBA-Dox nanocomplexes through TACE had a stronger anticancer effect than conventional doxorubicin (Dox) and it promoted the infiltration and activation of CD4+ and CD8+ T cells in the liver. Conclusions: This study provides insight into novel targeted therapies using nanocomplexes for the treatment of HCC.
JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder
Authors: Li Heli , Wang Xinyuan , Hu Cong , Li Hao , Xu Zhuoshuo , Lei Ping , Luo Xiaoping , Hao Yan
Published: September 2021

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by marked genetic heterogeneity. This study aimed to use gene expression datasets to explore candidate hub genes for ASD. Methods: In this study, two independent microarray datasets of the cerebellum of children with ASD were integratively analysed using NetworkAnalyst to screen crucial candidate genes and related signalling pathways. Upregulation of the two hub genes was validated by other datasets and an ASD mouse model. Results: NetworkAnalyst identified two upregulated genes as the most crucial genes in the cerebellum of children with ASD: Jun proto-oncogene (JUN) and platelet-derived growth factor receptor alpha (PDGFRA). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were enriched in the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and Rap1 signalling pathways. The analysis of all the differentially expressed genes (DEGs) of the two datasets using gene set enrichment analysis (GSEA) demonstrated the involvement of the IL-17 signalling pathway, which is related to the expression of JUN and PDGFRA. ImmuCellAI found that elevated expression of JUN and PDGFRA correlated with the abundance of Th17 and monocytes, suggesting that JUN and PDGFRA could regulate Th17 cell activation and monocyte infiltration. Our ASD mouse model of maternal immune activation demonstrated that JUN and PDGFRA were upregulated in ASD mice. Limitations: The function of JUN and PDGFRA in patients of ASD and different ASD mouse models require explore and validation, and the results should be replicated in more patients with ASD. Conclusions: JUN and PDGFRA are crucial candidate genes and related to the IL-17 signalling pathway in ASD patients.
It's in the Eye of the Beholder: Ocular Ultrasound Enhanced Monitoring of Neurotoxicity after CAR T-cell therapy
Authors: Garcia-Robledo Juan Esteban , Valencia-Sanchez Cristina , Knox Molly G. , Goodman Brent P. , Rosenthal Allison , Castro Januario E. , Patel Bhavesh
Published: September 2021

Usually used in emergency settings, bedside sonographic measurement of optic nerve sheath diameter can aid in diagnosing elevated intracranial pressure. We report a case of a 26-year-old male hospitalized for CAR T-cell therapy with Axicabtagene Ciloleucel for treatment of relapsed diffuse large B-cell lymphoma, who developed progressive symptoms of immune effector cell-associated neurotoxicity syndrome. Fundoscopic examination suggested the presence of blurred optic disc margins. Bedside ocular ultrasound revealed wide optic nerve sheath diameters and bulging optic discs bilaterally. The patient had a ventriculostomy placed for monitoring and received treatment with steroids and mannitol, as well as tocilizumab. After 7 days in the ICU, the patient recovered with no evidence of long-term neurological deficits.
Lipopolysaccharide Acting Via Toll Like Receptor 4 Transactivates The TGF-β Receptor in Vascular Smooth Muscle cells
Authors: Afroz Rizwana , Kumarapperuma Hirushi , Mohamad Raafat , Little Peter J , Kamato Danielle
Published: September 2021

Toll-like receptors (TLRs) recognise pathogen‑associated molecular patterns, which allow the detection of microbial infection by host cells. Bacterial derived toxin lipopolysaccharide activates TLR4 and leads to the activation of the Smad2 transcription factor. The phosphorylation of the Smad2 transcription factor is the result of the activation of the transforming growth factor-β receptor 1 (TGFBR1). Therefore, we sought to investigate LPS via TLR4 mediated Smad2C phosphorylation dependent on the (trans)activation of the TGFBR1. The invitro used human aortic vascular smooth muscle cells (HA-VSMCs) to assess the implications of TLR4 (trans)activation of the TGFBR1 in vascular pathophysiology. We show that LPS mediated Smad2 carboxy-terminal phosphorylation is inhibited in the presence of TGFBR1 inhibitor SB431542 in HA-VSMCs. Treatment with MyD88 and TRIF pathways antagonists does not affect LPS mediated phosphorylation of Smad2C; however, LPS mediated Smad2 phosphorylation was inhibited in the presence of MMP inhibitor, GM6001 and unaffected in the presence of ROCK inhibitor Y27632. LPS via transactivation of the TGFBR1 stimulates PAI-1 mRNA expression. TLRs are first in line to respond to exogenous invading substances and endogenous molecules; our findings characterise a novel signalling pathway in the context of cell biology. Identifying TLR transactivation of the TGFBR1 may provide future insight into the detrimental implications of pathogens in pathophysiology.
Determination of Anti-Phospholipase A2 and Anti-Thrombospondin Type 1 Domain-Containing Protein 7A in Latin Patients With Membranous Nephropathy
Authors: Battaini L. C. , Ranzani O. T. , Marçal L. J. , Antonangelo L. , Jorge L.B. , Bitencourt C.D. , Woronik V. , Malheiros D.M.A. , Yu L
Published: September 2021

BACKGROUND

Membranous nephropathy (MN) is caused by antibodies against podocyte antigens, of which the type M receptor of phospholipase A2 (PLA2R) and thrombospondin type-1 domain containing 7 A (THSD7A) are the mostly studied. The objectives of this study were to determine anti-PLA2R and anti-THSD7A serum antibodies and anti-PLA2R renal tissue prevalence in a Latin population with primary MN and to evaluate their role as biomarkers for disease activity. Additionally, the performance of the two available serum diagnostic methods - ELISA and indirect immunofluorescence - was evaluated for the diagnosis of MN.
METHODS

Fifty-nine patients, 29 MN, 18 lupus membranous nephropathy (LMN) and 12 focal and segmental glomerulosclerosis (FSGS) were evaluated for serum antibodies. Renal biopsies were also evaluated for the presence of anti-PLA2R. Twenty-one patients with MN were followed for 1 year.
RESULTS

Patients with LMN and FSGS were negative for both antibodies. All 29 MN were negative for anti-THSD7A; 16 MN were positive by ELISA and/or IFI, and 3 MN patients were positive only by IFI. Thus, ELISA test showed a 45% sensitivity and 97% specificity while the IFI showed a 55% and 100%, respectively. In patients with less than a year between biopsy and antibody collection, sensitivity increased to 79% and maintained specificity. Positive correlations were observed between the anti-PLA2R ELISA titer and proteinuria. Among the 28 MN renal biopsies, 20 presented anti-PLA2R positive staining, a 72% sensitivity.
CONCLUSIONS

The determination of anti-PLA2R antibodies in the Latin population showed similar rates as reported in other populations, and the IFI test presented greater sensitivity. A lower rate of remission was found among those with anti-PLA2R positive tests.
Remodeling of Conformational Dynamics Enhances Catalytic Activities of M1 Zinc-metallopeptidases from Lanthipeptide Biosynthesis
Authors: zhao chang , Sheng Wang-Jian , wang ying , Zheng Jie , Xie Xiangqian , Liang Yong , wei wanqing , Bao Rui , Wang Huan
Published: September 2021

Lanthipeptides are an important group of natural products with diverse biological functions, and their biosynthesis requires the removal of N-terminal leader peptides (LPs) by designated proteases. LanPM1 enzymes, a subgroup of M1 zinc-metallopeptidases, are recently identified as bifunctional proteases with both endo- and aminopeptidase activities to remove LPs of class III and class IV lanthipeptides. Herein, we report the biochemical and structural characterization of EryP as the LanPM1 enzyme from the biosynthesis of class III lanthipeptide erythreapeptin. We determined X-ray crystal structures of EryP in three conformational states, the open, intermediate and closed states and identified a unique inter-domain Ca binding site as a regulatory element to modulate its domain dynamics and proteolytic activity. Inspired by the regulatory Ca binding, we develop a strategy to engineer LanPM1 enzymes for enhanced catalytic activities by strengthening inter-domain associations and driving the conformational equilibrium toward their closed forms.
Resveratrol Blocks Retrotransposition of LINE-1 Through PPAR α and Sirtuin-6
Authors: Okudaira Noriyuki , Ishizaka Yukihito , Tamamori-Adachi Mimi
Published: September 2021

The retroelement long interspersed element-1 (LINE-1 or L1) comprises about 17% of the human genome. L1 retrotransposition is known to cause genomic instability and related disorders, and resveratrol suppresses this retrotransposition; however, the underlying mechanism is still not elucidated. Recent observations showed that low-molecular-weight compounds might induce L1 retrotransposition through unknown mechanisms. This study aimed to determine polyphenol resveratrol (RV)’s effect on L1-RTP (retrotransposition) in somatic cells. Surprisingly, RV completely blocked L1-RTP. Experiments using the PPARα inhibitor GW6471 or siRNA-mediated PPARα depletion showed that RV-mediated L1-RTP’s inhibition depended on peroxisome proliferator-activated receptor α (PPARα). We demonstrated that RV inhibits p38 and CREB phosphorylation, which are involved in MAPK signaling, and the L1-ORF1 protein’s chromatin recruitment. Furthermore, RV increased the expression of sirtuin-6 (SIRT6), which inhibited the activation of L1. The sirtuins family, SIRT1, SIRT6, and SIRT7, but not SIRT3, are involved in RV-mediated inhibition of L1-RTP. Overall, our findings suggest that RV directly modulates PPARα-mediated L1-RTP in somatic cells and that MAPK signaling interacts with SIRT1, SIRT6, and SIRT7 closely and may play a role in preventing human diseases such as cancer.
First Evidence of the Implication of Cuticular Based Mechanisms in Aedes Aegypti Populations Resistant To Pyrethroids and DDT in Cameroon
Authors: TCHAMEN Borel DJIAPPI , Mariette Nana-Ndjangwo Stella , Balabanidou Vasileia , Mavridis Konstantinos , Idene Makoudjou , Parfait Awono-Ambene , Wondji Charles , Timoléon Tchuinkam , Vontas John , Christophe Antonio-Nkondjio
Published: September 2021

Pyrethroid resistance is now expanding in the two main arboviruses vectors Aedes aegypti and Aedes albopictus from Cameroon. Although recent studies suggested the implication of target site (kdr) resistance and overexpression of detoxification enzymes as key mechanisms, the implication of additional mechanisms such as cuticular resistance has not been investigated. The present study assesses the possible implication of cuticle in Aedes species resistance to pyrethroids. High cuticular hydrocarbon (CHC) content was detected in Ae. aegypti populations from Douala and Yaoundé. The difference (38% increase) between the Douala and susceptible populations was found to be statistically significant.The study confirms the implication of cuticular-based mechanisms in resistant to pyrethroids and DDT Aedes aegypti mosquitoes from Cameroon.
Variations of Habitat Quality and Ecological Risk and Their Correlations With Landscape Metrics in a Robust Human Disturbed Coastal Region
Authors: Han Huiqing , Su Zhihua , Yang Guangbin
Published: September 2021

As impacted by strong intense human activity disturbance, the landscape pattern change significantly affects the habitat quality and ecological risk level in the coastal regions. Though numerous researches were conducted in coastal habitat quality and ecological risk, the correlations of habitat quality and ecological risk with landscape metrics in coastal regions have been rarely reported. A scientific question should be addressed is the scientific basis for the sustainable development of coastal regions. Accordingly, Xinggang town, a coastal region in southern China, was selected as a typical coastal region disturbed by robust human activities. Given high-precision remote sensing data, the temporal-spatial variations of habitat quality and ecological risk in the coastal region were analyzed by adopting the methods of InVEST model and ecological risk index, and the correlations of habitat quality and ecological risk with landscape metrics were examined. As indicated from the results, the deterioration of habitat quality and the increase in ecological risk in the coastal region under the disturbance of human activities exhibited obvious distance gradients. The gradient area close to the coastline was the area with the prominent variations of habitat quality and ecological risk. Most landscape metrics were positively correlated with habitat quality and ecological risk, and the correlations were different in a range of distance gradients. Under the rapid urbanization in the coastal region, the rapid expansion of built-up land and the decrease of natural landscapes significantly impacted the landscape pattern index and then altered the habitat quality and ecological risk level.
Putting Together the Puzzle of Ion Transfer in Single-Digit Carbon Nanotubes: Ab Initio Meets Mean-Field
Authors: Neklyudov Vadim , Freger Viatcheslav
Published: September 2021

Nature employs channel proteins to selectively pass water across cell membranes, which inspires search for bio-mimetic analogues. Carbon nanotube porins (CNTPs) are intriguing mimics of water channels, yet ion transport in CNTPs still poses questions. As alternative to continuum models, here we present a molecular mean-field model, computing ab initio all required thermodynamic quantities for KCl salt and H+ and OH- ions present in water. Starting from water transfer, the model considers transfer of free ions, along with ion-pair formation to address ion-ion interactions. High affinity to hydroxide, suggested by experiments and making it dominant charge carrier in CNTP, is revealed as an exceptionally favorable transfer of KOH pairs. Nevertheless, free ions, coexisting with less mobile ion-pairs, apparently control ion transport. The model explains well the observed effects of salt concentration and pH on conductivity, transport numbers, anion permeation and its activation energies, and current rectification. The proposed approach is extendable to other sub-nanochannels and help design novel osmotic materials and devices.
Identifying Extreme COVID-19 Mortality Risks in English Small Areas: A Disease Cluster Approach
Authors: Adin Aritz , Congdon Peter , Santafe Guzman , Ugarte Maria Dolores
Published: September 2021

The COVID-19 pandemic is having a huge impact worldwide and has highlighted the extent of health inequalities between countries but also in small areas within a country. Identifying areas with high mortality is important both of public health mitigation in COVID-19 outbreaks, and of longer term efforts to tackle social inequalities in health. In this paper we consider different statistical models and an extension of a recent method to analyze COVID-19 related mortality in English small areas during the first wave of the epidemic in the first half of 2020. We seek to identify hotspots, and where they are most geographically concentrated, taking account of observed area factors as well as spatial correlation and clustering in regression residuals, while also allowing for spatial discontinuities. Results show an excess of COVID-19 mortality cases in small areas surrounding London and in other small areas in North-East and and North-West of England. Models alleviating spatial confounding show ethnic isolation, air quality and area morbidity covariates having a significant and broadly similar impact on COVID-19 mortality, whereas nursing home location seems to be slightly less important.
A Comprehensive Evaluation Between Dexmedetomidine and Midazolam for Intraoperative Sedation in the Elderly: Protocol for a Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Huang Chunxia , Li Zunjiang , Long Yingxin , Li Dongli , Huang Manhua , Ding Banghan , Zhu Wei
Published: September 2021

Background: The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between Dexmedetomidine and Midazolam in many clinical randomized controlled trials (RCTs) were inconsistent and suspicious. We aimed to comprehensively evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly via meta-analysis and systematic reviews.Methods: RCTs regarding to the comparison of sedative effects and safety between Dexmedetomidine and Midazolam in elderly patients (aged ≥ 60 years) will be comprehensively searched from 2000.10 to 2021.05 through 4 English databases and 4 Chinese databases. After extraction in duplicate, the systematic review and meta-analysis will be performed on the primary outcomes (hemodynamic changes, sedative effect, cognitive function) and secondary outcomes (analgesic effect, surgical characteristics, complications or adverse reactions) for assessing the two therapy methods using Review manage software (Version 5.3). Sensitivity analysis will be conducted to evaluate the heterogeneity of the results, funnel plot and Egger’s test will be performed to analyze publication bias of the included studies, and test sequential analysis will be applied to assess the robustness and reliability of preliminary meta-analysis results. Finally, rating quality of evidence and strength of recommendations on the meta results will be summarized by rating quality of evidence and strength of recommendations (GRADE) approach. Discussion: This systematic review and meta-analysis will evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly, it will give an insight on the application of Dexmedetomidine and Midazolam, and will provide evidences-based reference for clinical decision makings.Systematic review registration: PROSPERO (CRD42021221897).
Age and Lymph Nodes Examination May Be Related to the Outcome of Ovarian Clear Cell Carcinoma: A SEER Analysis
Authors: Zhu Menghan , Jia Nan , Jiang Wei
Published: September 2021

AimTo analyze and compare the demographics, treatment, and survival rates in patients with ovarian clear cell carcinoma (OCCC).MethodsWe conducted a population-based retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1998 to 2016. Data of 4344 women with OCCC were compared, and survival was analyzed using the Kaplan–Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model.ResultsThere was no significant difference in cause specific survival (CSS) regardless of chemotherapy in stage I and stage II OCCC. In women with stage III/IV OCCC, there was an increased mortality in women without chemotherapy (5-year CSS 29.80% vs. 24.90%, p<0.001). Among stage I women younger than 60 years old, the 5-year CSS of those underwent chemotherapy was worse than that of non-chemotherapy (86.4% vs. 97.50%, p=0.002). Among these patients, omitting chemotherapy had improved CSS (HR 0.539; 95% CI 0.386-0.753), and omitting lymph nodes examination had decreased CSS (HR 1.666; 95% CI 1.230-2.256). In stage III/IV women who were 60 years or older, the 5-year CSS of those underwent chemotherapy was better than that of non-chemotherapy (32.60% vs. 24.30%, p<0.001). Among these patients, omitting chemotherapy (HR 1.769; 95% CI 1.385-2.258) and omitting lymph nodes examination (HR 1.709; 95% CI 1.371-2.130) had lower CSS.ConclusionChemotherapy has different effects in patients with OCCC at different stages and ages. Age and lymph nodes examination may be factors that affect the outcome of patients with OCCC.
Melan-A Expression in Poorly Differentiated Carcinoma of Lung: A Potential Diagnostic Pitfall
Authors: huang wenyong , Li Shuixian , Zhu Guofeng , Zeng Lei , Zheng Yueer , Huang Tao , Zhang Wen , Liao Shousheng , Liu Fanrong , Li Lixiang
Published: September 2021

BackgroundMelan-A/MART-1 is a melanocytic differentiation marker, which is recognized as an antigen on melanoma cells. It is relevant for pathologists as a useful diagnostic marker in the diagnosis of melanocytic tumors. However, the expressional pattern of Melan-A in poorly differentiated carcinoma of lung has never been reported so far.Case presentationHere, we report a 77-year-old female patient who presented with a large mass in the right lung and was subsequently diagnosed with a poorly differentiated carcinoma of lung. We unexpectedly found that the carcinoma in this patient exhibited diffuse Melan-A expression. ConclusionThis is the first case reported of a poorly differentiated carcinoma of lung with Melan-A expression. This report shows that Melan-A can express in poorly differentiated carcinoma, and highlights a potential diagnostic pitfall in the diagnosis of carcinoma, which urges pathologists to exercise caution in cases where Melan-A positivity and illustrates the need for further immunohistochemical or molecular examination to avoid misdiagnosis.
The Use of Molecular Markers to Investigate Possible Resistance to Heartworm Preventives in Dirofilaria Immitis Samples from Heartworm Positive Dogs in Europe
Authors: Curry Emily , Traversa Donato , Cárreton Elena , Kramer Laura , Sager Heinz , Young Lisa , Prichard Roger K
Published: September 2021

Background: Dirofilaria immitis is a parasitic filarial nematode. It is the causative agent of dirofilariosis, a potentially fatal pulmonary infection which primarily infects canids and felines. dirofilariosis infections are primarily controlled with a prophylactic macrocyclic lactone (ML) regimen. Recent evidence has confirmed the development of ML-resistant isolates in the US which are genetically distinct from wild-type populations. Previous research clinically validated 9 single nucleotide polymorphism (SNP) molecular markers associated with these ML resistance phenotypes isolated from the USA. Methods: In this study, three D. immitis US laboratory-maintained isolates: two putative susceptible isolates, Berkeley, and Georgia II, one putative resistant isolate, WildCat; and eleven European D. immitis clinical samples, from Italy, Spain, and Hungary were analyzed. The samples tested were fresh microfilaria (mf) in blood or adult female worms shipped in ethanol and rehydrated in phosphate buffered saline (PBS). After DNA extraction, each sample underwent MiSeq sequencing of regions encompassing the 9 SNP sites previously correlated with ML resistance. The nucleotide frequencies of the 9 SNP sites were analyzed and the pairwise fixation index (FST) of the top 2 SNP molecular markers were calculated in order to estimate the probability of identity with known resistant isolates.Results: In the three laboratory-maintained US D. immitis isolates Berkeley had a 2-SNP pairwise FST of 0.00, indicating a ML-susceptible genotype, WildCat had a 2-SNP pairwise FST of 0.33 indicating a ML-resistant genotype, and Georgia II had a 2-SNP pairwise FST of 0.07, which may indicate early selection for ML resistance. The genotype analysis of the European clinical samples showed that all eleven European samples had 2-SNP pairwise FST of 0.00, which indicates their genotypes are consistent with ML susceptibility. Conclusions: Prior to genotyping the European samples, it was possible that the positive heartworm infections could have arisen because of the development of ML-resistance or due to lack of owner compliance or incomplete use of heartworm preventives. Our results indicate no genomic evidence of ML-resistance and suggests that resistance has not developed, so far, in Europe, or been introduced via movement of infected dogs. However, vigilance is needed to maintain susceptibility to heartworm preventives in regions of the world so far without resistance.
Geographical Prevalence of SARS-CoV-2 Variants, August 2020 to July 2021.
Authors: Chan Wai Sing , Lam Yuk Man , Law Janet Hei Yin , Chan Tsun Leung , Ma Edmond Shiu Kwan , Tang Bone Siu Fai
Published: September 2021

Coronavirus disease 2019 (COVID-19) pandemic has progressed into second year. The etiologic agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into numerous lineages, some of which are gifted with transmissibility advantages. This underscores the importance of variant surveillance, to keep public health countermeasures and our understanding on the virus up-to-date. In the light of this, we extracted one-year genomic data (August 2020 to July 2021) from Global Initiative on Sharing All Influenza Data (GISAID) EpiCoV™ database and estimated monthly proportions of 11 SARS-CoV-2 variants in various geographical regions. From continental perspective, delta variant of concern (VOC) predominated in Africa, Asia, Europe, North America and Oceania, with proportions ranging from 67.58 to 98.31% in July 2021. In South America, proportion of the expanding delta VOC (23.24%) has been getting closer to the predominant yet diminishing gamma VOC (56.86%). We further analyzed monthly data on new COVID-19 cases, new deaths, vaccination status and variant proportions of 6 countries. Similar to continental data, delta VOC predominated in all countries except Brazil in July 2021. In most occasions, rise and predominance of alpha, beta, gamma, delta and zeta variants were accompanied with surges of new cases, especially after the time points of major lineage interchange. The ascending phases of new cases lasted for 1 to 5 months with 1.69- to 40.63-fold peak growth, whereas new death toll varied with regional vaccination status. Our data suggested surges of COVID-19 cases might be predicted from variant surveillance data. Despite vaccine breakthroughs by delta VOC, death tolls were more stable in countries with better immunization coverage. Another takeaway is the urgent need to improve vaccine efficacy against delta and emerging variants.