bluuebunny/crossref_metadata_2025 huggingface dataset:
hUMSCs Regulate the Differentiation of Ovarian Stromal Cells via TGF-β1/Smad3 Signaling Pathway to Inhibit Ovarian Fibrosis to Repair Ovarian Function in POI Rats
Authors: Cui Linlu , Bao Hongchu , Liu Zhongfeng , Man Xuejing , Liu Hongyuan , Hou Yun , Luo Qianqian , Wang Siyuan , Fu Qiang , Zhang Hongqin
Published: July 2020

Background: The basic pathological changes of primary ovarian insufficiency (POI) include ovarian tissue fibrosis and follicular development disorders. The human umbilical cord mesenchymal stem cells (hUMSCs) transplantation has been shown an effective method to improve the ovarian function in POI rat model; however, the exact mechanisms are still unclear. The purpose of this study is to investigate whether the recovery of ovarian function in POI rats are related to the inhibition of tissue fibrosis following hUMSCs transplantation. Furthermore, the transforming growth factor-β1 (TGF-β1) signaling pathway is explored to determine the mechanisms of ovarian function recovery through its inhibition of tissue fibrosis.Methods: The primary ovarian insufficiency (POI) rat model was established by intraperitoneal injection of chemotherapy drug cisplatin (CDDP) for 7 days, The levels of serum sex hormones were measured using enzyme-linked immunosorbent assay (ELISA). The tissue fibrosis in ovary was examined using masson staining and Sirus red staining. The collagen fibers in the ovarian tissues were detected by Western blot analysis. To investigate the mechanisms of ovarian function recovery following hUMSCs transplantation, ovarian stromal cells were isolated from the ovarian cortex of immature rats. The expression of Cytochrome P450 17A1 (Cyp17a1) and fibrosis marker of alpha smooth muscle Actin (α-SMA) in ovarian stromal cells were examined using immunofluorescence analysis. Also, the protein levels of Cyp17a1 and α-SMA in ovarian stromal cells were examined by western blot analysis. The expression of TGF-β1 and Smade3 signals were measured by Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.Results: The results show that the function of ovary in POI rats were significantly improved after hUMSCs transplantation. The expression of fibrosis markers (α-SMA) and production of Collagen Type I (Collagen Ⅰ) and Collagen Type Ⅲ (Collagen Ⅲ) in POI rats was significantly inhibited in POI rats following hUMSCs transplantation. In the cultured ovarian stromal cells, the decrease of TGF-β1 and p-Smade3 protein expression was observed in hUMSCs treated POI rats. The treatment with TGF-β1 inhibitor of SB431542 further confirmed this signal pathway was involved in the process. Conclusion: Our study demonstrated that the TGF-β1/Smad3 signaling pathway was involved in the inhibition of ovarian tissue fibrosis, which contributed to the restoration of ovarian function in POI rats following hUMSCs transplantation.
Life Satisfaction among a Clinical Eating Disorder Population
Authors: Claydon Elizabeth , DeFazio Caterina , Lilly Christa L. , Zullig Keith J.
Published: July 2020

Background
The primary objective was to understand life satisfaction (LS) of patients with eating disorder (ED) diagnoses in relation to eating pathology severity, personal/familial ED history, and key demographic and anthropometric variables. Methods: Participants (N = 60) completed the Satisfaction with Life Scale (SWLS), the Eating Pathology Severity Index (EPSI), and demographic questionnaires. Bivariate associations via correlations and multiple linear regression models were used to explore these relationships.
Results
The average SWLS score was 3.7 out of 7, suggesting below average LS. LS was statistically significantly associated with private insurance, past ED, EPSI muscle building, EPSI restricted eating, and EPSI negative attitudes. When included in multiple linear regression, the model explained 33% of the variability of LS [F (7, 56) = 3.4, p = 0.0054, R2 = 0.33]. EPSI muscle building remained the strongest predictor (β = 0.13, p = 0.04).
Conclusions
Based on the data, individuals who have/have had EDs on average score lower on the SWLS than the general population. Individuals scoring within this range typically experience significant issues in several areas of life or a substantial issue in one area. Findings suggest a need for interventions that focus on improving LS in hopes of simultaneously reducing ED symptoms.
Swimming Exercise Modifies Oxidative Stress in Skeletal and Cardiac Muscles of Diabetic Rats
Authors: Pio Talita Fernanda , Orzari Lucas Eduard , Alves Armindo Antônio , Silveira Paulo Cesar Lock , Esquis Marcelo Augusto Marretto , Andrade Thiago Antônio Moretti de , Mendes Maira Felonato , Dalia Rodrigo Augusto
Published: July 2020

Background: Oxidative stress is a key factor in the worsening of diabetes, requiring an increase in the activity of the antioxidant system, culminating in a balance in the body. The aim of the present study was to evaluate the redox state in the skeletal and cardiac muscles in rats induced to diabetes model and submitted to swimming exercise training for 4 weeks. Methods: Wistar rats were separated into the following four groups: untrained control (C); trained control (T); untrained alloxan-induced diabetes (D); trained alloxan-induced diabetes (TD). The animals were submitted to swimming exercise training for 4 weeks. The redox state of skeletal and cardiac muscles was analyzed by TBARS, -SH groups and, H2O2 production as well as by the SOD and Catalase activity. Besides, a histomorphometry analysis was performed in the cardiac muscle in which the total number of cardiomyocytes and the total area of collagen fibers were measured.Results: On the Soleus muscles, the TD group showed increased of H2O2 and Catalase compared to T group; and SOD compared to D group. About the red gastrocnemius, TD group presented higher SOD and lower Catalase relation to D group. Regarding to cardiac muscle, TD group presented lower TBARS than D group, while it was higher in -SH groups and Catalase compared to D group. Moreover, the swimming exercise led to a decrease in hyperglycemia, benefits in pathogenesis and physio-pathogenesis, evidenced by a reduced number of cardiomyocytes and area of collagen fibers. Conclusions: The swimming protocol exercise in diabetic rats was able to control the hyperglycemia, control of oxidative damage and minimize the fibrosis on cardiac muscle in diabetic rats.
Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids
Authors: Vasantha Shalini , Bhaduri Utsa , Ravikkumar Anjhana C , Rengarajan Anusha , Rao Satyanarayana
Published: July 2020

Background: H1T2/H1FNT is a germ cell specific linker histone variant expressed during spermiogenesis specifically in round and elongating spermatids. Infertile phenotype of homozygous H1T2 mutant male mice revealed the essential function of H1T2 for the DNA condensation and histone to protamine replacement in spermiogenesis. However, the mechanism by which H1T2 imparts the inherent polarity within spermatid nucleus including the additional protein partners and the genomic domains occupied by this linker histone are unknown.Results: Sequence analysis revealed the presence of Walker motif, SR domains and putative coiled-coil domains in the C-terminal domain of rat H1T2 protein. Genome wide occupancy analysis using highly specific antibody against the CTD of H1T2 demonstrated the binding of H1T2 to the LINE L1 repeat elements and to a significant percentage of the genic regions (promoter-TSS, exons and introns) of the rat spermatid genome. Immunoprecipitation followed by mass spectrometry analysis revealed the open chromatin architecture of H1T2 occupied chromatin encompassing the H4 acetylation and other histone PTMs characteristic of transcriptionally active chromatin. In addition, the present study has identified the interacting protein partners of H1T2 associated chromatin mainly as nucleo-skeleton components, RNA binding proteins and chaperones.Conclusions: Linker histone H1T2 possesses unique domain architecture which can account for the specific functions associated with chromatin remodeling events facilitating the initiation of histone to transition proteins/protamine transition in the polar apical spermatid genome. Our results directly establish the unique function of H1T2 in nuclear shaping associated with spermiogenesis by mediating the interaction between chromatin and nucleo-skeleton, positioning the epigenetically specialized chromatin domains involved in transcription coupled histone replacement initiation towards the apical pole of round/elongating spermatids.
Targeting monoamine oxidase A-regulated TAM polarization for cancer immunotherapy
Authors: Wang Yu-Chen , Wang Xi , Yu Jiaji , Ma Feiyang , Li Zhe , Zhou Yang , Zeng Samuel , Ma Xiaoya , Li Yanruide , Neal Adam , Huang Jie , To Angela , Clarke Nicole , Memarzadeh Sanaz , Pellegrini Matteo , Yang Lili
Published: July 2020

Targeting tumour-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumour microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observed MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibited decreased TAM immunosuppressive functions corresponding with enhanced antitumour immunity. MAOI treatment induced TAM reprogramming and suppressed tumour growth in preclinical mouse syngeneic and human xenograft tumour models. Combining MAOI and anti-PD-1 treatments resulted in synergistic tumour suppression. Clinical data correlation studies associated high intratumoural MAOA expression with poor patient survival in a broad range of cancers. We further demonstrated that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
A Case of Long-Term Survival after Splenectomy for Solitary Splenic Metastasis from Gastric Cancer
Authors: Obana Ayato , Komatsu Nobuo , Aiba Kazuma , Nakanishi Shinya , Abe Masakazu , Yamaguchi Toshiyuki , Hayashi Masahiro , Obi Hayato , Koyama Masamichi , Hashimoto Shinichi
Published: July 2020

Background: Very rarely does a splenic solitary metastasis arise from a gastric carcinoma because splenic metastasis is usually seen in association with widespread visceral metastasis. Splenectomy is considered to be a curative treatment; however, long-term prognosis after splenectomy has scarcely been reported. We report a case of a metachronous and solitary metastasis to the spleen from gastric cancer in which the patient achieved 5-year recurrence-free survival after splenectomy.Case Presentation: An 84-year-old man underwent an open total gastrectomy involving D1+ lymph nodes dissection for gastric cancer located in the cardia (pT3N1M0, pStage IIB). Eighteen months later, a 2-cm solitary hypodense lesion was detected in the spleen by computed tomography (CT). Twenty-three months later, the serum carcinoembryonic antigen (CEA) value elevated to 19.9 ng/ml, and abdominal CT revealed an increase in tumor size to 5 cm. Positron-emission tomography (PET)-CT revealed intense 18F-2-deoxy-2-fluoro-glucose (FDG) uptake in the spleen without the involvement of other organs and lymph nodes. We diagnosed him with solitary splenic metastasis from gastric cancer and performed a splenectomy 26 months after the first surgery. Histological examination revealed that the splenic tumor was a moderately differentiated adenocarcinoma, which was very similar to the primary gastric tumor; the lesion was diagnosed as a metastatic tumor from the previous gastric carcinoma. The patient remains healthy to date without recurrence, 5 years after the splenectomy. Conclusion: We experienced a case of a solitary splenic metastasis from gastric cancer in which 5-year recurrence-free survival was achieved after splenectomy. To determine the surgical indication in patients with splenic metastasis, it is important to differentiate between a solitary lesion or multiple metastasis. Especially, occult metastasis should be excluded by means of several months of follow-up with imaging tests and systemic FDG-PET surveys before splenectomy.
The simple surgery to safely extend the anhepatic time to 30 minutes for rat liver transplantation
Authors: Tang Gaofeng , Zhang Jiabin , Zhao Huibo , Wei Sidong , Zhou shaotang , Chen Guoyong
Published: July 2020

Background

Orthotopic rat liver transplantation (OLT) is widely used, it remains complicated although many renovations have been made.
Methods

OLT was performed for tolerance induction, including whole graft OLTs from close male Sprague Dawley (SD) rat to male SD (whole graft group, n = 21) and 30 minute anhepatic time group (AHT group, n = 11), OLT was performed from 50% male Lewis allograft to male Brown Norway (BN) rats to induce tolerance (half graft group, n = 28), Cyclosporine A was injected once daily for 14 days.
Results

For whole graft group, 30-day survival rate was 85.5% (18/21), the reasons of death were gas embolism due to the missed suturing in 2 cases, blood loss in 1 case. For AHT group, 30-day survival rate 72.7% (8/11), the causes of death were respiratory failure in 1 case, unknown in 2 cases. For tolerance group, 30-day survival rate was 64.3% (18/28), the reasons of death were diarrhea in 4 cases, wound dehiscence in 6 cases. There were no differences in survival in 3 groups (p = 0.289).
Conclusion

The anhepatic time can be extended simply through the change of clamping the diaphragm, which facilitates its application in the research.
Nanobarcodes with multidimensional optical information beyond diffraction limit
Authors: Jin Dayong , Wen Shihui , Liu Yongtao , Wang Fan , Lin Gungun , zhou jiajia , Shi Bingyang , Suh Yung Doug
Published: July 2020

Precise design and fabrication of heterogeneous nanostructures will enable nanoscale devices to integrate multiple desirable functionalities. But due to the diffraction limit (~200 nm), the optical uniformity and diversity within the heterogeneous functional nanostructures are hardly controlled and characterized. Here we report a set of nanobarcodes, each optically active section has its unique nonlinear responses to donut illumination patterns, so that one can discern each unit with super resolution. To achieve this, we first realized an approach of highly controlled epitaxial growth and produced a range of one-dimensional heterogeneous structures. Each section along the nanorod structure display tunable upconversion emissions, in four optically orthogonal dimensions, including colour, lifetime, excitation wavelength, and power dependency. Moreover, we demonstrated a 210 nm single nanorod as the smallest polychromatic light source for the on-demand generation of RGB photonic emissions. Remarkably, within a space of 50 nm, only 1/20th of the excitation wavelength, multiple codes can be successfully coded and decoded in 4 optical dimensions. This precision control enables the fabrication of super capacity geometrical barcodes with theoretical coding capacity up to (24-1)4. This work benchmarks our new ability towards the full control of sub-diffraction-limit optical diversities of single heterogeneous nanoparticles.
Analysis of N6-methyladenosine (m6A) methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer
Authors: Gong Pengju , Shao Youcheng , Yang Yan , Song Wenjing , He Xin , Zeng Yifan , Huang Sirui , Wei Lei , Zhang Jingwei
Published: July 2020

Background
Recently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating mRNA and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.
Materials and Methods
In this study, we used a serious of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL13, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13, and their relationship with immune infiltration in breast tumor tissues.
Results
The results showed that METTL14 and ZC3H13 were the down-regulated m6A “writers” in breast cancer. Survival outcomes analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, the down-regulation of them was associated with ER-, PR- and basal-like, TNBC patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion and metastasis of tumor cells. METTL14, ZC3H13 and APC expression levels had significant positive correlation with infiltrating levels of CD4 + T cells, CD8 + T cells, neutrophils, macrophages and Dendritic cells, and negatively with Treg cells in breast cancer.
Conclusions
This study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.
Prevalence of Overweight and Obesity, and Associations with Socio-Demographic Factors in Kuwait
Authors: Oguoma Victor M , Coffee Neil , Alsharrah Saad , Abu-Farha Mohamed , Al-Refaei Faisal H , Al-Mulla Fahd , Daniel Mark
Published: July 2020

Background: Kuwait is amongst countries in the Gulf region with high income economy. According to the World Health Organisation (WHO), one in five adults in the Gulf region is obese. The aim of this study was to estimate the prevalence of both overweight and obesity, and their relationships with socio-demographic factors, in Kuwait.Methods:A population-based survey of diabetes and obesity in Kuwait – part of the Kuwait Diabetes Epidemiology Program – was conducted between 2011-2013, targeting adults aged 18-82 years using the WHO STEPwise approach to non-communicable disease surveillance. Body mass index (BMI) was calculated to classify overweight and obesity, and waist circumference (WC) used to expressed central obesity. Multivariable logistic regression was used to estimate relationships between socio-demographic factors, overweight (25.0-29.9 kg/m2), obesity (≥30.0 kg/m2) or central obesity (WC≥80cm women; WC≥94cm men).Results:Records for gender (57% Men), age, BMI, governorate and nationality existed for 4963 individuals. Mean age and BMI were 43 years and 30kg/m2, respectively. Non-Kuwaiti nationals were more prevalent than Kuwaitis (87% vs 13%). Prevalence rates for overweight, obesity and central obesity were 38% (95%CI: 37-40%), 42% (95%CI: 41-44%) and 75% (95%CI: 73-76%), respectively. The youngest age group (18-29 years) had rates of 33% (95%CI: 28-39%), 25% (95%CI: 20-30%) and 49% (95%CI:43-55%) for overweight, obesity and central obesity, respectively. In covariate-adjusted analyses, the odds of being overweight was 23% greater for men than for women. Conversely, women had a 29% (95%CI: 4-60%) and 6-fold (95%CI: 5-9-fold) greater odds of obesity/central obesity, respectively, than men. Greater educational attainment, physical activity, and non-Kuwaiti status were associated with lower odds of obesity/central obesity. History of smoking, elevated blood pressure, higher income, being married, greater age and female sex related to greater odds of obesity/central obesity.Conclusion:Overweight was greater in men, obesity greater in women. Overweight and obesity prevalence were high in young adults ages 18-29 years, a significant public health concern. Efforts to integrate mandatory physical education to the school curriculum and promoting the creation of recreation spaces/parks to promote physical activities, will play a vital role in the early prevention of overweight/obesity in Kuwait.
Diagnosis and Prognostic Value of SPARC in Gastric Carcinoma: Database Mining for GCTA
Authors: Ying Diqi , Li Ding , Jin Xiao
Published: July 2020

Gastric carcinoma (GC) remains high incidence and mortality both in developed and developing countries. SPARC is extracellular non-structural matrix glycoprotein. Previous studies were closely associated with bone disease. However, the role of SPARC in GC remains largely unclear. In our study, we explored the diagnosis, prognosis and pathway enrichments value of SPARC in GC. Here, with the data from The Cancer Genome Atlas (TCGA), we used receiver operating characteristic (ROC) curve analysis to estimate the diagnosis value of the SPARC expression, Univariate and multivariate analysis to the prognosis, Gene set enrichment analysis (GSEA) to the signal pathway enrichments. As a result, SPARC expression was significantly higher in the GC tissue samples. Those with high SPARC expression of GC patients were worse prognosis. GSEA shows the gene sets related signal pathways including transforming growth factor (TGF) beta signaling pathway, pathways in cancer, Wnt signaling pathway, Mitogen-activated protein kinase (MAPK) signaling pathway etc. In brief, those results suggest that SPARC can serve as a potential biomarker for GC in diagnosis and prognosis.
Measles and Rubella Serosusceptibity Among Population Vaccinated with Different Schedule of Vaccination: The Potential Impact on Measles Elimination in Iran.
Authors: Saffar Hana , Khalifeloo Maryam , Saffar Mohammed-Jafar , Abdollahi Ali-Reza , Parsaei Mohammad-Reza , Ghorbani Gholam-Reza , Salarvand Samaneh , Aarabi Mohsen
Published: July 2020

Background: In addition to schedule 2-doses monovalent measles vaccine (mMV) immunization of Iranian children since 1984, a nationwide campaign of measles-rubella (MR) immunization among 5- 25 years-old population in December 2003 was conducted. From 2004 mMV was replaced with measles- mumps-rubella (MMR) vaccine. Despite a high vaccination coverage, outbreaks of measles occurred in the country. Study was designed to investigate seroimmunity against measles and rubella among various age groups of population who were vaccinated with different schedule since 1984. Also, immunologic response to revaccination in seronegative subjects was evaluated. Methods: From 1 November 2017 to 30 June 2018 a cross- sectional study among 7- 33 year old healthy population with documented history of measles vaccination was conducted. Based on their age and history of vaccination categorized as GA: 20-23 years old; vaccinated with 1-2 dose of mMV, and also MR revaccinated. GB: 15-19 years, vaccinated only with 2- doses of mMV at the ages of 9 and 15 months. GC: 12-14 years and GD: 7-11 years; vaccinated with 2- dose of MMR vaccine at the ages 15 months - 6 years, and 12-18 month respectively. Collected sera were assessed to measure antimeasles and antirubella IgG antibodies concentration. Four to 6 weeks after revaccination of seronegative subjects, antimeasles-antirubella IgM and IgG antibodies were rechecked. Collected data were analyzed using descriptive statistical methods.Results: Totally 635 individuals, 312 female were included. Relative distribution of subjects in each group was as: GA: 98, GB: 295, GC: 139, and GD: 103 persons. Overall, 12.28% and 18.4% of population were soronegative, and varied greatly between groups: 2%-0/0%, 15.2%- 25.0%, 11.5%- 17.2%; and 14.6%-18.4% to measles and rubella, respectively. After revaccination, 92% and 94.9% showed 1gG response to measles and rubella vaccine respectively.Conclusion: Despite high coverage rate with measles containing vaccine, a significant numbers of vaccinated subjects lost their seroprotection, possibly because of secondary vaccine failure. This may affect measles-rubella elimination goal in the country. If these data were confirmed by further studies, more strengthen regional/ national supplementary immunization activity should be considered.
The clinical characteristics and outcome of cryptococcal meningitis with AIDS in a tertiary hospital in China: An observational cohort study
Authors: Wu Liang , Xiao Jiang , Song Yangzi , Gao Guiju , Zhao Hongxin
Published: July 2020

Background We collected the clinical data of hospitalized AIDS patients who complicated with cryptococcal meningitis (CM) in nearly 10 years, to analyze the influencing factors of prognosis and provide help for early identification of severe patients, timely rescue measures and improvement of prognosis. Methods The 128 subjects were divided into two groups according to the effective/ineffective clinical treatment. Analyzed and compared the data from various aspects. Results 119 cases (93.0%) had headache, 109 (85.2%) had fever, 95 (74.2%) had nausea and vomiting, 52 (40.6%) had consciousness disorder. 101 patients (78.9%) were effective in clinical treatment, while 27 (21.1%) were ineffective. Multivariate Logistic regression analysis showed that the occurrence of cerebral herniation increased the risk of poor prognosis by 405 times, and the occurrence of disturbance of consciousness increased the risk of poor prognosis by 4.4 times. However, each week of extension of the course of induction therapy reduced the risk of poor prognosis by 0.683 times, and increased the effective outcome of clinical treatment by 1.5 times. In addition, the prognosis of patients with ventriculoperitoneal shunt or lumbar cisterna shunt decompression was better than that of patients without shunt therapy. Conclusions Cerebral hernia and disturbance of consciousness are risk factors for prognosis of AIDS patients with CM, and duration of induction therapy is a protective factor for prognosis. Anticryptococcal therapy with high efficiency and sufficient treatment time during induction period is especially critical for improving prognosis. Shunt decompression therapy may improve the prognosis of patients with AIDS complicated with CM.
Early leucine programming on protein utilization and mTOR signaling by DNA methylation in zebrafish (Danio rerio)
Authors: Zhu Qiang-Sheng , Wang Jie , he shan , Liang Xu-Fang , Xie Shuang , Xiao Qian-Qian
Published: July 2020

Background
Early nutritional programming affects a series of metabolism, growth and development in mammals. Fish also exhibit the developmental plasticity by early nutritional programming. However, little is known about the effect of early amino acid programming on growth and metabolism.
Methods
In the present study, zebrafish (Danio rerio) was used as the experimental animal to study whether early leucine stimulation can programmatically affect the mechanistic target of rapamycin (mTOR) signaling pathway, growth and metabolism in the later life, and to undercover the mechanism of epigenetic regulation. Zebrafish larvas at 3 days post hatching (dph) were raised with 1.0% leucine from 3 to 13 dph during the critical developmental stage, then back to normal water for 70 days (83 dph).
Results
The growth performance and crude protein content of zebrafish in the early leucine programming group were increased, and consistent with the activation of the mTOR signaling pathway and the high expression of genes involved in the metabolism of amino acid and glycolipid. Furthermore, we compared the DNA methylation profiles between the control and leucine-stimulated zebrafish, and found that the methylation levels of CG-differentially methylated regions (DMGs) and CHH-DMGs of genes involved in mTOR signaling pathway were different between the two groups. With quantitative PCR analysis, the decreased methylation levels of CG type of Growth factor receptor-bound protein 10 (Grb10), eukaryotic translation initiation factor 4E (eIF4E) and mTOR genes of mTOR signaling pathway in the leucine programming group, might contribute to the enhanced gene expression.
Conclusions
The early leucine programming could improve the protein synthesis and growth, which might be attributed to the methylation of genes in mTOR pathway and the expression of genes involved in protein synthesis and glycolipid metabolism in zebrafish. These results could be beneficial for better understanding of the epigenetic regulatory mechanism of early nutritional programming.
Assessment of the Susceptibility Status of Aedes aegypti (Diptera: Culicidae) Populations to Pyriproxyfen and Malathion in a National Wide Monitoring of Insecticide Resistance in Brazil, 2017-2018.
Authors: Campos Kauara Brito , Martins Ademir Jesus , Rodovalho Cynara de Melo , Bellinato Diogo Fernandes , Dias Luciana dos Santos , Macoris Maria de Lourdes da Graça , Andrighetti Maria Teresa Macoris , Lima José Bento Pereira , Obara Marcos Takashi
Published: July 2020

Background: In Brazil chemical control has been used since 1985. For the effectiveness of chemical control, it is essential to monitor the vector susceptibility to insecticides. This study aimed to describe bioassays standardization and to determine the susceptibility profile of Ae. aegypti populations to the products in use malathion and pyriproxyfen on national scale between 2017 and 2018, and to discuss the observed results impact in arboviruses control.Methods: The diagnostic-doses (DD) of pyriproxyfen and malathion were determined as the double of the inhibition of adult emergence (EI) and lethal doses for 99% of the Rockefeller reference strain, respectively. For the monitoring of natural populations, collections were performed in 132 Brazilian cities, through egg traps. Colonies were raised in the laboratory for one or two generations (F1 or F2) and submitted to susceptibility tests with larvae exposed to DD of pyriproxyfen (0.03 µg/L) and adults with the malathion DD herein obtained (20 µg), in addition to the World Health Organization (WHO) indicated DD (50 µg) in bottle assay. Dose-response bioassays with pyriproxyfen were performed with populations which did not achieved 98% EI in the DD assays. Results: Alteration of susceptibility to pyriproxyfen was recorded in 6 (4.5%) Ae. aegypti populations, with Resistance Ratio RR95 from 1.51 to 3.58. These populations were concentrated in Bahia and Ceará states. For malathion, 73 (55,3%) populations distributed all over the country were resistant when exposed to the local DD 20µg/bottle. On the other hand, no one population was resistant, and only 10 (7,6%) populations were considered with decreased susceptibility (mortality ratio between 90 and 98%) when the WHO DD (50 µg/bottle was used). These populations are in the 8 from 27 states.Conclusions: We evidenced the feasibility of conducting an insecticide resistance monitoring action at a national wide scale, employing standardized and strongly coordinated sampling methods and laboratory bioassays. We for the first time identified Brazilian Ae. aegypti populations with decreased susceptibility to pyriproxyfen. Local DD for malathion was more sensitive than the WHO DD to early detect decrease in susceptibility.
Lung Microbiota is Associated with Bacterial Detection and with Clinical Improvements in Severe Community-Acquired Pneumonia Patients
Authors: Du Sisi , Li Binbin , Wang Yimin , Xia Yudi , Shang Lianhan , Yu Donghao , Liu Zhibo , Wang Chunlei , Liu Xinmeng , Xiong Zhujia , Zou Xiaohui , Lu Binghuai , Liu Yingmei , Cao Bin
Published: July 2020

Background: Few studies have described the key features of the lung microbiota in patients with severe community-acquired pneumonia (SCAP). We conducted the study to identify the association between the lung microbiota on admission and the clinical prognosis in SCAP patients. Methods: The consecutive SCAP patients admitted from intensive care unit (ICU) were enrolled prospectively. 16S rRNA gene sequencing was applied to bronchoalveolar lavage fluid (BALF) collected within 48 hours. The clinical information was recorded during the stay of hospitalization. The primary endpoint was the rate of clinical improvements defined as a decrease of 2 categories and above on a 7-category ordinal scale within 14 days following bronchoscopy.Results: Sixty-seven patients were included. Multivariable Permutational multivariate analysis of variance (PERMANOVA) found that bacterial detection had the strongest independent relationship with the lung microbiota (R2=0.033; p=0.018), followed by acute kidney injury (AKI R2=0.032; p=0.011) and plasma MIP-1beta level (R2=0.027; p=0.044). Random forest identified that families Prevotellaceae, Moraxellaceae, Staphylococcaceae were the biomarkers related to bacterial detection. In the patients with positive bacteriology results, the mean relative abundance of families Prevotellaceae and Actinomycetaceae decreased while families Moraxellaceae, Staphylococcaceae and Streptococcaceae increased. Multivariable Cox regression showed that the increase in alpha-diversity and the abundance of families Prevotellaceae and Actinomycetaceae were associated with clinical improvements.Conclusions: The bacterial detection and patients’ intrinsic factors were associated with the lung microbiota. The increased alpha diversity and the enrichment of families Prevotellaceae and Actinomycetaceae in the lung microbiota were associated with clinical improvements.
Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations
Authors: Mikasi Sello Given , Isaacs Darren , Chotongo Rumbidzai , Ikomey George Mondinde , Cloete Ruben , Jacobs Graeme Brendon
Published: July 2020

Background The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG is clinically effective against all HIV-1 isolates previously showing resistance to INSTIs.Methods We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n=20) and (n=278) sequences data derived from HIV Los Alamos National Library (LANL) database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex. Results We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOP rates equal or above 50% were found for 66% of central core domain (CCD) positions, 44% C-terminal domain (CTD) positions and 35% of the N-terminal domain (NTD) positions.Conclusions Our analysis indicated that all mutations that resulted in a change in the number of interactions encompassing residues were found within the stable alpha-helix secondary structure element and not in close proximity to the drug active site. Our findings highlight the structural basis for HIV-1 IN interactions and that INSTIs will remain effective against CRF02_AG.
The Beneficial Use of Melanin in Inhibiting and Treating HCC Through Preventing CBC, Liver Enzymes, Oxidative Stress, and Lipid Peroxidation Alterations
Authors: Abdelhalim Mohamed Anwar K , Al-Mohy Yanallah H , Al-Ayed Mohammed S
Published: July 2020

Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancers and is a major global health problem. The present application relates to normalizing abnormal levels of hematological blood parameters, oxidative stress indicators, and liver enzyme levels in the rats using melanin, and particularly, to treating their abnormal levels, in addition to evaluate the role of melanin during and after the progression of HCC, which will be supplemented histologically. Hematological blood parameters such as white blood cells (WBCs), red blood cells (RBCs), hemoglobin (HGB), hematocrit (HCT), and platelets (PLTs); liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST); oxidative stress such as glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD); LP malondialdehyde (MDA) were evaluated in all groups of rats. Injection of Diethylnitrosamine (DEN) and 2-Acetyaminofluorine (2-AFF) induced HCC in the rats accompanied with a significant reduction in WBCs, RBCs, HGB, HCT, and PLTs, GSH-PX, and SOD; while a significant elevation was observed in ALT and AST, and MDA compared to the control. Melanin normalized all the above mentioned parameters during and after the progression of cancer towards their control values. These results demonstrate the beneficial use of melanin as a powerful antioxidant tool in inhibiting and treating HCC in the rats.
County-Level Longitudinal Clustering of COVID-19 Mortality to Incidence Ratio in the United States
Authors: Vahabi Nasim , Salehi Masoud , Duarte Julio , Mollalo Abolfazl , Michailidis George
Published: July 2020

Background: As of June 3, 2020, the mortality to incidence ratio (MIR) of COVID-19 was 5.8%. We utilized a longitudinal model-based clustering system based on the disease trajectories over time.Methods: County-level COVID-19 cases and deaths (March-June 2020), and a set of potential risk factors were collected for 3050 U.S. counties. We used growth mixture models to identify clusters of counties exhibiting similar COVID-19 MIR growth trajectories and risk-factors over time. Results: We identified clusters 1 (rural-areas of IA, NC, OK, VA, FL, GA, LA, OH states), and 7 (rural-areas of AR, CO, GA, KS, NE, TN, TX states) as the so-called “more vulnerable” clusters. Tuberculosis (OR=1.3), drug use disorder (OR=1.1), and particulate matter (OR=1.1) were significantly associated with increased odds of being in a more vulnerable cluster. Heart complications and cancer were the main risk factors increasing the COVID-19 MIR (range: 0.08%-0.72% MIR↑).Conclusion: We identified two county-clusters exhibiting the highest COVID-19 MIR trajectories, indicating that enhancing the capacity and access to healthcare resources would be key to successfully manage COVID-19 in these “vulnerable” clusters. These findings provide insights for public health policymakers on the groups of people and locations they need to pay particular attention while managing the COVID-19 epidemic.
An online tool for predicting the prognosis of cancer patients with SARS-CoV-2 infection: a multi-center study
Authors: Song Congkuan , Dong Zhe , Gong Hongyun , Liu Xiao-Ping , Dong Xiaorong , Wang Aifen , Chen Yuan , Song Qibin , Hu Weidong
Published: July 2020

Purpose: During the coronavirus disease 2019 (COVID-19) pandemic, oncologists face new challenges and they need to adjust their cancer management strategies as soon as possible to reduce the risk of SARS-CoV-2 infection and tumor recurrence. However, data on cancer patients with SARS-CoV-2 infection remains scarce. Methods: We performed a retrospective study of 223 cancer patients with SARS-CoV-2 from 26 hospitals in Hubei, China. An individualized nomogram was constructed based on multivariable Cox analysis. Considering the convenience of the nomogram application, an online tool was also created by shiny app. C-index, calibration curves and decision curve analysis (DCA) were performed to verify the prediction performance and clinical application of the nomogram.Results: Among cancer patients with SARS-CoV-2, there were significant differences in clinical characteristics between survivors and non-survivors, and lung cancer patients had similar short-time survival with other cancer patients. Male, dyspnea, elevated PCT, increased heart rate, elevated D-dimers, decreased platelets and so on were risk factors for these patients. Furthermore, good prediction performance of the online tool (dynamic nomogram: https://covid-19-prediction-tool.shinyapps.io/DynNomapp/). was also fully demonstrated with the C-index of 0.841 (95% CI: 0.782 - 0.900) in the development cohort and 0.780 (95% CI: 0.678-0.882) in the validation cohort. Conclusion: Overall, cancer patients with SARS-CoV-2 had unique clinical features, and the established online tool could guide clinicians to predict the prognosis of patients and to develop more rational treatment strategies for cancer patients during the COVID-19 epidemic.
Cytotoxic T-Lymphocyte Elicited Vaccine against SARS-CoV-2 employing Immunoinformatics Framework
Authors: Kumar Neeraj , Admane Nikita , Kumari Anchala , Sood Damini , Grover Sonam , Prajapati Vijay Kumar , Chandra Ramesh , Grover Abhinav
Published: July 2020

Development of effective counteragents against the novel coronavirus disease caused by SARS CoV-2 strains requires clear insights for understanding immune responses associated with it. The succumbing of available therapeutics utterly warrants the development of a potential vaccine to contest the deadly situation. Herein, we report Cytotoxic T-cell Lymphocytes immunomodulator by advanced immunoinformatics avenues for spike-glycoprotein of SARS CoV-2, which can generate robust immune response with convincing immunological parameters (Antigenicity, TAP affinity, MHC-binder) engendering an efficient viral vaccine. Strong binding of the CTL construct with MHC-1 and membrane-specific TLR2 was conferred through molecular docking and molecular dynamics simulation in an explicit system. Steep magnitude RMSD variation and compelling residual fluctuations existed in terminal residues and various loops of the β linker segments of TLR2-epitope (residues 105-156 and 239-254) to about 0.4nm. The reduced Rg value (3.3nm) and stagnant SASA analysis (275nm/S2/N after 8ns and 5ns) for protein surface and its orientation in exposed and buried regions suggests more compactness by strong binding of epitope. The CTL vaccine candidate establishes a high capability to elicit critical immune regulators, like T-cells and memory cells as proven by in silico immunization assays and can be further corroborated through in vitro and in vivo assays.
Prevalence and Susceptibility Patterns Associated with Staphylococcus Aureus Presence in Marketed Milk and Milk Products.
Authors: MACHARIA JOHN MACHARIA , Kaposztas Zsolt , Richard Cheruiyot , Andrew Nyerere K. , Muriithi Mathenge J. , Raposa Bence L.
Published: July 2020

The authors have requested that this preprint be removed from Research Square.
Recurrent Uterine Tumors Resembling Ovarian Sex-Cord Tumors with The Growth Regulation by Estrogen in Breast Cancer 1-Nuclear Receptor Coactivator 2 Fusion Gene: A Case Report and Literature Review
Authors: Chang Bin , Bai Qianming , Liang Lin , Ge Huijuan , Yao Qianlan
Published: July 2020

Background: Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare mesenchymal neoplasms predominantly arising in perimenopausal and postmenopausal women. UTROSCTs with growth regulation by estrogen in breast cancer 1 (GREB1)-rearrangement or GREB1-rearranged uterine tumors are exceptionally rare, with only 12 previously reported cases. Here, we report a case of UTROSCT with the GREB1-nuclear receptor coactivator 2 (NCOA2) fusion gene. Case Presentation: A 57-year-old woman presented with a 10.0-cm uterine mass. The tumor was composed of short spindle or epithelioid cells, arranged in diffused sheets, nested, and trabecular/cordlike. The tumor harbored the GREB1-NCOA2 fusion gene, as confirmed by RNA sequencing. The tumor recurred in the pelvis at 30 months after the initial diagnosis. We also compared the clinical and pathologic features of this case with those of the 12 previously published uterine GREB1-rearranged tumors. Of the combined 13 cases (present case and 12 previous cases), the mean age of patients was 64.8 years (range, 51‒74 years). Of the nine reported cases of GREB1-rearranged tumor with follow up, four cases recurred or metastasized (44.4%). Microscopically, most tumors (10/12, 83.3%) showed infiltrative growth, and two were well demarcated. Mitotic figures ranged from 0 to 14 per 10 high-power fields (2 mm2; mean: 3.6). Lymphovascular invasion and necrosis were each present in two cases (2/12, 16.7% and 2/7, 28.6%, respectively). Conclusions: This case provided further evidence that UTROSCTs with GREB1-rearrangement may have a high risk of recurrence. Further studies are necessary to clarify the clinical features of this type of tumor, particularly the prognosis, potential treatment, and range of possible molecular events.
Ensemble Flash Flood Predictions Using a High-Resolution Nationwide Distributed Rainfall-Runoff Model: Case Study of the Heavy Rain Event of July 2018 and Typhoon Hagibis in 2019
Authors: Sayama Takahiro , Yamada Masafumi , Sugawara Yoshito , Yamazaki Dai
Published: July 2020

The heavy rain event of July 2018 and Typhoon Hagibis in October 2019 caused severe flash flood disasters in numerous parts of western and eastern Japan. Flash floods need to be predicted over a wide range with long forecasting lead time for effective evacuation. The predictability of flash floods caused by the two extreme events are investigated by using a high-resolution (~ 150 m) nationwide distributed rainfall-runoff model forced by ensemble precipitation forecasts with 39-h lead time. Results of the deterministic simulation at nowcasting mode with radar and gauge composite rainfall could reasonably simulate the storm runoff hydrographs at many dam reservoirs over western Japan for the case of heavy rainfall in 2018 (F18) with the default parameter setting. For the case of Typhoon Hagibis in 2019 (T19), a similar performance was obtained by incorporating unsaturated flow effect in the model applied to Kanto region. The performance of the ensemble forecast was evaluated based on the bias scores and the relative operating characteristic curves, which suggested the higher predictability in peak runoff for T19. For the F18, the uncertainty arises due to the difficulty in accurately forecasting the storm positions by the frontal zone; as a result, the actual distribution of the peak runoff could not be well forecasted. Overall, this study showed that the predictability of flash floods was different between the two extreme events. The ensemble spreads contain quantitative information of predictive uncertainty, which can be utilized for the decision making of emergency responses against flash floods.
Identification of AAV serotypes for lung gene therapy in human embryonic stem cell derived lung organoids.
Authors: Meyer-Berg Helena , Yang Lucia Zhou , de Lucas María Pilar , Zambrano Alberto , Hyde Stephen C. , Gill Deborah R.
Published: July 2020

Gene therapy is being investigated for a range of serious lung diseases, such as cystic fibrosis and emphysema. Recombinant adeno-associated virus (rAAV) is a well-established, safe, viral-vector for gene delivery with multiple natural and artificial serotypes available displaying alternate cell, tissue and species-specific tropisms. Efficient AAV serotypes for the transduction of the conducting airways have been identified for several species; however, efficient serotypes for human lung parenchyma have not yet been identified. Here, we screened the ability of multiple AAV serotypes to transduce lung bud organoids (LBOs) - a model of human lung parenchyma generated from human embryonic stem cells. Microinjection of LBOs allowed us to model transduction from the luminal surface, similar to dosing via vector inhalation. We identified the natural rAAV2 and rAAV6 serotypes, along with synthetic rAAV6 variants, as having tropism for the human lung parenchyma. Positive staining of LBOs for surfactant proteins B and C confirmed distal lung identity and suggested the suitability of these vectors for the transduction of alveolar type II cells. Our findings establish LBOs as a new model for pulmonary gene therapy and stress the relevance of LBOs as a viral infection model of the lung parenchyma as relevant in SARS-CoV-2 research.