bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol for cluster randomized evaluation of reaching married adolescents - a gender-synchronized intervention to increase modern contraceptive use among married adolescent girls and young women and their husbands in Niger
Authors: Challa Sneha , DeLong Stephanie M. , Carter Nicole , Johns Nicole , Shakya Holly , Boyce Sabrina C. , Vera-Monroy Ricardo , Aliou Sani , Ibrahima Fatouma A. , Brooks Mohamad I. , Corneliess Caitlin , Moodie Claire , Nouhou Abdoul Moumouni , Souley Illa , Raj Anita , Silverman Jay G.
Published: December 2019

Background

Early marriage and early childbearing are highly prevalent in Niger with 75% of girls married before age 18 years and 42% of girls giving birth between ages 15 and 18 years. In 2012, only 7% of all 15–19-year-old married adolescents (male and female) reported use of a modern contraceptive method with barriers including misinformation, and social norms unsupportive of contraception. To meet the needs of married adolescents and their husbands in Niger, the Reaching Married Adolescents (RMA) program was developed with the goal of improving modern contraceptive method uptake in the Dosso region of Niger.

Methods

Using a four-arm cluster randomized control design, the RMA study seeks to assess whether household visits only (Arm 1), small group discussions only (Arm 2), or a combination of both (Arm 3), as compared to controls (no intervention – Arm 4), improve modern contraceptive method use among married adolescent girls and young women (AGYW), age 13–19 years-old, in three districts of the Dosso region. Intervention conditions were randomly assigned across the three districts, Dosso, Doutchi, and Loga. Within each district, eligible villages were assigned to either that intervention condition or to the control condition (12 intervention and 4 control per district). Across the three intervention conditions, community dialogues regarding modern contraceptive use were also implemented. Data for the study was collected at baseline (April – June 2016), at 24 months post-intervention (April – June 2018), and a final round of data collection will occur at 40 months post-intervention (October – December 2019).

Discussion

The RMA intervention is a gender-synchronized and community-based program implemented among married adolescent girls and their husbands in the context of rural Niger. The intervention is designed to provide education about modern contraception and to promote gender equity in order to increase uptake of modern contraceptive methods. Results from this cluster randomized control study will contribute to the knowledge base regarding the utility of male engagement as a strategy within community-level approaches to promote modern contraceptive method use in the high need context of West Africa.

Trial registration

Registered October 2017 - ClinicalTrials.gov NCT03226730.
Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients
Authors: Hasan-Olive Md Mahdi , Enger Rune , Hansson Hans-Arne , Nagelhus Erlend A. , Eide Per Kristian
Published: December 2019

Background

A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes.

Methods

Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels.

Results

We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry.

Conclusion

Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer’s disease.
Dynamic biospeckle analysis, a new tool for the fast screening of plant nematicide selectivity
Authors: O’Callaghan Felicity E. , Neilson Roy , MacFarlane Stuart A. , Dupuy Lionel X.
Published: December 2019

Background

Plant feeding, free-living nematodes cause extensive damage to plant roots by direct feeding and, in the case of some trichodorid and longidorid species, through the transmission of viruses. Developing more environmentally friendly, target-specific nematicides is currently impeded by slow and laborious methods of toxicity testing. Here, we developed a bioactivity assay based on the dynamics of light ‘speckle’ generated by living cells and we demonstrate its application by assessing chemicals’ toxicity to different nematode trophic groups.

Results

Free-living nematode populations extracted from soil were exposed to methanol and phenyl isothiocyanate (PEITC). Biospeckle analysis revealed differing behavioural responses as a function of nematode feeding groups. Trichodorus nematodes were less sensitive than were bacterial feeding nematodes or non-trichodorid plant feeding nematodes. Following 24 h of exposure to PEITC, bioactivity significantly decreased for plant and bacterial feeders but not for Trichodorus nematodes. Decreases in movement for plant and bacterial feeders in the presence of PEITC also led to measurable changes to the morphology of biospeckle patterns.

Conclusions

Biospeckle analysis can be used to accelerate the screening of nematode bioactivity, thereby providing a fast way of testing the specificity of potential nematicidal compounds. With nematodes’ distinctive movement and activity levels being visible in the biospeckle pattern, the technique has potential to screen the behavioural responses of diverse trophic nematode communities. The method discriminates both behavioural responses, morphological traits and activity levels and hence could be used to assess the specificity of nematicidal compounds.
Feasibility of hybrid TomoHelical- and TomoDirect-based volumetric gradient matching technique for total body irradiation
Authors: Hong Chae-Seon , Kim Min-Joo , Kim Jihun , Chang Kyung Hwan , Park Kwangwoo , Kim Dong Wook , Han Min Cheol , Yoon Hong In , Kim Jin Sung , Lee Ho
Published: December 2019

Background

Tomotherapy-based total body irradiation (TBI) is performed using the head-first position (HFP) and feet-first position (FFP) due to treatment length exceeding the 135 cm limit. To reduce the dosimetric variation at the match lines, we propose and verify a volumetric gradient matching technique (VGMT) by combining TomoHelical (TH) and TomoDirect (TD) modes.

Methods

Two planning CT image sets were acquired with HFP and FFP using 15 × 55 × 18 cm3of solid water phantom. Planning target volume (PTV) was divided into upper, lower, and gradient volumes. The junction comprised 2-cm thick five and seven gradient volumes (5-GVs and 7-GVs) to create a dose distribution with a gentle slope. TH-IMRT and TD-IMRT plans were generated with 5-GVs and 7-GVs. The setup error in the calculated dose was assessed by shifting dose distribution of the FFP plan by 5, 10, 15, and 20 mm in the longitudinal direction and comparing it with the original. Doses for 95% (D95) and 5% of the PTV (D5) were calculated for all simulated setup error plans. Absolute dose measurements were performed using an ionization chamber in the junction.

Results

The TH&TD plan produced a linear gradient in junction volume, comparable to that of the TH&TH plan. D5 of the PTV was 110% of the prescribed dose when the FFP plan was shifted 0.7 cm and 1.2 cm in the superior direction for 5-GVs and 7-GVs. D95 of the PTV decreased to < 90% of the prescribed dose when the FF plan was shifted 1.1 cm and 1.3 cm in the inferior direction for 5-GVs and 7-GVs. The absolute measured dose showed a good correlation with the calculated dose in the gradient junction volume. The average percent difference (±SD) in all measured points was − 0.7 ± 1.6%, and the average dose variations between depths was − 0.18 ± 1.07%.

Conclusion

VGMT can create a linear dose gradient across the junction area in both TH&TH and TH&TD and can minimize the dose sensitivity to longitudinal setup errors in tomotherapy-based TBI.
Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa
Authors: Oh Jin Kyun , Lima de Carvalho Jose Ronaldo , Sun Young Joo , Ragi Sara , Yang Jing , Levi Sarah R. , Ryu Joseph , Bassuk Alexander G. , Mahajan Vinit B. , Tsang Stephen H.
Published: December 2019

Background

Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome.

Results

Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain.

Conclusions

We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.
Voluntary wheel running promotes myelination in the motor cortex through Wnt signaling in mice
Authors: Zheng Jian , Sun Xuan , Ma Chaolin , Li Bao-ming , Luo Fei
Published: December 2019

Myelin of the central nervous system exhibits strong plasticity, and skill learning exercise promotes oligodendrogenesis and adaptive myelination. Increasing evidence shows that brain structures and functions are affected by physical activity. However, the impact of voluntary physical activity on central myelination and its underlying mechanism remains unclear. The present study aimed to investigate the effect of voluntary wheel running (VWR) on central oligodendrogenesis and adaptive myelination in mice. Adult C57BL/6 J mice were placed in running wheels and allowed for voluntary running 2 weeks. Myelin levels in the central nervous system were detected using western blotting, qRT-PCR, immunohistochemical staining, and electron microscopy. Oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) were detected using immunohistochemical staining and 5-bromo-2-deoxyuridine (BrdU) assays. Motor abilities of the animals were examined using open-field, rotarod running, and beam-walking behavioral paradigms. Vital molecules of Wnt signaling were detected, and the involvement of such molecules was verified using in vitro culture of OPCs. Our results showed that VWR significantly enhanced the myelination in the motor cortex. VWR promoted the proliferation and differentiation of OPCs, and the maturation of OLs. The VWR-regulated myelination was associated with the improved motor skill and decreased mRNA level of Wnt3a/9a, whereas stimulation of Wnt signaling pathway with Wnt3a or Wnt9a suppressed OPCs proliferation and differentiation in vitro. The present study demonstrated that physical activity is highly efficient at promoting myelination in the motor cortex, by enhancing the proliferation of OPCs and accelerating the generation of myelin, providing a step forward in understanding the beneficial effects of physical activity on central myelination and its underlying mechanism.
Targeting cancers through TCR-peptide/MHC interactions
Authors: He Qinghua , Jiang Xianhan , Zhou Xinke , Weng Jinsheng
Published: December 2019

Adoptive T cell therapy has achieved dramatic success in a clinic, and the Food and Drug Administration approved two chimeric antigen receptor-engineered T cell (CAR-T) therapies that target hematological cancers in 2018. A significant issue faced by CAR-T therapies is the lack of tumor-specific biomarkers on the surfaces of solid tumor cells, which hampers the application of CAR-T therapies to solid tumors. Intracellular tumor-related antigens can be presented as peptides in the major histocompatibility complex (MHC) on the cell surface, which interact with the T cell receptors (TCR) on antigen-specific T cells to stimulate an anti-tumor response. Multiple immunotherapy strategies have been developed to eradicate tumor cells through targeting the TCR-peptide/MHC interactions. Here, we summarize the current status of TCR-based immunotherapy strategies, with particular focus on the TCR structure, activated signaling pathways, the effects and toxicity associated with TCR-based therapies in clinical trials, preclinical studies examining immune-mobilizing monoclonal TCRs against cancer (ImmTACs), and TCR-fusion molecules. We propose several TCR-based therapeutic strategies to achieve optimal clinical responses without the induction of autoimmune diseases.
Mortaparib, a novel dual inhibitor of mortalin and PARP1, is a potential drug candidate for ovarian and cervical cancers
Authors: Putri Jayarani F. , Bhargava Priyanshu , Dhanjal Jaspreet Kaur , Yaguchi Tomoko , Sundar Durai , Kaul Sunil C. , Wadhwa Renu
Published: December 2019

Background

Mortalin is enriched in a large variety of cancers and has been shown to contribute to proliferation and migration of cancer cells in multiple ways. It has been shown to bind to p53 protein in cell cytoplasm and nucleus causing inactivation of its tumor suppressor activity in cancer cells. Several other activities of mortalin including mitochondrial biogenesis, ATP production, chaperoning, anti-apoptosis contribute to pro-proliferative and migration characteristics of cancer cells. Mortalin-compromised cancer cells have been shown to undergo apoptosis in in vitro and in vivo implying that it could be a potential target for cancer therapy.

Methods

We implemented a screening of a chemical library for compounds with potential to abrogate cancer cell specific mortalin-p53 interactions, and identified a new compound (named it as Mortaparib) that caused nuclear enrichment of p53 and shift in mortalin from perinuclear (typical of cancer cells) to pancytoplasmic (typical of normal cells). Biochemical and molecular assays were used to demonstrate the effect of Mortaparib on mortalin, p53 and PARP1 activities.

Results

Molecular homology search revealed that Mortaparib is a novel compound that showed strong cytotoxicity to ovarian, cervical and breast cancer cells. Bioinformatics analysis revealed that although Mortaparib could interact with mortalin, its binding with p53 interaction site was not stable. Instead, it caused transcriptional repression of mortalin leading to activation of p53 and growth arrest/apoptosis of cancer cells. By extensive computational and experimental analyses, we demonstrate that Mortaparib is a dual inhibitor of mortalin and PARP1. It targets mortalin, PARP1 and mortalin-PARP1 interactions leading to inactivation of PARP1 that triggers growth arrest/apoptosis signaling. Consistent with the role of mortalin and PARP1 in cancer cell migration, metastasis and angiogenesis, Mortaparib-treated cells showed inhibition of these phenotypes. In vivo tumor suppression assays showed that Mortaparib is a potent tumor suppressor small molecule and awaits clinical trials.

Conclusion

These findings report (i) the discovery of Mortaparib as a first dual inhibitor of mortalin and PARP1 (both frequently enriched in cancers), (ii) its molecular mechanism of action, and (iii) in vitro and in vivo tumor suppressor activity that emphasize its potential as an anticancer drug.
Immune gene expression profiling reveals heterogeneity in luminal breast tumors
Authors: Zhu Bin , Tse Lap Ah , Wang Difei , Koka Hela , Zhang Tongwu , Abubakar Mustapha , Lee Priscilla , Wang Feng , Wu Cherry , Tsang Koon Ho , Chan Wing-cheong , Law Sze Hong , Li Mengjie , Li Wentao , Wu Suyang , Liu Zhiguang , Huang Bixia , Zhang Han , Tang Eric , Kan Zhengyan , Lee Soohyeon , Park Yeon Hee , Nam Seok Jin , Wang Mingyi , Sun Xuezheng , Jones Kristine , Zhu Bin , Hutchinson Amy , Hicks Belynda , Prokunina-Olsson Ludmila , Shi Jianxin , Garcia-Closas Montserrat , Chanock Stephen , Yang Xiaohong R.
Published: December 2019

Background

Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.

Methods

We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.

Results

Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.

Conclusion

Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.
Within-species contamination of bacterial whole-genome sequence data has a greater influence on clustering analyses than between-species contamination
Authors: Pightling Arthur W. , Pettengill James B. , Wang Yu , Rand Hugh , Strain Errol
Published: December 2019

Although it is assumed that contamination in bacterial whole-genome sequencing causes errors, the influences of contamination on clustering analyses, such as single-nucleotide polymorphism discovery, phylogenetics, and multi-locus sequencing typing, have not been quantified. By developing and analyzing 720 Listeria monocytogenes, Salmonella enterica, and Escherichia coli short-read datasets, we demonstrate that within-species contamination causes errors that confound clustering analyses, while between-species contamination generally does not. Contaminant reads mapping to references or becoming incorporated into chimeric sequences during assembly are the sources of those errors. Contamination sufficient to influence clustering analyses is present in public sequence databases.
A novel protocol to isolate, detect and differentiate taeniid eggs in leafy greens and berries using real-time PCR with melting curve analysis
Authors: Frey Caroline F. , Oakley Jenna R. , Lobanov Vladislav A. , Marreros Nelson , Schurer Janna M. , Lalonde Laura F.
Published: December 2019

Background

Zoonotic taeniid cestodes are amongst the most important food-borne parasites affecting human health worldwide. Contamination of fresh produce with the eggs of Echinococcus granulosus (s.l.), Echinococcus multilocularis, and some Taenia species pose a potential food safety risk. However, very few studies have attempted to investigate the potential contamination of fresh produce with taeniid eggs and the available methods are not standardized for this purpose. Established protocols do exist for testing leafy greens and berries for contamination with protozoan parasites and are used in national surveillance programmes. This methodology could be suitable for the detection of taeniids. The objective of this project was to develop and standardize a sensitive and reliable method to detect contamination of leafy greens and berries with eggs of zoonotic taeniids and to differentiate between E. multilocularis, E. granulosus (s.l.) and Taenia spp.

Methods

We compared the efficacy of different wash solutions to remove Taenia spp. eggs from spiked produce, assessed two DNA extraction kits for their performance on Taenia spp. eggs, and adapted a published conventional multiplex PCR into a real-time PCR with fluorescence melting curve analysis (MCA) that was optimized for use on produce washes. Analytical specificity of this protocol was assessed using non-spiked produce washes as well as a variety of other potentially contaminating parasites.

Results

The protocol as established in this study had an analytical sensitivity of detecting five eggs per spiked sample for both romaine lettuce and strawberries. Unequivocal identification of E. multilocularis, E. granulosus (s.l.) and Taenia spp. was possible through MCA. Amplicon sequencing allowed identification of Taenia to the species level. The real-time PCR also amplified DNA from Dicrocoelium sp., but with a clearly discernable melting curve profile.

Conclusion

The new protocol for screening produce for taeniid contamination was highly sensitive. Melting curve analysis and the possibility of amplicon sequencing made this assay very specific. Once further validated, this method could be employed for surveillance of produce for contamination with taeniid parasites to assess potential risks for consumers.
Age-associated sperm DNA methylation patterns do not directly persist trans-generationally
Authors: Jenkins Timothy G. , James Emma R. , Aston Kenneth I. , Salas-Huetos Albert , Pastuszak Alexander W. , Smith Ken R. , Hanson Heidi A. , Hotaling James M. , Carrell Douglas T.
Published: December 2019

Background

The impact of aging on the sperm methylome is well understood. However, the direct, subsequent impact on offspring and the role of altered sperm DNA methylation alterations in this process remain poorly understood. The well-defined impact of aging on sperm DNA methylation represents an excellent opportunity to trace the direct, transgenerational transmission of these signals.

Results

We utilized the Illumina MethylationEPIC array to analyze the sperm of 16 patients with older (> 40 years of age) paternal grandfathers (‘old grand paternal age’ patients; OGPA) and 16 patients with younger (< 25 years of age) grandfathers (‘young grand paternal age’ patients; YGPA) identified through the Subfertility Health Assisted Reproduction and the Environment (SHARE) cohort to investigate differences in DNA methylation. No differentially methylated regions were identified between the OGPA and YGPA groups. Further, when assessing only the sites previously shown to be altered by age, no statistically significant differences between OGPA and YGPA were identified. This was true even despite the lower bar for significance after removing multiple comparison correction in a targeted approach. Interestingly though, in an analysis of the 140 loci known to have decreased methylation with age, the majority (~ 72%) had lower methylation in OGPA compared to YGPA though the differences were extremely small (~ 1.5%).

Conclusions

This study suggests that the robust and consistent age-associated methylation alterations seen in human sperm are ‘reset’ during large-scale epigenetic reprograming processes and are not directly inherited trans-generationally (over two generations). An extremely small trend was present between the YGPA and OGPA groups that resemble the aging pattern in older sperm. However, this trend was not significant and was so small that, if real, is almost certainly biologically inert.
Nickel-induced transcriptional changes persist post exposure through epigenetic reprogramming
Authors: Jose Cynthia C. , Wang Zhenjia , Tanwar Vinay Singh , Zhang Xiaoru , Zang Chongzhi , Cuddapah Suresh
Published: December 2019

Background

Nickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers. Our earlier studies showed that the nickel-exposure-induced genome-wide transcriptional changes, which persist even after the termination of exposure may underlie nickel pathogenesis. However, the mechanisms that drive nickel-induced persistent changes to the transcriptome remain elusive.

Results

To elucidate the mechanisms that underlie nickel-induced long-term transcriptional changes, in this study, we examined the transcriptome and the epigenome of human lung epithelial cells during nickel exposure and after the termination of exposure. We identified two categories of persistently differentially expressed genes: (i) the genes that were differentially expressed during nickel exposure; and (ii) the genes that were differentially expressed only after the termination of exposure. Interestingly, > 85% of the nickel-induced gene expression changes occurred only after the termination of exposure. We also found extensive genome-wide alterations to the activating histone modification, H3K4me3, after the termination of nickel exposure, which coincided with the post-exposure gene expression changes. In addition, we found significant post-exposure alterations to the repressive histone modification, H3K27me3.

Conclusion

Our results suggest that while modest first wave of transcriptional changes occurred during nickel exposure, extensive transcriptional changes occurred during a second wave of transcription for which removal of nickel ions was essential. By uncovering a new category of transcriptional and epigenetic changes, which occur only after the termination of exposure, this study provides a novel understanding of the long-term deleterious consequences of nickel exposure on human health.
The effect of genistein on lipid levels and LDLR, LXRα and ABCG1 expression in postmenopausal women with hyperlipidemia
Authors: Zhang Tao , Chi Xiao-Xing
Published: December 2019

Background

This study investigates the effect of genistein (Gen) on the lipid profiles and expression of low-density lipoprotein receptor (LDLR), liver X receptor α (LXRα) and ATP-binding cassette transporter G1 (ABCG1) in the plasma macrophages of postmenopausal women with hyperlipidemia in China.

Methods

This study considered 187 cases, where 160 postmenopausal women had hyperlipidemia. The subjects were divided into placebo group (PG) and experimental group (EG). EG received 60 mg/day of Gen, PG received placebo for 6 months. Body weight, height, waist circumference, body mass index and glucose levels were determined according to standard operating procedures. The triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1) and apolipoprotein-B (Apo-B) levels were detected in the plasma macrophages using ELISA. The protein and mRNA expression levels of LDLR, LXRα and ABCG1 were detected by western blot and real-time PCR techniques, respectively.

Results

Compared to the baseline, Gen effectively lowered TG, TC and LDL-C levels, whereas HDL-C levels as well as the protein and mRNA expression levels of LDLR, LXRα and ABCG1 (p < 0.05) were increased. There was a significant difference in the expression of LDLR protein between the two groups (p < 0.05). The mRNA expression levels of LDLR, LXRα and ABCG1 were significantly increased in the EG compared to the PG.

Conclusion

Gen effectively modulated the plasma lipid indices. The cholesterol-lowering effects of Gen may be attributed to its regulation on some of the key genes involved in cholesterol homeostasis.
A trend in prevalence of antimicrobial use and appropriateness of antimicrobial therapy in an acute care hospital from 2018 to 2019: repeated prevalence surveys in Japan
Authors: Komagamine Junpei , Yabuki Taku , Hiraiwa Taku
Published: December 2019

Objectives

The supply of cefazolin has been reduced dramatically since March 2019 in Japan. However, no studies have evaluated the effects of cefazolin shortage on the appropriateness of antimicrobial use. Therefore, we compared the appropriateness of inpatient antimicrobial drug use between the two surveys conducted in August 2018 and August 2019 in a Japanese hospital with no supply of cefazolin since the cefazolin shortage.

Results

In the 2019 survey, a total of 275 patients were included, and 256 patients were included in the 2018 survey. The prevalence of antimicrobial drug use did not change from 2018 to 2019 (28.5% versus 28.7%; p = 0.96). The proportion of cefazolin in all antimicrobial drugs used on the survey date significantly decreased from 2018 to 2019 (24.1% versus 0.0%; p < 0.001). The proportion of appropriate antimicrobial use in all antimicrobial therapies tended to be lower in 2019 than in 2018 (41.2% versus 60.6%; p = 0.06), and the proportion of unnecessary use of a broader spectrum of antimicrobial drugs significantly increased from 2018 to 2019 (4.7% versus 37.3%; p = 0.002). The shortage of cefazolin might lead to inappropriate use of other antimicrobial drugs.
Strengthening the community health worker programme for health improvement through enhancing training, supervision and motivation in Wakiso district, Uganda
Authors: Musoke David , Ssemugabo Charles , Ndejjo Rawlance , Atusingwize Edwinah , Mukama Trasias , Gibson Linda
Published: December 2019

Objective

The objective of the project was to strengthen the community health worker (CHW) programme in Ssisa sub-county, Wakiso district, Uganda by providing a coherent, structured and standardized training, supervision and motivation package so as to enhance their performance.

Results

The project trained all 301 CHWs who received non-financial incentives of t-shirts, gumboots and umbrellas, and 75 of them received solar equipment to support lighting their houses and charging phones. Twenty-four of the CHWs who had coordination roles received additional training. Three motorcycles were also provided to enhance transportation of CHW coordinators during their work including supervision. By end of the project, the CHWs had conducted 40,213 household visits, carried out health education sessions with 127,011 community members, and treated 19,387 children under 5 years of age. From the project evaluation, which used both quantitative and qualitative methods, 98% of the CHWs reported having improved competence in performance of their roles. In addition, the CHWs were highly motivated to do their work. The motorcycles were instrumental in supporting the work of CHW coordinators including monthly collection of reports and distribution of medicines. The project demonstrated that by improving training, supervision and motivation, performance of CHW programmes can be enhanced.
Wrapping culture plates with Parafilm M® increases Caenorhabditis elegans growth
Authors: Shinn-Thomas Jessica H. , Scanga Sara E. , Spica Patrick S. , Nariya Hardik K. , Klempic Emra , Brockett Mary R.
Published: December 2019

Objective

Parafilm M®is a moisture-resistant thermoplastic commonly used to seal Nematode Growth Media (NGM) agar plates on which the nematodeCaenorhabditis elegansis cultured. This practice reduces media dehydration and microbial contamination. However, the effects onC. elegansindividuals of placing this barrier between the external environment and the interior of the NGM plate are currently unknown. Our research aims to determine if this common practice engenders developmental changes, such as growth, that could subsequently and unintentionally alter experimental data. We compared the larval growth over 48 h of animals cultured on Parafilm-wrapped and unwrapped control NGM plates.

Results

Wrapping culture plates with Parafilm significantly accelerated and increased larval growth, with a 0.87 μm/h increase in growth rate (~ 6%) and a 37.90 μm increase in the change in growth (Δgrowth; ~ 5%) over 48 h. Therefore,C. elegansinvestigators should be aware that wrapping their experimental cultures with Parafilm may result in statistically detectable changes in worm growth and possibly other developmental processes.
YAP as a key regulator of adipo-osteogenic differentiation in human MSCs
Authors: Lorthongpanich Chanchao , Thumanu Kanjana , Tangkiettrakul Kantpitchar , Jiamvoraphong Nittaya , Laowtammathron Chuti , Damkham Nattaya , U-pratya Yaowalak , Issaragrisil Surapol
Published: December 2019

Background

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into several cell types, including cartilage, fat, and bone. As a common progenitor, MSC differentiation has to be tightly regulated to maintain the balance of their differentiation commitment. It has been reported that the decision process of MSCs into fat and bone cells is competing and reciprocal. Several factors have been suggested as critical factors that affect adipo-osteogenic decision, including melatonin and smad4. Yes-associated protein (YAP) is an important effector protein in the Hippo signaling pathway that acts as a transcriptional regulator by activating the transcription of the genes involved in cell proliferation and anti-apoptosis. The non-canonical role of YAP in regulating bone homeostasis by promoting osteogenesis and suppressing adipogenesis was recently demonstrated in a mouse model. However, it is unclear whether YAP is also crucial for modulating human MSC differentiation to fat and bone.

Methods

The expression level of YAP during MSC differentiation was modulated using pharmaceutical molecule and genetic experiments through gain- and loss-of-function approaches.

Results

We demonstrated for the first time that YAP has a non-canonical role in regulating the balance of adipo-osteogenic differentiation of human MSCs. The result from synchrotron radiation-based Fourier transform infrared (FTIR) microspectroscopy showed unique metabolic fingerprints generated from YAP-targeted differentiated cells that were clearly distinguished from non-manipulated control.

Conclusions

These results, thus, identify YAP as an important effector protein that regulates human MSC differentiation to fat and bone and suggests the use of FTIR microspectroscopy as a promising technique in stem cell research.
Vulnerable options pricing under uncertain volatility model
Authors: Zhou Qing , Li Xiaonan
Published: December 2019

In this paper, we consider the pricing problem of options with counterparty default risks. We study the asymptotic behavior of vulnerable option prices in the worst case scenario under an uncertain volatility model which contains both corporate assets and underlying assets. We propose a method to estimate the price of vulnerable options when the volatility of the underlying assets is within a small interval. By imposing additional conditions on the boundary condition and cutting the obtained Black–Scholes–Barenblatt equation into two Black–Scholes-like equations, we obtain an approximate method for solving the fully nonlinear partial differential equation satisfied by the price of vulnerable options under the uncertain volatility model.
Hemostasis of idiopathic recurrent epistaxis in children with microwave ablation: A prospective pilot case series
Authors: Lou Zheng-cai
Published: December 2019

Objective

We evaluated microwave ablation (MWA) for treatment of idiopathic recurrent anterior epistaxis (RAE) in children, in terms of technical feasibility, efficacy, and safety.

Study design

A prospective pilot case series.

Setting

Tertiary university hospital.

Methods

Children with idiopathic RAE were treated with endoscopic MWA and reevaluated at 1 and 4 weeks and at 6 months thereafter. The primary outcome was successful hemostasis on the day of the procedure. Secondary outcomes were the rebleeding rates after 1 and 4 weeks, and 6 months, and any complications.

Results

Of the 92 children with idiopathic RAE who met the inclusion criteria, the operation was interrupted in 7 children due to intraoperative noncooperation, and silver nitrate cautery was performed instead. All procedures were completed, and hemostasis was achieved within 10–20 s by MWA in 85 children. Two to four ablations were conducted. No recurrent epistaxis occurred and no severe MWA -related complications, such as septal perforation or synechiae formation, were observed at the 6-month follow-up.

Conclusions

Endoscopic MWA is a feasible and safe technique for the treatment of idiopathic pediatric RAE in the clinical setting, especially those cases that do not respond to in-office chemical cautery.
Gaseous mediators: an updated review on the effects of helium beyond blowing up balloons
Authors: Weber Nina C. , Preckel Benedikt
Published: December 2019

Noble gases, although supposed to be chemically inert, mediate numerous physiological and cellular effects, leading to protection against ischaemia-reperfusion injury in different organs. Clinically, the noble gas helium is used in treatment of airway obstruction and ventilation disorders in children and adults. In addition, studies from recent years in cells, isolated tissues, animals and finally humans show that helium has profound biological effects: helium applied before, during or after an ischaemic event reduced cellular damage, known as “organ conditioning”, in some tissue, e.g. the myocardium. Although extensive research has been performed, the exact molecular mechanisms behind these organ-protective effects of helium are yet not completely understood. In addition, there are significant differences of protective effects in different organs and animal models. A translation of experimental findings to the clinical situation has yet not been shown.
Optimization of silver nanoparticle synthesis by chemical reduction and evaluation of its antimicrobial and toxic activity
Authors: Quintero-Quiroz Catalina , Acevedo Natalia , Zapata-Giraldo Jenniffer , Botero Luz E. , Quintero Julián , Zárate-Triviño Diana , Saldarriaga Jorge , Pérez Vera Z.
Published: December 2019

Background

Chemical reduction has become an accessible and useful alternative to obtain silver nanoparticles (AgNPs). However, its toxicity capacity depends on multiple variables that generate differences in the ability to inhibit the growth of microorganisms. Thus, optimazing parameters for the synthesis of AgNPs can increase its antimicrobial capacity by improving its physical-chemical properties.

Methods

In this study a Face Centered Central Composite Design (FCCCD) was carried out with four parameters:
A
g
N
O
3
concentration, sodium citrate (TSC) concentration,
N
a
B
H
4
concentration and the pH of the reaction with the objective of inhibit the growth of microorganisms. The response variables were the average size of AgNPs, the peak with the greatest intensity in the size distribution, the polydispersity of the nanoparticle size and the yield of the process. AgNPs obtained from the optimization were characterized physically and chemically. The antimicrobial activity of optimized AgNPs was evaluated against
Staphylococcus aureus
,
Escherichia coli
,
Escherichia coli
AmpC resistant, and
Candida albicans
and compared with AgNPs before optimization. In addition, the cytotoxicity of the optimized AgNPs was evaluated by the colorimetric assay MTT (3- (4,5- Dimethylthiazol- 2- yl)- 2, 5 - Diphenyltetrazolium Bromide).

Results

It was found that the four factors studied were significant for the response variables, and a significant model (p < 0.05) was obtained for each variable. The optimal conditions were 8 for pH and 0.01 M, 0.0 6M, 0.01 M for the concentration of TSC,
A
g
N
O
3
, and
N
a
B
H
4
, respectively. Optimized AgNPs spherical and hemispherical were obtained, and 67.66% of it had a diameter less than 10.30 nm. A minimum bactericidal concentration (MBC) and minimum fungicidal Concentration (MFC) of optimized AgNPs was found against
Staphylococcus aureus
,
Escherichia coli
,
Escherichia coli
AmpC resistant, and
Candida albicans
at 19.89, 9.94, 9.94, 2.08
μ
g/mL, respectively. Furthermore, the lethal concentration 50 (
L
C
50
) of optimized AgNPs was found on 19.11
μ
g/mL and 19.60
μ
g/mL to Vero and NiH3T3 cells, respectively.

Conclusions

It was found that the factors studied were significant for the variable responses and the optimization process used was effective to improve the antimicrobial activity of the AgNPs.
The “Timeline Debriefing Tool”: a tool for structuring the debriefing description phase
Authors: Secheresse Thierry , Nonglaton Séverine
Published: December 2019

Several recent literature reviews have been published with the aim to determine how to optimise a debriefing. A main element found in these reviews was the importance of structuring the debriefing. Within the steps usually outlined in the debriefing, the description phase allows participants to describe their recollections and establish a shared mental model of what happened during the simulation. The description phase is used in many debriefing models but how to realise this description remains unclear. We provide an original tool to ensure a highly structured description phase: the “Timeline Debriefing Tool”.

The Timeline Debriefing Tool, or TDT, is constructed on visual support such as a whiteboard or a flipchart. It allows for a clear description phase, makes the process more dynamic, promotes exchanges between participants and establishes a clear and shared vision of the simulation in visual support which can be used by the instructor in the analysis phase. Moreover, the timeline allows participants to discover their performance gaps by themselves, thus beginning deeper cognitive processing in the participants’ mind and promoting reflection in the analysis phase.
Malaria hot spot along the foothills of Rakhine state, Myanmar: geospatial distribution of malaria cases in townships targeted for malaria elimination
Authors: Khine San Kyawt , Kyaw Nang Thu Thu , Thekkur Pruthu , Lin Zaw , Thi Aung
Published: December 2019

Background

Myanmar has targeted elimination of malaria by 2030. In three targeted townships of Rakhine state of Myanmar, a project is being piloted to eliminate malaria by 2025. The comprehensive case investigation (CCI) and geotagging of cases by health workers is a core activity under the project. However, the CCI data is not analyzed for obtaining information on geospatial distribution of cases and timeliness of diagnosis. In this regard, we aimed to depict geospatial distribution and assess the proportion with delayed diagnosis among diagnosed malaria cases residing in three targeted townships during April 2018 to March 2019.

Methods

This was a cross sectional analysis of CCI data routinely collected by national malaria control programme. The geocode (latitude and longitude) of the address was analysed using Quantum Geographic Information System software to deduce spot maps and hotspots of cases. The EpiData analysis software was used to summarize the proportion with delay in diagnosis (diagnosed ≥24 hours after the fever onset).

Results

Of the 171 malaria cases diagnosed during study period, the CCI was conducted in 157 (92%) cases. Of them, 127 (81%) cases reported delay in diagnosis, 138 (88%) cases were indigenous who got infection within the township and 13 (8%) were imported from outside the township. Malaria hotspots were found along the foothills with increase in cases during the rainy season. The indigenous cases were concentrated over the foothills in the northern and southern borders of Toungup township.

Conclusion

In the targeted townships for malaria elimination, the high proportion of the cases was indigenous and clustered at the foothill areas during rainy season. The programme should strengthen case surveillance and healthcare services in the areas with aggregation of cases to eliminate the malaria in the township. As high majority of patients have delayed diagnosis, the reasons for delay has to be explored and corrective measures needs to be taken.