bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling confinement and reversibility of threshold-dependent gene drive systems in spatially-explicit Aedes aegypti populations
Authors: Sánchez C. Héctor M. , Bennett Jared B. , Wu Sean L. , Rašić Gordana , Akbari Omar S. , Marshall John M.
Published: May 2020

Background

The discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently engineered threshold-dependent gene drive systems—reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UDMEL—to explore their ability to be confined and remediated.

Results

We simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika, and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UDMEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely.

Conclusions

Our analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.
Risk prediction models for dementia: role of age and cardiometabolic risk factors
Authors: Fayosse Aurore , Nguyen Dinh-Phong , Dugravot Aline , Dumurgier Julien , Tabak Adam G. , Kivimäki Mika , Sabia Séverine , Singh-Manoux Archana
Published: May 2020

Background

Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score is the only currently available midlife risk score for dementia. We compared CAIDE to Framingham cardiovascular Risk Score (FRS) and FINDRISC diabetes score as predictors of dementia and assessed the role of age in their associations with dementia. We then examined whether these risk scores were associated with dementia in those free of cardiometabolic disease over the follow-up.

Methods

A total of 7553 participants, 39–63 years in 1991–1993, were followed for cardiometabolic disease (diabetes, coronary heart disease, stroke) and dementia (N = 318) for a mean 23.5 years. Cox regression was used to model associations of age at baseline, CAIDE, FRS, and FINDRISC risk scores with incident dementia. Predictive performance was assessed using Royston’s R2, Harrell’s C-index, Akaike’s information criterion (AIC), the Greenwood-Nam-D’Agostino (GND) test, and calibration-in-the-large. Age effect was also assessed by stratifying analyses by age group. Finally, in multistate models, we examined whether cardiometabolic risk scores were associated with incidence of dementia in persons who remained free of cardiometabolic disease over the follow-up.

Results

Among the risk scores, the predictive performance of CAIDE (C-statistic = 0.714; 95% CI 0.690–0.739) and FRS (C-statistic = 0.719; 95% CI 0.693–0.745) scores was better than FINDRISC (C-statistic = 0.630; 95% CI 0.602–0.659); p < 0.001), AIC difference > 3; R2 32.5%, 32.0%, and 12.5%, respectively. When the effect of age in these risk scores was removed by drawing data on risk scores at age 55, 60, and 65 years, the association with dementia in all age groups remained for FRS and FINDRISC, but not for CAIDE. Only FRS at age 55 was associated with dementia in persons who remained free of cardiometabolic diseases prior to dementia diagnosis while no such association was observed at older ages for any risk score.

Conclusions

Our analyses of CAIDE, FRS, and FINDRISC show the FRS in midlife to predict dementia as well as the CAIDE risk score, its predictive value being also evident among individuals who did not develop cardiometabolic events. The importance of age in the predictive performance of all three risk scores highlights the need for the development of multivariable risk scores in midlife for primary prevention of dementia.
Efficacy of a competitive exclusion culture against extended-spectrum β-lactamase-producing Escherichia coli strains in broilers using a seeder bird model
Authors: Methner Ulrich , Rösler Uwe
Published: May 2020

Background

Administration of a competitive exclusion culture (CE culture) has the potential to induce protective effects in very young chicks against caecal colonisation by EEC (= extended-spectrum β-lactamases [ESBL] and AmpC-type [AmpC] beta-lactamases producing Escherichia coli). The study aimed to verify the protective capacity of a CE culture in broilers using the seeder bird model against EEC exposure of the chicks.

Results

Introduction of infected seeder birds resulted in rapid and strong caecal colonisation of four different EEC challenge strains tested in untreated contact broilers. Compared to controls the broilers pre-treated with the CE culture showed a considerable decrease in caecal load of different EEC challenge strains from about 3.0–3.5 log10 units (P < 0.05) on day 9 of life to 2.5–3.0 log10 units (P < 0.05) on day 37. A slightly higher protective level of the CE culture in layer birds than in broilers raises the question on reasons for possible differences in the efficacy of CE culture in broiler and layer breeds. Whether the diet’s protein content has an impact on both normal intestinal flora composition and the efficacy of CE cultures against EEC or other pathogens remains open and needs further elucidation.

Conclusions

Our findings suggest that CE cultures of undefined composition can be valuable to reduce the intestinal colonisation by EEC in newly hatched broilers.
Identification of new arylamine N-acetyltransferases and enhancing 2-acetamidophenol production in Pseudomonas chlororaphis HT66
Authors: Guo Shuqi , Wang Yunxiao , Wang Wei , Hu Hongbo , Zhang Xuehong
Published: May 2020

Background

2-Acetamidophenol (AAP) is an aromatic compound with the potential for antifungal, anti-inflammatory, antitumor, anti-platelet, and anti-arthritic activities. Due to the biosynthesis of AAP is not yet fully understood, AAP is mainly produced by chemical synthesis. Currently, metabolic engineering of natural microbial pathway to produce valuable aromatic compound has remarkable advantages and exhibits attractive potential. Thus, it is of paramount importance to develop a dominant strain to produce AAP by elucidating the AAP biosynthesis pathway.

Result

In this study, the active aromatic compound AAP was first purified and identified in genephzBdisruption strain HT66ΔphzB, which was derived fromPseudomonas chlororaphisHT66. The titer of AAP in the strain HT66ΔphzBwas 236.89 mg/L. Then, the genes involved in AAP biosynthesis were determined. Through the deletion of genesphzF,NatandtrpE, AAP was confirmed to have the same biosynthesis route as phenazine-1-carboxylic (PCA). Moreover, a new arylamine N-acetyltransferases (NATs) was identified and proved to be the key enzyme required for generating AAP by in vitro assay.P. chlororaphisP3, a chemical mutagenesis mutant strain of HT66, has been demonstrated to have a robust ability to produce antimicrobial phenazines. Therefore, genetic engineering, precursor addition, and culture optimization strategies were used to enhance AAP production inP. chlororaphisP3. The inactivation ofphzBin P3 increased AAP production by 92.4%. Disrupting the phenazine negative regulatory geneslonandrsmEand blocking the competitive pathway genepykAin P3 increased AAP production 2.08-fold, which also confirmed that AAP has the same biosynthesis route as PCA. Furthermore, adding 2-amidophenol to the KB medium increased AAP production by 64.6%, which suggested that 2-amidophenol is the precursor of AAP. Finally, by adding 5 mM 2-amidophenol and 2 mM Fe3+to the KB medium, the production of AAP reached 1209.58 mg/L in the engineered strain P3ΔphzBΔlonΔpykAΔrsmEusing a shaking-flask culture. This is the highest microbial-based AAP production achieved to date.

Conclusion

In conclusion, this study clarified the biosynthesis process of AAP inPseudomonasand provided a promising host for industrial-scale biosynthesis of AAP from renewable resources.
High expression of ESRP1 regulated by circ-0005585 promotes cell colonization in ovarian cancer
Authors: Deng Guanming , Zhou Xiaofang , Chen Le , Yao Ying , Li Junjun , Zhang Yun , Luo Chenhui , Sun Lijuan , Tang Jie
Published: May 2020

Background

Ovarian cancer is the third most common gynecological cancer in the world but the leading cause of death among gynecological malignancies. Epithelial splicing regulatory protein-1 (ESRP1), a key negative splicing regulator in epithelial-mesenchymal transition (EMT), has been proven to be overexpressed and may plays a role in epithelial ovarian cancer (EOC) progression. However, the functional roles of ESRP1 and the underlying mechanisms in this process still remain unclear.

Methods

Tumor invasion, migration, colony formation and animal experiments were used to study the malignant biological behavior of ESRP1. A vector-based system expressing circ-0005585 was established to investigate circRNA as a microRNAs sponge. RNA-Seq and cytoskeleton staining explored underlying mechanisms of ESRP1.

Results

Our results demonstrated that circ-0005585 regulates ESRP1 overexpression via sponging miR-23a/b and miR-15a/15b/16. Overexpression of ESRP1 suppresses EOC cell migration, but promotes colonization and drives a switch from mesenchymal to epithelial phenotype (MET) in association with actin cytoskeleton reorganization, mainly by alternative splicing EPB41L5 and RAC1. Furthermore, we have shown that high ESRP1 expression may be associated with immune-suppression in tumor immune microenvironment in vivo.

Conclusions

ESRP1 overexpression promotes MET status and correlates with actin cytoskeleton reorganization in EOC. ESRP1 plays an important role in EOC colonization. In addition, a miRs panel from two miR families can inhibit ESRP1, may provide an innovative approach for cancer theranostics.
OSskcm: an online survival analysis webserver for skin cutaneous melanoma based on 1085 transcriptomic profiles
Authors: Zhang Lu , Wang Qiang , Wang Lijie , Xie Longxiang , An Yang , Zhang Guosen , Zhu Wan , Li Yongqiang , Liu Zhihui , Zhang Xiaochen , Tang Panpan , Huo Xiaozheng , Guo Xiangqian
Published: May 2020

Background

Cutaneous melanoma is one of the most aggressive and lethal skin cancers. It is greatly important to identify prognostic biomarkers to guide the clinical management. However, it is technically challenging for untrained researchers to process high dimensional profiling data and identify potential prognostic genes in profiling datasets.

Methods

In this study, we developed a webserver to analyze the prognostic values of genes in cutaneous melanoma using data from TCGA and GEO databases. The webserver is named Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) which includes 1085 clinical melanoma samples. The OSskcm is hosted in a windows tomcat server. Server-side scripts were developed in Java script. The database system is managed by a SQL Server, which integrates gene expression data and clinical data. The Kaplan–Meier (KM) survival curves, Hazard ratio (HR) and 95% confidence interval (95%CI) were calculated in a univariate Cox regression analysis.

Results

In OSskcm, by inputting official gene symbol and selecting proper options, users could obtain KM survival plot with log-rank P value and HR on the output web page. In addition, clinical characters including race, stage, gender, age and type of therapy could also be included in the prognosis analysis as confounding factors to constrain the analysis in a subgroup of melanoma patients.

Conclusion

The OSskcm is highly valuable for biologists and clinicians to perform the assessment and validation of new or interested prognostic biomarkers for melanoma. OSskcm can be accessed online at: http://bioinfo.henu.edu.cn/Melanoma/MelanomaList.jsp.
Genetic polymorphism of merozoite surface protein-3 in Myanmar Plasmodium falciparum field isolates
Authors: Lê Hương Giang , Thái Thị Lam , Kang Jung-Mi , Lee Jinyoung , Moe Mya , Võ Tuấn Cường , Naw Haung , Myint Moe Kyaw , Htun Zaw Than , Kim Tong-Soo , Shin Ho-Joon , Na Byoung-Kuk
Published: May 2020

Background

Plasmodium falciparum merozoite surface protein-3 (PfMSP-3) is a target of naturally acquired immunity against P. falciparum infection and is a promising vaccine candidate because of its critical role in the erythrocyte invasion of the parasite. Understanding the genetic diversity of pfmsp-3 is important for recognizing genetic nature and evolutionary aspect of the gene in the natural P. falciparum population and for designing an effective vaccine based on the antigen.

Methods

Blood samples collected from P. falciparum-infected patients in Naung Cho and Pyin Oo Lwin, Myanmar, in 2015 were used in this study. The pfmsp-3 was amplified by polymerase chain reaction, cloned, and sequenced. Genetic polymorphism and natural selection of Myanmar pfmsp-3 were analysed using the programs DNASTAR, MEGA6, and DnaSP 5.10.00. Genetic diversity and natural selection of the global pfmsp-3 were also comparatively analysed.

Results

Myanmar pfmsp-3 displayed 2 different alleles, 3D7 and K1. The 3D7 allelic type was predominant in the population, but genetic polymorphism was less diverse than for the K1 allelic type. Polymorphic characters in both allelic types were caused by amino acid substitutions, insertions, and deletions. Amino acid substitutions were mainly occurred at the alanine heptad repeat domains, whereas most insertions and deletions were found at the glutamate rich domain. Overall patterns of amino acid polymorphisms detected in Myanmar pfmsp-3 were similar in the global pfmsp-3 population, but novel amino acid changes were observed in Myanmar pfmsp-3 with low frequencies. Complicated patterns of natural selection and recombination events were predicted in the global pfmsp-3, which may act as major driving forces to maintain and generate genetic diversity of the global pfmsp-3 population.

Conclusion

Global pfmsp-3 revealed genetic polymorphisms, suggesting that the functional and structural consequences of the polymorphisms should be considered in designing a vaccine based on PfMSP-3. Further examination of genetic diversity of pfmsp-3 in the global P. falciparum population is necessary to gain in-depth insight for the population structure and evolutionary aspect of global pfmsp-3.
A systematic review and meta-analysis of haematological malignancies in residents living near petrochemical facilities
Authors: Jephcote Calvin , Brown David , Verbeek Thomas , Mah Alice
Published: May 2020

Background

The petrochemical industry is a major source of hazardous and toxic air pollutants that are recognised to have mutagenic and carcinogenic properties. A wealth of occupational epidemiology literature exists around the petrochemical industry, with adverse haematological effects identified in employees exposed to ‘low’ concentrations of aromatic hydrocarbons (benzene, toluene, ethylbenzene, and xylene). Releases from the petrochemical industry are also thought to increase the risk of cancer incidence in fenceline communities. However, this emerging and at times inconclusive evidence base remains fragmented. The present study’s aim was to conduct a systematic review and meta-analysis of epidemiological studies investigating the association between incidences of haematological malignancy and residential exposure to the petrochemical industry.

Methods

Epidemiological studies reporting the risk of haematological malignancies (Leukaemia, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, and Multiple myeloma) were included where the following criteria were met: (i) Cancer incidence is diagnosed by a medical professional and coded in accordance to the International Classification of Diseases; (ii) A clear definition of fenceline communities is provided, indicating the proximity between exposed residents and petrochemical activities; and (iii) Exposure is representative of normal operating conditions, not emergency events. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks and their 95% confidence intervals were pooled across studies for the four categories of haematological malignancy, using a random effects meta-analysis.

Results

The systematic review identified 16 unique studies, which collectively record the incidence of haematological malignancies across 187,585 residents living close to a petrochemical operation. Residents from fenceline communities, less than 5 km from a petrochemical facility (refinery or manufacturer of commercial chemicals), had a 30% higher risk of developing Leukaemia than residents from communities with no petrochemical activity. Meanwhile, the association between exposure and rarer forms of haematological malignancy remains uncertain, with further research required.

Conclusions

The risk of developing Leukaemia appears higher in individuals living near a petrochemical facility. This highlights the need for further policy to regulate the release of carcinogens by industry.

Graphical abstract
The Trp64Arg polymorphism in β3 adrenergic receptor (ADRB3) gene is associated with adipokines and plasma lipids: a systematic review, meta-analysis, and meta-regression
Authors: Luo Zhi , Zhang Ting , Wang Shengping , He Yuxian , Ye Qiutang , Cao Wenzhai
Published: May 2020

Background

Recently, some studies claim that adipokines may modulate plasma lipids. More interestingly, the ADRB3 Trp64Arg polymorphism may regulate adipokines and play an essential role in lipids metabolism. This study aims to clarify the associations of ADRB3 Trp64Arg polymorphism with plasma adipokines and lipid levels.

Methods

Twenty-two studies (5527 subjects) and 121 studies (54,059 subjects) were respectively identified for the association analyses of adipokines and lipids. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to estimate the strength of the Trp64Arg variant in adipokines and plasma lipids. All results were recalculated after eliminating the studies with heterogeneity.

Results

The carriers of the C allele (Arg at 64th position was encoded by the C allele) had higher levels of leptin and lower levels of adiponectin than the non-carriers. The carriers of the C allele had higher levels of triglycerides (TG), total cholesterol (TC), and lower levels of high-density lipoprotein cholesterol (HDL-C) than the non-carriers. Subgroup analysis certified an ethnicity (Asians), disease status (obesity), and gender (females) specific association. Sensitivity analysis indicated that the analysis results were robust and stable. Meta-regression indicated that obesity was related to adiponectin.

Conclusions

The C allele carriers of Trp64Arg polymorphism had a slight but significant influence on lipid levels, and the remarkable effects specific existed in obese Asian women. The associations of Trp64Arg polymorphism with dyslipidemia may partly be mediated by the effect of this polymorphism on adipokines. The association of Trp64Arg polymorphism with obesity may partly be mediated by the effect of this polymorphism on adipokines. The C allele carriers had abnormal levels of adipokines and lipids, and it indicated that the Trp64Arg polymorphism might represent a genetic risk factor for coronary artery disease (CAD).
Living as an infertile woman: the case of southern and northern Ghana
Authors: Ofosu-Budu Dorcas , Hanninen Vilma
Published: May 2020

Background

Infertility is detrimental to the health of married couples, especially women. Despite the consequences associated with the condition, little is done to reduce the repercussions. This study throws more light on the lived experiences of infertile women and on how they can be helped to improve their own condition.

Methodology

We interviewed 30 infertile married women in the Northern and Ashanti regions of Ghana, 15 from each region. A qualitative method, phenomenological study design and thematic analysis was employed to explore their lived experiences.

Results

Due the huge stigma, some women reported that their loved ones encouraged them to try to conceive. Others revealed that, they were considering relocating from their current communities to reduce the insults, intense pressure, stress, and stigma. Though some revealed maltreatment from their husbands and in-laws, others stated their husbands disclosed their fertility status to their own family members to avoid these families pressuring these women.

Conclusions

To reduce the stigma, pronatalist societies urgently need education and sensitization. Would-be couples should be counselled to have a plan to deal with such occurrences should they experience them.
Human immunodeficiency virus is a driven factor of human papilloma virus among women: evidence from a cross-sectional analysis in Yaoundé, Cameroon
Authors: Sosso Samuel Martin , Tchouaket Michel Carlos Tommo , Fokam Joseph , Simo Rachel Kamgaing , Torimiro Judith , Tiga Aline , Lobe Elise Elong , Ambada Georgia , Nange Achille , Semengue Ezechiel Ngoufack Jagni , Nka Alex Durand , Tala Valère , Chenwi Collins , Abba Aissatou , Ka’e Aude Christelle , Yagai Bouba , Colizzi Vittorio , Ndjolo Alexis
Published: May 2020

Background

Human papillomavirus (HPV) is the leading cause of cervical cancers, causing 270.000 deaths annually worldwide of which 85% occur in developing countries with an increasing risk associated to HIV infection. This study aimed at comparing HPV’s positivity and genotype distribution in women according to their HIV status and determinants.

Methods

A comparative study was carried out in 2012 at the Chantal BIYA International Reference Centre (CIRCB) among 278 women enrolled consecutively at the General Hospital and the Gynaeco-Obstetric and Paediatric Hospital of the City of Yaoundé. HPV genotyping was performed by real-time PCR, HIV serological screening by serial algorithm, CD4 T cell phenotyping by flow cytometry and HIV viral load by Abbott m2000RT. Statistical analyses were performed using Microsoft Excel 2016 and Graph Pad version 6.0 software; with P < 0.05 considered statistically significant.

Results

Globally, mean age was 37 ± 3 years; median CD4-count for HIV+ was 414 cells/mm3 [IQR: 264.75–588] and median viremia was 50 RNA copies/mL [IQR: < 40–8288]. Overall HPV rate was 38.49% (107/278); 58.88% for single women vs. others (28.97% married, 2.80% divorced, 9.34% for widows), OR: 2.164; p = 0.0319. Following HIV status, HPV rate was 43.48% (80/184) among HIV+ vs. 28.72% (27/94) among HIV- (OR: 1.937; p < 0.0142); HPV genotypes among HIV+ vs. HIV- were respectively distributed as follows: genotype 16 (3.75% vs. 0.00%, p = 0.57), genotype 18 (3.75% vs. 3.70%, p = 1.00), co-infection 16 and others (8.75% vs. 7.40%, p = 1.00), co-infection 18 and others (8.75% vs. 11.11%, p = 0.71), co-infection 16, 18 and others (2.50% vs. 0.00%, p = 1.00) and other genotypes (72.50% vs. 77.78%, p = 0.80). Among HIV+ participants, HPV rate following CD4 was 62.88% (61/97) for CD4 < 500 vs. 35.71% (20/56) for CD4 ≥ 500 (OR: 3.05; p = 0.0012) while HPV rate following HIV viremia was 42.71% (41/96) with < 1000 RNA copies/ml vs. 66.00% (33/50) with > 1000 RNA copies/ml (OR = 0.384; p = 0.009).

Conclusion

In Yaoundé, HPV rate appear to be very high, with higher rates of genotypes other than 16 and 18. In the event of HIV infection, the risk of HPV positivity is two times higher, favoured essentially by immunodeficiency. Thus, HIV-infected women should be closely monitored to prevent the emergence of cervical cancer.
Accuracy of intraoral scans in the mixed dentition: a prospective non-randomized comparative clinical trial
Authors: Liczmanski Konrad , Stamm Thomas , Sauerland Cristina , Blanck-Lubarsch Moritz
Published: May 2020

Objective

In-vivo accuracy of intraoral scans of complete mixed dentitions of patients in active treatment have not yet been investigated. The aim was to test the hypothesis that dimensional differences between intraoral scans and conventional alginate impressions in the mixed dentition are clinically irrelevant.

Methods

Trial design: Prospective non-randomized comparative clinical trial. Based on sample size calculation 44 evaluable mixed dentition jaws of patients in active orthodontic treatment were included. Each patient received an alginate impression following an intraoral scan (TRIOS® Ortho). Plaster cast was fabricated and scanned with an external scanner (ATOS-SO®). Both STL datasets were analyzed with the 3D inspection and mesh processing software GOM Inspect®. Statistical analysis comprised sample size calculation, t-test as well as nonparametric tests.

Results

The absolute mean difference between digital plaster casts and intraoral scans is 0.022 mm ± 0.027 mm (median 0.015 mm). The obtained measurements are in the range of comparable studies on full arch permanent dentitions. Gender, the size of the jaw represented by the dentition stage and upper respectively lower jaw, as well the malocclusion have no effect on the total deviations between digital plaster casts and intraoral scans. Detectable impression errors were bubbles in fissures and marginal ridges as well as incomplete alginate flow and detachment from the tray. Detectable scanning errors were incomplete distal surface of the most distal molar.

Conclusion

Dimensional differences between intraoral scans and conventional alginate impressions in the mixed dentition are clinically irrelevant for orthodontic purposes. In all clinical situations of active treatment in the mixed dentition, the intraoral scans are more detailed and less error-prone.
Systematic analysis and identification of the absorption and metabolic components of Zengye decoction in type 2 diabetic rats by HPLC-ESI-Q-TOF–MS/MS
Authors: Chang Shanquan , Wang Mei , Tian Yushan , Qi Jin , Qiu Zhixia
Published: May 2020

Background

Zengye decoction (ZYD) has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Exploring the fate of various components of ZYD in vivo is of considerable significance for pharmacological research and molecular mechanism elaboration. However, the systematic analysis on the metabolic behavior of chemical components of ZYD in T2DM rats has not been reported.

Methods

To screen and characterize the complex chemical compositions of ZYD, and metabolism fate in plasma, urine, bile, and feces of T2DM rats, the model of T2DM rats was prepared. A rapid procedure using high-performance liquid chromatography coupled with electrospray ionization quadrupole time of flight tandem mass spectrometry (HPLC-ESI-Q-TOF–MS/MS) was established. Data were acquired and analyzed by Agilent MassHunter Workstation Qualitative Analysis software version B.07.00 and PCDL manager B.07.00.

Results

A total of 80 compounds were identified or tentatively characterized in ZYD, 31 more than previously detected. Besides, 36 prototype components and 49 metabolites of ZYD were found and characterized in T2DM rats, and the proposed fragmentation pathways and possible metabolic behaviors of the main types of compounds were described.

Conclusions

This study developed the understanding of the composition of ZYD as well as the cleavage rules and metabolic pathways of the prototype compounds. Besides, this study provided abundant data for further research and for study of the metabolism of traditional Chinese medicine prescriptions.
ERα-36 regulates progesterone receptor activity in breast cancer
Authors: Konan Henri-Philippe , Kassem Loay , Omarjee Soleilmane , Surmieliova-Garnès Ausra , Jacquemetton Julien , Cascales Elodie , Rezza Amélie , Trédan Olivier , Treilleux Isabelle , Poulard Coralie , Le Romancer Muriel
Published: May 2020

Background

Alterations in estrogen and progesterone signaling, via their respective receptors, estrogen receptor alpha (ERα) and progesterone receptor (PR), respectively, are largely involved in the development of breast cancer (BC). The recent identification of ERα-36, a splice variant of ERα, has uncovered a new facet of this pathology. Although ERα-36 expression is associated with poor prognosis, metastasis development, and resistance to treatment, its predictive value has so far not been associated with a BC subtype and its mechanisms of action remain understudied.

Methods

To study ERα-36 expression in BC specimens, we performed immunochemical experiments. Next, the role of ERα-36 in progesterone signaling was investigated by generating KO clones using the CRISPR/CAS9 technology. PR signaling was also assessed by proximity ligation assay, Western blotting, RT-QPCR, and ChIP experiments. Finally, proliferation assays were performed with the IncuCyte technology and migration experiments using scratch assays.

Results

Here, we demonstrate that ERα-36 expression at the plasma membrane is correlated with a reduced disease-free survival in a cohort of 160 BC patients, particularly in PR-positive tumors, suggesting a crosstalk between ERα-36 and PR. Indeed, we show that ERα-36 interacts constitutively with PR in the nucleus of tumor cells. Moreover, it regulates PR expression and phosphorylation on key residues, impacting the biological effects of progesterone.

Conclusions

ERα-36 is thus a regulator of PR signaling, interfering with its transcriptional activity and progesterone-induced anti-proliferative effects as well as migratory capacity. Hence, ERα-36 may constitute a new prognostic marker as well as a potential target in PR-positive BC.
Evaluation of resistance to pyrethroid and organophosphate adulticides and kdr genotyping in Aedes aegypti populations from Roraima, the northernmost Brazilian State
Authors: Hayd Ramão Luciano Nogueira , Carrara Luana , de Melo Lima Joel , de Almeida Nathalia Coelho Vargas , Lima José Bento Pereira , Martins Ademir Jesus
Published: May 2020

Background

Roraima, the northernmost State in Brazil, borders Venezuela and Guyana. Although mostly covered by the tropical forests, the urban centers of this state are highly infested with Ae. aegypti and are endemic for dengue, Zika and chikungunya. We accessed the insecticide resistance status of Ae. aegypti populations from the capital Boa Vista, two cities on international borders (Pacaraima and Bonfim) and Rorainópolis bordering Amazonas State, in order to evaluate the chemical control efficacy in these localities.

Methods

Tests with World Health Organization (WHO)-like tubes impregnated with the pyrethroid deltamethrin (0.05% and 0.12%) and the organophosphate malathion (0.7%) were conducted with Ae. aegypti from Boa Vista, Pacaraima, Bonfim and Rorainópolis, collected in 2016 and 2018. Genotyping of kdr mutations, related to resistance to pyrethroids, was performed for the SNP variations at sites 1016 and 1534 of the voltage gated sodium channel gene (NaV) with a TaqMan qPCR approach.

Results

Aedes albopictus was absent in our collections, and therefore only Ae. aegypti was tested. All Ae. aegypti populations were susceptible to 0.7% malathion in 2016; however, mortality dropped to under 90% in Bonfim and Pacaraima populations in 2018. All populations were resistant to 0.05% deltamethrin in both years. The time that 50% of females suffered knockdown (KdT50) under exposure to 0.05% deltamethrin was 3.3–5.9-fold longer in mosquitoes from the natural populations compared to the susceptible Rockefeller strain. Only the Pacaraima population (2018) remained resistant to 0.12% deltamethrin. Kdr genotyping revealed the absence of the wild-type NaVS haplotype (1016Val + 1534Phe) in the populations from Roraima, indicating that all tested insects had a genetic background for pyrethroid resistance. The double kdr NaVR2 haplotype (1016Ile + 15434Cys) was present in higher frequencies in all populations except for Rorainópolis, where this haplotype seems to have arrived recently.

Conclusions

These results are important for the knowledge about insecticide resistance status of Ae. aegypti populations from Roraima and will help improve vector control strategies that may be applied to diverse localities under similar geographical and urban conditions.
Changes of circulating neuregulin 4 and its relationship with 25-hydroxy vitamin D and other diabetic vascular complications in patients with diabetic peripheral neuropathy
Authors: Yan Pijun , Zhang Zhihong , Miao Ying , Xu Yong , Zhu Jianhua , Wan Qin
Published: May 2020

Background

Neuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), however, the pathological mechanism remains poorly understood. The purpose of our study was to investigate the association of circulating Nrg4 with DPN and 25-hydroxy vitamin D [25(OH)D], a multifunctional secosteroid hormone that regulates other neurotrophic factors and adipokines gene expression, and other diabetic vascular complications.

Methods

Circulating Nrg4 levels were measured with an ELISA kit in 164 newly diagnosed type 2 diabetes mellitus (nT2DM) patients. The relationship between circulating Nrg4 and DPN and other parameters was analyzed.

Results

Circulating Nrg4 levels were significantly lower in nT2DM patients with DPN than those without, and subjects in the highest quartile of circulating Nrg4 had significantly lower vibration perception threshold (VPT), the prevalence of DPN, the proportion of persons with VPT > 25 V, and significantly higher circulating 25(OH)D (all P < 0.01). Moreover, circulating Nrg4 was positively and independently associated with 25(OH)D, and was negatively with VPT (P < 0.01 or P < 0.05), but showed no associations with the prevalence of peripheral arterial disease, diabetic nephropathy, and diabetic retinopathy (all P > 0.05). Additionally,the prevalence of DPN and risk of DPN development were progressively decreased with increasing circulating Nrg4 quartiles, independently of potential confounding factors.

Conclusions

These data demonstrate that decreased levels of circulating Nrg4 might lead to the development of DPN through its close interaction with circulating 25(OH)D not with other diabetic vascular complications. Further prospective studies are needed to identify our findings in these populations.
Co-culture of hWJMSCs and pACs in double biomimetic ACECM oriented scaffold enhances mechanical properties and accelerates articular cartilage regeneration in a caprine model
Authors: Zhang Yu , Hao Chunxiang , Guo Weimin , Peng Xiaoyu , Wang Mingjie , Yang Zhen , Li Xu , Zhang Xueliang , Chen Mingxue , Sui Xiang , Peng Jiang , Lu Shibi , Liu Shuyun , Guo Quanyi , Jiang Qing
Published: May 2020

Background

The dedifferentiation of chondrocytes and the unstable chondrogenic differentiation status of pluripotent mesenchymal stem cells (MSCs) are immense issues in cell-based articular cartilage repair and regenerative strategies. Here, to improve the cartilage characteristics of seed cells, a double biomimetic acellular cartilage extracellular matrix (ACECM)-oriented scaffold was used to mimic the cartilage microenvironment for human umbilical cord Wharton’s jelly-derived MSCs (hWJMSCs) and primary cartilage cells (pACs) to regenerate hyaline cartilage.

Methods

A double biomimetic ACECM-oriented scaffold was created from the cartilage extracellular matrix of pig articular cartilage using pulverization decellularization freeze-drying procedures. hWJMSCs and pACs were co-cultured at ratios of 50:50 (co-culture group, ACCC), 0:100 (ACAC group) and 100:0 (ACWJ group) in the ACECM-oriented scaffold, and the co-culture system was implanted in a caprine model for 6 months or 9 months to repair full-thickness articular cartilage defects. The control groups, which had no cells, comprised the blank control (BC) group and the ACECM-oriented scaffold (AC) group. Gross morphology and magnetic resonance imaging (MRI) as well as histological and biomechanical evaluations were used to characterize the cartilage of the repair area.

Results

Relative to the control groups, both the gross morphology and histological staining results demonstrated that the neotissue of the ACCC group was more similar to native cartilage and better integrated with the surrounding tissue. Measurements of glycosaminoglycan content and Young’s modulus showed that the repair areas had more abundant cartilage-specific content and significantly higher mechanical strength in the ACCC group than in the control groups, especially at 9 months. On MRI, the T2-weighted signal of the repair area was homogeneous, and the oedema signal disappeared almost completely in the ACCC group at 9 months. HLA-ABC immunofluorescence staining demonstrated that hWJMSCs participated in the repair and regeneration of articular cartilage and escaped surveillance and clearance by the caprine immune system.

Conclusion

The structure and components of double biomimetic ACECM-oriented scaffolds provided a cartilage-like microenvironment for co-cultured seed cells and enhanced the biomechanics and compositions of neotissue. This co-culture system has the potential to overcome the dedifferentiation of passage chondrocytes and the unstable chondrogenic differentiation status of MSCs.
Inhibition of LSD1 promotes the differentiation of human induced pluripotent stem cells into insulin-producing cells
Authors: Yang Xiao-Fei , Zhou Shu-Yan , Wang Ce , Huang Wei , Li Ning , He Fei , Li Fu-Rong
Published: May 2020

Background

Human induced pluripotent stem cells (hiPSCs) represent a potentially unlimited source of pancreatic endocrine lineage cells. Although insulin-producing β cells derived from hiPSCs have been successfully induced, much work remains to be done to achieve mature β cells. Lysine-specific demethylase 1 (LSD1) plays an important role in the regulation of hiPSC self-renewal and differentiation. We propose a new strategy to acquire insulin-producing cells (IPCs) from hiPSCs by knocking down LSD1.

Methods

Knockdown of LSD1 in hiPSCs with five shRNA. Assessment of the effects of shRNA on hiPSC proliferation, cell cycle, and apoptosis. Using knockdown hiPSCs with 31.33% LSD1 activity, we achieved a four-step differentiation into IPCs and test its differentiation efficiency, morphology, and marker genes and proteins. We implanted the IPCs into the renal subcapsular of SCID-Beige diabetic mice to evaluate the hypoglycemic effect in vivo. We tested LSD1 and HDAC1 whether they are present in the CoREST complex through IP-WB, and analyzed LSD1, CoREST, HDAC1, H3K4me2/me3, and H3K27me3 protein expression before and after knockdown of LSD1.

Results

Differentiated hiPSCs were 38.32% ± 3.54% insulin-positive cells and released insulin/C-peptide in response to glucose stimulus in a manner comparable to adult human islets. Most of the IPCs co-expressed mature β cell-specific markers. When transplanted under the left renal capsule of SCID-Beige diabetic mice, these IPCs reversed hyperglycemia, leading to a significant increase in the definitive endoderm cells. IP-WB results showed that LSD1, HDAC1, and CoREST formed a complex in hiPSCs. Chip-PCR results showed that LSD1, HDAC1, and CoREST were enriched in the same district during the SOX17 and FOXA2 promoter region. Inhibition of LSD1 would not affect the level of CoREST but decreased the HDAC1 expressions. The H3K4me2/me3 and H3K9act level of SOX17 and FOXA2 promoter region increased after inhibited of LSD1, and promoted transcriptional activation. The H3K4me2/me3 and H3K9act level of OCT4 and SOX2 promoter region decreased with the transcriptional repressed.

Conclusions

LSD1 regulated histone methylation and acetylation in promoter regions of pluripotent or endodermal genes. Our results suggest a highly efficient approach to producing IPCs from hiPSCs.
Shadow and extended shadow cost sharing associated to informal long-term care: the case of Spain
Authors: Del Pozo-Rubio Raúl , Moya-Martínez Pablo , Ortega-Ortega Marta , Oliva-Moreno Juan
Published: May 2020

Background

A large part of the long-term care is provided by non-professional caregivers, generally without any monetary payment but a value economic of time invested. The economic relevance of informal caregivers has been recognized in Spain; however, public provision may still be scarce. The objective of this paper is to estimate the economic burden associated with informal long-term care that should assume the families through a new concept of cost sharing that consider opportunity costs of time provided by informal caregivers.

Methods

The study sample includes all dependent adults in Spain. Socioeconomic information and the number of hours of informal care was collected through the Spanish Disability and Dependency Survey. The terms of shadow and extended shadow cost sharing were defined as the difference between the maximum potential amount of money that families could receive for the provision of informal care and the amount that actually they received and the value of informal care time with respect to the amount received, respectively.

Results

53.87% of dependent persons received an economic benefit associated to informal care. The average weekly hours of care were 71.59 (92.62 without time restrictions). Shadow cost sharing amounted to, on average, two thirds, whereas the State financed the remaining third. In terms of extended shadow cost sharing, the State financed between 3% and 10% of informal care provided by caregivers.

Conclusions

This study reveals the deficient support received for the provision of informal care in Spain. More than 90% of informal care time is not covered by the economic benefits that families receive from the State.
Early sepsis markers in patients admitted to intensive care unit with moderate-to-severe diabetic ketoacidosis
Authors: Blanchard Florian , Charbit Judith , Van der Meersch Guillaume , Popoff Benjamin , Picod Adrien , Cohen Regis , Chemouni Frank , Gaudry Stephane , Bihan Helene , Cohen Yves
Published: May 2020

Background

Bacterial infections are frequent triggers for diabetic ketoacidosis. In this context, delayed antibiotic treatment is associated with increased morbidity and mortality. Unnecessary administration of antimicrobial therapy might however, also negatively impact the prognosis. The usefulness of sepsis markers in diabetic ketoacidosis has not been assessed. Thus, we sought to investigate diagnostic performances of clinical and biological sepsis markers during diabetic ketoacidosis.

Methods

In this monocentric retrospective cohort study, all consecutive episodes of diabetic ketoacidosis (defined as pH ≤ 7.25, glycaemia > 300 mg/dL and presence of ketones) admitted in intensive care unit were included. A proven bacterial infection was defined as bacteriological documentation on any bacterial sample. Clinical (presence of fever: temperature > 38 °C and presence of hypothermia: temperature < 36 °C) and biological markers (whole blood count, neutrophils count, neutrophils-to-lymphocytes count ratio and procalcitonin), recorded at admission, were compared according to the presence or absence of a proven bacterial infection.

Results

Between 2011 and 2018, among 134 episodes of diabetic ketoacidosis, 102 were included (91 patients). Twenty out of 102 were infected. At admission, procalcitonin (median: 3.58 ng/mL vs 0.52 ng/mL, p < 0.001) and presence of fever (25% vs 4%, p = 0.007) were different between episodes with and without proven bacterial infection in both univariate and multivariate analysis. Whole blood count, neutrophils count, neutrophils-to-lymphocytes count ratio and presence of hypothermia were not different between both groups. The diagnostic performance analysis for procalcitonin revealed an area under the curve of 0.87 with an optimal cutoff of 1.44 ng/mL leading to a sensitivity of 0.90 and a specificity of 0.76. Combining procalcitonin and presence of fever allowed to distinguish proven bacterial infection episodes from those without proven bacterial infection. Indeed, all patients with procalcitonin level of more than 1.44 ng/mL and fever had proven bacterial infection episodes. The presence of one of these 2 markers was associated with 46% of proven bacterial infection episodes. No afebrile patient with procalcitonin level less than 1.44 ng/mL had a proven bacterial infection.

Conclusion

At admission, combining procalcitonin and presence of fever may be of value to distinguish ketoacidosis patients with and without proven bacterial infection, admitted in intensive care unit.
Fundamental limits of single anchor-based cooperative localization in millimeter wave systems
Authors: Zhao Feng , Huang Tiancheng , Wang Donglin
Published: May 2020

Thanks to massive antenna arrays in millimeter wave communications, a much higher resolution can be achieved for the estimation of angle of arrival. By taking full advantage of beamforming capability and high angular resolution in millimeter wave systems, a single anchor is sufficient to obtain a good position estimation for agents by combining angle of arrival and time of arrival. In this paper, a single-anchor based cooperative localization is proposed for millimeter wave systems. Fundamental limits of cooperative localization with a single anchor is investigated, where all nodes are equipped with massive antenna arrays. Bounds of time-based range and position estimation are derived by Crámer-Rao bound in general multipath channels. For the single-anchor based cooperative localization, the structure of the fisher information matrix is investigated and the relationship between ranging accuracy and positioning accuracy is theoretically clarified. Numerical results demonstrate a consistency with theory behind the proposed millimeter wave’s cooperative localization network.