bluuebunny/crossref_metadata_2025 huggingface dataset:
Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway
Authors: Pomytkin Igor , Krasil’nikova Irina , Bakaeva Zanda , Surin Alexander , Pinelis Vsevolod
Published: December 2019

Aim

An impaired biological response to insulin in the brain, known as central insulin resistance, was identified during stroke and traumatic brain injury, for which glutamate excitotoxicity is a common pathogenic factor. The exact molecular link between excitotoxicity and central insulin resistance remains unclear. To explore this issue, the present study aimed to investigate the effects of glutamate-evoked increases in intracellular free Ca2+concentrations [Ca2+]iand mitochondrial depolarisations, two key factors associated with excitotoxicity, on the insulin-induced activation of the insulin receptor (IR) and components of the Akt/ mammalian target of rapamycin (mTOR) pathway in primary cultures of rat cortical neurons.

Methods

Changes in [Ca2+]iand mitochondrial inner membrane potentials (ΔΨm) were monitored in rat cultured cortical neurons, using the fluorescent indicators Fura-FF and Rhodamine 123, respectively. The levels of active, phosphorylated signalling molecules associated with the IR/Akt/mTOR pathway were measured with the multiplex fluorescent immunoassay.

Results

When significant mitochondrial depolarisations occurred due to glutamate-evoked massive influxes of Ca2+into the cells, insulin induced 48% less activation of the IR (assessed by IR tyrosine phosphorylation, pY1150/1151), 72% less activation of Akt (assessed by Akt serine phosphorylation, pS473), 44% less activation of mTOR (assessed by mTOR pS2448), and 38% less inhibition of glycogen synthase kinase β (GSK3β) (assessed by GSK3β pS9) compared with respective controls. These results suggested that excitotoxic glutamate inhibits signalling via the IR/Akt/mTOR pathway at multiple levels, including the IR, resulting in the development of acute neuronal insulin resistance within minutes, as an early pathological event associated with excitotoxicity.
MYCN and PRC1 cooperatively repress docosahexaenoic acid synthesis in neuroblastoma via ELOVL2
Authors: Ding Yi , Yang Jie , Ma Yawen , Yao Tengteng , Chen Xingyu , Ge Shengfang , Wang Lihua , Fan Xianqun
Published: December 2019

Background

The MYCN amplification is a defining hallmark of high-risk neuroblastoma. Due to irregular oncogenes orchestration, tumor cells exhibit distinct fatty acid metabolic features from non-tumor cells. However, the function of MYCN in neuroblastoma fatty acid metabolism reprogramming remains unknown.

Methods

Gas Chromatography-Mass Spectrometer (GC-MS) was used to find the potential target fatty acid metabolites of MYCN. Real-time PCR (RT-PCR) and clinical bioinformatics analysis was used to find the related target genes. The function of the identified target gene ELOVL2 on cell growth was detected through CCK-8 assay, Soft agar colony formation assay, flow Cytometry assay and mouse xenograft. Chromatin immunoprecipitation (ChIP) and Immunoprecipitation-Mass Spectrometer (IP-MS) further identified the target gene and the co-repressor of MYCN.

Results

The fatty acid profile of MYCN-depleted neuroblastoma cells identified docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with anti-tumor activity, significantly increased after MYCN depletion. Compared with MYCN single-copy neuroblastoma cells, DHA level was significantly lower in MYCN-amplified neuroblastoma cells. RT-PCR and clinical bioinformatics analysis discovered that MYCN interfered DHA accumulation via ELOVL fatty acid elongase 2 (ELOVL2) which is a rate-limiting enzyme of cellular DHA synthesis. Enforced ELOVL2 expression in MYCN-amplified neuroblastoma cells led to decreased cell growth and counteracted the growth-promoting effect of MYCN overexpression both in vitro and vivo. ELOVL2 Knockdown showed the opposite effect in MYCN single-copy neuroblastoma cells. In primary neuroblastoma, high ELOVL2 transcription correlated with favorable clinical tumor biology and patient survival. The mechanism of MYCN-mediated ELOVL2 inhibition contributed to epigenetic regulation. MYCN recruited PRC1 (Polycomb repressive complex 1), catalysed H2AK119ub (histone 2A lysine 119 monoubiquitination) and inhibited subsequent ELOVL2 transcription.

Conclusions

The tumor suppressive properties of DHA and ELOVL2 are repressed by the MYCN and PRC1 jointly, which suggests a new epigenetic mechanism of MYCN-mediated fatty acid regulation and indicates PRC1 inhibition as a potential novel strategy to activate ELOVL2 suppressive functions.
A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock
Authors: Braga Daniele , Barcella Matteo , Herpain Antoine , Aletti Federico , Kistler Erik B. , Bollen Pinto Bernardo , Bendjelid Karim , Barlassina Cristina
Published: December 2019

Background

Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock.

Methods

We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes withpvalue < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock.

Results

In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend.

Conclusions

This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS.

Trial registration

ClinicalTrials.gov,NCT02141607. Registered 19 May 2014.
Plasma cell-free DNA (cfDNA) as a predictive and prognostic marker in patients with metastatic breast cancer
Authors: Fernandez-Garcia Daniel , Hills Allison , Page Karen , Hastings Robert K. , Toghill Bradley , Goddard Kate S. , Ion Charlotte , Ogle Olivia , Boydell Anna Rita , Gleason Kelly , Rutherford Mark , Lim Adrian , Guttery David S. , Coombes R. Charles , Shaw Jacqueline A.
Published: December 2019

Background

Breast cancer (BC) is the most common cancer in women, and despite the introduction of new screening programmes, therapies and monitoring technologies, there is still a need to develop more useful tests for monitoring treatment response and to inform clinical decision making.

The purpose of this study was to compare circulating cell-free DNA (cfDNA) and circulating tumour cells (CTCs) with conventional breast cancer blood biomarkers (CA15-3 and alkaline phosphatase (AP)) as predictors of response to treatment and prognosis in patients with metastatic breast cancer (MBC).

Methods

One hundred ninety-four female patients with radiologically confirmed MBC were recruited to the study. Total cfDNA levels were determined by qPCR and compared with CELLSEARCH® CTC counts and CA15-3 and alkaline phosphatase (AP) values. Blood biomarker data were compared with conventional tumour markers, treatment(s) and response as assessed by RECIST and survival.

Non-parametric statistical hypothesis tests were used to examine differences, correlation analysis and linear regression to determine correlation and to describe its effects, logistic regression and receiver operating characteristic curve (ROC curve) to estimate the strength of the relationship between biomarkers and clinical outcomes and value normalization against standard deviation to make biomarker values comparable. Kaplan–Meier estimator and Cox regression models were used to assess survival. Univariate and multivariate models were performed where appropriate.

Results

Multivariate analysis showed that both the amount of total cfDNA (p value = 0.024, HR = 1.199, CI = 1.024–1.405) and the number of CTCs (p value = 0.001, HR = 1.243, CI = 1.088–1.421) are predictors of overall survival (OS), whereas total cfDNA levels is the sole predictor for progression-free survival (PFS) (p value = 0.042, HR = 1.193, CI = 1.007–1.415) and disease response when comparing response to non-response to treatment (HR = 15.917, HR = 12.481 for univariate and multivariate analysis, respectively). Lastly, combined analysis of CTCs and cfDNA is more informative than the combination of two conventional biomarkers (CA15-3 and AP) for prediction of OS.

Conclusion

Measurement of total cfDNA levels, which is a simpler and less expensive biomarker than CTC counts, is associated with PFS, OS and response in MBC, suggesting potential clinical application of a cheap and simple blood-based test.
NEDD4 expression is associated with breast cancer progression and is predictive of a poor prognosis
Authors: Wan Lingfeng , Liu Tao , Hong Zhipeng , Pan You , Sizemore Steven T. , Zhang Junran , Ma Zhefu
Published: December 2019

Background

A role for neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) in tumorigenesis has been suggested. However, information is lacking on its role in breast tumor biology. The purpose of this study was to determine the role of NEDD4 in the promotion of the growth and progression of breast cancer (BC) and to evaluate the clinicopathologic and prognostic significance of NEDD4.

Methods

The impact of NEDD4 expression in BC cell growth was determined by Cell Counting Kit-8 and colony formation assays. Formalin-fixed paraffin-embedded specimens were collected from 133 adjacent normal tissues (ANTs), 445 BC cases composed of pre-invasive ductal carcinoma in situ (DCIS, n = 37), invasive ductal carcinomas (IDC, n = 408, 226 without and 182 with lymph node metastasis), and 116 invaded lymph nodes. The expression of NEDD4 was analyzed by immunohistochemistry. The association between NEDD4 expression and clinicopathological characteristics was analyzed by chi-square test. Survival was evaluated using the Kaplan–Meier method, and curves were compared using a log-rank test. Univariate and multivariate analyses were performed using the Cox regression method.

Results

NEDD4 promoted BC growth in vitro. In clinical retrospective studies, 16.5% of ANTs (22/133) demonstrated positive NEDD4 staining. Strikingly, the proportion of cases showing NEDD4-positive staining increased to 51.4% (19/37) in DCIS, 58.4% (132/226) in IDC without lymph node metastasis, and 73.1% (133/182) in BC with lymph node metastasis (BCLNM). In addition, NEDD4-positive staining was associated with clinical parameters, including tumor size (P = 0.030), nodal status (P = 0.001), estrogen receptor status (P = 0.035), and progesterone receptor status (P = 0.023). Moreover, subset analysis in BCLNM revealed that high NEDD4 expression correlated with an elevated risk of relapse (P = 0.0276). Further, NEDD4 expression was an independent prognostic predictor. Lastly, the rates for 10-year overall survival and disease-free survival were significantly lower in patients with positive NEDD4 staining than those in BC patients with negative NEDD4 staining BC (P = 0.0024 and P = 0.0011, respectively).

Conclusions

NEDD4 expression is elevated in BC and is associated with BC growth. NEDD4 correlated with clinicopathological parameters and predicts a poor prognosis. Thus, NEDD4 is a potential biomarker of poor prognosis and a potential therapeutic target for BC treatment.
The global forum on bioethics in research meeting, “ethics of alternative clinical trial designs and methods in low- and middle-income country research”: emerging themes and outputs
Authors: Hunt Adrienne , Saenz Carla , Littler Katherine
Published: December 2019

Alternative clinical trial designs and methods are increasingly being used in place of the conventional individually randomised controlled trial (RCT) in high-income and in low-income and middle-income country (LMIC) research. These approaches - including adaptive, cluster-randomised and stepped-wedge designs and controlled human infection models - offer a number of potential advantages, including being more efficient and making the clinical trial process more socially acceptable. However, these designs and methods are generally not familiar to researchers, research ethics committees and regulators and their ethical implications have not received sufficient international attention from the bioethics, research, and policymaking communities working together. The ethics of alternative clinical trial designs and methods in LMIC research was chosen as a topic for the 2017 Global Forum on Bioethics in Research (GFBR). The meeting opened a global dialogue about this emerging issue in research ethics and gave voice to the LMIC perspective. It identified the need to take a multidisciplinary approach and to develop capacity amongst researchers and research ethics committees and regulators to propose, review and regulate these novel designs and methods. Building skills and infrastructure will empower researchers to choose from a broad range of designs and methods and adopt the most scientifically suitable, efficient, ethical and context-appropriate of these. The need for capacity development is most pressing from the LMIC perspective, where limited resources create an urgency to seek the most efficient trial design and method. The aim of this paper is to encourage broad debate about this complex area of research. By opening up this debate, GFBR aims to promote the appropriate and ethical use of novel designs and methods so their full potential to address the health needs in LMICs can be realised.
Ethics of alternative trial designs and methods in low-resource settings
Authors: van der Graaf Rieke , Cheah Phaik Yeong
Published: December 2019

This editorial introduces articles in this Special Issue, which are based on presentations given at the 2017 meeting of the Global Forum of Bioethics in Research meeting. The main themes presented at the meeting were the use of cluster randomized trials, stepped-wedge cluster randomized trials, and controlled human infection models in research conducted in low-resource settings. The editorial sets out which ethical issues may arise in the context of alternative trial designs and describes the articles in this issue that addresses some or more of the ethical issues, such as justification of the research design, risk-benefit evaluations and consent.
When could human challenge trials be deployed to combat emerging infectious diseases? Lessons from the case of a Zika virus human challenge trial
Authors: Palacios Ricardo , Shah Seema K.
Published: December 2019

Human challenge trials (HCTs) deliberately infect participants in order to test vaccines and treatments in a controlled setting, rather than enrolling individuals with natural exposure to a disease. HCTs are therefore potentially powerful tools to prepare for future outbreaks of emerging infectious diseases. Yet when an infectious disease is emerging, there is often substantial risk and uncertainty about its complications, and few available interventions, making an HCT ethically complex. In light of the need to consider ethical issues proactively as a part of epidemic preparedness, we use the case of a Zika virus HCT to explore whether and when HCTs might be ethically justified to combat emerging infectious diseases. We conclude that emerging infectious diseases could be appropriate candidates for HCTs and we identify relevant considerations and provide a case example to illustrate when they might be ethically acceptable.
Evaluation of antibody responses to the early transcribed membrane protein family in Plasmodium vivax
Authors: Lee Seong-Kyun , Han Jin-Hee , Park Ji-Hoon , Ha Kwon-Soo , Park Won Sun , Hong Seok-Ho , Na Sunghun , Cheng Yang , Han Eun-Taek
Published: December 2019

Background

Malaria parasites form intracellular membranes that separate the parasite from the internal space of erythrocytes, and membrane proteins from the parasites are exported to the host via the membrane. In our previous study, Plasmodium vivax early transcribed membrane protein (PvETRAMP) 11.2, an intracellular membrane protein that is highly expressed in blood-stage parasites, was characterized as a highly immunogenic protein in P. vivax malaria patients. However, the other PvETRAMP family proteins have not yet been investigated. In this study, PvETRAMPs were expressed and evaluated to determine their immunological profiles.

Methods

The protein structure and amino acid alignment were carried out using bioinformatics analysis software. A total of six PvETRAMP family proteins were successfully expressed and purified using a wheat germ cell free protein expression system and the purified proteins were used for protein microarray and immunization of mice. The localization of the protein was determined with serum against PvETRAMP4. IgG subclasses were assessed from the immunized mice.

Results

In silico analysis showed that P. vivax exhibits nine genes encoding the ETRAMP family. The ETRAMP family proteins are relatively small molecules with conserved structural features. A total of 6 recombinant ETRAMP proteins were successfully expressed and purified. The serum positivity of P. vivax malaria patients and healthy individuals was evaluated using a protein microarray method. Among the PvETRAMPs, ETRAMP4 showed the highest positivity rate of 62%, comparable to that of PvETRAMP11.2, which served as the positive control, and a typical export pattern of PvETRAMP4 was observed in the P. vivax parasite. The assessment of IgG subclasses in mice immunized with PvETRAMP4 showed high levels of IgG1 and IgG2b. PvETRAMP family proteins were identified and characterized as serological markers.

Conclusions

The relatively high antibody responses to PvETRAMP4 as well as the specific IgG subclasses observed in immunized mice suggest that the ETRAMP family is immunogenic in pathogens and can be used as a protein marker and for vaccine development.
Show us your ticks: a survey of ticks infesting dogs and cats across the USA
Authors: Saleh Meriam N. , Sundstrom Kellee D. , Duncan Kathryn T. , Ientile Michelle M. , Jordy Julia , Ghosh Parna , Little Susan E.
Published: December 2019

Background

A variety of tick species infest dogs and cats in North America. Although most of these species also readily feed on people, national data regarding the species and abundance of ticks on dogs and cats are lacking. Here we report a large-scale study of ticks from dogs and cats in the USA over a 12-month period.

Methods

Tick submissions were invited from veterinary practices in all 50 states. Ticks were submitted with information about the pet and the attachment sites of each tick marked on a biopsy chart. Upon receipt, ticks were identified to species and stage using morphologic keys; when necessary, species identification was confirmed molecularly.

Results

From February 2018 through January 2019, 10,978 ticks were submitted from 1494 dogs and 336 cats in 49 states and ticks were collected in every month. Dog and cat infestation intensities ranged from 1 to 4765 and from 1 to 38 (median = 1, mean = 6.7 and 2.6), respectively. Dogs were primarily infested withDermacentor variabilis(532/1494; 35.6%),Ixodes scapularis(409/1494; 27.4%),Amblyomma americanum(345/1494; 23.1%) andRhipicephalus sanguineus(172/1494; 11.5%). Cats were primarily infested withI. scapularis(156/336; 46.4%),A. americanum(99/336; 29.5%) andD. variabilis(60/336; 17.9%). Other submitted ticks includedA. maculatum,Haemaphysalis longicornis,Otobius megnini, and less commonDermacentorspp. andIxodesspp. Co-infestations were documented in 93 dogs and 14 cats. Reported attachment sites of common tick species differed. In dogs,A. americanumwas most commonly attached to the abdomen, axillary, and inguinal regions;D. variabilisandI. scapularisto the head, neck, and back; andR. sanguineusto the head, neck, abdomen, legs, and feet. In cats,I. scapulariswas most commonly attached to the head andA. americanumwas most commonly attached to the tail and perianal region.

Conclusions

These data confirm that dogs and cats in the USA are at risk of tick infestation throughout the year and that tick species present in the region have apparent attachment site preferences.
High-throughput sequencing of CD4+ T cell repertoire reveals disease-specific signatures in IgG4-related disease
Authors: Wang Liwen , Zhang Panpan , Li Jieqiong , Lu Hui , Peng Linyi , Ling Jing , Zhang Xuan , Zeng Xiaofeng , Zhao Yan , Zhang Wen
Published: December 2019

Background

CD4+T cells play critical roles in the pathogenesis of IgG4-related disease (IgG4-RD). The aim of this study was to investigate the TCR repertoire of peripheral blood CD4+T cells in IgG4-RD.

Methods

The peripheral blood was collected from six healthy controls and eight IgG4-RD patients. TCR β-chain libraries of CD4+T cells were constructed by 5′-rapid amplification of cDNA ends (5′-RACE) and sequenced by Illumina Miseq platform. The relative similarity of TCR repertoires between samples was evaluated according to the total frequencies of shared clonotypes (metric F), correlation of frequencies of shared clonotypes (metric R), and total number of shared clonotypes (metric D).

Results

The clonal expansion and diversity of CD4+T cell repertoire were comparable between healthy controls and IgG4-RD patients, while the proportion of expanded and coding degenerated clones, as an indicator of antigen-driven clonal expansion, was significantly higher in IgG4-RD patients. There was no significant difference in TRBV and TRBJ gene usage between healthy controls and IgG4-RD patients. The complementarity determining region 3 (CDR3) length distribution was skewed towards longer fragments in IgG4-RD. Visualization of relative similarity of TCR repertoires by multi-dimensional scaling analysis showed that TCR repertoires of IgG4-RD patients were separated from that of healthy controls in F and D metrics. We identified 11 IgG4-RD-specific CDR3 amino acid sequences that were expanded in at least 2 IgG4-RD patients, while not detected in healthy controls. According to TCR clonotype networks constructed by connecting all the CDR3 sequences with a Levenshtein distance of 1, 3 IgG4-RD-specific clusters were identified. We annotated the TCR sequences with known antigen specificity according to McPAS-TCR database and found that the frequencies of TCR sequences associated with each disease or immune function were comparable between healthy controls and IgG4-RD patients.

Conclusion

According to our study of CD4+T cells from eight IgG4-RD patients, TCR repertoires of IgG4-RD patients were different from that of healthy controls in the proportion of expanded and coding degenerated clones and CDR3 length distribution. In addition, IgG4-RD-specific TCR sequences and clusters were identified in our study.
The effect of comorbidities for the prognosis of community-acquired pneumonia: an epidemiologic study using a hospital surveillance in Japan
Authors: Nguyen Mai Thi Ngoc , Saito Nobuyuki , Wagatsuma Yukiko
Published: December 2019

Objective

Pneumonia is a common but serious illness that continues to present significant morbidity and mortality. Although the effect of severity at admission on outcome has been well reported, the role of comorbidity is still not widely understood. The Charlson Comorbidity Index measures comorbidity with a well-established history of predicting long-term outcome but its utility in pneumonia prognosis is still limited. Here, we use the Charlson Comorbidity Index and hospital surveillance data to investigate associations between comorbidities and in-hospital mortality due to community-acquired pneumonia.

Results

Among the 535 eligible adult patients (69.0% male, median [IQR] age, 79 [70–84] years), 100 (18.7%) acquired severe to extremely severe pneumonia. The median [IQR] CCI was 1 [1–3]. Malignancy (129 of 535, 24.1%), chronic pulmonary diseases (113 of 535, 21.1%) and congestive heart failure (103 of 535, 19.3%) were frequent. Higher Charlson Comorbidity Index scores were associated with higher risk of in-hospital mortality (OR 1.28; 95% CI 1.07–1.53). These results support the inclusion of comorbid burden in predicting community-acquired pneumonia outcome.
Cross-sectional imaging of acute gynaecologic disorders: CT and MRI findings with differential diagnosis—part I: corpus luteum and haemorrhagic ovarian cysts, genital causes of haemoperitoneum and adnexal torsion
Authors: Tonolini Massimo , Foti Pietro Valerio , Costanzo Valeria , Mammino Luca , Palmucci Stefano , Cianci Antonio , Ettorre Giovanni Carlo , Basile Antonio
Published: December 2019

Acute gynaecologic disorders are commonly encountered in daily clinical practice of emergency departments (ED) and predominantly occur in reproductive-age women. Since clinical presentation may be nonspecific and physical findings are often inconclusive, imaging is required for a timely and accurate diagnosis. Although ultrasound is the ideal non-invasive first-line technique, nowadays multidetector computed tomography (CT) is extensively used in the ED, particularly when a non-gynaecologic disorder is suspected and differential diagnosis from gastrointestinal and urologic diseases is needed. As a result, CT often provides the first diagnosis of female genital emergencies. If clinical conditions and scanner availability permit, magnetic resonance imaging (MRI) is superior to CT for further characterisation of gynaecologic abnormalities, due to the excellent soft-tissue contrast, intrinsic multiplanar capabilities and lack of ionising radiation.

The purpose of this pictorial review is to provide radiologists with a thorough familiarity with gynaecologic emergencies by illustrating their cross-sectional imaging appearances. The present first section will review the CT and MRI findings of corpus luteum and haemorrhagic ovarian cysts, gynaecologic haemoperitoneum (from either ruptured corpus luteum or ectopic pregnancy) and adnexal torsion, with an emphasis on differential diagnosis. Additionally, comprehensive and time-efficient MRI acquisition protocols are provided.
Pre-aggregation of scalp progenitor dermal and epidermal stem cells activates the WNT pathway and promotes hair follicle formation in in vitro and in vivo systems
Authors: Su Yiqun , Wen Jie , Zhu Junrong , Xie Zhiwei , Liu Chang , Ma Chuan , Zhang Qun , Xu Xin , Wu Xunwei
Published: December 2019

Background

Billions of dollars are invested annually by pharmaceutical companies in search of new options for treating hair loss conditions; nevertheless, the challenge remains. One major limitation to hair follicle research is the lack of effective and efficient drug screening systems using human cells. Organoids, three-dimensional in vitro structures derived from stem cells, provide new opportunities for studying organ development, tissue regeneration, and disease pathogenesis. The present study focuses on the formation of human hair follicle organoids.

Methods

Scalp-derived dermal progenitor cells mixed with foreskin-derived epidermal stem cells at a 2:1 ratio aggregated in suspension to form hair follicle-like organoids, which were confirmed by immunostaining of hair follicle markers and by molecular dye labeling assays to analyze dermal and epidermal cell organization in those organoids. The hair-forming potential of organoids was examined using an in vivo transplantation assay.

Results

Pre-aggregation of dermal and epidermal cells enhanced hair follicle formation in vivo. In vitro pre-aggregation initiated the interactions of epidermal and dermal progenitor cells resulting in activation of the WNT pathway and the formation of pear-shape structures, named type I aggregates. Cell-tracing analysis showed that the dermal and epidermal cells self-assembled into distinct epidermal and dermal compartments. Histologically, the type I aggregates expressed early hair follicle markers, suggesting the hair peg-like phase of hair follicle morphogenesis. The addition of recombinant WNT3a protein to the medium enhanced the formation of these aggregates, and the Wnt effect could be blocked by the WNT inhibitor, IWP2.

Conclusions

In summary, our system supports the rapid formation of a large number of hair follicle organoids (type I aggregates). This system provides a platform for studying epithelial-mesenchymal interactions, for assessing inductive hair stem cells and for screening compounds that support hair follicle regeneration.
Drosophila Prominin-like, a homolog of CD133, interacts with ND20 to maintain mitochondrial function
Authors: Wang Xuexiang , Zheng Huimei , Jia Zexiao , Lei Zhaoying , Li Mengyao , Zhuang Qianqian , Zhou Hui , Qiu Yue , Fu Yong , Yang Xiaohang , Xi Yongmei , Yan Qingfeng
Published: December 2019

Background

Drosophila Prominin-like is a homolog of mammalian CD133, which is recognized as a biomarker for stem cells. The interacting proteins of CD133 and their biological functions remain elusive.

Results

In this study, we using yeast two-hybrid assays, GST pull-down assay and co-immunoprecipitation (Co-IP) methods found that Drosophila Prominin-like interacts with ND20, a subunit of mitochondrial respiratory complex I. Bioinformatics analysis suggests that Prominin-like is a six-transmembrane glycoprotein which localizes on cellular membranes. Immunostaining and mitochondrial fractionation indicate that Drosophila Prominin-like could localize in the mitochondria. The knockdown of prominin-like in S2 cells resulted in transient mitochondrial dysfunctions as evidenced by reduced ATP production, elevated ROS generation and an accompanied reduction in mitochondrial proteins. Mitochondrial dysfunctions were detected in aged prominin-like mutant flies.

Conclusion

Our data indicates that Prominin-like acts to maintain mitochondrial function through its interaction with ND20 which, itself, is active in the mitochondrial electron transport chain. Our study provides insights into a novel molecular mechanism of Drosophila prominin-like and suggests a similar function of CD133 in mammals.
Association between component-resolved diagnosis of house dust mite and efficacy of allergen immunotherapy in allergic rhinitis patients
Authors: Huang Yanran , Wang Chengshuo , Lin Xi , Lou Hongfei , Cao Feifei , Li Wenhan , Zhang Yuan , Zhang Luo
Published: December 2019

Data regarding clinical relevance of house dust mite (HDM) components over allergen immunotherapy (AIT) for allergic rhinitis (AR) are lacking. 18 adult AR patients receiving HDM-AIT for 52 weeks were followed up to assess serum levels of sIgE and sIgG4 to HDM components. The study showed that Der p1, p2, p23, Der f1 and f2, are important sensitizing components of HDM, of which Der p1 appears to be the most clinically relevant allergenic component for effective AIT.
Integrating spatial accessibility in the design of volcano evacuation plans in the French West Indies (Guadeloupe and Martinique)
Authors: Leone Frédéric , Komorowski Jean-Christophe , Gherardi-Leone Monique , Lalubie Guillaume
Published: December 2019

This article provides a spatial and comparative approach to evaluate the territorial accessibility in the event of a volcanic crisis in the French West Indies. A spatial assessment of resources and populations exposed to volcanic hazards is performed, followed by an assessment of the risk of territorial isolation due to lahars. Modelling of the risk of terrestrial isolation builds upon graph-based computations and indices that take into account the specific vulnerability of river-crossing structures and the knowledge of historical lahars. Another application of the graphs concerns scenarios for the evacuation of population, the sole efficient response to an eruption. This results in an optimised division of areas to evacuate in order to assess the potential reduction of the load on the road network. These different results are integrated into a prototype for evacuation maps intended for local authorities. The situation of Guadeloupe is of greater concern than that in Martinique, given the level of exposure, the potential losses of accessibility in case of lahars, and the greater and on-going volcanic unrest of La Soufrière volcano in Guadeloupe.
The subway microbiome: seasonal dynamics and direct comparison of air and surface bacterial communities
Authors: Gohli Jostein , Bøifot Kari Oline , Moen Line Victoria , Pastuszek Paulina , Skogan Gunnar , Udekwu Klas I. , Dybwad Marius
Published: December 2019

Background

Mass transit environments, such as subways, are uniquely important for transmission of microbes among humans and built environments, and for their ability to spread pathogens and impact large numbers of people. In order to gain a deeper understanding of microbiome dynamics in subways, we must identify variables that affect microbial composition and those microorganisms that are unique to specific habitats.

Methods

We performed high-throughput 16S rRNA gene sequencing of air and surface samples from 16 subway stations in Oslo, Norway, across all four seasons. Distinguishing features across seasons and between air and surface were identified using random forest classification analyses, followed by in-depth diversity analyses.

Results

There were significant differences between the air and surface bacterial communities, and across seasons. Highly abundant groups were generally ubiquitous; however, a large number of taxa with low prevalence and abundance were exclusively present in only one sample matrix or one season. Among the highly abundant families and genera, we found that some were uniquely so in air samples. In surface samples, all highly abundant groups were also well represented in air samples. This is congruent with a pattern observed for the entire dataset, namely that air samples had significantly higher within-sample diversity. We also observed a seasonal pattern: diversity was higher during spring and summer. Temperature had a strong effect on diversity in air but not on surface diversity. Among-sample diversity was also significantly associated with air/surface, season, and temperature.

Conclusions

The results presented here provide the first direct comparison of air and surface bacterial microbiomes, and the first assessment of seasonal variation in subways using culture-independent methods. While there were strong similarities between air and surface and across seasons, we found both diversity and the abundances of certain taxa to differ. This constitutes a significant step towards understanding the composition and dynamics of bacterial communities in subways, a highly important environment in our increasingly urbanized and interconnect world.
“Service with open arms”: enhancing community healthcare experiences for individuals with a history of incarceration
Authors: Walsh-Felz Devin , Westergaard Ryan , Waclawik Gabrielle , Pandhi Nancy
Published: December 2019

Background

The criminal justice-involved population has a higher disease burden than the general population and a high risk of death post-incarceration. However, this group underutilizes healthcare, especially preventive and primary care services. Sixteen in-person, semi-structured interviews were conducted with formerly incarcerated individuals in Milwaukee to explore health impacts of incarceration, barriers and facilitators to healthcare access, and what ideal health service provision would look like following incarceration. Interviews were transcribed, coded, and analyzed using an immersion/crystallization approach.

Results

Overall, people perceived incarceration to have a negative impact on their physical and mental health and expressed dissatisfaction with care in correctional settings. Many faced lapses in care following incarceration, frequently due to insurance challenges.

Conclusions

Participants offered advice for designing an ideal clinic including formal coordination with corrections and provision of additional social services. Staff demeanor that created a welcoming and caring environment was highlighted as an important component and facilitator of care.
Evaluation of the acute toxicity, phototoxicity and embryotoxicity of a residual aqueous fraction from extract of the Antarctic moss Sanionia uncinata
Authors: da Silva Fernandes Andréia , Brito Lara Barroso , Oliveira Gisele Augusto Rodrigues , Ferraz Elisa Raquel Anastácio , Evangelista Heitor , Mazzei José Luiz , Felzenszwalb Israel
Published: December 2019

Background

Ultraviolet (UV) radiation is the main exogenous inductor of skin damage and so photoprotection is important to control skin disorders. The Antarctic mossSanionia uncinatais an important source of antioxidants and the photoprotective activity of its organic extracts has been investigated. This study aimed to evaluate the potential photoprotection, cytotoxicity and embryotoxicity of residual aqueous fraction (AF) from the mossS. uncinata.

Methods

UV-visible spectrum and SPF (sun protection factor) were determined by spectrophotometry. Embryotoxicity potential was evaluated by Fish embryo-larval toxicity test using zebrafish (Danio rerio) as organism model. Cell death assays by water-soluble tetrazolium salt (WST-1) and lactate dehydrogenase (LDH) were investigated using HaCaT keratinocyte cell line cultured in monolayers and three dimensions (3D). Phototoxicity and association with UV-filters were performed by 3T3 neutral red uptake test.

Results

The AF showed sharp absorption bands in the UV region and less pronounced in the visible region. The SPF was low (2.5 ± 0.3), but the SPF values of benzophenone-3 and octyl-methoxycinnamate increased ~ 3 and 4 times more, respectively, in association with AF. The AF did not induce significant lethal and sublethal effects on zebrafish early-life stages. In monolayers, the HaCaT cell viability, evaluated by WST-1, was above 70% by ≤0.4 mg AF/mL after 48 and 72-h exposure, whereas ≤1 mg AF/mL after 24-h exposure. The LDH assay showed that the cell viability was above 70% by ≤0.4 mg AF/mL even after 72-h exposure, but ≤1 mg/mL after 24 and 48-h exposure. In 3D cell culture, an increased cell resistance to toxicity was observed, because cell viability of HaCaT cell by WST-1 and LDH was above ~ 90% when using ≤1 and 4 mg AF/mL, respectively. The AF demonstrated values of photo irritation factor < 2 and of photo effect < 0.1, even though in association with UV-filters.

Conclusions

The residual AF absorbs UV-vis spectrum, increased SPF values of BP-3 and OMC and does not induce embryotoxicity to zebrafish early life-stage. The cell death assays allowed establishing non-toxic doses of AF and phototoxicity was not detected. AF ofS. uncinatapresents a good potential for skin photoprotection against UV-radiation.
Assessing the significance of course materials for graduate program admission
Authors: Khaydarov Firdavs , Peterson Haley R. , Miller Carrie Lewis
Published: December 2019

Enrollment into graduate programs continue to increase. Given major changes occurring within education (e.g., online courses and OER integration), it is imperative for faculty and students to be aware of the impact these changes could entail to those with higher education aspirations. The use of Open Educational Resources (OER) is one important change that has occurred with respect to the types of academic materials used in higher education courses. The use of OER has significantly expanded over the past decade. Resources accessible under the caption of OER are free and available in the public domain. Currently, there is little information regarding how these changes might affect graduate school applications or admission. The purpose of this study was to examine the importance of academic materials used in undergraduate classes in the evaluation of individuals for graduate admission. The results indicated that academic materials are the least important factor utilized for admission criteria. This result may indicate that the use of Open Educational Resources, low cost or free course materials with a copyright license that allows for reuse, should not impact the likelihood of a student being accepted into a graduate program.
The 2017 Nishinoshima eruption: combined analysis using Himawari-8 and multiple high-resolution satellite images
Authors: Kaneko Takayuki , Maeno Fukashi , Yasuda Atsushi , Takeo Minoru , Takasaki Kenji
Published: December 2019

Nishinoshima volcano suddenly resumed eruptive activity in April 2017 after about 1.5 years of dormancy since its previous activity in 2013–2015. Nishinoshima is an uninhabited isolated island. We analyzed the eruption sequence and the eruptive process of the 2017 eruption (17 April–10 August: 116 days) by combining high-temporal-resolution images from Himawari-8 and high-spatial-resolution images from the ALOS-2, Landsat-8, and Pleiades satellites. We used these data to discuss how temporal variations in the lava effusion rate affected the flow formations and topographical features of the effused lava. The total effused volume was estimated to be 1.6 × 107 m3, and the average effusion rate was 1.5 × 105 m3/day (1.7 m3/s). Based on variations in the thermal anomalies in the 1.6-μm band of Himawari-8, which roughly coincided with that of the lava effusion rate estimated by ALOS-2, the activity was segmented into five stages. In Stage 1 (17–30 April: 14 days), the lava effusion rate was the highest, and lava flowed to the west and southwest. Stage 2 (1 May–5 June: 36 days) showed a uniform decrease in flow, and lava flowed to the southwest and formed the southwestern lava delta. During Stage 3 (6–15 June: 10 days), the lava effusion rate increased in a pulsed manner, the flow direction changed from southwestward to westward, and a narrow lava flow effused from the southern slope of the cone. In Stage 4 (16 June–31 July: 46 days), the lava effusion rate decreased and lava flowed westward through lava tubes, enlarging the western lava delta. Around the end of July, lava effusion mostly stopped. Finally, in Stage 5 (1–10 August: 10 days), explosive eruptions occurred sporadically. The variation in lava effusion rate seemed to play an important role in forming different flow patterns of lava on Nishinoshima. In Stages 1 and 3, lava flowed in multiple directions, while in Stages 2 and 4, it flowed in single direction, probably because the effusion rate was lower. A pulsed increase in the lava effusion rate during Stage 3 caused new breaks and disturbances of the lava passages near the vents, which resulted in changes in flow directions. Differences in the size of lava lobes between the southwestern and western deltas are also considered to result from differences in the lava effusion rate.
Miniaturization effect of electroosmotic self-propulsive microswimmer powered by biofuel cell
Authors: Yamanaka Toshiro , Arai Fumihito
Published: December 2019

For future medical microrobotics, we have proposed the concept of the electroosmotic self-propulsive microswimmer powered by biofuel cell. According to the derived theoretical model, its self-propulsion velocity is inversely proportional to the length of the microswimmer, while it is proportional to the open circuit potential generated by the biofuel cell which does not depend on its size. Therefore, under conditions where those mechanisms work, it can be expected that the smaller its microswimmer size, the faster its self-propulsion velocity. Because of its remarkable feature, this concept is considered to be suitable as propulsion mechanisms for future medical microrobots to move inside the human body through the vascular system, including capillaries. We have already proved the mechanisms by observing the several 10 μm/s velocity of 100 μm prototypes fabricated by the optical photolithography using several photomasks and alignment steps. However, the standard photolithography was not suitable for further miniaturization of prototypes due to its insufficient resolution. In this research, we adopted femtosecond-laser 3D microlithography for multi-materials composing of the conductive polymer composites and nonconductive polymer composite and succeeded in fabricating 10 μm prototypes. Then we demonstrated more than 100 μm/s velocity of the prototype experimentally and proved its validity of the smaller and faster feature.
Effect of Different Physical Training Forms on Change of Direction Ability: a Systematic Review and Meta-analysis
Authors: Nygaard Falch Hallvard , Guldteig Rædergård Håvard , van den Tillaar Roland
Published: December 2019

Background

The ability to perform a rapid change of direction (COD) is a critical skill in numerous court- and field-based sports. The aim of this review is to investigate the effect of different physical training forms on COD performance.

Methods

A systematic review of the literature was undertaken using the following databases: PubMed, SPORTDiscus and Google Scholar. Studies were eligible if they met the following criteria: (1) a COD test measuring performance before and after the training intervention, with specific description of the test in terms of length and number of changes in a direction with specified angles, (2) involve training intervention like plyometric, strength, sprint, specific COD training, or a combination of these training forms targeting the lower extremities, (3) the study had to state training background in terms of which sport they participated in and their competitive level and a detailed methodological description. Non-English articles were excluded. Percentage difference and effect sizes were calculated in order to compare the effects of different training interventions.

Results

A range of studies performing plyometrics, strength, sprint, specific COD training, training with post-activation potentiation or a combination of these training forms were examined. The percentage of change and effect size (ES) were calculated. Seventy-four studies met the inclusion criteria, comprising 132 experimental groups and 1652 unique subjects. The review revealed no clear consensus on which training form is optimal to develop COD performance. All training forms resulted in an increase in performance from almost no ES to large ES.

Conclusions

The results of the study indicate that COD ability is a specific skill, whereas the COD task, the sports require determines which training form is the most effective to develop COD ability. Training targeting improvement in COD performance should address the duration of the training in line with which energy system is utilized. The complexity of the COD task with respect to the individual athlete must be considered. Consequently, the number of changes in direction and the angles of the task are relevant when organizing training.