bluuebunny/crossref_metadata_2025 huggingface dataset:
Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16
Authors: Guo Songhe , Chen Jun , Chen Fangfang , Zeng Qiuyao , Liu Wan-Li , Zhang Ge
Published: November 2020

Objective

Exosomes released from tumour cells are packed with unique RNA and protein cargo, and they are emerging as an important mediator in the communication network that promotes tumour progression. The facultative intracellular bacterium Fusobacterium nucleatum (Fn) is an important colorectal cancer (CRC)-associated bacterium. To date, the function of exosomes from Fn-infected CRC cells has not been explored.

Design

Exosomes were isolated by sequential differential centrifugation and verified by transmission electron microscopy, NanoSight analysis and Western blotting. Given that exosomes have been shown to transport miRNAs and proteins to alter cellular functions, we performed miRNA sequencing and proteome analysis of exosomes from Fn-infected and non-infected cells. The biological role and mechanism of exosomes from Fn-infected cells in CRC tumour growth and liver metastasis were determined in vitro and in vivo.

Results

We demonstrated that exosomes delivered miR-1246/92b-3p/27a-3p and CXCL16/RhoA/IL-8 from Fn-infected cells into non-infected cells to increase cell migration ability in vitro and promote tumour metastasis in vivo. Finally, both circulating exosomal miR-1246/92b-3p/27a-3p and CXCL16 levels were closely associated with Fn abundance and tumour stage in patients with CRC.

Conclusion

This study suggests that Fn infection may stimulate tumour cells to generate miR-1246/92b-3p/27a-3p-rich and CXCL16/RhoA/IL-8 exosomes that are delivered to uninfected cells to promote prometastatic behaviours.
Does being on HIV antiretroviral therapy increase the risk of syphilis? An analysis of a large national cohort of MSM living with HIV in England 2009–2016
Authors: Allen Hester , Kirwan Peter , Brown Alison E , Mohammed Hamish , Hughes Gwenda , Marks Michael , Delpech Valerie
Published: November 2020

Objective

A resurgence in bacterial STIs, notably syphilis, among gay, bisexual and other men who have sex with men (MSM) has been detected in England. A Canadian modelling study postulated that antiretroviral therapy (ART) may increase susceptibility to syphilis. We assess the association between ART and syphilis incidence in a comprehensive national cohort of MSM living with HIV in England.

Methods

National surveillance data were used to create a cohort of MSM attending for both HIV and STI care in England between 2009 and 2016. Survival analysis was used to calculate the incidence of infectious syphilis during periods on and off ART. Multivariable Poisson regression was used to assess the association between ART use and syphilis, after adjustment for potential confounders, including, as a proxy measure for high-risk behaviour, being diagnosed with >1 other STI prior to a syphilis diagnosis.

Results

19 428 HIV diagnosed MSM contributed 112 960 person-years of follow-up from 2009 to 2016. The overall rate of syphilis was 78.0 cases per 1000 person-years follow-up. Syphilis rates were higher among men receiving ART (36.8) compared with those who did not (28.4) (absolute rate difference 4.7 cases per 1000 person-years). Multivariable analysis showed no statistical association between receiving ART and syphilis. Increased risk of syphilis was found in MSM aged 25–34 (HR 1.89, 95% CI 1.43 to 2.51) and in those diagnosed with two other STIs (HR 5.83, 95% CI 5.37 to 6.32).

Conclusion

While we observed a small increase in the rate of syphilis among those on ART, when adjusting for potential confounding factors, including a proxy measure for high-risk behaviour, there was no evidence of an increased risk of syphilis in MSM receiving ART. High-risk sexual behaviour markers were the main risk factors for syphilis, and our results highlight the need for STI prevention interventions in MSM living with HIV to target these particularly high-risk sexual networks.
Ask Dr Google: what STI do I have?
Authors: Lee Pin Ming , Foster Rosalind , McNulty Anna , McIver Ruthy , Patel Prital
Published: November 2020

Objectives

Between 2013 and 2014, a third of Australian adults reported using the internet to investigate medical symptoms before consulting a medical practitioner. However, there is limited evidence regarding internet health information seeking behaviour (HISB) in sexual health. This study aims to determine the frequency, predictors and accuracy of internet HISB for sexual health self-diagnosis.

Methods

A cross-sectional paper-based survey, available in English, Chinese and Thai, was conducted during April to August 2019 at the Sydney Sexual Health Centre (SSHC). Symptomatic patients were recruited to answer an 18-item survey on their HISB, self-assessed diagnosis, anxiety and health literacy. Survey responses were correlated with SSHC electronic medical record data including participant demographics and clinician diagnosis. Data analyses were performed using Stata V.14.

Results

The majority of participants searched the internet (355; 79.1%) before attending clinic, and of these only 16.9% made a correct self-diagnosis. Multivariate analyses demonstrated that relative to Australian-born participants, people born in Asia were twice as likely to undertake internet HISB (adjusted OR (AOR) 2.41, 95% CI 1.25 to 4.64, p<0.01), and those born in Latin America were more likely to self-diagnose correctly (AOR 3.35, 95% CI 1.20 to 9.37, p<0.01). On average, participants who searched the internet scored higher relative to those who did not search, on measures of feeling generally tense (2.26, 95% CI 2.16 to 2.7 and 1.86, 95% CI 1.67 to 2.05, p<0.001), upset (1.96, 95% CI 1.85 to 2.08 and 1.53, 95% CI 1.35 to 1.72, p<0.001) and worried (2.55, 95% CI 2.44 to 2.65, and 2.16, 95% CI 1.95 to 2.38, p=0.001).

Conclusions

This study has filled important gaps in the literature and highlighted the high prevalence of adults engaging in HISB for sexual health information. Of concern are the increased levels of anxiety and low accuracy of self-diagnoses associated with HISB. Strategies to direct patients to reputable and user-friendly health websites that mitigate anxiety and misinterpretation of online health information should be explored.
Diverging trends in US male-female condom use by STI risk factors: a nationally representative study
Authors: Copen Casey E , Dittus Patricia J , Leichliter Jami S , Kumar Sagar , Aral Sevgi O
Published: November 2020

Objective

Condom use behaviours are proximal to recent STI increases in the USA, yet it remains unclear whether the use of condoms has changed over time among unmarried, non-cohabiting young men who have sex with women (MSW) and how this variability is influenced by STI risk factors.

Methods

To examine condom use over time among MSW aged 15–29, we used three cross-sectional surveys from the 2002, 2006–2010 and 2011–2017 National Survey of Family Growth. We estimated weighted percentages, adjusted prevalence ratios (APRs) and 95% confidence intervals (CI) to assess changes in condom use, stratified by whether MSW reported any STI risk factors in the past 12 months (ie, perceived partner non-monogamy, male-to-male sex, sex in exchange for money or drugs, sex partner who injects illicit drugs, or an HIV-positive sex partner).

Results

We observed a divergence in trends in condom use at last sex between men aged 15 –29 with STI risk factors in the past 12 months and those without such history. We saw significant declines in condom use from 2002 to 2011–2017 among men with STI risk factors (APR=0.80, 95% CI 0.68 to 0.95), specifically among those aged 15–19 (APR=0.73, 95% CI 0.57 to 0.94) or non-Hispanic white (APR=0.71, 95% CI 0.54 to 0.93). In contrast, trends in condom use among men with no STI factors remained stable or increased. Across all time periods, the most prevalent STI risk factor reported was perception of a non-monogamous female partner (23.0%–26.9%). Post-hoc analyses examined whether condom use trends changed once this variable was removed from analyses, but no different patterns were observed.

Conclusions

While STIs have been increasing, men aged 15–29 with STI risk factors reported a decline in condom use. Rising STI rates may be sensitive to behavioural shifts in condom use among young MSW with STI risk factors.
Determination of reverse transcriptase inhibitor resistance mutations in HIV-1 infected children in Côte d’Ivoire
Authors: Camara-Cisse Massara , Djohan Youzan Ferdinad , Toni Thomas d’Aquin , Dechi Jean-Jacques Renaud , N’Din Jean-Louis Philippe , Lohoues Esmel Essis , Monde Absalome Aké , Gogbe Leto Olivier , Brou Emmanuel , Fieni Flore , Mansour Franck Adéoti , Aby Roland , Kouakou Kouadio , Chenal Henri
Published: November 2020

Treatment scale-up is leading to a progressive increase in HIV resistance to antiretrovirals, especially in children. To assess resistance to reverse transcriptase inhibitors (RTIs) in HIV-1 infected children in Côte d’Ivoire, genotypic resistance tests were performed and interpreted using the ANRS algorithm ( www.hivfrenchresistance.org ). Phylogenetic trees were created using BioEdit v7 and Mega7 software. The frequency of resistance to at least one RTI was 79%. It was 88% for nucleoside reverse transcriptase inhibitors (NRTIs), 71% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 63% for both classes (NRTI + NNRTI). The frequency of resistance was 50% for the ZDV + 3TC + EFV combination, 42% for the ABC + 3TC + EFV combination, and 8% for the TDF + 3TC + EFV combination. Frequently encountered resistance mutations were for NRTIs: M184V (88%), TAMs (67%), T215F/I/V/Y (33%), and L74I/V (24%); for NNRTIs: K103N/S (74%), P225H (26%), and G190A/E/Q (24%). The synthesis of phylogenetic analyses showed the predominance of the viral subtype CRF02_AG (85%). These results show a high prevalence of resistance to RTIs in children infected with HIV-1. Hence the interest of a more accessible monitoring of viral load and genotypic resistance tests in HIV-1 infected children undergoing treatment in Côte d’Ivoire.
Scalable Control of Positive Systems
Authors: Rantzer Anders , Valcher Maria Elena
Published: November 2020

In this article, we first present some foundational results about the stability and positive stabilization of continuous-time positive systems. Necessary and sufficient conditions for achieving stability are provided, together with some desired performance in terms of disturbance attenuation. These conditions are expressed in terms of linear programming and scale well with the system size. We then discuss the interconnection of positive subsystems by means of a static output feedback that preserves positivity, and propose conditions to achieve both stability and the asymptotic alignment of the closed-loop output to a desired vector. Finally, we describe some results for a class of parameterized positive systems. The second part of the article presents some interesting applications of the results presented in the first part. Specifically, control problems for heating networks, formation control, power control in wireless communication, and the evolutionary dynamics of cancer and HIV are formalized and solved as optimal control problems for positive systems.
Investigation of Two Mycobacterium abscessus Outbreaks in Quebec Using Whole Genome Sequencing
Authors: Wuzinski Michelle , Soualhine Hafid , Valliere Emilie , Akochy Pierre-Marie , Cloutier Nancy , Petkau Aaron , Kaplen Brynn , Duchesne Maryse , Villeneuve Jasmin , Sharma Meenu K.
Published: November 2020

In recent decades, nontuberculous mycobacteria (NTM) infections are of emerging public health concern and have contributed towards significant clinical and economic burden globally. One such rapid growing mycobacteria, Mycobacterium abscessus, can cause clonal outbreaks, and these bacteria exhibit a highly resistant antimicrobial susceptibility profile. Here, we present an investigation of two small outbreaks of M. abscessus: first in a pediatric clinic setting and second in a tattoo parlour from Quebec. Two whole genome sequencing approaches were utilized for genotyping: MAB‐MLST, a multilocus sequencing typing scheme containing housekeeping, identification, and antimicrobial resistance genes, and SNVPhyl that uses phylogenetics to determine single nucleotide variations between strains. MAB‐MLST results showed that the pediatric outbreak strains had two distinct sequence types, demonstrating that one strain did not belong to the outbreak, while all tattoo outbreak isolates belonged to the same sequence type. SNVPhyl results were similar to MAB‐MLST results and showed that the pediatric outbreak strains tightly clustered together with 0‐1 SNVs between isolates, a sharp contrast between unrelated strains used as controls. Similar results were seen for tattoo outbreak cases with 3‐11 SNVs between isolates. NTM infections can be difficult to identify, and outbreak investigations can be complicated. Thus, WGS tools can be used in public health outbreak investigations as they provide high discriminatory power.
Exosomal Long Noncoding RNAs: Insights into Emerging Diagnostic and Therapeutic Applications in Lung Cancer
Authors: Karimzadeh Mohammad Reza , Seyedtaghia Mohammad Reza , Soudyab Mohammad , Nezamnia Maria , Kidde Jason , Sahebkar Amirhossein
Published: November 2020

Lung cancer is the most common cause of cancer-related deaths worldwide. Annually, millions of people die from lung cancer because of late detection and ineffective therapies. Recently, exosomes have been introduced as new therapeutic players with the potential to improve upon current diagnostic and treatment options. Exosomes are small membranous vesicles produced during endosomal merging. This allows for cell packaging of nucleic acids, proteins, and lipids and transfer to adjacent or distant cells. While exosomes are a part of normal intercellular signaling, they also allow malignant cells to transfer oncogenic material leading to tumor spread and metastasis. Exosomes are an interesting field of discovery for biomarkers and therapeutic targets. Among exosomal materials, lncRNAs have priority; lncRNAs are a class of noncoding RNAs longer than 200 base pairs. In the case of cancer, primary interest regards their oncogene and tumor suppressor functions. In this review, the advantages of exosomal lncRNAs as biomarkers and therapeutic targets will be discussed in addition to reviewing studies of their application in lung cancer.
Clinical Characterization of Ulcerative Colitis in Patients with Primary Sclerosing Cholangitis
Authors: Murasugi Shun , Ito Ayumi , Omori Teppei , Nakamura Shinichi , Tokushige Katsutoshi
Published: November 2020

Objectives. The clinical/colonoscopic features of ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC), the prognostic impact of UC, and the utility of UC screening in PSC patients are unknown. We characterized UC associated with PSC and assessed UC’s impact on the prognosis of PSC and the importance of colonoscopic UC screening in PSC patients. Methods. We retrospectively analyzed the cases of 77 patients treated for PSC at a single center (April 2000–July 2019). We reviewed the clinical/colonoscopic profiles of the concurrent UC patients and compared the clinical profiles, survival, and primary causes of death between the patients with/without UC (

n
=
35

/

n
=
42

). The details of all patients’ colonoscopies were reviewed. Results. The concurrent UC group: 17 men, 18 women, diagnosed with PSC at the mean (SD) age of 36 (17) years; 21 patients (60%) had no UC symptoms. Colonoscopy revealed pancolitis in all patients, predominantly affecting the right-sided colon in 30 patients (86%). Lesions were scattered. Backwash ileitis (

n
=
13

, 37%) and rectal sparing (

n
=
18

, 51%) were observed. Most patients had mild UC; some had moderate or more severe UC (median Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 2; range, 1–5). Ludwig’s stage determined by liver biopsy did not correlate with the Mayo endoscopic score for UC. The patients with UC were diagnosed with PSC at a significantly younger age than those without UC (mean (SD), 36 [17] years vs. 55 [19] years,

p
<
0.0001

) and had a significantly higher 5-year survival rate (97.1% vs. 70.5%,

p
=
0.0028

). UC was detected in 19 of 34 asymptomatic patients (56%) who underwent colonoscopy screening. Conclusions. Our cohort’s clinical/colonoscopic features of UC associated with PSC are more moderate or severe UC than previous cases. The coexistence of UC might affect the prognosis of PSC. In this regard, colonoscopy in PSC patients is an important examination for determining prognosis. There is also asymptomatic UC in patients with PSC. In this regard, screening for colonoscopy in PSC patients is essential. When a diagnosis of PSC is made, immediate colonoscopy is a priority with UC complications in mind.
Least Squares Estimation for Discretely Observed Stochastic Lotka–Volterra Model Driven by Small
α
-Stable Noises
Authors: Wei Chao , Wei Yan , Zhou Yingying
Published: November 2020

Stochastic Lotka–Volterra model driven by small

α

-stable noises is used to describe population dynamics perturbed by random environment. However, parameters in the model are always unknown. The contrast function is given to obtain least squares estimators. The consistency and the rate of convergence of the least squares estimators are proved, and the asymptotic distribution of the estimators are derived by Markov inequality, Cauchy–Schwarz inequality, and Gronwall’s inequality. Some numerical examples are provided to verify the effectiveness of the estimators.
Finite-Time Antisaturation Tracking Control for Hypersonic Vehicle with Uncertain Dynamics
Authors: Cui Yuwei , He Yushan , Li Aijun , Li Jun , Song Shuo
Published: November 2020

This paper concentrates on the problem of finite-time altitude and velocity tracking control for hypersonic flight vehicles that encounter unmodeled dynamics and input saturations. An adaptive neural finite-time backstepping control strategy is constructed by designing modified virtual commands and compensation signals. The minimum learning parameter algorithm based on a radial basis function is employed to approximate the unknown dynamics with low computational burden. Furthermore, an auxiliary system is established to cope with the nonlinearity caused by actuator saturation. It is concluded by a Lyapunov-based analysis that the finite-time stability is guaranteed under the developed architecture. Finally, numeral simulation is provided to demonstrate the effectiveness of the proposed controller.
Risk Transmission of the Regions in the Yangtze River Economic Belt
Authors: Wu Xianbo , Hui Xiaofeng
Published: November 2020

This study mainly uses the method of effective transfer entropy (ETE) to study the risk transmission in each year among the 11 provinces and municipalities in the Yangtze River Economic Belt during the last five years. From the results of the risk transmission network, centralities of the regions, and maximum spanning trees, it can be seen that, in the years of 2015 and 2016, the risk transmission in the Yangtze River Economic Belt is relatively large, and in 2015, Shanghai is the main risk exporter. This may be mainly due to the violent turbulence in the Chinese stock market, and in 2016, although Chinese stock market is in a stable position, the whole risk transmission is still high, but the difference from 2015 is that the input and output risk of each province and municipality are more uniform and are no longer like Shanghai as the main exporter of risk in 2015. From the perspective of risk spillover, the overall trend is from the western region of China to the central region, and finally to the eastern region. Specifically, from the results of the maximum spanning tree, except the stock market crash period in 2015, Chongqing, Guizhou, and Yunnan (the western region) are the main exporters of risk, while Jiangsu, Zhejiang, and Shanghai (the eastern region) are often at the edge at this time, and from the results of the centrality of the region indexes, Hubei, Jiangxi, and Anhui (the central region) are in the hub position of risk transmission.
Characterization of Shale Pore Structure by Multitechnique Combination and Multifractal Analysis and Its Significance
Authors: Liu Dengke , Tian Tao , Liang Ruixiang , Yang Fu , Ye Feng
Published: November 2020

Understanding pore structure would enable us to obtain a deeper insight into the fluid mechanism in porous media. In this research, multifractal analysis by various experiments is employed to analyze the pore structure and heterogeneity characterization in the source rock in Ordos Basin, China. For this purpose, imaging apparatus, intrusion tests, and nonintrusion methods have been used. The results show that the objective shale reservoir contains complex pore network, and minor pores dominant the pore system. Both intrusion and nonintrusion methods detected pore size distributions show multifractal nature, while the former one demonstrates more heterogeneous features. The pore size distributions acquired by low temperature adsorption and nuclear magnetic resonance have relatively good consistence, indicating that similar pore network detection method may share the same mechanism, and the full-ranged pore size distributions need to be acquired by multitechniques. Chlorite has an obvious impact on the heterogeneity of pore structure in narrow pore size range, while illite and I/S mixed layer influence that in wide range. Kerogen index is the fundamental indicators of geochemical parameters. With the decrease of averaged small and middle/large pore radius, the heterogeneity of pore structures increase in narrow and wide ranges, respectively. This work employed a comprehensive methodology based on multitechniques and helps to explore how pore networks affect reservoir quality in shale reservoirs.
Experiencia del Laboratorio de Ahorro para el Retiro en América Latina y el Caribe
Authors: Bosch Mariano , Caballero ­Gustavo , Cofré ­Fabián , González ­Stephanie , Hand Anne , Keller Lukas , Silva María Teresa , Rodríguez Catalina
Published: November 2020

Este artículo presenta un resumen de la experiencia que el Laboratorio de Ahorro para el Retiro (LAR) del Banco Interamericano de Desarrollo (BID) ha desarrollado en sus cuatro años de existencia para promover el ahorro previsional voluntario en países como Chile, Colombia, México y Perú.
Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma
Authors: Salama April K.S. , Palta Manisha , Rushing Christel N. , Selim M. Angelica , Linney Kristen N. , Czito Brian G. , Yoo David S. , Hanks Brent A. , Beasley Georgia M. , Mosca Paul J. , Dumbauld Chelsae , Steadman Katelyn N. , Yi John S. , Weinhold Kent J. , Tyler Douglas S. , Lee Walter T. , Brizel David M.
Published: November 2020

Purpose:

In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma.

Patients and Methods:

Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550–4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy.

Results:

Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%–83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4+ T-cell subsets.

Conclusions:

Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.
A Novel Neoplastic Fusion Transcript, RAD51AP1-DYRK4, Confers Sensitivity to the MEK Inhibitor Trametinib in Aggressive Breast Cancers
Authors: Liu Chia-Chia , Veeraraghavan Jamunarani , Tan Ying , Kim Jin-Ah , Wang Xian , Loo Suet Kee , Lee Sanghoon , Hu Yiheng , Wang Xiao-Song
Published: November 2020

Purpose:

Luminal B breast tumors are more aggressive estrogen receptor–positive (ER+) breast cancers characterized by aggressive clinical behavior and a high risk of metastatic dissemination. The underlying pathologic molecular events remain poorly understood with a paucity of actionable genetic drivers, which hinders the development of new treatment strategies.

Experimental Design:

We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by reverse transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell, and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, Western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms.

Results:

Here we report a novel tumor-specific chimeric transcript RAD51AP1-DYRK4 preferentially expressed in luminal B tumors. Analysis of 200 ER+ breast tumors detected RAD51AP1-DYRK4 overexpression in 19 tumors (9.5%), which is markedly enriched in the luminal B tumors (17.5%). Ectopic expression of RAD51AP1-DYRK4, but not wild-type RAD51AP1, leads to marked activation of MEK/ERK signaling, and endows increased cell motility and transendothelial migration. More importantly, RAD51AP1-DYRK4 appears to endow increased sensitivity to the MEK inhibitor trametinib through attenuating compensatory activation of HER2/PI3K/AKT under MEK inhibition.

Conclusions:

This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.
Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling
Authors: Dwyer Amy R. , Kerkvliet Carlos Perez , Krutilina Raisa I. , Playa Hilaire C. , Parke Deanna N. , Thomas Warner A. , Smeester Branden A. , Moriarity Branden S. , Seagroves Tiffany N. , Lange Carol A.
Published: November 2020

Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e., via knock-out or add-back) had little effect on primary tumor volume, but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in-frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor–stimulated cell motility relative to SH3-del, KM, or wild-type PTK6 controls. Reverse-phase protein array revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model.

Implications:

The SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC via RhoA and AhR, identified herein as novel therapeutic targets in PTK6+ breast tumors.
Hidradenitis Suppurativa: Proposal of Classification in Two Endotypes with Two-Step Cluster Analysis
Authors: González-Manso Anxo , Agut-Busquet Eugènia , Romaní Jorge , Vilarrasa Eva , Bittencourt Flavia , Mensa Anna , Cantó Elisabeth , Aróstegui Juan I. , Vidal Silvia
Published: November 2020

Introduction: Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent disorder of the pilosebaceous unit. Currently, several attempts have been made to classify this disease according to its pathogenesis and clinical manifestations. We attempted at classifying 103 patients using two-step cluster analysis. Methods: The final model included body mass index, C-reactive protein (CRP), and serum concentrations of IL-1, IL-6, IL-17, and IL-10 as continuous variables, and sex, later/early onset, anterior/posterior lesion sites, presence/absence of sinus tracts, nodules and abscesses, positive/negative history of pilonidal sinus, and presence/absence of mutations in gamma-secretase subunits (APH1A, APH1B, MEFV, NCSTN, PSEN1, PSEN2, PSENEN, PSTPIP1) as qualitative variables. Results: The resultant model defined two groupings or clusters: cluster 1 (64.9% of patients) characterized by nonobese males, with nodular lesions in posterior sites, early-onset HS, higher IL-10, presence of gamma-secretase mutations, and history of pilonidal sinus; and cluster 2 (35.1% of patients) characterized by obese females or males, with lesions in anterior sites, more presence of sinus tracts and abscesses and less nodules, later-onset HS, and higher concentrations of IL-1, CRP, IL-17, and IL-6. Severity measures (Hurley, HS-PGA, and IHS4) and tobacco use were discarded because the analysis found them to be less relevant for clustering. Conclusion: Our resultant model confirms the clinical impression that HS is a disease spectrum with two pathogenic poles defining two clusters or endotypes. The probability of having severe disease was equally distributed in the two clusters. The variable with the highest predictive value for clustering was involvement of typical anterior sites (axillae, submammary) or atypical posterior sites (back, gluteal). Serum concentrations of interleukins, tobacco use, and sex had a lower predictive power for clustering.
Chromosomal Locations of a Non-LTR Retrotransposon, Menolird18, in Cucumis melo and Cucumis sativus, and Its Implication on Genome Evolution of Cucumis Species
Authors: Setiawan Agus B. , Teo Chee H. , Kikuchi Shinji , Sassa Hidenori , Kato Kenji , Koba Takato
Published: November 2020

Mobile elements are major regulators of genome evolution through their effects on genome size and chromosome structure in higher organisms. Non-long terminal repeat (non-LTR) retrotransposons, one of the subclasses of transposons, are specifically inserted into repetitive DNA sequences. While studies on the insertion of non-LTR retrotransposons into ribosomal RNA genes and other repetitive DNA sequences have been reported in the animal kingdom, studies in the plant kingdom are limited. Here, using FISH, we confirmed that Menolird18, a member of LINE (long interspersed nuclear element) in non-LTR retrotransposons and found in Cucumis melo, was inserted into ITS and ETS (internal and external transcribed spacers) regions of 18S rDNA in melon and cucumber. Beside the 18S rDNA regions, Menolird18 was also detected in all centromeric regions of melon, while it was located at pericentromeric and sub-telomeric regions in cucumber. The fact that FISH signals of Menolird18 were found in centromeric and rDNA regions of mitotic chromosomes suggests that Menolird18 is a rDNA and centromere-specific non-LTR retrotransposon in melon. Our findings are the first report on a non-LTR retrotransposon that is highly conserved in 2 different plant species, melon and cucumber. The clear distinction of chromosomal localization of Menolird18 in melon and cucumber implies that it might have been involved in the evolutionary processes of the melon (C. melo) and cucumber (C. sativus) genomes.
Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death
Authors: Rogers Albert J. , Selvalingam Anojan , Alhusseini Mahmood I. , Krummen David E. , Corrado Cesare , Abuzaid Firas , Baykaner Tina , Meyer Christian , Clopton Paul , Giles Wayne , Bailis Peter , Niederer Steven , Wang Paul J. , Rappel Wouter-Jan , Zaharia Matei , Narayan Sanjiv M.
Published: November 2020

Rationale:

Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside.

Objective:

To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes.

Methods and Results:

We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76–1.00) and 0.91 for mortality (95% CI, 0.83–1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF.

Conclusions:

Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.
Thoughts on the Language of Sirach 36:1–22
Authors: Reymond Eric D.
Published: November 2020

Certain words in the prayer of Sir 36:1–22 that appear to be secondary exhibit nationalistic and eschatological tones that are otherwise alien to the book of Ben Sira. These elements likely reflect the interpretation and reading of the text in the course of its transmission in the first millennium CE. In its present form, therefore, the nationalistic/eschatological themes are accented in a way that might not have been the case in earlier versions.
The Hebrew of the Dead Sea Scrolls and the Tiberian Reading Tradition
Authors: Hornkohl Aaron D.
Published: November 2020

The most authentic portrait of Second Temple Hebrew is afforded by the Dead Sea Scrolls, especially by those texts actually composed in Hellenistic and Roman times. On salient linguistic points Dead Sea Scrolls Hebrew agrees with the vocalization of the Tiberian reading tradition against the testimony of the written, i.e., consonantal, tradition of Masoretic Classical Biblical Hebrew material. This article presents a case study. On the one hand, these Dead Sea-Tiberian vocalization affinities are evidence of the relatively late character of their respective linguistic traditions and of the secondary character of the developments in the Tiberian reading tradition vis-à-vis the classical biblical written tradition. On the other hand, these same affinities demonstrate that the Tiberian pronunciation tradition is plausibly regarded as one that crystallized in the Second Temple Period, rather than in Byzantine or medieval times. Lastly, since joint Dead Sea-Tiberian reading departures from the classical biblical consonantal tradition constitute a tiny minority of their relevant linguistic data, most of which are characterized by historical continuity and/or linguistic heterogeneity of comparable historical depth, it is clear that the Second Temple crystallization of Dead Sea Scrolls Hebrew and the Tiberian reading tradition in no way preclude their routine preservation of authentic Iron Age features.
Is There a Negative Polarity Item ‮דבר‬‎ in DSS Hebrew?
Authors: Moshavi Adina
Published: November 2020

A negative polarity item (NPI) is a word or expression that occurs grammatically in negative clauses and a variety of other types of clauses such as interrogatives and conditionals, but not in ordinary affirmative sentences. Examples from classical Biblical Hebrew include the pronoun ‮מאומה‬‎ “anything” and the semantically-bleached noun ‮דבר‬‎ “a thing,” which has been produced from the ordinary noun ‮דבר‬‎ “word, matter, action” by the process of grammaticalization. This paper examines the noun ‮דבר‬‎ in the non-biblical DSS with the purpose of determining whether it is used as there as an NPI, as in Biblical Hebrew, or as an ordinary semantically-bleached noun, as in Rabbinic Hebrew. The results show that the diachronic development of ‮דבר‬‎ in the DSS appears to be at an earlier stage than classical Biblical Hebrew, despite the later dating of the scrolls. This finding is explained as a special kind of pseudo-classicism.
Distribution of gamma-aminobutyric acid (GABA) in the central nervous system of the male mud crab, Scylla olivacea
Authors: Khornchatri Kanjana , Saetan Jirawat , Mukem Sirirak , Sobhon Prasert , Thongbuakaew Tipsuda
Published: November 2020

Gamma-aminobutyric acid (GABA) is a neurotransmitter that is widely spread in vertebrate and invertebrate nervous systems and modulates essential physiological roles. Previous studies have reported the distribution of several neurotransmitters throughout the central nervous system (CNS) of decapod crustaceans. However, the existence and distribution of GABA in the mud crab’s, Scylla olivacea, CNS has still not been reported. In this study, we investigated the distribution of GABA using immunohistochemistry. The result revealed that GABA immunoreactivity (-ir) was observed in neurons and fibres throughout the CNS, including the eyestalk, brain, and ventral nerve cord of S. olivacea. Therefore, the existence and extensive distribution pattern of GABA in the CNS of the male mud crab suggest its possible roles in feeding, locomotion, and also reproduction.
A new record of Porcellana persica Haig, 1966 (Decapoda, Anomura, Porcellanidae) from the Arabian Sea, India
Authors: Josileen Jose , Maheswarudu G. , Jinesh P. T. , Sreesanth L. , Ragesh N. , Lakshmi Pillai S.
Published: November 2020

Porcellana persica Haig, 1966 was collected from off the Kerala coast, Arabian Sea, India. This is the first record of both the genus and the species from Indian waters. The taxonomic characters are similar to the findings of Haig (1966), who described the species, and possibly this is the first detailed report on the species after her original description.
Innovation-Supporting Effect of Government Versus Private Venture Capital: Evidence from Chinese Listed Companies
Authors: Tao Xiaohui , Li Yang
Published: November 2020

Venture capital (VC) can promote the innovation of invested enterprises through financial support, social networking, and intellectual capital. Based on data of Chinese listed companies from 2003 to 2016, this study, firstly, compares the impact of government and private VC on enterprise innovation using Possion regression, and applies the ITCV method and Negative Binomial Regression for Robustness Examination, then, explores the relationship between their shareholding percentage and enterprise innovation with threshold test. The results show that: the performance of private VC is significantly positive and in line. With the increasing shareholding percentage of private VC, the innovation of invested enterprises increases. The overall performance of government VC, however, is not significant, and the shareholding percentage of government VC also has no significant impact on the innovation of invested companies. Additional testing revealed that a “threshold effect” however exists in the impact of the shareholding percentage of government VC on innovation: within a certain range, the higher the shareholding percentage, the more significant the impact on innovations becomes, but beyond that range, the percentage is inversely related to innovation.
Inscribed Spherical Agate Gemstone from the Anapa Region Revisited
Authors: Andreeva Eugenia N.
Published: November 2020

The paper focuses on one very unusual magical object originating from the territory of the Bosporan kingdom: an agate stone amulet with a rather extensive inscription found in the vicinity of ancient Gorgippia. The author summarizes the history of scholarly discussion on the subject and analyses Chr. Faraone’s “magical handbook” hypothesis putting forward some arguments against it. The paper not only revisits the reading of the text, but treats the artefact as a unity of the material object and the inscription there upon.
Non-Urban Societies of the Crimea and Their Response to Changes in the External World
Authors: Mordvintseva Valentina I.
Published: November 2020

The paper presents a comparative analysis of burial assemblages of ‘barbarian’ élites located on the territory of the Crimea between Chersonesos Taurica and the Bosporan kingdom dating from the 3rd century BC to the mid-3rd century AD. The main goal of the research is to define indications of self-identities of the Crimean non-urban societies represented by their élites and to outline their networking inside and outside the peninsula as well as their changes during four chronological periods. The research is based on the precondition that networking in the political sphere is closely connected to the exchange of symbols of power and status. In material culture, such symbols might be represented by the so-called ‘prestige objects’. Changes in the assortment of these items observed over a long time-span are helping to visualize the development of internal and external relationships of social élites.
Scythian Leather Quiver from Bulgakovo
Authors: Daragan Marina N.
Published: November 2020

What were items of Scythian archer’s equipment? What materials were used, and how were they produced? These issues remain currently practically unknown. Objects made from organic materials (wood, leather, and textile) in Scythian burials are lost or provide little information. For this reason almost nothing about Scythian archery equipment (bow and quiver) has been known for a long time. This article describes and analyzes the only well preserved quiver found in the Scythian burial of the 4th century BC in the North Pontic Region. The details of a leather quiver bag, a wooden stiffening plate, wooden painted arrows with bronze arrowheads have survived.
A Man against a War: Rui Barbosa and the Struggle against a Thought
Authors: de Macedo Paulo Emílio Vauthier , Araújo Brenda Maria Ramos
Published: November 2020

This article aims to demonstrate that Rui Barbosa’s role at the Hague Peace Conference of 1907 and his speech at the Buenos Aires Law School, in 1916, are a continuum. On both occasions, he not only defended the same principles, the rule of law over force and the juridical equality of nations, and mainly, fought the same enemy: a doctrine, the ‘Borussian militarist doctrine’. From the standpoint of a contextualist historiography, this text recreates that struggle. This work employs the inductive method of approach as well as primary and secondary bibliographical sources.
Best Practices in Track Two Diplomacy
Authors: Jones Peter
Published: November 2020

While “Track Two Diplomacy” has been intensively researched since its founding some 60 years ago, much remains to be done to explore important gaps in our understanding of these dialogues. Track Two presents unusual research problems, given its operational and often confidential nature. The contributions to this special issue of International Negotiation tackle some of the key issues confronting the field in an effort to present where we stand in terms of best practices and where further thought and research is required.
Karl Barth’s Christological Ecclesiology: A Historical Development
Authors: Yang Jae
Published: November 2020

This paper traces the historical development of Karl Barth’s ecclesiology by analysing three representative works: The Epistle to the Romans, the Göttingen Dogmatics, and the Church Dogmatics. It argues that Barth’s theological turning point was a shift away from an early period Christology, which emphasised an eschatological time/eternity dialectic, culminating in the resurrection, towards a Christology that emphasised the anhypostatic union of Christ’s two natures, that culminated in the incarnation. Thus Barth gave an increasingly positive valuation of the church as an historical institution.
東河賽夏語中客語、閩南語和日語借詞之音韻探討
Authors: 改擺刨 菈露打赫斯 , 林 鴻瑞 , 齊 莉莎
Published: November 2020

本文從音韻的觀點針對東河賽夏語中客語、閩南語及日語借詞展開更全面的比較研究。研究發現賽夏語的借音共15個，包括13個輔音以及2個元音。客語詞彙大量借入賽夏語，影響最深，除了來自日語的借音/d, g, z/ 外，客語概括閩南語和日語對賽夏語語音系統的影響。

本文也檢視及比較了在賽夏語中借詞所主導之音節結構的規則。客語和閩南語的規則相同，而日語的規則則有些不同。客語和閩南語單音節詞，借進賽夏語之後，為了符合實詞雙音節以上的規律，發生音節重整。日語單音節借詞借進賽夏語之後直接重疊。客語、閩南語與日語元音起首音節，借進賽夏語之後，為了符合賽夏語輔音起首之原則，自動加上喉塞音。客語與閩南語音節元音結尾，無論在第一音節或是第二音節，皆會元音延長；日語的規則則不同，第一音節不變，在第二音節會加上喉塞音。

最後，本文發現有些借詞同時來自客語、閩南語和／或日語造成有雙式借詞或三式借詞，須仔細地辨認每個借詞的來源，同時需要考量許多複雜的因素，包括發音人對不同語言熟悉度、借音以及音節結構的規則。