bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of the plasma treatment effect on PET with a newly designed atmospheric pressure plasma jet
Authors: Onyshchenko Iuliia , De Geyter Nathalie , Morent Rino
Published: June 2017

In this work, two different plasma jet designs (typical design and with geometrical modification) operating in argon are used to examine the influence of the additional plate on the created hydrophilic polyethylene terephthalate (PET) region. The surface analyses techniques (contact angle measurements and X‐ray photoelectron spectroscopy [XPS]) clearly show that the introduction of an additional plate in the plasma jet set‐up only has a significant impact on the hydrophilic footprint when using a small capillary‐sample distance of 2 mm. Comsol Multiphysics is used to explain the effect of the plasma jet design modification on the hydrophilic footprint. The simulations reveal a completely different gas flow pattern for the set‐up with the modified geometry.
Powder selection for hydrothermally processed sol–gel composite barium strontium titanate capacitors
Authors: Po Justin , Sayer Michael , Freundorfer Alois , Simpson Eric
Published: June 2017

Ba0.7Sr0.3TiO3 (BST) capacitors for high frequency circuits have been fabricated at 175 °C on epoxy‐based copper‐clad printed circuit boards, having a glass transition temperature of ∼200 °C by hydrothermal processing of dried BST acetate‐based sol–gel powder slurries. The film thickness was 2–10 μm. BST powders were prepared respectively as ceramic derived powders processed from oxide mixtures fired to 1100 °C, sol–gel derived powders fired to 750 and 1100 °C, and a low temperature solution process dried at 500 °C. The performance of the capacitor was determined by both the dielectric properties of the powder and the interaction between the crystallizing gel and the powder surface. High relative permittivity is obtained for sol–gel derived powders fired to 750 °C, while high voltage tunability is a characteristic of the ceramic derived powders. Low temperature powders are ineffective. The difference is attributed to the nature of the crystalline interface formed between the surface of the powder particles and the hydrothermally crystallized BST formed from the dried gel within the composite. The optimum molar concentration of the hydrothermal solution was 0.1 M with a Ba content larger than that of the powder. Capacitor composites having a relative permittivity of up to 300 at 20 MHz were demonstrated.
Manganese‐Mediated Homolytic Aromatic Substitution with Phosphinylidenes
Authors: Berger Olivier , Montchamp Jean‐Luc
Published: June 2017

Carbon‐phosphorus (C−P) bond‐forming reactions via homolytic aromatic substitution (HAS) of non‐functionalized substrates with phosphinylidene P(O)H compounds is becoming a useful synthetic tool for the preparation of aryl and heteroaryl phosphonates, phosphinates, and phosphine oxides. This review specifically covers recent work using manganese‐mediated free radical processes. Several research groups employ expensive Mn(OAc)3, whereas our own contributions focus on the novel and inexpensive Mn(OAc)2/MnO2 system.
Health Reform in the South: Re‐Tracing Robert Kennedy's Steps in Mississippi and Kentucky
Authors: Jones David K.
Published: June 2017

It has been nearly 50 years since Robert Kennedy's iconic trips to the Mississippi Delta (1967) and Appalachian Kentucky (1968). What he found shocked him. “It's unacceptable in this country that we should have this kind of poverty. And I think we need to do something about it.” This paper explores whether the conditions that produce health have improved in these two areas 50 years later. Are people healthier? A comparative case study examining health in these two regions is a unique way to understand the progress and shortcomings of the Affordable Care Act (ACA). I use the social ecological framework as a guide to focus on the social determinants of health in two of the least healthy places in the United States. Access to insurance and medical care is important, but will not produce health if housing is unsafe, food systems are inadequate, and poverty remains pervasive.
Correlates of Cervical Cancer Screening Among Adult Latino Women: A 5‐Year Follow‐Up
Authors: Rojas Patria , Li Tan , Ravelo Gira J. , Dawson Christyl , Sanchez Mariana , Sneij Alicia , Wang Weize , Kanamori Mariano , Cyrus Elena , De La Rosa Mario R.
Published: June 2017

Background: Latinas have the highest incidence rates of cervical cancer in the United States, and Latinas in the United States are less likely to utilize cervical cancer screening. We used secondary data analysis of a nonclinical convenience sample (n = 316 women at baseline; n = 285 at 5‐year follow‐up) to examine correlates of cervical cancer screening among adult Latina women. Univariate and multiple logistic regression models using generalized estimated equations (GEE) algorithm were utilized to assess the influence of the independent variables. Women who reported their main health‐care source as community health clinics, women who were sexually active, and women who reported that a health‐care provider discussed HIV prevention with them were more likely to report having had a cervical cancer screening (aOR = 2.06; CI = 1.20, 3.52). The results suggest a need for continued efforts to ensure that medically underserved women (e.g., Latina women) receive counseling and education about the importance of preventive cervical cancer screening.
Surgical Human Resources According to Types of Health Care Facility: An Assessment in Low‐ and Middle‐Income Countries
Authors: Sheik Ali Shirwa , Jaffry Zahra , Cherian Meena N. , Kunjumen Teena , Nkwowane Annette M. , Leather Andrew J. M. , Von Muhlenbrock Hernan Montenegro , Kelley Edward , Campbell James
Published: June 2017

Background

A robust health care system providing safe surgical care to a population can only be achieved in conjunction with access to competent surgical personnel. It has been reported that 5 billion people do not have access to safe, affordable surgical and anaesthesia care when needed. This study aims to fill the existing gap in evidence by quantifying shortfalls in trained personnel delivering safe surgical and anaesthetic care in low‐ and middle‐income countries (LMICs) according to the type of health care facility.

Methods

We conducted secondary analysis of 1323 health facilities, in 35 low‐ and middle‐income countries using facility‐based cross‐sectional data from the World Health Organization Situational Analysis Tool to Assess Emergency and Essential Surgical Care.

Results

The majority of surgical and anaesthetic care in LMICs was provided by general doctors (range 13.8–41.1%; mean 27.1%). Non‐physicians made up a significant proportion of the surgical workforce in LMICs. 26.76% of the surgical and anaesthetic workforce was provided by clinical medical officers and nurses. Private/NGO/mission hospitals, large, well‐resourced institutions had the highest proportion of surgeons compared to any other type of health care facility at 27.92%. This compares to figures of 18.2 and 19.96% of surgeons at health centres and subdistrict/community hospitals, respectively, representing the lowest level of health facility.

Conclusions

We highlight the significant proportion of non‐physicians delivering surgical and anaesthetic care in LMICs and illustrate wide variations according to the type of health care facility.
The Advent of Ultra‐high Volume Thoracic Surgical Centers in Shanghai
Authors: Sihoe Alan D. L. , Han Baohui , Yang Timothy Y. , Pan Changqing , Jiang Gening , Fang Vincent W. T.
Published: June 2017

Background

A core principle in surgery is that high surgical volumes are conducive toward better outcomes. Ultra‐high volume centers (UHVCs) have now emerged in thoracic surgery in China that now perform a volume of thoracic operations far greater than even traditional international centers of excellence.

Methods

In 2016, two hospitals in Shanghai performed over 10,000 major pulmonary, esophageal and mediastinal resections each. A qualitative analysis of the lessons learned in achieving such large operation volumes was undertaken.

Results

The advent of these UHVCs gives important insights for not only thoracic surgeons, but for surgical oncologists and surgeons globally. First, these ultra‐high volumes were achieved to a large degree by cancer screening—but the success of the screening programs relies on reaching wider patient groups and allowing for affordable ‘self‐screening.’ Second, the ultra‐high clinical volumes at UHVCs offer unique opportunities for surgical training and research, potentially changing paradigms for academic surgery. Third, these ultra‐high volumes may place new stresses on existing healthcare resources and prompt novel management strategies in response.

Conclusions

The UHVCs represent a revolutionary development in modern surgery, and it behooves surgeons to both accept the challenges and harness the advantages they may bring.
Diffusion-weighted imaging for assessment of synovial inflammation in juvenile idiopathic arthritis: a promising imaging biomarker as an alternative to gadolinium-based contrast agents
Authors: Barendregt Anouk M. , van Gulik E. Charlotte , Lavini Cristina , Nusman Charlotte M. , van den Berg J. Merlijn , Schonenberg-Meinema Dieneke , Dolman Koert M. , Kuijpers Taco W. , Hemke Robert , Maas Mario
Published: June 2017

Objectives

To compare dynamic-contrast-enhanced MRI (DCE) and diffusion-weighted imaging (DWI) in quantifying synovial inflammation in juvenile idiopathic arthritis (JIA).

Methods

Regions of interest (ROI) were drawn in the synovium of JIA patients on T1 DCE and T2 DWI, followed by extraction of the maximum enhancement (ME), maximum initial slope (MIS), time to peak (TTP), % of different time intensity curve shapes (TIC) and apparent diffusion coefficient (ADC) of the ROIs. Mann-Whitney-U test was used for comparing parameters between MRI-active and -inactive patients (defined by the juvenile arthritis MRI scoring system). Spearman’s rank was used to analyse the correlation between DCE and DWI.

Results

Thirty-five JIA patients (18 MRI active and 17 MRI inactive) were included. Median age was 13.1 years and 71% were female. ME, MIS, TTP, % TIC 5 and ADC were significantly different in MRI-active versus MRI-inactive JIA with median ADC 1.49 × 10-3mm2/s in MRI-active and 1.25 × 10-3mm2/s in MRI-inactive JIA, p = 0.001, 95% confidence interval of difference in medians =0.11-0.53 × 10-3mm2/s. ADC correlated to ME, MIS and TIC 5 shapes (r = 0.62, r = 0.45, r = -0.51, respectively, all p < 0.05).

Conclusions

Similar to DCE parameters, DWI-derived ADC is significantly different in MRI-active JIA as compared to MRI-inactive JIA. The non-invasiveness of DWI combined with its possibility to detect synovial inflammation shows the potential of DWI.

Key Points

• MRI can quantify: dynamic contrast-enhanced and diffusion-weighted MRI can quantify synovitis

• Both DWI and DCE can differentiate active from inactive JIA

• The DWI-derived apparent diffusion coefficient (ADC) is higher in active JIA

• DWI is non-invasive and thus safer and more patient-friendly

• DWI is a potentially powerful and non-invasive imaging biomarker for JIA
Meta-Analysis and the Myth of Generalizability
Authors: Tett Robert P. , Hundley Nathan A. , Christiansen Neil D.
Published: June 2017

Rejecting situational specificity (SS) in meta-analysis requires assuming that residual variance in observed correlations is due to uncorrected artifacts (e.g., calculation errors). To test that assumption, 741 aggregations from 24 meta-analytic articles representing seven industrial and organizational (I-O) psychology domains (e.g., cognitive ability, job interviews) were coded for moderator subgroup specificity. In support of SS, increasing subgroup specificity yields lower mean residual variance per domain, averaging a 73.1% drop. Precision in mean rho (i.e., low SD(rho)) adequate to permit generalizability is typically reached at SS levels high enough to challenge generalizability inferences (hence, the “myth of generalizability”). Further, and somewhat paradoxically, decreasingKwith increasing precision undermines certainty in meanrand Var(r) as meta-analytic starting points. In support of the noted concerns, only 4.6% of the 741 aggregations met defensibly rigorous generalizability standards. Four key questions guiding generalizability inferences are identified in advancing meta-analysis as a knowledge source.
Politics and Health at the WHO Regional Office for South East Asia: The Case of Portuguese India, 1949–61
Authors: Saavedra Monica
Published: June 2017

This paper analyses how the 1950–61 conflict between Portugal and India over the territories that constituted Portuguese India (Goa, Daman and Diu) informed Portugal’s relations with the World Health Organization’s Regional Office for South East Asia (SEARO). The ‘Goa question’ determined the way international health policies were actually put into place locally and the meaning with which they were invested. This case study thus reveals the political production of SEARO as a dynamic space for disputes and negotiations between nation-states in decolonising Asia. In this context, health often came second in the face of contrasting nationalistic projects, both colonial and post-colonial.
Medical Experts and Agnotology in the Fumes Controversy of the Huelva Copper Mines (1888–1890)
Authors: Guillem-Llobat Ximo
Published: June 2017

Huelva’s copper mines (Spain) have been active for centuries but in the second half of the nineteenth century extractive activities in Riotinto, Tharsis, and other mines in the region were intensified in order to reach world leadership. The method used in these mines for copper extraction from low grade ores generated continuous emissions of fumes that were extremely controversial. The inhabitants had complained about the fumes for decades but as activity intensified so did complaints. The killing of anti-fumes demonstrators in 1888 led to the passing of a Royal Decree banning the open-air roasting of ore and to the drafting of numerous reports on the hazards of the fumes. Major state and provincial medical institutions, as well as renowned hygienists and engineers, took part in the assessment, contributing to a scientific controversy especially rich in content. In my paper I will analyse the production and circulation of knowledge and ignorance about the impact of fumes on public health, as well as the role of medical experts and expertise in the controversy. The analysis will focus on the reports drafted between the 1888 ban and its 1890 repeal, and will show the changing nature of the expert assessment and the numerous paths followed by experts in producing ignorance. The paper will conclude by considering other stakeholders, who may shed some light on the reasons behind the performance of the medical experts.
Lifespans of the European Elite, 800–1800
Authors: Cummins Neil
Published: June 2017

I analyze the adult age at death of 115,650 European nobles from 800 to 1800. Longevity began increasing long before 1800 and the Industrial Revolution, with marked increases around 1400 and again around 1650. Declines in violent deaths from battle contributed to some of this increase, but the majority must reflect other changes in individual behavior. There are historic spatial contours to European elite mortality; Northwest Europe achieved greater adult lifespans than the rest of Europe even by 1000ad.
Common Tongue: The Impact of Language on Educational Outcomes
Authors: Jain Tarun
Published: June 2017

This article investigates the impact of official language policies on education using state formation in India. Colonial provinces consisted of some districts where the official language matched the district's language and some where it did not. Linguistically mismatched districts have 18.0 percent lower literacy rates and 20.1 percent lower college graduation rates, driven by difficulty in acquiring education due to a different medium of instruction in schools. Educational achievement caught up in mismatched districts after the 1956 reorganization of Indian states on linguistic lines, suggesting that political reorganization can mitigate the impact of mismatched language policies.
Start-up Nation? Slave Wealth and Entrepreneurship in Civil War Maryland
Authors: González Felipe , Marshall Guillermo , Naidu Suresh
Published: June 2017

Slave property rights yielded a source of collateral as well as a coerced labor force. Using data from Dun and Bradstreet linked to the 1860 census and slave schedules in Maryland, we find that slaveowners were more likely to start businesses prior to the uncompensated 1864 emancipation, even conditional on total wealth and human capital, and this advantage disappears after emancipation. We assess a number of potential explanations, and find suggestive evidence that this is due to the superiority of slave wealth as a source of collateral for credit rather than any advantage in production. The collateral dimension of slave property magnifies its importance to historical American economic development.
Invasive alien species on islands: impacts, distribution, interactions and management
Authors: RUSSELL JAMES C. , MEYER JEAN-YVES , HOLMES NICK D. , PAGAD SHYAMA
Published: June 2017

Invasive alien species (IASs) on islands have broad impacts across biodiversity, agriculture, economy, health and culture, which tend to be stronger than on continents. Across small-island developing states (SIDSs), although only a small number of IASs are widely distributed, many more, including those with greatest impact, are found on only a small number of islands. Patterns of island invasion are not consistent across SIDS geographic regions, with differences attributable to correlated patterns in island biogeography and human development. We identify 15 of the most globally prevalent IASs on islands. IAS impacts on islands are exacerbated through interactions with a number of other global change threats, including over-exploitation, agricultural intensification, urban development and climate change. Biosecurity is critical in preventing IAS invasion of islands. Eradication of IASs on islands is possible at early stages of invasion, but otherwise is largely restricted to invasive mammals, or otherwise control is the only option. Future directions in IAS management and research on islands must consider IASs within a broader portfolio of threats to species, ecosystems and people's livelihoods on islands. We advocate for stronger collaborations among island countries and territories faced with the same IASs in similar socio-ecological environments.
Gender, Diversity, and Methods in Political Science: A Theory of Selection and Survival Biases
Authors: Shames Shauna L. , Wise Tess
Published: June 2017

At a recent major political science conference, Tamara (not her real name) presented an in-depth qualitative study several years in the making, only to have the panelist speaking after her begin his remarks by saying, “And now back to the hard-core data.” By this, he meant quantitative, large-n data, which his work utilized. This moment highlights a series of tensions in our field relating to gender and methodology, and their effects, which this article explores and elucidates.
Hierarchical porous carbons with layer-by-layer motif architectures from confined soft-template self-assembly in layered materials
Authors: Wang Jie , Tang Jing , Ding Bing , Malgras Victor , Chang Zhi , Hao Xiaodong , Wang Ya , Dou Hui , Zhang Xiaogang , Yamauchi Yusuke
Published: June 2017

Although various two-dimensional (2D) nanomaterials have been explored as promising capacitive materials due to their unique layered structure, their natural restacking tendency impedes electrolyte transport and significantly restricts their practical applications. Herein, we synthesize all-carbon layer-by-layer motif architectures by introducing 2D ordered mesoporous carbons (OMC) within the interlayer space of 2D nanomaterials. As a proof of concept, MXenes are selected as 2D hosts to design 2D–2D heterostructures. Further removing the metal elements from MXenes leads to the formation of all-carbon 2D–2D heterostructures consisting of alternating layers of MXene-derived carbon (MDC) and OMC. The OMC layers intercalated with the MDC layers not only prevent restacking but also facilitate ion diffusion and electron transfer. The performance of the obtained hybrid carbons as supercapacitor electrodes demonstrates their potential for upcoming electronic devices. This method allows to overcome the restacking and blocking of 2D nanomaterials by constructing ion-accessible OMC within the 2D host material.
In-beam measurement of the hydrogen hyperfine splitting and prospects for antihydrogen spectroscopy
Authors: Diermaier M. , Jepsen C. B. , Kolbinger B. , Malbrunot C. , Massiczek O. , Sauerzopf C. , Simon M. C. , Zmeskal J. , Widmann E.
Published: June 2017

Antihydrogen, the lightest atom consisting purely of antimatter, is an ideal laboratory to study the CPT symmetry by comparison with hydrogen. With respect to absolute precision, transitions within the ground-state hyperfine structure (GS-HFS) are most appealing by virtue of their small energy separation. ASACUSA proposed employing a beam of cold antihydrogen atoms in a Rabi-type experiment, to determine the GS-HFS in a field-free region. Here we present a measurement of the zero-field hydrogen GS-HFS using the spectroscopy apparatus of ASACUSA’s antihydrogen experiment. The measured value of νHF=1,420,405,748.4(3.4) (1.6) Hz with a relative precision of 2.7 × 10−9 constitutes the most precise determination of this quantity in a beam and verifies the developed spectroscopy methods for the antihydrogen HFS experiment to the p.p.b. level. Together with the recently presented observation of antihydrogen atoms 2.7 m downstream of the production region, the prerequisites for a measurement with antihydrogen are now available within the ASACUSA collaboration.
The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites
Authors: Ha Kyungsoo , Ma Chengxian , Lin Han , Tang Lichun , Lian Zhusheng , Zhao Fang , Li Ju-Mei , Zhen Bei , Pei Huadong , Han Suxia , Malumbres Marcos , Jin Jianping , Chen Huan , Zhao Yongxiang , Zhu Qing , Zhang Pumin
Published: June 2017

Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). While HDR can only occur in S/G2, NHEJ can happen in all cell cycle phases (except mitosis). How then is the repair choice made in S/G2 cells? Here we provide evidence demonstrating that APCCdh1 plays a critical role in choosing the repair pathways in S/G2 cells. Our results suggest that the default for all DSBs is to recruit 53BP1 and RIF1. BRCA1 is blocked from being recruited to broken ends because its recruitment signal, K63-linked poly-ubiquitin chains on histones, is actively destroyed by the deubiquitinating enzyme USP1. We show that the removal of USP1 depends on APCCdh1 and requires Chk1 activation known to be catalysed by ssDNA-RPA-ATR signalling at the ends designated for HDR, linking the status of end processing to RIF1 or BRCA1 recruitment.
Pyrazinamide and derivatives block ethylene biosynthesis by inhibiting ACC oxidase
Authors: Sun Xiangzhong , Li Yaxin , He Wenrong , Ji Chenggong , Xia Peixue , Wang Yichuan , Du Shuo , Li Hongjiang , Raikhel Natasha , Xiao Junyu , Guo Hongwei
Published: June 2017

Ethylene is an important phytohormone that promotes the ripening of fruits and senescence of flowers thereby reducing their shelf lives. Specific ethylene biosynthesis inhibitors would help to decrease postharvest loss. Here, we identify pyrazinamide (PZA), a clinical drug used to treat tuberculosis, as an inhibitor of ethylene biosynthesis in Arabidopsis thaliana, using a chemical genetics approach. PZA is converted to pyrazinecarboxylic acid (POA) in plant cells, suppressing the activity of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), the enzyme catalysing the final step of ethylene formation. The crystal structures of Arabidopsis ACO2 in complex with POA or 2-Picolinic Acid (2-PA), a POA-related compound, reveal that POA/2-PA bind at the active site of ACO, preventing the enzyme from interacting with its natural substrates. Our work suggests that PZA and its derivatives may be promising regulators of plant metabolism, in particular ethylene biosynthesis.
Identification of the elementary structural units of the DNA damage response
Authors: Natale Francesco , Rapp Alexander , Yu Wei , Maiser Andreas , Harz Hartmann , Scholl Annina , Grulich Stephan , Anton Tobias , Hörl David , Chen Wei , Durante Marco , Taucher-Scholz Gisela , Leonhardt Heinrich , Cardoso M. Cristina
Published: June 2017

Histone H2AX phosphorylation is an early signalling event triggered by DNA double-strand breaks (DSBs). To elucidate the elementary units of phospho-H2AX-labelled chromatin, we integrate super-resolution microscopy of phospho-H2AX during DNA repair in human cells with genome-wide sequencing analyses. Here we identify phospho-H2AX chromatin domains in the nanometre range with median length of ∼75 kb. Correlation analysis with over 60 genomic features shows a time-dependent euchromatin-to-heterochromatin repair trend. After X-ray or CRISPR-Cas9-mediated DSBs, phospho-H2AX-labelled heterochromatin exhibits DNA decondensation while retaining heterochromatic histone marks, indicating that chromatin structural and molecular determinants are uncoupled during repair. The phospho-H2AX nano-domains arrange into higher-order clustered structures of discontinuously phosphorylated chromatin, flanked by CTCF. CTCF knockdown impairs spreading of the phosphorylation throughout the 3D-looped nano-domains. Co-staining of phospho-H2AX with phospho-Ku70 and TUNEL reveals that clusters rather than nano-foci represent single DSBs. Hence, each chromatin loop is a nano-focus, whose clusters correspond to previously known phospho-H2AX foci.
CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome
Authors: Bürgi Jérôme , Kunz Béatrice , Abrami Laurence , Deuquet Julie , Piersigilli Alessandra , Scholl-Bürgi Sabine , Lausch Ekkehart , Unger Sheila , Superti-Furga Andrea , Bonaldo Paolo , van der Goot F. Gisou
Published: June 2017

Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/ANTXR2), a transmembrane surface protein, cause hyaline fibromatosis syndrome (HFS), a severe genetic disorder that is characterized by large subcutaneous nodules, gingival hypertrophy and severe painful joint contracture. Here we show that CMG2 is an important regulator of collagen VI homoeostasis. CMG2 loss of function promotes accumulation of collagen VI in patients, leading in particular to nodule formation. Similarly, collagen VI accumulates massively in uteri of Antxr2−/− mice, which do not display changes in collagen gene expression, and leads to progressive fibrosis and sterility. Crossing Antxr2−/− with Col6a1−/− mice leads to restoration of uterine structure and reversion of female infertility. We also demonstrate that CMG2 may act as a signalling receptor for collagen VI and mediates its intracellular degradation.
Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth
Authors: Kershaw R M , Roberts D , Wragg J , Shaaban A M , Humphreys E , Halsall J , Price L , Bicknell R , Gaston K , Jayaraman P-S
Published: June 2017

Breast tumours progress from hyperplasia to ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). PRH/HHEX (proline-rich homeodomain/haematopoietically expressed homeobox) is a transcription factor that displays both tumour suppressor and oncogenic activity in different disease contexts; however, the role of PRH in breast cancer is poorly understood. Here we show that nuclear localization of the PRH protein is decreased in DCIS and IBC compared with normal breast. Our previous work has shown that PRH phosphorylation by protein kinase CK2 prevents PRH from binding to DNA and regulating the transcription of multiple genes encoding growth factors and growth factor receptors. Here we show that transcriptionally inactive phosphorylated PRH is elevated in DCIS and IBC compared with normal breast. To determine the consequences of PRH loss of function in breast cancer cells, we generated inducible PRH depletion in MCF-7 cells. We show that PRH depletion results in increased MCF-7 cell proliferation in part at least due to increased vascular endothelial growth factor signalling. Moreover, we demonstrate that PRH depletion increases the formation of breast cancer cells with cancer stem cell-like properties. Finally, and in keeping with these findings, we show that PRH overexpression inhibits the growth of mammary tumours in mice. Collectively, these data indicate that PRH plays a tumour suppressive role in the breast and they provide an explanation for the finding that low PRH mRNA levels are associated with a poor prognosis in breast cancer.
MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells
Authors: Rattanasinchai C , Llewellyn B J , Conrad S E , Gallo K A
Published: June 2017

Mixed-lineage kinase 3 (MLK3), a mitogen-activated protein kinase kinase kinase (MAP3K), has critical roles in metastasis of triple-negative breast cancer (TNBC), in part by regulating paxillin phosphorylation and focal adhesion turnover. However the mechanisms and the distinct step(s) of the metastatic processes through which MLK3 exerts its influence are not fully understood. Here we report that in non-metastatic, estrogen receptor-positive breast cancer (ER+ BC) cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), which is accompanied by elevation of matrix metalloproteinases (MMPs), MMP-1 and MMP-9. MLK3-induced ER+ BC cell invasion is abrogated by FRA-1 silencing, demonstrating that MLK3 drives invasion through FRA-1. Conversely, in metastatic TNBC models, high FRA-1 levels are significantly reduced upon depletion of MLK3 by either gene silencing or by the CRISPR/Cas9n editing approach. Furthermore, ablation of MLK3 or MLK inhibitor treatment decreases expression of both MMP-1 and MMP-9. Consistent with the role of tumor cell-derived MMP-1 in endothelial permeability and transendothelial migration, both of these are reduced in MLK3-depleted TNBC cells. In addition, MLK inhibitor treatment or MLK3 depletion, which downregulates MMP-9 expression, renders TNBC cells defective in Matrigel invasion. Furthermore, circulating tumor cells derived from TNBC-bearing mice display increased levels of FRA-1 and MMP-1 compared with parental cells, supporting a role for the MLK3–FRA-1–MMP-1 signaling axis in vascular intravasation. Our results demonstrating the requirement for MLK3 in controlling the FRA-1/MMPs axis suggest that MLK3 is a promising therapeutic target for treatment of TNBC.
Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons
Authors: Allette Yohance M. , Kim Youngsook , Randolph Aaron L. , Smith Jared A. , Ripsch Matthew S. , White Fletcher A.
Published: June 2017

Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.
Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis
Authors: Maver Ales , Lavtar Polona , Ristić Smiljana , Stopinšek Sanja , Simčič Saša , Hočevar Keli , Sepčić Juraj , Drulović Jelena , Pekmezović Tatjana , Novaković Ivana , Alenka Hodžić , Rudolf Gorazd , Šega Saša , Starčević-Čizmarević Nada , Palandačić Anja , Zamolo Gordana , Kapović Miljenko , Likar Tina , Peterlin Borut
Published: June 2017

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.
Natural variation in Arabidopsis thaliana Cd responses and the detection of quantitative trait loci affecting Cd tolerance
Authors: Fischer Sina , Spielau Thomas , Clemens Stephan
Published: June 2017

Metal tolerance is often a result of metal storage or distribution. Thus, with the goal of advancing the molecular understanding of such metal homeostatic mechanisms, natural variation of metal tolerance in Arabidopsis thaliana was investigated. Substantial variation exists in tolerance of excess copper (Cu), zinc (Zn) and cadmium (Cd). Two accessions, Col-0 and Bur-0, and a recombinant inbred line (RIL) population derived from these parents were chosen for further analysis of Cd and Zn tolerance variation, which is evident at different plant ages in various experimental systems and appears to be genetically linked. Three QTLs, explaining in total nearly 50% of the variation in Cd tolerance, were mapped. The one obvious candidate gene in the mapped intervals, HMA3, is unlikely to contribute to the variation. In order to identify additional candidate genes the Cd responses of Col-0 and Bur-0 were compared at the transcriptome level. The sustained common Cd response of the two accessions was dominated by processes implicated in plant pathogen defense. Accession-specific differences suggested a more efficient activation of acclimative responses as underlying the higher Cd tolerance of Bur-0. The second hypothesis derived from the physiological characterization of the accessions is a reduced Cd accumulation in Bur-0.
High-throughput mass spectrometry analysis revealed a role for glucosamine in potentiating recovery following desiccation stress in Chironomus
Authors: Thorat Leena , Oulkar Dasharath , Banerjee Kaushik , Gaikwad Sushama M. , Nath Bimalendu B.
Published: June 2017

Desiccation tolerance is an essential survival trait, especially in tropical aquatic organisms that are vulnerable to severe challenges posed by hydroperiodicity patterns in their habitats, characterized by dehydration-rehydration cycles. Here, we report a novel role for glucosamine as a desiccation stress-responsive metabolite in the underexplored tropical aquatic midge, Chironomus ramosus. Using high- throughput liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) analysis, biochemical assays and gene expression studies, we confirmed that glucosamine was essential during the recovery phase in C. ramosus larvae. Additionally, we demonstrated that trehalose, a known stress-protectant was crucial during desiccation but did not offer any advantage to the larvae during recovery. Based on our findings, we emphasise on the collaborative interplay of glucosamine and trehalose in conferring overall resilience to desiccation stress and propose the involvement of the trehalose-chitin metabolic interface in insects as one of the stress-management strategies to potentiate recovery post desiccation through recruitment of glucosamine.
Complex neuroanatomy in the rostrum of the Isle of Wight theropod Neovenator salerii
Authors: Barker Chris Tijani , Naish Darren , Newham Elis , Katsamenis Orestis L. , Dyke Gareth
Published: June 2017

The discovery of large, complex, internal canals within the rostra of fossil reptiles has been linked with an enhanced tactile function utilised in an aquatic context, so far in pliosaurids, the Cretaceous theropod Spinosaurus, and the related spinosaurid Baryonyx. Here, we report the presence of a complex network of large, laterally situated, anastomosing channels, discovered via micro-focus computed tomography (μCT), in the premaxilla and maxilla of Neovenator, a mid-sized allosauroid theropod from the Early Cretaceous of the UK. We identify these channels as neurovascular canals, that include parts of the trigeminal nerve; many branches of this complex terminate on the external surfaces of the premaxilla and maxilla where they are associated with foramina. Neovenator is universally regarded as a ‘typical’ terrestrial, predatory theropod, and there are no indications that it was aquatic, amphibious, or unusual with respect to the ecology or behaviour predicted for allosauroids. Accordingly, we propose that enlarged neurovascular facial canals shouldn’t be used to exclusively support a model of aquatic foraging in theropods and argue instead that an enhanced degree of facial sensitivity may have been linked with any number of alternative behavioural adaptations, among them defleshing behaviour, nest selection/maintenance or social interaction.
TCRP1 transcriptionally regulated by c-Myc confers cancer chemoresistance in tongue and lung cancer
Authors: Jia Xiaoting , Zhang Zhijie , Luo Kai , Zheng Guopei , Lu Minying , Song Ying , Liu Hao , Qiu Huisi , He Zhimin
Published: June 2017

Previously, we cloned a new gene termed ‘tongue cancer resistance-associated protein 1’ (TCRP1), which modulates tumorigenesis, enhances cisplatin (cDDP) resistance in cancers, and may be a potential target for reversing drug resistance. However, the mechanisms for regulating TCRP1 expression remain unclear. Herein, we combined bioinformatics analysis with luciferase reporter assay and ChIP assay to determine that c-Myc could directly bind to TCRP1 promoter to upregulate its expression. TCRP1 upregulation in multidrug resistant tongue cancer cells (Tca8113/PYM) and cisplatin-resistant A549 lung cancer cells (A549/DDP) was accompanied by c-Myc upregulation, compared to respective parental cells. In tongue and lung cancer cells, siRNA-mediated knockdown of c-Myc led to decrease TCRP1 expression, whereas overexpression c-Myc did the opposite. Moreover, TCRP1 knockdown attenuated chemoresistance resulting from c-Myc overexpression, but TCRP1 overexpression impaired the effect of c-Myc knockdown on chemosensitivity. Additionally, in both human tongue and lung cancer tissues, c-Myc protein expression positively correlated with TCRP1 protein expression and these protein levels were associated with worse prognosis for patients. Combined, these findings suggest that c-Myc could transcriptionally regulate TCRP1 in cell lines and clinical samples and identified the c-Myc-TCRP1 axis as a negative biomarker of prognosis in tongue and lung cancers.
Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor
Authors: Zhen Xiangkai , Li Bowen , Hu Fen , Yan Shufeng , Meloni Gabriele , Li Huiliang , Shi Ning
Published: June 2017

Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel β-sheets with 7 main strands, packing against each other, forming a β-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn’t affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development.
Iodine-125 Brachytherapy Prophylaxis after Radiofrequency Ablation Cannot Benefit Patients in High Risk of Locoregional Hepatocellular Carcinoma Recurrence
Authors: Tu Jian-Fei , Ding Ya-Hui , Chen Li , Ying Xi-Hui , Zhang Deng-Ke , Wu Fa-Zong , Zhao Zhong-Wei , Ji Jian-Song , Zhang Wang-Gang , Zou Hai
Published: June 2017

This study evaluated if iodine-125 brachytherapy prophylaxis after radiofrequency ablation (RFA) prolongs time to recurrence (TTR) and overall survival (OS) of patients in high risk of locoregional hepatocellular carcinoma (HCC) recurrence. 116 patients with total tumor necrosis after RFA were divided into iodine-125 brachytherapy prophylaxis treatment group and control group. The primary endpoint was TTR, and secondary endpoints were OS and treatment-related adverse events. There were no significant differences among the baseline characteristics of two subgroups patients. The mean iodine-125 particles were 29.8 (26.59 ± 12.51 mCi) per patient. The mean follow-up was 25 months, and mean TTR of treatment and control groups were 21.7 and 15.9 months (P = 0.733); mean OS of two subgroups were 41.7 and 40.9 months (P = 0.316). There were no significant differences of 1-, 2-, 3-, 4-and 5-years TTR and OS and patients’ immunity pre- and 1 month post-treatment. Extrahepatic metastasis was found to have a statistically significant influence on TTR, and AFP, extrahepatic metastasis were found to have a statistically significant influence on OS by multivariate analysis. There was no major complications and procedure related death. Iodine-125 brachytherapy prophylaxis after RFA can’t improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.
LNA/DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts
Authors: Touznik Aleksander , Maruyama Rika , Hosoki Kana , Echigoya Yusuke , Yokota Toshifumi
Published: June 2017

Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy. AONs are utilized to block intronic splicing silencer number 1 (ISS-N1) on intron 7 of SMN2, which causes exon 7 inclusion of the mRNA and the recovery of the expression of functional SMN protein from the endogenous SMN2 gene. We developed novel locked nucleic acid (LNA)-based antisense oligonucleotides (LNA/DNA mixmers), which efficiently induce exon 7 inclusion in SMN2 and restore the SMN protein production in SMA patient fibroblasts. The mixmers are highly specific to the targeted sequence, and showed significantly higher efficacy than an all-LNA oligonucleotide with the equivalent sequence. These data suggest that use of LNA/DNA mixmer-based AONs may be an attractive therapeutic strategy to treat SMA.
Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
Authors: Hatanaka Masayuki , Anderson-Baucum Emily , Lakhter Alexander , Kono Tatsuyoshi , Maier Bernhard , Tersey Sarah A. , Tanizawa Yukio , Evans-Molina Carmella , Mirmira Raghavendra G. , Sims Emily K.
Published: June 2017

Under conditions of high fat diet (HFD) consumption, glucose dyshomeostasis develops when β-cells are unable to adapt to peripheral insulin demands. Few studies have interrogated the molecular mechanisms of β-cell dysfunction at the level of mRNA translation under such conditions. We sought to address this issue through polyribosome profile analysis of islets from mice fed 16-weeks of 42% HFD. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation with a significant reduction in the polyribosome/monoribosome ratio forPdx1mRNA. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated evidence of oxidative stress and DNA damage, as well as activation of p53. Experiments in MIN-6 β-cells revealed that treatment with doxorubicin to directly induce DNA damage mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. Finally, HFD-islets demonstrated reduced expression of multiple ribosome biogenesis genes and the key translation initiation factor eIF4E. We propose a heretofore unappreciated effect of chronic HFD on β-cells, wherein continued DNA damage owing to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation.
Machine learning workflow to enhance predictions of Adverse Drug Reactions (ADRs) through drug-gene interactions: application to drugs for cutaneous diseases
Authors: Raja Kalpana , Patrick Matthew , Elder James T. , Tsoi Lam C.
Published: June 2017

Adverse drug reactions (ADRs) pose critical public health issues, affecting over 6% of hospitalized patients. While knowledge of potential drug-drug interactions (DDI) is necessary to prevent ADR, the rapid pace of drug discovery makes it challenging to maintain a strong insight into DDIs. In this study, we present a novel literature-mining framework for enhancing the predictions of DDIs and ADR types by integrating drug-gene interactions (DGIs). The ADR types were adapted from a DDI corpus, including i) adverse effect; ii) effect at molecular level; iii) effect related to pharmacokinetics; and iv) DDIs without known ADRs. By using random forest classifier our approach achieves an F-score of 0.87 across the ADRs classification using only the DDI features. We then enhanced the performance of the classifier by including DGIs (F-score = 0.90), and applied the classification model trained with the DDI corpus to identify the drugs that might interact with the drugs for cutaneous diseases. We successfully predict previously known ADRs for drugs prescribed to cutaneous diseases, and are also able to identify promising new ADRs.