bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential binding of tetrodotoxin and its derivatives to voltage‐sensitive sodium channel subtypes (Nav1.1 to Nav1.7)
Authors: Tsukamoto Tadaaki , Chiba Yukie , Wakamori Minoru , Yamada Tomoshi , Tsunogae Shunsuke , Cho Yuko , Sakakibara Ryo , Imazu Takuya , Tokoro Shouta , Satake Yoshiki , Adachi Masaatsu , Nishikawa Toshio , Yotsu‐Yamashita Mari , Konoki Keiichi 
Published: August 2017

Background and PurposeThe development of subtype‐selective ligands to inhibit voltage‐sensitive sodium channels (VSSCs) has been attempted with the aim of developing therapeutic compounds. Tetrodotoxin (TTX) is a toxin from pufferfish that strongly inhibits VSSCs. Many TTX analogues have been identified from marine and terrestrial sources, although their specificity for particular VSSC subtypes has not been investigated. Herein, we describe the binding of 11 TTX analogues to human VSSC subtypes Nav1.1–Nav1.7.Experimental ApproachEach VSSC subtype was transiently expressed in HEK293T cells. The inhibitory effects of TTX analogues on each subtype were assessed using whole‐cell patch‐clamp recordings.Key ResultsThe inhibitory effects of TTX on Nav1.1–Nav1.7 were observed in accordance with those reported in the literature; however, the 5‐deoxy‐10,7‐lactone‐type analogues and 4,9‐anhydro‐type analogues did not cause inhibition. Chiriquitoxin showed less binding to Nav1.7 compared to the other TTX‐sensitive subtypes. Two amino acid residues in the TTX binding site of Nav1.7, Thr1425 and Ile1426 were mutated to Met and Asp, respectively, because these residues were found at the same positions in other subtypes. The two mutants, Nav1.7 T1425M and Nav1.7 I1426D, had a 16‐fold and 5‐fold increase in binding affinity for chiriquitoxin, respectively.Conclusions and ImplicationsThe reduced binding of chiriquitoxin to Nav1.7 was attributed to its C11–OH and/or C12–NH2, based on reported models for the TTX‐VSSC complex. Chiriquitoxin is a useful tool for probing the configuration of the TTX binding site until a crystal structure for the mammalian VSSC is solved.
Rheumatoid arthritis fibroblast-like synoviocytes co-cultured with PBMC increased peripheral CD4+CXCR5+ICOS+ T cell numbers
Authors: Tang Y , Wang B , Sun X , Li H , Ouyang X , Wei J , Dai B , Zhang Y , Li X 
Published: August 2017

Summary‘Circulating’ T follicular helper cells (Tfh), characterized by their surface phenotypes CD4+chemokine receptor 5 (CXCR5)+ inducible co-stimulatory molecule (ICOS)+, have been identified as the CD4+ T cell subset specialized in supporting the activation, expansion and differentiation of B cells. Fibroblast-like synoviocytes (FLS) are critical in promoting inflammation and cartilage destruction in rheumatoid arthritis (RA), and the interaction between FLS and T cells is considered to facilitate FLS activation and T cell recruitment. However, it remains unknown whether RA-FLS co-cultured with activated peripheral blood mononuclear cells (PBMC) has immunoregulatory effects on peripheral Tfh. In the present study, we co-cultured RA-FLS with or without anti-CD3/CD28-stimulated PBMC. The results showed that RA-FLS co-cultured with stimulated PBMC could increase the numbers of CD4+CXCR5+ICOS+ T cells of RA PBMC possibly via the production of interleukin (IL)-6, a critical cytokine involved in the differentiation of Tfh cells. We also observed increased reactive oxygen species (ROS) levels in the co-culture system of RA-FLS and PBMC. The percentage of CD4+CXCR5+ICOS+ T cells was decreased when ROS production was inhibited by N-acetyl-L-cysteine (NAC), a specific inhibitor which can decrease ROS production. In addition, we showed that the higher levels of tumour necrosis factor (TNF)-α and IL-1β in the co-culture system and the blocking of TNF receptor 2 (TNF-R2) and IL-1β receptor (IL-1βR) both decreased the numbers of CD4+CXCR5+ICOS+ T cells. Our study reveals a novel mechanistic insight into how the interaction of RA-FLS and PBMC participates in the RA pathogenesis, and also provides support for the biologicals application for RA.
Echocardiographic evaluation of patients presenting with acutely decompensated heart failure in the setting of dietary or medication noncompliance—Is there a role?
Authors: Goyfman Michael , Kort Smadar 
Published: August 2017

BackgroundReevaluating patients who are admitted with heart failure (HF) exacerbation using echocardiogram is a common and appropriate indication. However, it is unknown whether it is appropriate to reevaluate such patients when the exacerbation is attributed to patients’ noncompliance with self‐care behaviors, where the presumption is that the underlying HF biology is stable.MethodsEchocardiograms on all patients hospitalized for HF exacerbation attributed to dietary or medication noncompliance were retrospectively assessed for the presence of significant changes from prior echocardiogram.ResultsA total of 559 charts of patients admitted with heart failure exacerbation were reviewed, of which 125 patients (22%) were thought to have dietary or medication noncompliance as the etiology. Fifty‐three patients (42%) had a follow‐up echocardiogram performed during the index admission. The likelihood of being reevaluated by an echocardiogram during admission was not affected by the clinical service that the patient was admitted to, the patient's gender, or age. Eighty percent of echocardiograms performed within a year of prior study and 78% of echocardiograms performed >1 year revealed at least one significant change. The most common changes identified were an increase in left atrium diameter, worsening of pulmonary artery systolic pressure and worsening ejection fraction. There was no correlation between the time interval of between echocardiograms and the likelihood of a significant change.ConclusionsRepeat echocardiograms in patients admitted with HF exacerbation due to noncompliance revealed significant changes in the majority of patients studied. The changes may reflect worsening in cardiac function in addition to the presumed etiology of noncompliance.
Expression and significance of Pim‐3 kinase in adult T‐cell leukemia
Authors: Ishikawa Chie , Senba Masachika , Hashimoto Tadashi , Imaizumi Atsushi , Mori Naoki 
Published: August 2017

AbstractBackgroundHuman T‐cell leukemia virus type 1 (HTLV‐1) causes adult T‐cell leukemia (ATL). Viral Tax protein plays a major role in ATL development. Pim family of serine/threonine kinases is composed of Pim‐1, ‐2, and ‐3. The potential of Pim family as a target in ATL was analyzed.MethodsRT‐PCR and Western blotting were used to determine the expression of Pim kinases, Tax, and intracellular signal molecules. Knockdown of Pim‐3 and RelA was performed using small interfering RNA. The effects on cell proliferation, viability, cell cycle, and apoptosis were analyzed by WST‐8, propidium iodide, and APO2.7 assay. NF‐κB DNA binding activity was investigated by electrophoretic mobility shift assay.ResultsPim‐3 expression was restricted to HTLV‐1–infected T‐cell lines. Tax induced Pim‐3 expression through NF‐κB. Knockdown of Pim‐3 showed growth inhibition of HTLV‐1–infected T cells. NJC97‐NH, a novel inhibitor of the Pim‐1/3 kinases, inhibited cell viability. NJC97‐NH induced G2/M cell cycle arrest associated with downregulation of cyclin A and cyclin B1 expression, as well as apoptosis accompanied with downregulation of XIAP and Mcl‐1 expression through inhibition of NF‐κB pathway, mediated through decrease in IκBα and RelA phosphorylation.ConclusionPim‐3 is a potentially suitable target for the development of novel therapeutic agents against ATL.
Elevated serum uric acid level was a notable adverse event during combination therapy with sofosbuvir and ribavirin
Authors: Sato Ken , Naganuma Atsushi , Nagashima Tamon , Hoshino Takashi , Uehara Daisuke , Arai Yousuke , Horiuchi Katsuhiko , Yuasa Kazuhisa , Takayama Hisashi , Arai Hirotaka , Hatanaka Takeshi , Ohyama Tatsuya , Tahara Hiroki , Sohara Naondo , Kobayashi Takeshi , Horiguchi Norio , Yamazaki Yuichi , Kakizaki Satoru , Kusano Motoyasu , Yamada Masanobu , Murase Takayo , Nakamura Takashi 
Published: August 2017

AimCombination therapy with sofosbuvir and ribavirin (SOF/RBV) has been recently available for chronic hepatitis C patients with genotype 2 (CHG2) in Japan. The domestic phase III clinical trial showed a high antiviral effect with a relatively safe adverse event (AE) profile. Our aim was to report an important AE detected during treatment.MethodsA prospective multi‐institutional study of 12‐week combination therapy with SOF/RBV for CHG2 was carried out to evaluate efficacy and safety.ResultsThe eligible subjects included 142 patients. Out of 50 assessable patients, 16% of the patients were diagnosed with hyperuricemia. The proportions of subjects with grade 1, grade 3, and grade 4 hyperuricemia were 12, 2, and 2%, respectively. Serum uric acid (UA) levels at week 1 of the therapy (W1) were numerically the highest during therapy in patients with hyperuricemia, and the ratio of W1/baseline serum UA levels was significantly higher than that of post‐treatment week 4 or 8/baseline serum UA levels in assessable patients. Serum UA levels at W1 were significantly correlated with body mass index. The difference between serum UA levels at W1 and baseline serum UA levels was significantly correlated with the difference between serum creatinine levels at W1 and baseline serum creatinine levels.ConclusionsElevated serum UA level was a notable AE associated with SOF/RBV therapy for CHG2. However, because of the small number of subjects, the exact frequency of AEs should be re‐evaluated with larger cohorts. We need to remember that elevated serum UA level might develop during the therapy, especially at W1.
Work/life balance policy in Germany: Promoting equal partnership in families
Authors: Adema Willem , Clarke Chris , Frey Valerie , Greulich Angela , Kim Hyunsook , Rattenhuber Pia , Thévenon Olivier 
Published: August 2017

AbstractAcross the OECD, public policies seek to support parents in achieving their desired work/life balance. This article introduces the background to and issues at stake in promoting equal partnerships in families in Germany. Families in Germany face considerable challenges to spending more time together and achieving a more gender‐balanced reconciliation of work and family life, as paid work hours for fathers are long on full‐time jobs and many women are in part‐time jobs. Family policy can play an important role and Germany has made substantial progress in supporting families ahead of and after the birth of a child. Important in this regard are the parental leave reforms of 2007 and 2015 and the extension of childcare supports that better enable fathers and mothers to combine work and family commitments. The article assesses recent developments in family policies in Germany while also drawing from the experiences of countries with longstanding policies to support work/life balance and strengthen gender equality.
SUBJECTIVISM, UTILITY, AND AUTONOMY
Authors: Lottenbach Hans 
Published: August 2017

Abstract:Taking as a starting point a thesis of David Gauthier's about the status of Rational Choice Theory. I discuss the relation between a subjectivist theory of value and an account of rational agency that leaves room for autonomy. I argue that if autonomy presupposes an activity of practical reason, the maximization of subjective expected utility (as prescribed by Rational Choice Theory) cannot serve as the principle of practical reason.
WHAT SHOULD WE TREAT AS AN END IN ITSELF?
Authors: Dean Richard 
Published: August 2017

Abstract:One formulation of the Categorical Imperative tells us to treat humanity as an end in itself. It has become common to think that ‘humanity’ (die Menschheit) here refers to some minimal power of rationality that is necessarily possessed by any rational agent, but I argue that this common reading is misguided. Instead, ‘humanity’ refers to a good will, the will of a being who is committed to moral principles. This good will reading of ‘humanity’ is not only suggested by passages in which Kant specifically discusses humanity, but also is more consistent with the main ideas of Kant's ethics.
An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes
Authors: Polak David , Shapira Lior 
Published: August 2017

AbstractAimTo provide an update of the review by Taylor (Journal of Clinical Periodontology, 2013, 40, S113) regarding the scientific evidence of the biological association between periodontitis and diabetes.MethodsLiterature searches were performed using MeSH terms, keywords and title words and were published between 2012 and November 2016. All publications were screened for their relevance. The data from the articles were extracted and summarized in tables and a narrative review.ResultsSmall‐scale molecular periodontal microbiome studies indicate a possible association between altered glucose metabolism in pre‐diabetes and diabetes and changes in the periodontal microbiome, with no evidence for casual relationships. Clinical and animal studies found elevated gingival levels of IL1‐β, TNF‐α, IL‐6, RANKL/OPG and oxygen metabolites in poorly controlled diabetes. In addition, individuals with diabetes and periodontitis exhibit high levels of circulating TNF‐α, CRP and mediators of oxidative stress, and successful periodontal treatment reduces their levels.ConclusionsThe elevated pro‐inflammatory factors in the gingiva of patients with poorly controlled diabetes suggest a biological pathway that may aggravate periodontitis. Some evidence suggests that the systemic inflammatory burden in periodontitis has the potential to affect diabetes control, but no studies addressed the impact of successful periodontal therapy on the pathophysiological mechanisms involved in systemic complications of diabetes.
Esthetic dermatology and emotional well‐being according to gender
Authors: Martínez‐González Maria Covadonga , Martínez‐González Raquel‐Amaya , Guerra‐Tapia Aurora 
Published: August 2017

SummaryIntroductionThere has been an increase in the demand for esthetic dermatology treatments within the general population. The purpose of this study was to analyze, within the scope of general population, the relationship between people's perception of esthetic dermatology treatments and emotional well‐being, as well as for differences in gender.MethodsThe Aesthetic Dermatology and Emotional Well‐Being (DEBIE) Scale, [Journal of Cosmetic Dermatology vol. 13 (2014) 336‐345] was applied to 770 Spanish people over 18 years old. The scale is structured according to six factors and classified into two dimensions: (1) Emotional Well‐Being and (2) Perception of Aesthetic Dermatology. Cronbach alpha for the total scale was very high (0.90). Data analysis includes the following: (1) bivariate correlations with Pearson's coefficient; (2) gender differences through Student's t test, and (3) the effect size through R2 and Cohen's d.ResultsA statistically significant relationship which is directly proportional has been identified between the degree of emotional well‐being of people (self‐esteem and assertiveness, optimism, and motivation) and the knowledge and attitude toward Aesthetic Dermatology. There are statistically significant differences according to gender: Women have a lower level of emotional well‐being than men, as well as greater knowledge and more positive attitude toward Aesthetic Dermatology.ConclusionsPeople who are familiar with Aesthetic Dermatology and have a better attitude toward it, are also more self‐confident, more optimistic and more motivated; with emotional strength. Regarding gender, it is expected that women may seek more consultation and esthetic dermatology treatments than men do.
Exercise might prevent cirrhosis in overweight and obese adults
Authors: Jan Cheng‐Feng , Nfor Oswald Ndi , Huang Jing‐Yang , Hsu Shu‐Yi , Ko Pei‐Chieh , Wu Min‐Chen , Ho Chien‐Chang , Liaw Yung‐Po 
Published: August 2017

AbstractBackground & AimsExercise in overweight patients with liver disease has improved liver enzymes, insulin levels and quality of life. Scientific evidence is incomplete regarding the role of exercise in the prevention of cirrhosis. We investigated the effect of exercise on the occurrence of cirrhosis in obese and overweight adults.MethodsExercise was assessed using the 2012 Adult Preventive Medical Service dataset while cirrhosis was identified using the National Health Insurance Research Database. All participants were aged 40 years and older. Unconditional logistic regression was used to estimate the odds ratios for cirrhosis.ResultsOverall, 1586 overweight and 1525 obese adults were identified with cirrhosis. Weekly exercise >150 min was significantly protective for cirrhosis in obese men and women. However, exercise <150 min/wk was significantly protective only in men compared to women. For weekly exercise >150 mins, the odds ratio for cirrhosis in obese men and women was 0.701 (95% CI: 0.584‐0.841) and 0.736 (95% CI: 0.562‐0.964) respectively. The adjusted odds ratios in overweight men and women were 0.734 (95% CI: 0.622‐0.866) and 0.503 (CI: 0.37‐0.684). For weekly exercise <150 min/wk, overweight and obese men had odds ratios of 0.879 (CI: 0.0.788‐0.98) and 0.874 (CI: 0.782‐0.977) compared to 0.918 (95% CI: 0.778‐1.083) and 0.916 (95% CI: 0.780‐1.075) in overweight and obese women respectively.ConclusionsModerate exercise might significantly prevent obese and overweight adults from developing cirrhosis. The benefits appear to be greater for persons who exceed the minimum recommendations of 150 min/wk.
Clonal characteristics of paired infiltrating and circulating B lymphocyte repertoire in patients with primary biliary cholangitis
Authors: Tan Yan‐guo , Wang Xiao‐feng , Zhang Ming , Yan Hui‐ping , Lin Dong‐dong , Wang Yu‐qi , Zhang Hai‐ping , Yu Xin‐qiu , Liao Hui‐yu , Wang Yi‐peng , Lv Fu‐dong , Gao Zu‐hua 
Published: August 2017

AbstractBackgroundPBC is a prototypical autoimmune liver disease characterized by portal lymphoplasmacyte infiltration. ALD is a prototypical environment‐driven disease, featured by mild lymphocyte infiltration. We hypothesize that B cells are more involved in the pathogenesis of PBC. By analysing the infiltrating B cell repertoire, we aimed to unveil greater oligoclonal expansion and active clonal exchange between liver and periphery in PBC than in ALD patients.MethodsUsing NGS of Ig H chain genes, we analysed the liver‐infiltrating and paired peripheral B lymphocyte repertoire from nine PBC and four ALD patients.ResultsIn the liver of PBC and ALD patients, (i) roughly 10% of the B lymphocytes were clonally related and highly expressed, and there were also lineages that underwent extensive clonal expansion; (ii) there was different use of IGHV/IGHJ segments between PBC and ALD, suggesting distinct Ag exposure backgrounds, but this did not lead to a significant difference in their clonal expansion level. Analysis of data sets from paired samples further revealed, (iii) direct clonal exchange and evolutionally related B cell clones between the infiltrating and peripheral repertoire; (iv) the seeding of the infiltrating clones to periphery, and peripheral ones to the liver, for further extensive evolution.ConclusionsThe oligoclonally expanded nature of the infiltrating B cell repertoire implies B cell immunity is involved in the pathogenesis of both diseases. The observed clonal exchange might provide an approach to identify and monitor the infiltrating B cells through the periphery.
Cherchez l'Electron
Authors: Mäser Pascal 
Published: August 2017

SummaryWho wouldn't want to have a drug that is activated only in the target cell? Prodrugs that are metabolically triggered inside the pathogen but not in the host are an attractive concept in antimicrobial chemotherapy. Of particular interest are bioreductive prodrugs such as nitro compounds or quinones that can initiate cytotoxic redox cascades and release active metabolites. The critical points for the selectivity of such molecules are, what is the source of the electrons that activate the prodrug, and which are the enzymes that catalyze the reduction? Meredith et al. conceive an elegant approach to answer these questions, making use of reverse genetics in Trypanosoma brucei. By overexpression of key reductase genes, they engineer trypanosomal indicator lines that are hypersensitive to particular bioreductive prodrugs and allow to discriminate between one‐electron and two‐electron transfer activation mechanisms. Indicator lines that are also defective in DNA repair further indicate whether the resultant metabolites interfere with the parasite's genome. This set of T. brucei indicator lines provides a tool for the deconvolution of the mechanisms of prodrug activation and drug action that will facilitate the rational development of bioreductive prodrugs for parasite chemotherapy.
Transcript‐level expression control of plant NLR genes
Authors: Lai Yan , Eulgem Thomas 
Published: August 2017

SummaryPlant NLR genes encode sensitive immune receptors that can mediate the specific recognition of pathogen avirulence effectors and activate a strong defence response, termed effector‐triggered immunity. The expression of NLRs requires strict regulation, as their ability to trigger immunity is dependent on their dose, and overexpression of NLRs results in autoimmunity and massive fitness costs. An elaborate interplay of different mechanisms controlling NLR transcript levels allows plants to maximize their defence capacity, whilst limiting negative impact on their fitness. Global suppression of NLR transcripts may be a prerequisite for the fast evolution of new NLR variants and the expansion of this gene family. Here, we summarize recent progress made towards a comprehensive understanding of NLR transcript‐level expression control. Multiple mechanistic steps, including transcription as well as co‐/post‐transcriptional processing and transcript turn‐over, contribute to balanced base levels of NLR transcripts and allow for dynamic adjustments to defence situations.
Eocene Pachynolophinae (Perissodactyla, Palaeotheriidae) from China, and their palaeobiogeographical implications
Authors: Bai Bin 
Published: August 2017

AbstractThe Eocene perissodactyl family Palaeotheriidae has traditionally been considered to be a nearly endemic European group within Equoidea, but a few palaeotheres have been reported from Asia. Here, I reanalyse a maxilla containing M1–3 from the Lunan Basin, Yunnan Province, China. This element was initially assigned to a new tapiromorph species, Lophialetes yunnanensis, but is here placed in a new genus Lophiohippus within Pachynolophinae based mainly on the absence of mesostyles, the strongly oblique metalophs, the strong development of lophodonty, parastyles overlapping metastyles of preceding teeth and situated mesial to the paracone, and the fact that M3 is longer than wide and has a large and buccally deflected metastyle. Lophiohippus differs from European Anchilophus and Paranchilophus in that the parastyles are situated mesial or even slightly lingual, rather than mesiobuccal, to the paracones, and M3 is markedly relatively larger than M1. I further reanalyse Qianohippus magicus from the Shinao Basin of Guizhou Province, China, in which the complete dentition is known. Qianohippus is characterized by a molariform P2 and non‐molariform P3–4; a relatively high degree of lophodonty; the absence of mesostyles; an angular bending in the protoloph on P3‐M3 and the metaloph on M1–3 at the paraconule and metaconule, respectively; and weakly developed ‘metastylid’ on the lower cheek teeth. A cladistic analysis supports a close relationship between Lophiohippus yunnanensis and Paranchilophus, and suggests that Qianohippus is closely related to some derived pachynolophs. The appearance of the pachynolophins Lophiohippus and Qianohippus in China supports the existence of a biogeographical connection between Europe and Asia in the Middle‐Late Eocene, and the dispersal route was probably along the Tethyan microcontinents in the south.