bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR–/–ApoB100/100 mice
Authors: Blanco Fabiana , Heinonen Suvi E , Gurzeler Erika , Berglund Lisa M , Dutius Andersson Anna-Maria , Kotova Olga , Jönsson-Rylander Ann-Cathrine , Ylä-Herttuala Seppo , Gomez Maria F 
Published: March 2018

Aims: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease. Methods & Results: IGF-II/LDLR–/–ApoB100/100 mice were generated by crossbreeding low-density lipoprotein receptor–deficient mice that synthesize only apolipoprotein B100 (LDLR–/–ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR–/–ApoB100/100 mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells. Conclusion: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.
A Bayesian basket trial design using a calibrated Bayesian hierarchical model
Authors: Chu Yiyi , Yuan Ying 
Published: March 2018

Background: The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates. Methods: We propose a novel calibrated Bayesian hierarchical model approach to evaluate the treatment effect in basket trials. In our approach, the shrinkage parameter that controls information borrowing is not regarded as an unknown parameter. Instead, it is defined as a function of a similarity measure of the treatment effect across tumor subgroups. The key is that the function is calibrated using simulation such that information is strongly borrowed across subgroups if their treatment effects are similar and barely borrowed if the treatment effects are heterogeneous. Results: The simulation study shows that our method has substantially better controlled type I error rates than the Bayesian hierarchical model. In some scenarios, for example, when the true response rate is between the null and alternative, the type I error rate of the proposed method can be inflated from 10% up to 20%, but is still better than that of the Bayesian hierarchical model. Limitation: The proposed design assumes a binary endpoint. Extension of the proposed design to ordinal and time-to-event endpoints is worthy of further investigation. Conclusion: The calibrated Bayesian hierarchical model provides a practical approach to design basket trials with more flexibility and better controlled type I error rates than the Bayesian hierarchical model. The software for implementing the proposed design is available at http://odin.mdacc.tmc.edu/~yyuan/index_code.html
Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting β2-agonists delivered via a pressurized metered-dose inhaler
Authors: Van Holsbeke Cedric , De Backer Jan , Vos Wim , Marshall Jonathan 
Published: March 2018

Background: Functional respiratory imaging (FRI) uses three-dimensional models of human lungs and computational fluid dynamics to simulate functional changes within airways and predict the deposition of inhaled drugs. This study used FRI to model the effects of different patient inhalation and drug formulation factors on lung deposition of an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination, administered by a pressurized metered-dose inhaler. Methods: Three-dimensional models of the lungs of six patients with asthma (mean forced expiratory volume in 1 s, 83%), treated with an ICS/LABA, were included. FRI modelling was used to simulate (1) the effects on lung deposition of inhalation duration and particle size [fine particle fraction (FPF), proportion of particles <5 µm; and mass median aerodynamic diameter (MMAD), average size of inhalable particles]; (2) deposition of fluticasone propionate/formoterol (FP/FORM) 125/5 µg; and (3) how inhalation profiles and flow rates affected FP/FORM deposition. Results: Total lung depositions (TLDs) following 1-, 3- and 5-s inhalations were 22.8%, 36.1% and 41.6% (metered dose), respectively, and central-to-peripheral deposition (C:P) ratios were 1.81, 0.86 and 0.61, respectively. TLD increased with increasing FPF, from ~8% at 10% FPF to ~36% at 40% FPF (metered dose); by contrast, MMAD had little effect on TLD, which was similar across MMADs (1.5–4.5 µm) at each FPF. FP/FORM deposited throughout central and peripheral airways with gradual (sinusoidal) and sharp (rapid) inhalations. TLD ranged from 35.8 to 44.0% (metered dose) for gradual and sharp inhalations at 30 and 60 L/min mean flow rates. Conclusions: These data provide important insights into the potential effects of inhalation characteristics (inhalation profile and duration) and aerosol formulation (FPF) on lung deposition of inhaled therapies. FRI thus represents a useful alternative to scintigraphy techniques. Future FRI studies will further our understanding of the deposition of inhaled drugs and help improve the management of asthma.
RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice
Authors: Morita Ken , Tokushige Chieko , Maeda Shintaro , Kiyose Hiroki , Noura Mina , Iwai Atsushi , Yamada Maya , Kashiwazaki Gengo , Taniguchi Junichi , Bando Toshikazu , Hirata Masahiro , Kataoka Tatsuki R. , Nakahata Tatsutoshi , Adachi Souichi , Sugiyama Hiroshi , Kamikubo Yasuhiko 
Published: March 2018

Key Points
RUNX transcription factors potentially transactivate E-selectin expression in the vascular niche. RUNX inhibitor disrupts engraftment of AML cells in the bone marrow, possibly by attenuating E-selectin expression.
Tension-dependent regulation of mammalian Hippo signaling through LIMD1
Authors: Ibar Consuelo , Kirichenko Elmira , Keepers Benjamin , Enners Edward , Fleisch Katelyn , Irvine Kenneth D. 
Published: March 2018

ABSTRACT
Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins – AJUBA, LIMD1 and WTIP – exhibit tension-dependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and LATS family proteins is also influenced by cell density, and by Rho activation. We establish that junctional localization of LATS kinases requires LIMD1, and that LIMD1 is also specifically required for the regulation of LATS kinases and YAP1 by Rho. Our results identify a biomechanical pathway that contributes to regulation of mammalian Hippo signaling, establish that this occurs through tension-dependent LIMD1-mediated recruitment and inhibition of LATS kinases in junctional complexes, and identify roles for this pathway in both Rho-mediated and density-dependent regulation of Hippo signaling.
Developmental milestones at one year for the offspring of mothers with congenital hypothyroidism: a population-based study
Authors: Léger Juliane , Forhan Anne , Dos Santos Sophie , Larroque Béatrice , Ecosse Emmanuel , Charles Marie-Aline , Heude Barbara 
Published: March 2018

Objective
Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH.

Design and methods
We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills.

Results
After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52–6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21–3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P < 0.04).

Conclusions
Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment.
Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial
Authors: Johannsson Gudmundur , Feldt-Rasmussen Ulla , Håkonsson Ida Holme , Biering Henrik , Rodien Patrice , Tahara Shigeyuki , Toogood Andrew , Rasmussen Michael Højby , _ _ , _ _ , Biering Henrik , Karges Wolfram , Mann Alexander , Christiansen Jens Sandahl , Hansen Troels Krarup , Andersen Marianne , Feldt-Rasmussen Ulla , Borresen Sine , Rodien Patrice , Borson-Chazot Françoise , Kerlan Véronique , Cariou Bertrand , Verges Bruno , Tahara Shigeyuki , Matsuno Akira , Takano Koji , Tagami Tetsuya , Takahashi Yutaka , Takahashi Toshikazu , Yamamoto Masahiro , Johannsson Gudmundur , Höybye Charlotte , Erfurth Eva-Marie , Drake William , Higham Claire , Murray Robert , Toogood Andrew , Brooke Antonia 
Published: March 2018

Objective
Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed.

Design
26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939).

Methods
Male or female patients aged 18–79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).

Results
Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171).

Conclusions
In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.
Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation
Authors: Chatterjee Sumana , Shapiro Lucy , Rose Stephen J , Mushtaq Talat , Clayton Peter E , Ten Svetlana B , Bhangoo Amrit , Kumbattae Uma , Dias Renuka , Savage Martin O , Metherell Louise A , Storr Helen L 
Published: March 2018

Background
Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Ψ patients and their responses to rhIGF1 therapy.

Methods
20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA.

Results
10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: −4.1 ± 0.95, IGF1 SDS: −2.8 ± 1.4; IGFBP3 SDS: −3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132–255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (−3.2 ± 1.0) was higher than pre-treatment height SDS (−4.3 ± 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8; P = 0.02).

Conclusion
In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ GHR mutations. rhIGF1 treatment improved height outcomes.
Ku DNA End-Binding Activity Promotes Repair Fidelity and Influences End-Processing During Nonhomologous End-Joining in Saccharomyces cerevisiae
Authors: Emerson Charlene H , Lopez Christopher R , Ribes-Zamora Albert , Polleys Erica J , Williams Christopher L , Yeo Lythou , Zaneveld Jacques E , Chen Rui , Bertuch Alison A 
Published: March 2018

Abstract
The Ku heterodimer acts centrally in nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB). Saccharomyces cerevisiae Ku, like mammalian Ku, binds and recruits NHEJ factors to DSB ends. Consequently, NHEJ is virtually absent in yeast Ku null (yku70∆ or yku80∆) strains. Previously, we unexpectedly observed imprecise NHEJ proficiency in a yeast Ku mutant with impaired DNA end-binding (DEB). However, how DEB impairment supported imprecise NHEJ was unknown. Here, we found imprecise NHEJ proficiency to be a feature of a panel of DEB-impaired Ku mutants and that DEB impairment resulted in a deficiency in precise NHEJ. These results suggest that DEB-impaired Ku specifically promotes error-prone NHEJ. Epistasis analysis showed that classical NHEJ factors, as well as novel and previously characterized NHEJ-specific residues of Ku, are required for the distinct error-prone repair in a Ku DEB mutant. However, sequencing of repair junctions revealed that imprecise repair in Ku DEB mutants was almost exclusively characterized by small deletions, in contrast to the majority of insertions that define imprecise repair in wild-type strains. Notably, while sequencing indicated a lack of Pol4-dependent insertions at the site of repair, Pol2 exonuclease activity, which mediates small deletions in NHEJ, contributed to imprecise NHEJ in a Ku DEB mutant. The deletions were smaller than in Ku-independent microhomology-mediated end-joining (MMEJ) and were neither promoted by Mre11 nuclease activity nor Sae2. Thus, the quality of Ku’s engagement at the DNA end influences end-processing during NHEJ and DEB impairment unmasks a Ku-dependent error-prone pathway of end-joining distinct from MMEJ.
Fungal Community Structure of Macroalga Ulva Intestinalis Revealed by Miseq Sequencing
Authors: Agusman Agusman , Danqing Feng 
Published: March 2018

Since algae are well known as the host of fungi, the information about total fungal community associated with alga is needed to give the initial data that is useful for natural product discovery. The study on total fungal community associated with marine macroalga U. intestinalis from Xiamen-China was carried out using MiSeq, a powerful platform for microbial ecology studies. Metagenomics DNA was isolated from surfaces of the U. intestinalis thallus and rocks colonized by this alga and 18S ribosomal RNA region was sequenced using MiSeq Illumina to yield 81360 sequences from 162720 reads, which average read length is 245.61 bp. The sequences were assigned to operational taxonomic units (OTUs), where 101 genera represent 5 phyla, 17 classes and 64 families of fungal. Ascomycota was the highest abundance share of fungal community at phylum level. Meanwhile Aspergillus, Blastobotrys, Alternaria, Knufia, and Fusarium were some of dominant genera found associated with U. intestinalis which have been reported as the promising source of natural products. By using MiSeq platform, this study revealed the total community structure of algicolous fungi associated with U. intestinalis.
Konsepsi jihad dalam konteks kehidupanmodern: pemikiran Sayyid Sabiq dan Abu Bakar Jabir al-Jazayri
Authors: Shaffat Idri 
Published: March 2018

Recently, the term of jihad has been used by certain people for improper purposes. At the time of theProphet and the classical Islamic period, jihad meant as an effort to uphold and fight for Islam with awealth, soul, body, mind, and deeds. Nowdays certain people have been understanding and applyingthis term in the form of terror. They understand it solely as ‘the holy war’ against the unbelievers withparadise as a reward for martyrs who died for it. In the name of jihad, in this decade there are manybombings in Indonesia and other hemisphere. Bomb terrors not only occur in non-Muslim countriesbut also in Muslim countries which also cause Muslim victims. The question then is what are theiractions really the jihad as it is thought by Islam? To answer this question, this paper tries to explain theconcept of jihad in the perspective of two scholars who live in contemporary era, namely Sayyid Sabiqand Abu Bakr Jabir al-Jazayri by examining definition of jihad concept, legal basis and implementationof jihad, categories of jihad, and orientation of jihad understanding in the context of modern life.Through this study it is expected that the solution of jihad formulation in the context of modern lifecan be clarified and resolved.
Pelembagaan norma hukum Islam dalamperaturan daerah di Indonesia
Authors: Sirajuddin M 
Published: March 2018

The main problem of this paper is how political policy direction of local government and communityresponse to the institutionalization of norms of Islamic law in Indonesia’s local regulations. This paperuses the theoretical framework of thought which devides three Islamic groups, namely ideologicalIslamic group, moral-ethical Islamic group, and the middle way of Islam. In this paper, the direction ofgovernment policy was oriented towards the third Islamic group’s concept which institutionalizes theShari’a as a rule of formal government, but most of the only aspects of private law only, while theresponse of the majority of the community is oriented in a second Islamic group which requires theinstitutionalization of religious ethical values which the terms of Shari’ah institutionalized in thenational legal system. Therefore, the results of surveys and responses among Indonesian thinkers moreinquire the existence of the institutionalization of norms of Islamic law than accept it. However, if anyshould be institutionalized, they would prefer the public aspects of Shari’a which should be institution-alized and implemented.
Pembaruan pemikiran hukum keluargaIslam di Indonesia
Authors: Ismail Ismail 
Published: March 2018

Islamic family law or ahwal al-shakhsiyyah has prevailed in Indonesia since the inception of the law no. 1year 1974 concerning with marriage and the compilation of Islamic law in Indonesia (KHI) in 1991.Islamic family law run in Indonesia is not exactly the same as those contained in the books of classicaljurisprudence (fiqh). From its materials has been found in the legislation, there are a number of newprovisions that was different from those classical Islamic jurisprudence such as in marriage record, agerestrictions of marriage, polygamy, inheritance and wasiah wajibah etc. These new provisions were issuedby scholars and contemporary Islamic jurists in the context of law reform.
Rekonstruksi teori maslahah dan signifikansinya dalam pengembangan ekonomi Islam
Authors: Waluyo Nur Agus 
Published: March 2018

The article traces to find the significance of maslahah to solve Islamic economics problems in the ageof globalization. The age of globalization supported by information technologies revolution makes allaspects of human life changes rapidly especially in economic activities. Islamic economic developmentrequired ijtihad with respect to the reality. In the context of ijtihad, Islamic economic require to be wokeup in the frame of maqasid shari‘ah. Maslahah, as important part of maqasid, need to be placed proportion-ally. Benefit, maslahah, and benediction (falah) will be reached only if Islamic values and principles areimplemented in the economic behavior. Neglecting to one of them will make it cripple. Applycation ofeconomic principles without Islamic values will only give material benefit, while principal execution andvalue will bear benediction and benefit or maslahah eternity world. Therefore consumer whose applyingsufficiency principle in buying goods, will buy goods so that minimum requirement of him fufilled. Hewill sought to fulfill the requirement without require to look into the availibility of goods to others. Onthe contrary if only executed principle, hence it will yield earthly benefit.
Examining Validity and Reliability of a Mathematics Assessment Tool for K-2 Students
Authors: Siebert Carl F. , Brendefur Jonathan L. 
Published: March 2018

The Primary Math Assessment (PMA) tool is increasingly being used in multiple districts in a northwestern state. The PMA provides both screening and diagnostic information in six domains to assess mathematical proficiency in young students in their early educational years. A previous study using multidimensional Rasch analyses found support for the PMA’s six-dimensional theoretical framework, and that the PMA is a reliable mathematics assessment for early grades. This study extended the examination of a Rasch model, implementing exploratory and confirmatory factor analysis, Item Response Theory, and Differential Item Functioning analyses. In doing so, this study found an IRT 2-PL model to fit best with these data and provided ways to improve the accuracy of measuring mathematical proficiency in early grades.