bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anisotropic quantum cosmology with minimally coupled scalar field
Authors: Ghosh Saumya , Gangopadhyay Sunandan , Panigrahi Prasanta K. 
Published: August 2019

In this paper, we perform the Wheeler–DeWitt quantization for Bianchi type I anisotropic cosmological model in the presence of a scalar field minimally coupled to the Einstein–Hilbert gravity theory. We also consider the cosmological (perfect) fluid to construct the matter sector of the model whose dynamics plays the role of time. After obtaining the Wheeler–DeWitt equation from the Hamiltonian formalism, we then define the self-adjointness relations properly. Doing that, we proceed to get a solution for the Wheeler–DeWitt equation and construct a well-behaved wave function for the universe. The wave packet is next constructed from a superposition of the wave functions with different energy eigenvalues together with a suitable weight factor which renders the norm of the wave packet finite. It is then concluded that the Big-Bang singularity can be removed in the context of quantum cosmology.
Computing Hypergeometric Functions Rigorously
Authors: Johansson Fredrik 
Published: August 2019

We present an efficient implementation of hypergeometric functions in arbitrary-precision interval arithmetic. The functions
0
F
1
,
1
F
1
,
2
F
1
, and
2
F
0
(or the Kummer
U
-function) are supported for unrestricted complex parameters and argument, and, by extension, we cover exponential and trigonometric integrals, error functions, Fresnel integrals, incomplete gamma and beta functions, Bessel functions, Airy functions, Legendre functions, Jacobi polynomials, complete elliptic integrals, and other special functions. The output can be used directly for interval computations or to generate provably correct floating-point approximations in any format. Performance is competitive with earlier arbitrary-precision software and sometimes orders of magnitude faster. We also partially cover the generalized hypergeometric function

p

F

q

and computation of high-order parameter derivatives.
Sex differences in GABAergic neurotransmission to rat DMV neurons
Authors: Jiang Yanyan , Babic Tanja , Travagli R. Alberto 
Published: August 2019

Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle. NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.
Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation
Authors: Singh Pankaj K. , Deorukhkar Amit A. , Venkatesulu Bhanu P. , Li Xiaolin , Tailor Ramesh , Bomalaski John S. , Krishnan Sunil 
Published: August 2019

Abstract
Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosensitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent in vivo studies in two xenograft models confirmed significant tumor growth delays, which were associated with enhanced expression of ER stress proteins and apoptosis markers and reduced expression of proliferation and angiogenesis markers. ADI-PEG20 augmented the effects of radiation by triggering the ER stress pathway, leading to apoptosis in pancreatic tumor cells.
Development of Therapeutic Anti-JAGGED1 Antibodies for Cancer Therapy
Authors: Masiero Massimo , Li Demin , Whiteman Pat , Bentley Carol , Greig Jenny , Hassanali Tasneem , Watts Sarah , Stribbling Stephen , Yates Jenna , Bealing Ellen , Li Ji-Liang , Chillakuri Chandramouli , Sheppard Devon , Serres Sébastien , Sarmiento-Soto Manuel , Larkin James , Sibson Nicola R. , Handford Penny A. , Harris Adrian L. , Banham Alison H. 
Published: August 2019

Abstract
The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology has been firmly established, making them appealing therapeutic targets for cancer treatment. Here, we report the development and characterization of human/rat-specific JAG1-neutralizing mAbs. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 ortholog. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells, and block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired three-dimensional growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal-expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor-negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic growth. MRI imaging demonstrated that this was associated with a substantial improvement in blood–brain barrier function and tumor perfusion. Lastly, JAG1-targeting antibody treatment did not cause any detectable toxicity, further supporting its clinical potential for cancer therapy.
Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice
Authors: Burova Elena , Hermann Aynur , Dai Jie , Ullman Erica , Halasz Gabor , Potocky Terra , Hong Seongwon , Liu Matt , Allbritton Omaira , Woodruff Amy , Pei Jerry , Rafique Ashique , Poueymirou William , Martin Joel , MacDonald Douglas , Olson William C. , Murphy Andrew , Ioffe Ella , Thurston Gavin , Mohrs Markus 
Published: August 2019

Abstract
In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigen-presenting cell bioassay, REGN3767 alone, or in combination with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.
A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity
Authors: Vega Mario I. , Shi Yijiang , Frost Patrick , Huerta-Yepez Sara , Antonio-Andres Gabriela , Hernandez-Pando Rogelio , Lee Jihye , Jung Michael E. , Gera Joseph F. , Lichtenstein Alan 
Published: August 2019

Abstract
Prior work indicates DEPTOR expression in multiple myeloma cells could be a therapeutic target. DEPTOR binds to mTOR via its PDZ domain and inhibits mTOR kinase activity. We previously identified a drug, which prevented mTOR–DEPTOR binding (NSC126405) and induced multiple myeloma cytotoxicity. We now report on a related therapeutic, drug 3g, which induces proteasomal degradation of DEPTOR. DEPTOR degradation followed drug 3g binding to its PDZ domain and was not due to caspase activation or enhanced mTOR phosphorylation of DEPTOR. Drug 3g enhanced mTOR activity, and engaged the IRS-1/PI3K/AKT feedback loop with reduced phosphorylation of AKT on T308. Activation of TORC1, in part, mediated multiple myeloma cytotoxicity. Drug 3g was more effective than NSC126405 in preventing binding of recombinant DEPTOR to mTOR, preventing binding of DEPTOR to mTOR inside multiple myeloma cells, in activating mTOR and inducing apoptosis in multiple myeloma cells. In vivo, drug 3g injected daily abrogated DEPTOR expression in xenograft tumors and induced an antitumor effect although modest weight loss was seen. Every-other-day treatment, however, was equally effective without weight loss. Drug 3g also reduced DEPTOR expression in normal tissues. Although no potential toxicity was identified in hematopoietic or hepatic function, moderate cardiac enlargement and glomerular mesangial hypertrophy was seen. DEPTOR protected multiple myeloma cells against bortezomib suggesting anti-DEPTOR drugs could synergize with proteasome inhibitors (PI). Indeed, combinations of drug NSC126405 + bortezomib were synergistic. In contrast, drug 3g was not and was even antagonistic. This antagonism was probably due to prevention of proteasomal DEPTOR degradation.
U3-1402, a Novel HER3-Targeting Antibody–Drug Conjugate, for the Treatment of Colorectal Cancer
Authors: Koganemaru Shigehiro , Kuboki Yasutoshi , Koga Yoshikatsu , Kojima Takashi , Yamauchi Mayumi , Maeda Naoyuki , Kagari Takashi , Hirotani Kenji , Yasunaga Masahiro , Matsumura Yasuhiro , Doi Toshihiko 
Published: August 2019

AbstractHER3 is overexpressed in several cancers, including colorectal cancer. Although therapies with anti-HER3 antibodies have been investigated, significant clinical benefits have not been reported. U3-1402 is a novel HER3-antibody–drug conjugate (ADC) composed of the HER3 antibody patritumab and a novel topoisomerase I inhibitor, DX-8951 derivative (DXd). The sensitivity of DXd was evaluated by a growth inhibition assay. The antitumor activity of U3-1402 was evaluated in a murine xenograft model in which its effects on cells, with a range of HER3 expression levels, were compared with those of patritumab alone, irinotecan, control-ADC, and saline. In the growth inhibition assay, all colorectal cancer cell lines were sensitive to DXd. In the tumor xenograft model, significant tumor regression with U3-1402 was observed both in the DiFi cell line (high HER3 expression; KRAS wild type) and in SW620 (high HER3 expression; KRAS mutation), but no treatment effect was observed in Colo320DM (low HER3 expression). Notably, SW620 tumor growth was significantly suppressed with U3-1402 compared with the saline-treated group (P &lt; 0.001) and showed greater activity compared with the irinotecan group. By contrast, patritumab alone, control-ADC, and saline did not significantly differ in tumor growth inhibition. The antitumor activity of U3-1402 was dependent on HER3 expression level, but not on KRAS mutation status. These results support further investigation of development strategies for U3-1402 in patients with HER3-expressing colorectal cancer.
ОСОБЛИВОСТІ УЛЬТРАСТРУКТУРНОЇ РЕОРГАНІЗАЦІЇ ПЕРЕДСЕРДНИХ КАРДІОМІОЦИТІВ ПРИ ЕКСПЕРИМЕНТАЛЬНІЙ ТЕРМІЧНІЙ ТРАВМІ ТА ЗА УМОВ ЗАСТОСУВАННЯ ЛІОФІЛІЗОВАНИХ КСЕНОДЕРМОТРАНСПЛАНТАТІВ
Authors: Hetmaniuk I. B. , Nebesna Z. M. , Lykhatskyi P. H. , Shuturma O. Ya. 
Published: August 2019

Опікова травма у розвинених країнах є одним із найпоширеніших видів ушкоджень мирного часу. Лікування опіків визначається складністю та багатоплановістю, термічні ушкодження – одні з найнебезпечніших, вони призводять до руйнування складних білків – основи клітин і тканин органів. Ключову роль при розвитку та патогенезі опікової хвороби, що розвивається після термічної травми ІІІ ступеня, відіграє серцево-судинна система.
Мета дослідження – встановити закономірності ультраструктурних змін у передсердних кардіоміоцитах після тяжкої термічної травми за умов застосування ліофілізованих ксенодермотрансплантатів.
Матеріали і методи. Опік ІІІ ступеня наносили під кетаміновим наркозом мідними пластинами, нагрітими у кип’яченій воді до температури 97–100 оС. Евтаназію тварин проводили після кетамінового наркозу шляхом декапітації. Розміри ділянки ураження склали 18–20 % епільованої поверхні тіла морських свинок. Для електронно-мікроскопічного дослідження брали шматочки передсердь, фіксували у 2,5 % розчині глютаральдегіду, постфіксували 1 % розчином тетраокису осмію на фосфатному буфері. Подальшу обробку проводили згідно з загальноприйнятою методикою [3]. Ультратонкі зрізи, виготовлені на ультрамікротомі LKB-3, контрастували уранілацетатом, цитратом свинцю відповідно до методу Рейнольдса та вивчали в електронному мікроскопі ПЕМ-125 К.
Результати досліджень та їх обговорення. В експерименті вивчено субмікроскопічні зміни передсердних кардіоміоцитів після тяжкої термічної травми в умовах проведення ранньої некректомії та застосуванні ліофілізованих ксенодермотрансплантів для закриття опікової рани. Встановлено, що після опіку III ступеня відбуваються значні ультраструктурні зміни в передсердних кардіоміоцитах, ступінь ураження яких збільшувався в динаміці експерименту. При стадіях опікового шоку та ранньої токсемії у структурах серця розвиваються пристосувально-компенсаторні процеси, а при стадіях пізньої токсемії та септикотоксемії – наявні глибокі незворотні деструктивні зміни. Доведено, що використання ліофілізованих ксенодермотрансплантатів після ранньої некректомії уражених тканин запобігає розвитку деструктивних змін у компонентах серця на ранніх термінах досліду, активізує регенераторні процеси скоротливих та ендокринних міоцитів передсердь на пізніх термінах експерименту.
Висновки. Застосування ліофілізованих ксенодермотрансплантатів позитивно впливає на перебіг регенераторних процесів та покращує стан ультраструктури передсердя в динаміці експерименту. На ранніх термінах досліду застосування ліофілізованої ксеношкіри зменшує ступінь ушкодження цитоплазматичних мембран кардіоміоцитів передсердь, активізуються регенераторні процеси в клітинах.
Polyunsaturated Fatty Acid Impact on Clinical Outcomes in Acute Coronary Syndrome Patients With Dyslipidemia: Subanalysis of HIJ‐PROPER
Authors: Arashi Hiroyuki , Yamaguchi Junichi , Kawada‐Watanabe Erisa , Koyanagi Ryo , Sekiguchi Haruki , Mori Fumiaki , Haruta Shoji , Ishii Yasuhiro , Murasaki Satoshi , Suzuki Kazuhito , Yamauchi Takao , Ogawa Hiroshi , Hagiwara Nobuhisa 
Published: August 2019

Background

This study aimed to examine the impact of baseline eicosapentaenoic acid (
EPA
) to arachidonic acid (
AA
) ratio on clinical outcomes of patients with acute coronary syndrome.

Methods and Results

In the HIJ‐PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1734 patients with acute coronary syndrome and dyslipidemia were randomly assigned to pitavastatin+ezetimibe therapy or pitavastatin monotherapy. We divided the patients into 2 groups based on
EPA
/
AA
ratio on admission (cutoff 0.34 μg/mL as median of baseline
EPA
/
AA
ratio) and examined their clinical outcomes. The primary end point comprised all‐cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris, or ischemia‐driven revascularization. Percentage reduction of low‐density lipoprotein cholesterol and triglyceride from baseline to follow‐up was similar regardless of baseline
EPA
/
AA
ratio. Despite the mean low‐density lipoprotein cholesterol level during follow‐up being similar between the low‐ and high‐
EPA
/
AA
groups, the mean triglyceride levels during follow‐up were significantly higher in the low‐ than in the high‐
EPA
/
AA
group. After 3 years of follow‐up, the cumulative incidence of the primary end point in patients with low
EPA
/
AA
was 27.2% in the pitavastatin+ezetimibe group compared with 36.6% in the pitavastatin‐monotherapy group (hazard ratio 0.69; 95%
CI
, 0.52‐0.93;
P
=0.015). However, there was no effect of pitavastatin+ezetimibe therapy on the primary end point in patients with high
EPA
/
AA
(hazard ratio 0.92; 95%
CI
, 0.70‐1.20;
P
=0.52).

Conclusions

Among acute coronary syndrome patients who have dyslipidemia and low
EPA
/
AA
ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy.

Clinical Trial Registration

URL
:
http://www.umin.ac.jp/ctr
. Unique identifier:
UMIN
000002742
Targeted Infarction of the Internal Capsule in the Rat Using Microstimulation Guidance
Authors: Wen Tong-Chun , Sindhurakar Anil , Ramirez Violeta Contreras , Park HongGeun , Gupta Disha , Carmel Jason B. 
Published: August 2019

Background and Purpose—
Lacunar strokes are subcortical infarcts with small size and high disability rates, largely due to injury of the corticospinal tract in the internal capsule (IC). Current rodent models of lacunar infarcts are created based on stereotactic coordinates. We tested the hypothesis that better understanding of the somatotopy of the IC and guiding the lesion with electrical stimulation would allow a more accurate lesion to the forelimb axons of the IC.

Methods—
We performed electrophysiological motor mapping and viral tracing to define the somatotopy of the IC of Sprague Dawley rats. For the lesion, we used an optrode, which contains an electrode to localize forelimb responses and an optical fiber to deliver light. The infarct was induced when light activated the photothrombotic agent Rose Bengal, which was administered systemically.

Results—
We found largely a separate distribution of the forelimb and hindlimb axons in the IC, both by microstimulation mapping and tract tracing. Microstimulation-guided IC lesions ablated the forelimb axons of the IC in rats and caused lasting forelimb impairments while largely preserving the hindlimb axons of the IC and surrounding gray matter.

Conclusions—
Stimulation guidance enabled selective and reproducible infarcts of the forelimb axons of the IC in rats.

Visual Overview—

An online
visual overview
is available for this article.
Andalusi Contests, Syrian Media Content: the Poetic Ritual Ijāzah
Authors: England Samuel 
Published: August 2019

Abstract
This article moves the poetic ijāzah from the periphery, where modern scholars have generally placed it, to a central position in Arabic poetry and mass media. The ijāzah was well developed before its adoption in the western Mediterranean, but Cordoban, Sevillian, and expatriate Sicilian poets distinguished the competitive improvised poem from corollary works in the Middle East, where it had first been invented. I argue that it is precisely the Andalusi innovations to the ijāzah’s formal development that have allowed traditional criticism to minimize its importance, against a larger trend of popular audiences appreciating performed ijāzahs, on stage and in mass media. Modern Arabic theatre and television have found enthusiastic audiences for the Andalusi poetic dialogue, a phenomenon that frames my Classical research. Media outlets, including those working closely with government officials, stage the ijāzah in ways that maximize its ideological value. As they use it to promote secularism and putatively benevolent dictatorship, propelling Andalusi literature into current Middle Eastern politics, we critics should seek to understand the dialogic form in its contemporary, insistently political phase of development.
Healthcare Services Utilisation by Eritrean Immigrants in Indianapolis, Indiana, United States of America
Authors: Ndou Nthomeni Dora , Mavhandu-Mudzusi Azwihangwisi Helen , Asgedom Mesgane Girmai , Anokwuru Rafiat 
Published: August 2019

Abstract
Immigrants in the United States of America (usa) face challenges regarding the utilisation of healthcare services. Issues include difficulty to access healthcare services. Qualitative descriptive phenomenological design was used in the analysis. Data were collected using a semi-structured interview format with eight conveniently selected Eritrean immigrants living in Indianapolis. Data were analysed using Interpretive Phenomenological Analysis Framework for data analysis. The findings indicate that the cultural beliefs, socioeconomic status, immigration status of Eritrean emigrants and the policies related to financing healthcare services for migrants in Indianapolis have a huge impact on determining the utilisation of healthcare services by Eritrean immigrants in Indianapolis. It is concluded that there is limited access by Eritrean immigrants in Indianapolis to healthcare services. There is a need for policy revision regarding the financing of healthcare services for immigrants and the provision of services to improve access and accommodate cultural diversity.