bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis and Application of Chinese Language and Literature Teaching Program Based on Computer Multimedia Technology
Authors: Wu Zhaodi
Published: April 2023

With the rapid development of 5G network and information technology, the means of modern multimedia are becoming more and more perfect. Many enterprises and industry organizations have entered the information age, and the field of higher education cannot lag behind because of its practical importance of training talents. The major of Chinese language and literature has a great influence on the development of the country’s soft power. The current teaching mode is backward and old-fashioned, paying more attention to the examination-oriented education of theoretical knowledge, and the practical training of comprehensive quality is still insufficient. This paper plans to design an intelligent classroom teaching system. Under the intelligent control of multimedia, the system can assist teachers to formulate flexible and rich teaching programs of Chinese language and literature. Finally, the weight distribution of the teaching evaluation system designed in this paper is reasonable, and the material library of the system is set up scientifically and comprehensively. After several groups of simulation verification, the improved teaching scheme helped the students who participated in the experiment to improve their academic performance by nearly 30 points. While maintaining the interest in Chinese language, the accuracy of spam article recognition algorithm is more than 85%, and the highest result can reach 94.5%.
Comparative Assessment of Compression Strength of Solid Biobriquette using Different Binding Materials
Authors: Bency P. , Anish M. , Jayaprakash V. , Jayaprabakar J. , Yanmaz Ekrem , Joy Nivin , Ramulu Perumalla Janaki
Published: April 2023

Charcoal and firewood are the most common cooking fuels, despite the fact that they represent a variety of social and economic environmental difficulties in many affluent countries. Apart from the environmental implications of deforestation and resource loss, indoor air pollution caused by cooking with solid fuels causes 2 million fatalities each year. Biobriquettes are then utilized as a substitute for oils. Briquettes are also employed as carbon sources for cooking in various industries such as power plants, brick factories, and bakeries. Five specific binding materials were tested in this study for manual densification of cabbage waste, including beef tallow oil, starch, cassava binder, sodium silicate, and vinyl ester resin. The briquettes are made from a combination of 80% densified biological waste and 20% binder material. The sample density ranges from 545.564 to 591.278 kg/m3. The samples with the highest calorific value were beef tallow oil and vinyl ester resin, which had 5,357.26 and 5,800.79 kcal/kg respectively. The content of the samples were ashes, fixed carbon content, volatile material, and total humidity is 6.47% ± 1.13%, 18.43% ± 6%, 70.68% ± 6%, and 4.42% ± 4%, respectively. The sample with the most calorific value and densification is the one with the inorganic binder mixture.
Solving Differential Equation via Orthogonal Branciari Metric Spaces
Authors: Prakasam Senthil Kumar , Gnanaprakasam Arul Joseph , Mani Gunaseelan , Kumar Santosh
Published: April 2023

In this paper, we investigate an orthogonal

L

⋆

-contraction map concept and prove the fixed-point theorem in an orthogonal complete Branciari metric space (OCBMS). We also provide illustrative examples to support our theorems. We demonstrated the existence of a uniqueness solution to the fourth-order differential equation using a more orthogonal

L

⋆

contraction operator in OCBMS as an application of the main results.
Thymus linearis Extracts Ameliorate Indices of Metabolic Syndrome in Sprague Dawley Rats
Authors: Younatan Yamema , Majid Muhammad , Phull Abdul Rehman , Baig Muhammad Waleed , Irshad Nadeem , Fatima Humaira , Nasir Bakht , Zafar Aroosa , Majid Abdul , Parveen Amna , Haq Ihsan-ul
Published: April 2023

Ethnopharmacological Relevance. Thymus linearis Benth. in Wall is extensively used and sold in Gilgit Baltistan province of Pakistan for the amelioration of conditions like obesity and diabetes. However, this ethnomedicinal use still lacks any scientific backing. Based upon this traditional use, the present study was designed to scientifically validate its role in the prevention of metabolic syndrome. Materials and Methods. The extract library (n-hexane (NH), ethyl acetate (EA), methanol (M), distilled water (DW), and combined extract (CE)) was standardized using in vitro phytochemical, antioxidant, and α-amylase inhibition assays, after which the protective effect of selected “hit,” i.e., CE against metabolic syndrome, was determined in vivo, using rats fed a high-fat diet supplemented with additional cholesterol administration. CE was administered to Sprague Dawley rats in high dose as 100 mg/kg in carboxymethyl cellulose (CMC) (1 ml; 0.75% in DW) and low-dose group as 50 mg/kg in CMC (0.5 ml; 0.75% in DW). After 10 weeks, the effects of CE on insulin resistance, lipid metabolism, nonalcoholic fatty liver disease (NAFLD), oxidative stress, and genotoxicity were assessed through histological, biochemical, and hematological investigations. Results. Phytochemical analysis including RP-HPLC analysis of the extracts showed that flavonoids and phenolics (myricetin, kaempferol, and apigenin), previously known to be effective against obesity and diabetes, are present in the extracts. Antioxidant studies revealed that the plant possesses a highly significant (

p
<
0.05

) concentration of antioxidants. Satisfactory α-amylase inhibitory activity was also observed in in vitro experiments. In vivo studies showed that CE-administered animals had significantly (

p
<
0.05

) lower weight gain and smaller adipocytes than the control group. Moreover, CE resisted any significant (

p
<
0.05

) change in the organ weights. Analogous to findings from its traditional use, the plant extract had a positive modulatory effect on insulin resistance and hyperglycemia. The study also indicated that CE resisted high-fat diet-induced disturbance in lipid profile and countered any pathological changes in liver enzymes caused by fat-infused diet. Furthermore, a study on endogenous antioxidant levels indicated that CE was effective in maintaining catalase and peroxidase levels within the normal range and resisted the effects of lipid peroxidation of thiobarbituric acid reactive substances. Conclusion. In principle, the current study’s findings scientifically validate the implication of T. linearis in metabolic syndrome and recommend further studies on molecular insights of the observed therapeutic activity.
Integrating Solar Photovoltaic Power Source and Biogas Energy-Based System for Increasing Access to Electricity in Rural Areas of Tanzania
Authors: Mwakitalima Isaka J. , Rizwan Mohammad , Kumar Narendra
Published: April 2023

Renewable energy is the best option for the challenge of dwindling natural resources and energy scarcity. The utilization of solar photovoltaic (PV) systems is the best option for eliminating the energy deficit in Tanzania due to the available great potential of solar energy. Animal manure is a significant source of waste in rural locations which can be transformed into biogas fuel by an anaerobic process. Livestock and agriculture greatly support economically the majority of the sub-Saharan African (SSA) region’s rural population including Tanzania, and excreta from cattle are beneficial for biogas fuel production. Unfortunately, the high potential of animal waste for generating electricity is underutilized. Integrating solar energy sources and biogas fuel derived from animal manure is useful for mitigating energy shortage, power instability, and environmental issues. Off-grid solar PV biogas-based hybrid microgrid systems for rural electrification applications in the Tanzanian environment are limited, and also, most of the studies are extensively carried out using soft computing tools especially hybrid optimization of multiple energy resources (HOMER) software with limited applications of artificial intelligence (AI) optimization techniques. This paper presents technoeconomic viability analysis for a hybrid renewable energy supply system (HRESS) for the Simboya village in Mbeya region, Tanzania. Off-grid HRESS is designed and optimized to meet the load of the chosen location executed using HOMER software and the grey wolf optimization (GWO) method. The microgrid is anticipated to supply daily maximum demand of 63.41 kW. The residential load profile equals 30 kW representing 50% of the daily demand. Optimization results by the HOMER platform indicate that the system has a total net present cost (NPC) and levelized cost of energy (LCOE) of $106,383.50 and $0.1109/kWh, respectively. Furthermore, this paper presents the optimization and sensitivity analysis results acquired by the GWO method under varied values of Loss of Electrical Power Probability (LEPP). Total NPC and LCOE based on LEPP values of 0, 0.04, and 0.06 are $85,106.8, $79,545.99, and $71,747.36 and $0.0887/kWh, $0.0316/kWh, and $0.0102/kWh, respectively. HRESS is economically and environmentally beneficial for supplying electricity to the selected area and worldwide in similar situations.
The Impacts of the Multiscale Built Environment on Commuting Mode Choice: Spatial Heterogeneity, Moderating Effects, and Implications for Demand Estimation
Authors: Jian Wenliang , Liu Xiaoxiao , Liu Hao , Hu Yongshi , Gao Liangpeng
Published: April 2023

Promoting the usage of sustainable commuting modes requires in-depth understanding about residents’ commuting mode choice behavior. This study presents an empirical study to investigate the relationship between the built environment and commuting mode choice using CLDS 2016 cross-city questionnaire data. Several multilevel multinomial logit models including the null model, base model, and moderating effect model are developed to analyze the effects of built environments at both city and neighborhood levels on commuting mode choice. Estimation results of the null model reveal the significant spatial heterogeneities in commuting mode choice across different cities and different neighborhoods within a specific city. We then explore the potential built environment variables yielding the spatial heterogeneity via the base model. Results show that the built environment at the city level (including the urbanization rate, number of public transportation vehicles, metro operating mileage, GDP, city population density, and road area per capita) and neighborhood level (including neighborhood population density, air quality, neighborhood location, and land use diversity) could partially explain the spatial heterogeneities in commuting mode choice. In addition, the moderating effects of these built environments on the link between commuting time and commuting mode choice are examined. Results imply that the urbanization rate and neighborhood population density moderate the effect of commuting time on choosing nonmotorized modes, while neighborhood location moderates the effect of commuting time on choosing public transit. Also, the mode shares of nonmotorized mode and public transit under different levels of commuting time are estimated in different built environment contexts. The findings of this study are expected to provide serviceable support for urban planning and transportation policy making.
Figure S4 from Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer
Authors: Sperger Jamie M. , Helzer Kyle T. , Stahlfeld Charlotte N. , Jiang Dawei , Singh Anupama , Kaufmann Katherine R. , Niles David J. , Heninger Erika , Rydzewski Nicholas R. , Wang Liguo , Wang Liewei , Yang Rendong , Ren Yanan , Engle Jonathan W. , Huang Peng , Kyriakopoulos Christos E. , Slovin Susan F. , Soule Howard R. , Zhao Shuang G. , Kohli Manish , Tagawa Scott T. , Cai Weibo , Dehm Scott M. , Lang Joshua M.
Published: April 2023

Figure S4. Biodistribution Study
Supplementary Tables 1 from Proteostasis Modulation in Germline Missense von Hippel Lindau Disease
Authors: Chittiboina Prashant , Mandal Debjani , Bugarini Alejandro , Asuzu David T. , Mullaney Dustin , Mastorakos Panagiotis , Stoica Stefan , Alvarez Reinier , Scott Gretchen , Maric Dragan , Elkahloun Abdel , Zhuang Zhengping , Chew Emily Y. , Yang Chunzhang , Linehan Marston , Lonser Russell R.
Published: April 2023

Supplementary tables in tabs.
Figure S3 from Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer
Authors: Sperger Jamie M. , Helzer Kyle T. , Stahlfeld Charlotte N. , Jiang Dawei , Singh Anupama , Kaufmann Katherine R. , Niles David J. , Heninger Erika , Rydzewski Nicholas R. , Wang Liguo , Wang Liewei , Yang Rendong , Ren Yanan , Engle Jonathan W. , Huang Peng , Kyriakopoulos Christos E. , Slovin Susan F. , Soule Howard R. , Zhao Shuang G. , Kohli Manish , Tagawa Scott T. , Cai Weibo , Dehm Scott M. , Lang Joshua M.
Published: April 2023

Figure S3. Scatter plot of gene expression for genes shown in Figure 3D isolated from matched anti-EPCAM vs anti-TROP-2 captured CTCs at the same timepoint.
Figure S1 from Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer
Authors: Sperger Jamie M. , Helzer Kyle T. , Stahlfeld Charlotte N. , Jiang Dawei , Singh Anupama , Kaufmann Katherine R. , Niles David J. , Heninger Erika , Rydzewski Nicholas R. , Wang Liguo , Wang Liewei , Yang Rendong , Ren Yanan , Engle Jonathan W. , Huang Peng , Kyriakopoulos Christos E. , Slovin Susan F. , Soule Howard R. , Zhao Shuang G. , Kohli Manish , Tagawa Scott T. , Cai Weibo , Dehm Scott M. , Lang Joshua M.
Published: April 2023

Figure S1. Correlation of TACSTD2 with Prostate Cancer Cell Surface Markers.
Supplementary Data from Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
Authors: Meric-Bernstam Funda , Sweis Randy F. , Hodi F. Stephen , Messersmith Wells A. , Andtbacka Robert H.I. , Ingham Matthew , Lewis Nancy , Chen Xinhui , Pelletier Marc , Chen Xueying , Wu Jincheng , Dubensky Thomas W. , McWhirter Sarah M. , Müller Thomas , Nair Nitya , Luke Jason J.
Published: April 2023

Supplementary tables and figure legends
Figure S2 from Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
Authors: Meric-Bernstam Funda , Sweis Randy F. , Hodi F. Stephen , Messersmith Wells A. , Andtbacka Robert H.I. , Ingham Matthew , Lewis Nancy , Chen Xinhui , Pelletier Marc , Chen Xueying , Wu Jincheng , Dubensky Thomas W. , McWhirter Sarah M. , Müller Thomas , Nair Nitya , Luke Jason J.
Published: April 2023

Pre- and on-treatment images of injected lesions from patients with a confirmed or unconfirmed response
Supplementary Data from EBV-Upregulated B7-H3 Inhibits NK cell–Mediated Antitumor Function and Contributes to Nasopharyngeal Carcinoma Progression
Authors: Chen Haiwen , Duan Xiaobing , Deng Xiaohong , Huang Yingping , Zhou Xiang , Zhang Shanshan , Zhang Xiao , Liu Pingjuan , Yang Chaopin , Liu Guojun , Ren Qinqin , Xiong Yan , Zhu Bo , Zhang Jiexia , Xiang Tong
Published: April 2023

Supplementary Figures and Tables
Data from Anti–PD-1 and Extended Half-life IL2 Synergize for Treatment of Murine Glioblastoma Independent of Host MHC Class I Expression
Authors: Tritz Zachariah P. , Ayasoufi Katayoun , Wolf Delaney M. , Owens Carley A. , Malo Courtney S. , Himes Benjamin T. , Fain Cori E. , Goddery Emma N. , Yokanovich Lila T. , Jin Fang , Hansen Michael J. , Parney Ian F. , Wang Chensu , Moynihan Kelly D. , Irvine Darrell J. , Wittrup K. Dane , Diaz Marcano Rosa M. , Vile Richard G. , Johnson Aaron J.
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite preclinical successes, most interventions have failed to extend patient survival by more than a few months. Treatment with anti—programmed cell death protein 1 (anti–PD-1) immune checkpoint blockade (ICB) monotherapy has been beneficial for malignant tumors such as melanoma and lung cancers but has yet to be effectively employed in GBM. This study aimed to determine whether supplementing anti–PD-1 ICB with engineered extended half-life IL2, a potent lymphoproliferative cytokine, could improve outcomes. This combination therapy, subsequently referred to as enhanced checkpoint blockade (ECB), delivered intraperitoneally, reliably cures approximately 50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extends median survival of the treated cohort. In the CT2A model, characterized as being resistant to CBI, ECB caused a decrease in CT2A tumor volume in half of measured animals similar to what was observed in GL261-bearing mice, promoting a trending survival increase. ECB generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Through employment of depletion strategies, ECB's efficacy was shown to be independent of host MHC class I–restricted antigen presentation but reliant on CD4 T cells. These results demonstrate ECB is efficacious against the GL261 glioma model through an MHC class I–independent mechanism and supporting further investigation into IL2-supplemented ICB therapies for tumors of the central nervous system.
FIGURE 6 from Uncovering the Protective Neurologic Mechanisms of Hypofractionated FLASH Radiotherapy
Authors: Alaghband Yasaman , Allen Barrett D. , Kramár Eniko A. , Zhang Richard , Drayson Olivia G.G. , Ru Ning , Petit Benoit , Almeida Aymeric , Doan Ngoc-Lien , Wood Marcelo A. , Baulch Janet E. , Ballesteros-Zebadua Paola , Vozenin Marie-Catherine , Limoli Charles L.
Published: April 2023

FLASH irradiation protected against prolonged inflammation found in CONV mice, 6 months after irradiation. Representative images of reactive microglia CD68 (red) and DAPI (blue) in the male mouse hippocampus (A) and representative images of IBA1 (green), TLR4 (red), and DAPI (blue; Scale bar = 100 μm; B). C, Quantification of CD68 immunofluorescence in the hippocampus and medial prefrontal cortex. Male (left) and female (right) mice exposed to FLASH-RT exhibit no significant change in CD68 expression while CONV mice expressed a neuroinflammatory response. D, Quantification of IBA1 and TLR4 colocalization in the hippocampus and medial prefrontal cortex. Male and female mice exhibited decreased levels of the neuroinflammatory mediator TLR4 when compared with CONV irradiation. E, Inflammatory cytokines measured using ELISA. IL1α exhibited elevated expression after CONV-RT exposure when compared with controls while FLASH induced no changes. No significant changes were observed in TNFα or IL1β. All data were analyzed using a one-way ANOVA followed by Bonferroni multiple comparison test (n = 4/sex/treatment, two sections analyzed/region/animal). *, P ≤ 0.05; **, P ≤ 0.01; ****, P ≤ 0.0001.
Supplementary Table S1 from A very long-acting exatecan and its synergism with DNA damage response inhibitors
Authors: Fontaine Shaun D , Carreras Christopher W , Reid Ralph R , Ashley Gary W , Santi Daniel V
Published: April 2023

In vitro t1/2 values for cleavage of PEG-Exa (3A).
Data from A very long-acting exatecan and its synergism with DNA damage response inhibitors
Authors: Fontaine Shaun D , Carreras Christopher W , Reid Ralph R , Ashley Gary W , Santi Daniel V
Published: April 2023

Abstract
Exatecan is a very potent inhibitor of topoisomerase I and anticancer agent. It has been intensively studied as a single agent, a large macromolecular-conjugate and as the payload component of antigen-dependent antibody-drug conjugates. The present work describes an antigen-independent conjugate of exatecan with polyethylene glycol (PEG) that slowly releases free exatecan. Exatecan was conjugated to a 4-arm 40kDa PEG through a β-eliminative cleavable linker. Pharmacokinetic studies in mice showed that the conjugate has an apparent circulating half-life of 12 h, which reflects a composite of both the rate of renal elimination (half-life ~18 h) and release of exatecan (half-life ~40 h). Remarkably, a single low dose of 10 μmol/kg PEG-Exa – only ~0.2 μmol/mouse – caused complete suppression of tumor growth of BRCA1-deficient MX-1 xenografts lasting over 40 d. A single low dose of 2.5 μmol/kg PEG-exatecan administered with low but efficacious doses of the PARPi talazoparib showed strong synergy and caused significant tumor regression. Further, the same low, single dose of PEG-exatecan administered with the ATRi VX970 at doses of the DNA damage response inhibitor that do not affect tumor growth show high tumor regression, strong synergy and synthetic lethality.
Expression of Toll-Like Receptors in the Lung Tissue of Mouse Fetuses Generated by in vitro Embryo Culture and Embryo Transfer
Authors: Doğan Göksel , Karagenç Nedim , Esmen Kerem , Kul Bengi Çınar , Yeşilkaya Hasan , Akgün Şakir , Orman Mehmet Nurullah , Sandıkçı Mustafa , Eren Ülker , Ünsal Hümeyra , Karagenç Levent
Published: April 2023

Mouse fetuses generated by in vitro embryo culture and embryo transfer exhibit impaired lung development, altered composition of pulmonary epithelial cells associated with downregulation of several genes involved in lung development and toll-like receptor (TLR) signaling pathway. The aims of the present study were to determine the expression of all TLRs and to examine if the expression of TLRs, along with genes involved in TLR signaling pathway, is altered in the lung tissue of mouse fetuses generated through embryo culture and embryo transfer. Two experimental (EGs) and one control (CG) group were included in the study. Embryos cultured at 5% CO2-95% air for 95 h or less than 24 h were transferred to pseudo-pregnant females to obtain fetuses comprising EGin vitro (n = 18) and EGin vivo (n = 18), respectively. Fetuses obtained from naturally ovulating females on day 18 of pregnancy served as the CG (n = 18). Western blot and immunohistochemistry were used to determine the expression of TLR proteins. The expression of transcripts encoding TLRs, and the genes involved in TLR signaling pathway (Lbp, Pik3r1, Pik3cb, Nfkbia, and Fos), was determined using qRT-PCR. While all TLRs were expressed by cells lining the bronchial/bronchiolar epithelium of lung tissues in all groups, some of the TLRs were expressed in a specific pattern. When compared to CG, the expression of transcripts encoding TLR-2, -3, -4, -5, -7, -8, -9, -12, -13, Lbp, Pik3r1, Pik3cb, Nfkbia, and Fos was significantly downregulated in both EGs. It appears that stress imposed on embryos at preimplantation stages of development is associated with downregulation of TLRs, along with some of the genes involved in TLR signaling pathway, in the lung tissue during the perinatal period. It remains to be determined if downregulation of TLRs, along with the genes involved in TLR signaling pathway, has any functional consequences in the adult lung tissue.
Increased Serum EphrinA1 Is Associated with Parenchymal Hematoma after Ischemic Stroke
Authors: Wu Xinmao , Tao Wendan , Wang Yanan , Wu Qian , Ye Chen , Song Xindi , Guo Xiaonan , Liu Junfeng
Published: April 2023

Introduction: Previous preclinical studies reported that the level of serum EphrinA1 was associated with blood-brain barrier disruption; however, its role in predicting parenchymal hematoma (PH) after ischemic stroke is underexplored. We aimed to explore the association between the level of serum EphrinA1 and PH in patients with ischemic stroke. Methods: Patients with ischemic stroke after onset from West China Hospital, Sichuan University, were prospectively enrolled between January 2017 and December 2019. The level of serum EphrinA1 at baseline was measured after admission. PH was diagnosed as hematoma within the infarct territory detected on the brain CT/MRI scans within 7 days after onset but not on the initial scan according to European Cooperative Acute Stroke Study (ECASS) III criteria. The association between the level of serum EphrinA1 and PH after ischemic stroke was assessed by multiple logistic regression analysis. Results: A total of 667 patients were included in the final analysis. The mean age was 67.20 ± 14.31 years, and 57.87% (368/667) were males. Of the 667 patients, 65 (9.75%) patients had PH. The median of EphrinA1 on admission was 82.83 ng/mL (IQR, 70.11–93.75 ng/mL). Compared with patients without PH, those with PH had a higher level of serum EphrinA1 (p = 0.024). Patients were divided into 3 categories based on EphrinA1 tertiles (T1, <79.11 ng/mL, n = 223; T2, 79.11–93.75 ng/mL, n = 222; and T3, >93.75 ng/mL, n = 222). After adjusting for age, sex, atrial fibrillation, smoking, statins, antiplatelets, Trail of Org 10172 in Acute Stroke Treatment (TOAST) classification and National Institutes of Health Stroke Scale (NIHSS) score ≥15, patients in the second and third EphrinA1 tertiles showed a significant increase in PH compared with those in the lowest tertile (OR 2.44, 95% CI: 1.10–5.40, p = 0.028; OR 2.61, 95% CI: 1.19–5.74, p = 0.017, respectively). Additionally, adjusting for reperfusion therapy (thrombolysis and/or endovascular therapy), only patients in the highest group (tertile 3) had a significantly higher risk of PH compared to the lowest group (OR 2.30, 95% CI: 1.03–5.13, p = 0.042). Conclusion: Higher serum EphrinA1 is independently associated with a higher risk of PH after ischemic stroke. Future studies with larger sample sizes are needed to validate our findings and elucidate the potential role of EphrinA1 in PH.
“Fazer à sua custa” em busca das mercês prometidas: a iniciativa particular dos sertanistas Antônio Pires de Campos e Antônio Gomes Leite nas guerras contra os povos Jê e na criação de aldeias coloniais nos sertões de Goiás e Piauí - 1742-1751
Authors: Mori Robert
Published: April 2023

Em meados do século XVIII, a expansão dos luso-brasileiros afetou os povos Jê que viviam nos sertões de Goiás e do Piauí. Para tentar conter as incursões guerreiras indígenas, a Coroa portuguesa contratou Antônio Pires de Campos e Antônio Gomes Leite visando a prática de guerras, assim como seus pactos e a criação de aldeamentos a partir da iniciativa particular, ou seja, dos sertanistas. Dessa forma, a partir dos indícios das fontes e da literatura especializada, discutimos as práticas desses homens e dos soldados indígenas que capitaneavam. Sustentamos a tese de que suas ações, para além da busca das mercês prometidas, tiveram papel direto no genocídio, na conquista de territórios e na gestão do trabalho indígena via administração; e indireto, na expansão e na consolidação das fronteiras portuguesas a partir de Goiás e de Mato Grosso.
A inscrição de Behistun (c. 520 a.C.): tradução do texto Persa Antigo para o Português, introdução crítica e comentários
Authors: Araujo Matheus Treuk Medeiros de
Published: April 2023

A inscrição monumental Aquemênida no monte Behistun (Bisitun), na província iraniana do Kermanshah (oeste do Irã), narra a versão oficial da ascensão de Dario ao poder na Pérsia Antiga. Em três línguas e grafias (persa antigo, elamita e acadiano), este inestimável documento histórico foi essencial para a decifração do cuneiforme no século XIX. Ele também se prestou à reconstrução da história do Império Aquemênida, anteriormente conhecida mormente graças aos relatos das fontes gregas e bíblicas. Devido à relevância e singularidade da Inscrição de Behistun, propõe-se uma tradução direta do persa antigo para o português, ampliando o acesso do público leigo e especializado ao documento. Comentários históricos abordando as principais discussões relativas à inscrição acompanham o texto.
As reflexões sobre a reforma administrativa ultramarina em Portugal (1950-1967)
Authors: Azevedo Ana Carina
Published: April 2023

Este artigo examina as reflexões sobre as possibilidades de aplicação no Ultramar dos princípios de reforma da Administração Pública estudados na Metrópole. A análise se inicia na década de 1950, abordando as lógicas de planificação económica e termina em 1967, ano em que é criado o Secretariado da Reforma Administrativa, o primeiro órgão central coordenador da reforma. Tratando-se de um estudo inovador de uma temática ainda pouco abordada pela historiografia, a investigação recorreu a uma vasta lista de fontes arquivísticas. Estas são oriundas, sobretudo, dos Ministérios das Finanças e Ambiente, que guardam, respetivamente, a documentação produzida pelos órgãos de estudo da reforma administrativa e o arquivo do planeamento económico. Recorre, também, a uma variedade de fontes impressas publicadas pelos organismos em análise.
Elevated LDL Cholesterol Increases Microvascular Endothelial VWF and Thromboinflammation After Myocardial Infarction
Authors: Ozawa Koya , Packwood William , Varlamov Oleg , Muller Matthew , Xie Aris , Wu Melinda D. , Abraham-Fan Rue-Jen , López José A. , Lindner Jonathan R.
Published: April 2023

Background:

In reperfused myocardial infarction, VWF (von Willebrand factor)-mediated platelet adhesion contributes to impaired microvascular reflow and possibly also to postmyocardial infarction inflammation. We hypothesized that postischemic thromboinflammatory processes are worsened by elevated LDL (low-density lipoprotein) cholesterol.

Methods:

Myocardial ischemia-reperfusion or sham procedure was performed in wild-type mice and hyperlipidemic mice deficient for the LDL receptor and Apobec-1 (apolipoprotein-B mRNA editing enzyme catalytic polypeptide-1; DKO [double knockout]). DKO subgroups were treated with N-acetylcysteine, which inhibits pro-adhesive VWF multimers or with recombinant ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs-13), which enzymatically cleaves endothelial surface-associated VWF. Myocardial contrast echocardiography perfusion imaging and molecular imaging for VWF, platelet glycoprotein Ibα, and leukocyte CD18 (cluster of differentiation) were performed 30 minutes post-reperfusion. Histology, infarct sizing, and echocardiography were performed at 1.5 or 72 hours; late echocardiography was performed at day 21.

Results:

After ischemia-reperfusion, DKO compared with wild-type mice had ≈2-fold higher (
P
<0.05) risk area signal for microvascular platelet adhesion, VWF, and CD18; greater impairment in microvascular reflow, and 2-fold larger infarct size. Treatment of DKO mice with N-acetylcysteine and ADAMTS13 reduced molecular imaging signal for microvascular platelet adhesion, VWF, and CD18; improved early microvascular reflow; and reduced eventual infarct size. ADAMTS13 suppressed the postmyocardial infarction neutrophil and monocyte infiltration, enhanced the time-dependent recovery of left ventricular systolic function, and prevented late left ventricular remodeling.

Conclusions:

In reperfused myocardial infarction, elevated LDL cholesterol promotes thromboinflammation through excess microvascular endothelial VWF and platelet adhesion, resulting in less microvascular reflow and larger infarct size. In the presence of elevated LDL cholesterol, therapies that suppress endothelial-associated VWF can promote recovery of left ventricular function and protect against remodeling.
Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors
Authors: Khachigian Levon M. , Varcoe Ramon L. , Suoranta Tuisku , Laham-Karam Nihay , Ylä-Herttuala Seppo
Published: April 2023

Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected. PAD remains a growing global health problem as the population continues to age and diabetes incidence grows. Many patients with PAD, most notably those with critical limb ischemia, fail attempts at surgical and percutaneous intervention to improve blood flow and are at risk of amputation. Gene therapy provides an opportunity to change the clinical course of PAD in these patients via strategies that increase vascular supply through angiogenesis and arteriogenesis improving muscle perfusion and function in ischemic legs. This article discusses gene therapy approaches in the context of PAD, both intermittent claudication and critical limb ischemia, and the promise of adeno-associated virus–based strategies delivering not just VEGFs (vascular endothelial growth factors) but a range of other mediators as potential new therapeutics. We also highlight challenges and failures in the clinical translation of gene therapy for PAD and how at least some of these obstacles may be overcome using adeno-associated virus.
Effect of Total SMS Activity on LDL Catabolism in Mice
Authors: Li Zhiqiang , He Mulin , Chen Guangzhi , Souaiaia Tade , Worgall Tilla S. , Jiang Xian-Cheng
Published: April 2023

Background:

Sphingomyelin (SM) and cholesterol are 2 key lipid partners on cell membranes and on lipoproteins. Many studies have indicated the influence of cholesterol on SM metabolism. This study examined the influence of SM biosynthesis on cholesterol metabolism.

Methods:

Inducible global
Sms1
KO (knockout)/global
Sms2
KO mice were prepared to evaluate the effect of whole-body SM biosynthesis deficiency on lipoprotein metabolism. Tissue cholesterol, SM, ceramide, and glucosylceramide levels were measured. Triglyceride production rate and LDL (low-density lipoprotein) catabolism were measured. Lipid rafts were isolated and LDL receptor mass and function were evaluated. Also, the effects of exogenous sphingolipids on hepatocytes were investigated.

Results:

We found that total SMS (SM synthase) depletion significantly reduced plasma SM levels. Also, the total deficiency significantly induced plasma cholesterol, apoB (apolipoprotein B), and apoE (apolipoprotein E) levels. Importantly, total SMS deficiency, but not SMS2 deficiency, dramatically decreased LDL receptors in the liver and attenuated LDL uptake through the receptor. Further, we found that total SMS deficiency greatly reduced LDL receptors in the lipid rafts, which contained significantly lower SM and significantly higher glucosylceramide, as well as cholesterol. Furthermore, we treated primary hepatocytes and Huh7 cells (a human hepatoma cell line) with SM, ceramide, or glucosylceramide, and we found that only SM could upregulate LDL receptor levels in a dose-dependent fashion.

Conclusions:

Whole-body SM biosynthesis plays an important role in LDL cholesterol catabolism. The total SMS deficiency, but not SMS2 deficiency, reduces LDL uptake and causes LDL cholesterol accumulation in the circulation. Given the fact that serum SM level is a risk factor for cardiovascular diseases, inhibiting SMS2 but not SMS1 should be the desirable approach.
Additive Effect of
APOE
Rare Variants on the Phenotype of Familial Hypercholesterolemia
Authors: Marmontel Oriane , Abou-Khalil Yara , Bluteau Olivier , Cariou Bertrand , Carreau Valérie , Charrière Sybil , Divry Eléonore , Gallo Antonio , Moulin Philippe , Paillard François , Peretti Noel , Rabès Jean-Pierre , Varret Mathilde , Carrié Alain , Di Filippo Mathilde
Published: April 2023

Background:

Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in
LDLR
,
APOB
, or
PCSK9
genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in
APOE
. Here we study the phenotype of 21 adult patients, double heterozygotes for rare
LDLR
and rare
APOE
variants (
LDLR+APOE
) in a national wide French cohort.

Methods:

LDLR
,
APOB
,
PCSK9
, and
APOE
genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the
LDLR+APOE
carriers (n=21) and the carriers of the same
LDLR
causative variants alone (n=22).

Results:

The prevalence of
LDLR+APOE
carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in
LDLR+APOE
patients than in
LDLR
patients (9.14±2.51 versus 7.43±1.59 mmol/L,
P=0
.0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in
LDLR+APOE
carriers than in
LDLR
carriers (10.83±3.45 versus 7.43±1.59 mmol/L,
P=0
.0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in
LDLR+APOE
patients than in
LDLR
carriers (70% versus 30%,
P=0
.026).

Conclusions:

Although an incomplete penetrance should be taken into account for
APOE
variant classification, these results suggest an additive effect of deleterious
APOE
variants on ADH phenotype highlighting the relevance of
APOE
sequencing.
Popular Dietary Patterns: Alignment With American Heart Association 2021 Dietary Guidance: A Scientific Statement From the American Heart Association
Authors: Gardner Christopher D. , Vadiveloo Maya K. , Petersen Kristina S. , Anderson Cheryl A.M. , Springfield Sparkle , Van Horn Linda , Khera Amit , Lamendola Cindy , Mayo Shawyntee M. , Joseph Joshua J. ,   on behalf of the American Heart Association Council on Lifestyle and Cardiometabolic Health
Published: April 2023

The evolution of dietary guidelines from isolated nutrients to broader dietary pattern recommendations results from growing knowledge of the synergy between nutrients and their food sources as they influence health. Macronutrient and micronutrient needs can be met by consuming various dietary patterns, but guidance is often required to facilitate population-wide adherence to wise food choices to achieve a healthy dietary pattern. This is particularly true in this era with the proliferation of nutrition misinformation and misplaced emphasis. In 2021, the American Heart Association issued a scientific statement outlining key principles of a heart-healthy dietary pattern that could be operationalized in various ways. The objective of this scientific statement is to assess alignment of commonly practiced US dietary patterns with the recently published American Heart Association criteria, to determine clinical and cultural factors that affect long-term adherence, and to propose approaches for adoption of healthy dietary patterns. This scientific statement is intended to serve as a tool for clinicians and consumers to evaluate whether these popular dietary pattern(s) promote cardiometabolic health and suggests factors to consider when adopting any pattern to improve alignment with the 2021 American Heart Association Dietary Guidance. Numerous patterns strongly aligned with 2021 American Heart Association Dietary Guidance (ie, Mediterranean, DASH [Dietary Approaches to Stop Hypertension], pescetarian, vegetarian) can be adapted to reflect personal and cultural preferences and budgetary constraints. Thus, optimal cardiovascular health would be best supported by developing a food environment that supports adherence to these patterns wherever food is prepared or consumed.
Electronic Nicotine Delivery Systems and Cardiovascular/Cardiometabolic Health
Authors: Mears Matthew J. , Hookfin Harrison L. , Bandaru Priya , Vidal Pablo , Stanford Kristin I. , Wold Loren E.
Published: April 2023

The use of electronic nicotine delivery systems, specifically electronic cigarettes (e-cig), has risen dramatically within the last few years; the demographic purchasing these devices is now predominantly adolescents that are not trying to quit the use of traditional combustible cigarettes, but rather are new users. The composition and appearance of these devices has changed since their first entry into the market in the late 2000s, but they remain composed of a battery and aerosol delivery system that is used to deliver breakdown products of propylene glycol/vegetable glycerin, flavorings, and potentially nicotine or other additives. Manufacturers have also adjusted the type of nicotine that is used within the liquid to make the inhalation more palatable for younger users, further affecting the number of youth who use these devices. Although the full spectrum of cardiovascular and cardiometabolic consequences of e-cig use is not fully appreciated, data is beginning to show that e-cigs can cause both short- and long-term issues on cardiac function, vascular integrity and cardiometabolic issues. This review will provide an overview of the cardiovascular, cardiometabolic, and vascular implications of the use of e-cigs, and the potential short- and long-term health effects. A robust understanding of these effects is important in order to inform policy makers on the dangers of e-cigs use.
Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT‐AF II
Authors: Yao Ren Jie Robert , Holmes DaJuanicia N. , Andrade Jason G. , Levin Adeera , Piccini Jonathan P. , Fordyce Christopher B.
Published: April 2023

Background

Nonvitamin K oral anticoagulants require dose adjustment based on kidney function.The most common estimate of kidney function employed in clinical practice is estimated glomerular filtration rate (eGFR); however, product monographs recommend the use of the Cockcroft‐Gault estimated creatinine clearance (eCrCl) for dose adjustment.

Methods and Results

The authors included patients enrolled in the ORBIT‐AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II) trial. Dosing was considered inappropriate when use of eGFR resulted in a lower (undertreatment) or higher (overtreatment) dose than that recommended by the eCrCl. The primary outcome of major adverse cardiovascular and neurological events was a composite of cardiovascular death, stroke or systemic embolism, new‐onset heart failure, and myocardial infarction. Among 8727 in the overall cohort, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients. Among 2184 patients with chronic kidney disease (CKD), the agreement between eCrCl and eGFR was 79.9% to 80.7%. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban users, 5.7% of dabigatran users, and 4.6% apixaban users). At 1 year, undertreated patients in the CKD group had significantly greater major adverse cardiovascular and neurological events (adjusted hazard ratio, 2.93 [95% CI, 1.08–7.92]) compared with the group with appropriate nonvitamin K oral anticoagulants dosing (
P
=0.03).

Conclusions

The prevalence of misclassification of nonvitamin K oral anticoagulants dosing was high when using eGFR, particularly among patients with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off‐label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose adjustment in all patients with AF receiving nonvitamin K oral anticoagulants.
Impact of Neighborhood Socioeconomic Status on Outcomes Following First‐Stage Palliation of Single Ventricle Heart Disease
Authors: Sengupta Aditya , Bucholz Emily M. , Gauvreau Kimberlee , Newburger Jane W. , Schroeder Margaret , Kaza Aditya K. , del Nido Pedro J. , Nathan Meena
Published: April 2023

Background

The impact of neighborhood socioeconomic status (SES) on outcomes following first‐stage palliation of single ventricle heart disease remains incompletely characterized.

Methods and Results

This was a single‐center, retrospective review of consecutive patients who underwent the Norwood procedure from January 1, 1997 to November 11, 2017. Outcomes of interest included in‐hospital (early) mortality or transplant, postoperative hospital length‐of‐stay, inpatient cost, and postdischarge (late) mortality or transplant. The primary exposure was neighborhood SES, assessed using a composite score derived from 6 US census‐block group measures related to wealth, income, education, and occupation. Associations between SES and outcomes were assessed using logistic regression, generalized linear, or Cox proportional hazards models, adjusting for baseline patient‐related risk factors. Of 478 patients, there were 62 (13.0%) early deaths or transplants. Among 416 transplant‐free survivors at hospital discharge, median postoperative hospital length‐of‐stay and cost were 24 (interquartile range, 15–43) days and $295 000 (interquartile range, $193 000–$563 000), respectively. There were 97 (23.3%) late deaths or transplants. On multivariable analysis, patients in the lowest SES tertile had greater risk of early mortality or transplant (odds ratio [OR], 4.3 [95% CI, 2.0–9.4;
P
<0.001]), had longer hospitalizations (coefficient 0.4 [95% CI, 0.2–0.5;
P
<0.001]), incurred higher costs (coefficient 0.5 [95% CI, 0.3–0.7;
P
<0.001]), and had greater risk of late mortality or transplant (hazard ratio, 2.2 [95% CI, 1.3–3.7;
P
=0.004]), compared with those in the highest tertile. The risk of late mortality was partially attenuated with successful completion of home monitoring programs.

Conclusions

Lower neighborhood SES is associated with worse transplant‐free survival following the Norwood operation. This risk persists throughout the first decade of life and may be mitigated with successful completion of interstage surveillance programs.
Remote Cardiovascular Hypertension Program Enhanced Blood Pressure Control During the COVID‐19 Pandemic
Authors: Lee Simin Gharib , Blood Alexander J. , Cannon Christopher P. , Gordon William J. , Nichols Hunter , Zelle David , Scirica Benjamin M. , Fisher Naomi D. L.
Published: April 2023

Background

The COVID‐19 pandemic disrupted traditional health care; one fallout was a drastic decrease in blood pressure (BP) assessment. We analyzed the pandemic's impact on our existing remote hypertension management program's effectiveness and adaptability.

Methods and Results

This retrospective observational analysis evaluated BP control in an entirely remote management program before and during the pandemic. A team of pharmacists, nurse practitioners, physicians, and nonlicensed navigators used an evidence‐based clinical algorithm to optimize hypertensive treatment. The algorithm was adapted during the pandemic to simplify BP control. Overall, 1256 patients (605 enrolled in the 6 months before the pandemic shutdown in March 2020 and 651 in the 6 months after) were a median age of 63 years old, 57% female, and 38.2% non‐White. Among enrolled patients with sustained hypertension, 51.1% reached BP goals. Within this group, rates of achieving goal BP improved to 94.6% during the pandemic from 75.8% prepandemic (
P
<0.0001). Mean baseline home BP was 141.7/81.9 mm Hg during the pandemic and 139.8/82.2 prepandemic, and fell ≈16/9 mm Hg in both periods (
P
<0.0001). Maintenance during the pandemic was achieved earlier (median 11.8 versus 19.6 weeks,
P
<0.0001), with more frequent monthly calls (8.2 versus 3.1,
P
<0.0001) and more monthly home BP recordings per patient (32.4 versus 18.9,
P
<0.0001), compared with the prepandemic period.

Conclusions

A remote clinical management program was successfully adapted and delivered significant improvements in BP control and increased home BP monitoring despite a nationally observed disruption of traditional hypertension care. Such programs have the potential to transform hypertension management and care delivery.