bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Dynamic Splitting Method for Production Based on Material Balance Theory and Catastrophe Theory in Tight Gas Reservoirs
Authors: Hao Shengye , Qiu Xinyu , Liu Pengcheng , Chen Xiaoxia
Published: June 2021

Splitting methods play a significant role in the coproduction of tight reservoirs which are characterized by vertical multilayer superimposition. It directly affects the accuracy of reservoir performance analysis and detailed descriptions. However, conventional splitting methods are limited to a few factors and static factors without considering the effect of layer parameter change. In this study, sensitivity analysis was carried out on five factors that affect the production splitting in coproduction wells. The research shows that in the production process, multiple parameters have a direct impact on the production of layers. Different parameters, which have to be included to split production, have different scale effects on layer production. Comparing the results of the KH method with the numerical simulation results, the limitation of the KH method for yield splitting is illustrated. A novel dynamic splitting method for production (DPSM) was proposed. This method is based on two primary methods, which are the multifactor static method for production splitting of gas (GPSM) and water (WPSM) and use the catastrophe theory and material balance equation (MBE) and obtain the final results by iterative method. The advantage of this method is that more accurate results in the production process are obtained by selecting eight factors, which contain 6 static factors and 2 dynamic factors, for research. It is more in line with the production practice that the ultimate results of production splitting vary with the production process. The accuracy and practicality of the results had been verified by numerical simulation. This method has practical significance for production splitting in tight gas reservoirs.
Experimental Analysis of Bending Stiffness Characteristics of Grouted Double Mortise‐Tenon Joint for Prefabricated Metro Station Structure
Authors: Yang Xiuren , Lin Fang , Huang Meiqun
Published: June 2021

The grouted mortise‐tenon joint, invented as the connection between the large prefabricated components, is the key to the prefabricated underground structures, and the double‐tenon joint is most widely used in the prefabricated metro station structure. This paper conducts characteristic analysis of bending stiffness with a 1 : 1 prototype test in key working direction of different joint types for grouted double mortise‐tenon joint. The results show that the double‐tenon joint is characteristic of variable stiffness under different loads. Change laws of double‐tenon joint bending stiffness without and with auxiliary pretightening device in tension side and compression side are also discussed. The correlations for calculating double‐tenon joint bending stiffness with various axial loads and bending moments are derived at last, which offers the theory foreshadowing of similar joints.
Conjugated Hyperbilirubinemia in Infants: Is There Still a Role for ERCP?
Authors: Stovicek Jan , Hlava Stepan , Keil Radan , Drabek Jiri , Lochmannova Jindra , Koptová Petra , Wasserbauer Martin , Frybova Barbora , Snajdauf Jiri , Kotalova Radana , Rygl Michal
Published: June 2021

Over a twenty-year period, we performed 255 ERCP procedures in infants aged up to 1 year. ERCP was indicated in cholestatic infants with suspicion of biliary obstruction. The most common diagnosis was biliary atresia (48%), choledochal cysts (13%), and choledocholithiasis (4%). The procedure complication rate was 13.7%. Hyperamylasemia occurred in 12.9%. More severe complications were rare‐0.8% of ERCP procedure. There were no cases of postprocedural pancreatitis or death. Our study has proved that ERCP is a safe and reliable method in this age group. Its high specificity and negative predictive value for extrahepatic biliary atresia can prevent unnecessary surgeries in patients with normal bile ducts or endoscopically treatable pathologies.
P3H4 Overexpression Serves as a Prognostic Factor in Lung Adenocarcinoma
Authors: Jin Xiangfeng , Zhou Haiqing , Song Jianfang , Cui Hong , Luo Yiren , Jiang Haiping
Published: June 2021

Background. The present study is aimed at evaluating the functional and clinical values of P3H4 in lung adenocarcinoma. Moreover, we also investigated the downstream pathways that P3H4 might participate in. Methods. The differential expression analysis was used to identify genes differentially expressed in lung adenocarcinoma tissues as compared with normal tissues. Survival analysis was used to test the association between P3H4 and survival time. Gene set enrichment analysis was conducted to explore the downstream pathways. CCK8 and transwell were employed to examine the impact of P3H4 on cell phenotypes. Results. P3H4 was highly upregulated in LUAD tissues at both RNA and protein levels. Moreover, the LUAD patients, who had high expression of P3H4, were also observed to have shorter disease-free survival and overall survival. These results demonstrated that P3H4 could be used as a prognostic biomarker for LUAD. Moreover, we also found that it was the copy number alterations (CNAs), not DNA methylation, that regulated the RNA expression of P3H4, indicating that its upregulation might be partially resulted from the CNAs. Furthermore, functional experiments revealed that the A549 and H1299 cells with siRNA treatment (siP3H4) exhibited significantly decreased cell proliferation after 24 hours, migratory ability, and invasiveness. Functionally, the upregulated proteins in the P3H4 high expression group were mainly enriched in tumor microenvironment-related pathways such as phagosome, focal adhesion, and ECM-receptor interaction and cancer-related pathways such as bladder cancer pathway, proteoglycans in cancer, and hippo signaling pathway. Conclusion. The present study systematically evaluated the functional and clinical values of P3H4 in LUAD, and explored the related biological pathways. P3H4 might promote LUAD progression through regulating tumor microenvironment-related pathways.
Icariin Promotes Survival, Proliferation, and Differentiation of Neural Stem Cells In Vitro and in a Rat Model of Alzheimer’s Disease
Authors: Ma Denglei , Zhao Lihong , Zhang Li , Li Yali , Zhang Lan , Li Lin
Published: June 2021

Alzheimer’s disease (AD) involves the degeneration of cholinergic neurons in the basal forebrain. Neural stem cell (NSC) transplantation has emerged as a promising therapeutic approach for treating AD. Icariin (ICA) is the main active component in Epimedium, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of ICA on the proliferation and differentiation of NSCs in the basal forebrain of a fimbria-fornix transection (FFT) rat model. In the present study, ICA promoted the survival, proliferation, and migration of NSCs in vitro. In FFT rats, ICA promoted the proliferation and differentiation of NSCs into neurons and increased the number of cholinergic neurons in the MS and VDB of the basal forebrain. These results suggest that combination therapy of ICA oral administration and NSC transplantation may provide a new potential and effective approach for AD therapy.
Pycnogenol® Supplementation Prevents Recurrent Urinary Tract Infections/Inflammation and Interstitial Cystitis
Authors: Ledda A. , Hu S. , Cesarone M. R. , Belcaro G. , Dugall M. , Feragalli B. , Cotellese R. , Hosoi M. , Ippolito E. , Corsi M. , Luzzi R.
Published: June 2021

This open pilot registry study aimed to evaluate and compare the prophylactic effects of Pycnogenol® or cranberry extract in subjects with previous, recurrent urinary tract infections (UTI) or interstitial cystitis (IC). Methods. Inclusion criteria were recurrent UTI or IC. One subject group was supplemented with 150 mg/day Pycnogenol®, another with 400 mg/day cranberry extract, and a group served as a control in a 2-month open follow-up. Results. 64 subjects with recurrent UTI/IC completed the study. The 3 groups of subjects were comparable at baseline. All subjects had significant symptoms (minor pain, stranguria, repeated need for urination, and lower, anterior abdominal pain) at inclusion. In the course of the study, the subjects reported no tolerability problems or side effects. The incidence of UTI symptoms, in comparison with the period before inclusion in the standard management (SM) group, decreased significantly; there was a more pronounced decrease in the rate of recurrent infections in the Pycnogenol® group (

p
<
0.05

). The improvement in patients supplemented with Pycnogenol® was significantly superior to the effects of cranberry. At the end of the study, all subjects in the Pycnogenol® group were infection-free (

p
<
0.05

vs. cranberry). Significantly, more subjects were completely symptom-free after 2 months of management with Pycnogenol® (20/22) than with SM (18/22) and cranberry (16/20). Conclusions. This pilot registry suggests that 60 days of Pycnogenol® supplementation possibly decrease the occurrence of UTIs and IC without side effects and with an efficacy superior to cranberry.
KoRASA: Pipeline Optimization for Open-Source Korean Natural Language Understanding Framework Based on Deep Learning
Authors: Hwang Myeong-Ha , Shin Jikang , Seo Hojin , Im Jeong-Seon , Cho Hee
Published: June 2021

Since the emergence of deep learning-based chatbots for knowledge services, numerous research and development projects have been conducted in various industries. A high demand for chatbots has drastically increased the global market size; however, the limited functional scalability of open-domain chatbots is a challenge to their application to industries. Moreover, as most chatbot frameworks employ English, it is necessary to create chatbots customized for other languages. To address this problem, this paper proposes KoRASA as a pipeline-optimization method, which uses a deep learning-based open-source chatbot framework to understand the Korean language. KoRASA is a closed-domain chatbot that is applicable across a wide range of industries in Korea. KoRASA’s operation consists of four stages: tokenization, featurization, intent classification, and entity extraction. The accuracy and F1-score of KoRASA were measured based on datasets taken from common tasks carried out in most industrial fields. The algorithm for intent classification and entity extraction was optimized. The accuracy and F1-score were 98.2% and 98.4% for intent classification and 97.4% and 94.7% for entity extraction, respectively. Furthermore, these results are better than those achieved by existing models. Accordingly, KoRASA can be applied to various industries, including mobile services based on closed-domain chatbots using Korean, robotic process automation (RPA), edge computing, and Internet of Energy (IoE) services.
Inerting Strategy for a Demonstration-Scale Hot Cell Facility Based on Experiences from Pilot-Scale Argon Cell Facility Operation and CFD Analysis
Authors: Yu Seungnam , Lim Jaehoon , Cho Ilje , Han Jonghui
Published: June 2021

Pyroprocessing is being developed at Korea Atomic Energy Research Institute (KAERI), and in recent years, all process equipment required for integrated processes have been examined in the PyRoprocess-integrated Inactive DEmonstration (PRIDE) facility. Based on the successful operation of a pilot-scale facility, a conceptual design for this scale-up facility was actualized. Implementing a “demonstration-scale” hot cell facility is challenging as it is intended to supersede PRIDE and satisfy the increased requirements of larger-scale facilities. This study focused on an inerting strategy for a larger-scale (demonstration-scale) hot cell facility to achieve conditions equivalent to those in a pilot-scale gas-tight argon cell facility. The study applies the inerting strategy to a demonstration-scale hot cell facility beyond that of the currently existing pilot-scale hot cell facility and performs computational fluid dynamics (CFD) simulation with various flow rates to determine an appropriate approach for inerting the target facility. To this end, practical constraints on the simulation are introduced based on experiences from the existing pilot-scale facility. The results show that the purging flow rate should be accurately predicted, and a variable flow rate should be applied to achieve hot cell inerting effectively. The required purging time and amount of inerting source are essential factors in the larger-scale hot cell facility. The study results can be helpful in the design of large hot cell facilities operated under inert conditions.
Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer
Authors: Wei Jing , Yin Lijuan , Li Jingjing , Wang Jing , Pu Tianjie , Duan Peng , Lin Tzu-Ping , Gao Allen C. , Wu Boyang Jason
Published: June 2021

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC.

Significance:

MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.
A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes
Authors: Calagua Carla , Ficial Miriam , Jansen Caroline S. , Hirz Taghreed , del Balzo Luke , Wilkinson Scott , Lake Ross , Ku Anson T. , Voznesensky Olga , Sykes David B. , Saylor Philip J. , Ye Huihui , Signoretti Sabina , Kissick Haydn , Sowalsky Adam G. , Balk Steven P. , Einstein David J.
Published: June 2021

Purpose:

A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear.

Experimental Design:

We selected PD-L1–positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci.

Results:

One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.

Conclusions:

A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.
RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer
Authors: Koh Siang-Boon , Ross Kenneth , Isakoff Steven J. , Melkonjan Nsan , He Lei , Matissek Karina J. , Schultz Andrew , Mayer Erica L. , Traina Tiffany A. , Carey Lisa A. , Rugo Hope S. , Liu Minetta C. , Stearns Vered , Langenbucher Adam , Saladi Srinivas Vinod , Ramaswamy Sridhar , Lawrence Michael S. , Ellisen Leif W.
Published: June 2021

Purpose:

While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.

Experimental Design:

We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.

Results:

We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing.

Conclusions:

These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
Identification and Validation of T-cell Receptors TargetingRASHotspot Mutations in Human Cancers for Use in Cell-based Immunotherapy
Authors: Levin Noam , Paria Biman C. , Vale Nolan R. , Yossef Rami , Lowery Frank J. , Parkhurst Maria R. , Yu Zhiya , Florentin Maria , Cafri Gal , Gartner Jared J. , Shindorf Mackenzie L. , Ngo Lien T. , Ray Satyajit , Kim Sanghyun P. , Copeland Amy R. , Robbins Paul F. , Rosenberg Steven A.
Published: June 2021

Purpose:

Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for “off-the-shelf” adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes.

Experimental Design:

In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested.

Results:

Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS.

Conclusions:

The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for “off-the-shelf” ACTs.
Parotid Myoepithelial Carcinoma in a Pediatric Patient with Multiple Recurrences: Case Report
Authors: Bravo Thompson Harold , Lim Law Maria , Vergara Vasquez Ruth , Castillo Fernandez Omar
Published: June 2021

Myoepithelial carcinoma of the salivary glands is a rare entity, with scarce amount of case reports in the literature. Due to its infrequency, its diagnosis is usually difficult and uncertain. Although there are reports of locoregional recurrences and distant metastases, its low incidence and varied biological behavior limits the clinical evidence that can be used to predict the prognosis and determine the course of treatment. We present a 23-year-old female patient without past medical history with an initial 1-year history of volume increase in the right parotid region of tumor aspect and painful on palpation. As a malignancy was suspected, a total parotidectomy was performed, reporting in the deep lobe a parotid myoepithelial carcinoma with vascular and neural invasion, negative borders, and 3–9 negative regional nodes. During her 16-year clinical evolution, she presented approximately every 2 years and a total of 9 locoregional recurrences and hepatic metastases, including cervical lymphoid nodules, temporal bone, frontal bone, and temporal fossa. Those recurrences have been treated with coordinated efforts between repeated external radiotherapy, chemotherapy, and multiple surgical resections. Myoepithelial tumors represent only 1.0–1.5% of all salivary gland tumors. The literature reports suggest a high incidence of locoregional recurrences and distant metastases in de novo myoepithelial carcinomas. Due to its rarity, treatment continues to be based on the experience of medical staff.
The Real-World Data Challenges Radar: A Review on the Challenges and Risks regarding the Use of Real-World Data
Authors: Grimberg Frank , Asprion Petra Maria , Schneider Bettina , Miho Enkelejda , Babrak Lmar , Habbabeh Ali
Published: June 2021

Background: The life science industry has a strong interest in real-world data (RWD), a term that is currently being used in many ways and with varying definitions depending on the source. In this review article, we provide a summary overview of the challenges and risks regarding the use of RWD and its translation into real-world evidence and provide a classification and visualization of RWD challenges by means of the RWD Challenges Radar. Summary: Based on a systematic literature search, we identified 3 types of challenges – organizational, technological, and people-based – that must be addressed when deriving evidence from RWD to be used in drug approval and other applications. It further demonstrates that numerous different aspects, for example, related to the application field and the associated industry, must be considered. A key finding in our review is that the regulatory landscape must be carefully assessed before utilizing RWD. Key Messages: Establishing awareness and insight into the challenges and risks regarding the use of RWD will be key to taking full advantage of the RWD potential. As a result of this review, an “RWD Challenges Radar” will support the establishment of awareness by providing a comprehensive overview of the relevant aspects to be considered when employing RWD.
Escoliose e Cifose de Scheuermann: o trajeto da documentação museológica de coleções arqueológicas no Museu de Arqueologia e Etnologia da Universidade Federal da Bahia
Authors: Ballardo Luciana Messeder , Mendonça Elizabete de Castro
Published: June 2021

Esta pesquisa integra o trabalho de doutorado “Gestão de coleções arqueológicas musealizadas: dos métodos de campo à documentação museológica”, vinculada ao Programa de Pós-Graduação em Museologia e Patrimônio da Universidade Federal do Estado do Rio de Janeiro (PPGMUS-UNIRIO), e tem como objetivo analisar quais critérios podem orientar propostas de requalificação ou substituição de sistemas documentais em instituições museológicas que incorporam coleções arqueológicas. A abordagem desenvolveu-se por meio de análise comparativa da formação das coleções e do percurso da documentação museológica. Preliminarmente, evidenciou-se que os diagnósticos dos sistemas antecessores desconsideraram as especificidades das coleções arqueológicas e a falta de enlace entre os profissionais de Arqueologia e Museologia resultaram numa documentação museológica que não apresenta informações significativas para a investigação arqueológica.
Aplicação da técnica de eye tracking em pesquisas envolvendo a tomada de decisão: uma análise bibliométrica dos estudos publicados entre 2009 e 2019
Authors: Lehnhart Eliete dos Reis , Radons Daiane Lindner , Tagliapietra Rafaela Dutra , Tontini Julia
Published: June 2021

Este trabalho investiga a produção de estudos que envolvem o uso de eye tracking em pesquisas sobre tomada de decisão, por meio de uma análise bibliométrica de trabalhos publicados na Web of Science, no período de 2009 a 2019. Como objetivos específicos, pretende-se: i) realizar uma análise bibliométrica dos estudos que utilizaram a técnica de eye tracking em pesquisas sobre tomada de decisão nas áreas de administração; ii) identificar as estratégias de pesquisa dos artigos selecionados de acordo com os parâmetros do índice h. Para tanto, analisaram-se as estratégias de pesquisa empregadas pelos 18 estudos incluídos nos parâmetros do índice h. Os resultados evidenciaram que 2018 foi o ano que apresentou o maior número de trabalhos, que as categorias negócios e gestão lideram o ranking das publicações e que todos os trabalhos estão vinculados à área de Economia e Negócios, sendo alguns associados a outras áreas. Sobre a autoria desses estudos, observou-se uma distribuição homogênea entre o número de artigos por autor com um predomínio norte-americano nas publicações sobre o tema. No que se refere às estratégias de pesquisa, a maioria corresponde aos estudos quantitativos, explicativos, fazendo uso da abordagem experimental, tendo utilizado para a coleta de dados o eye tracking.
Biografias e autobiografias como fontes de informação e memória
Authors: Gonçalves Rita de Cássia , Silveira Fabrício José Nascimento da
Published: June 2021

Este artigo tem por objetivo explorar a dupla função do gênero biografia: fonte de informação e memória. Amparado em revisão bibliográfica inscrita em perspectivas multidisciplinares, buscou-se apreender as especificidades do gênero biográfico e caracterizar as produções dele derivadas – notadamente as biografias e autobiografias – tanto como fontes de informação quanto como recursos sociais de produção e disseminação de memórias individuais, sociais e históricas. Como resultado, pontua-se que os escritos autobiográficos e as biografias, por estarem intimamente imbricados ao “espírito de sua época”, não devem ser percebidos como uma narrativa caracterizada pela sucessão de eventos encadeados cronológica e linearmente, mas, antes, como fruto de escolhas, negociações e contingências que, em seu conjunto, modulam uma imagem razoavelmente delineada de determinado sujeito e de suas experiências vivenciais. Nesses termos, podem nos informar sobre as circunstâncias históricas, políticas, culturais e sociais de uma época, tanto quanto sobre as singularidades de uma vida privada, seja ela de pessoas comuns ou daqueles que se tornaram “heróis nacionais” ou, ainda, modelos de virtude.
Endothelial Recovery in Bare Metal Stents and Drug-Eluting Stents on a Single-Cell Level
Authors: Cornelissen Anne , Guo Liang , Fernandez Raquel , Kelly Michael C. , Janifer Christine , Kuntz Salome , Sakamoto Atsushi , Jinnouchi Hiroyuki , Sato Yu , Paek Ka Hyun , Kolodgie Frank D. , Romero Maria E. , Surve Dipti , Virmani Renu , Finn Aloke V.
Published: June 2021

Objective:

Healing processes, particularly reendothelialization, are essential for vascular homeostasis after plain old balloon angioplasty and stent implantation. Drug-eluting stents (DES) are commonly used for percutaneous coronary intervention because restenosis rates are reduced as compared with bare metal stents (BMS). However, in addition to understanding the nature of regenerated endothelial cells, concerns over incomplete stent healing persist, and the molecular effects of antiproliferative drug coatings on endothelium remain poorly understood.

Approach and Results:

We used the rabbit iliac artery model to analyze differences in stent endothelialization in BMS and DES. Histology and immunohistochemistry confirmed that stent coverage was significantly greater in BMS than in DES at 30 days after stent implantation. Single-cell RNA sequencing revealed a more immature transcriptomic signature of neointimal endothelial cell harvested from stented arteries in comparison with native and plain old balloon angioplasty–treated arteries. Whereas the genetic signature of BMS was overall proangiogenic with enrichment of genes involved in endothelial proliferation, sprouting, and migration, as well as extracellular matrix assembly, DES-derived endothelial cell showed upregulation of genes associated with angiogenesis inhibition and endothelial activation.

Conclusions:

Single-cell RNA sequencing analysis identified unique transcriptional changes within regenerated endothelium after plain old balloon angioplasty and stent implantation. These data suggest unique endothelial transcriptional differences, which characterize the different response of the endothelium to vascular injury and may help explain why long-term responses in DES remain suboptimal.
Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits
Authors: Wei Zhe , Chong Hoshun , Jiang Qixia , Tang Yuhang , Xu Jinhong , Wang Haoquan , Shi Yanteng , Cui Le , Li Jing , Zhang Yujing , Xue Yunxing , Li Jutang , Liu George , Chen Xi , Wang Dongjin , Zhang Chen-Yu , Jiang Xiaohong
Published: June 2021

Rationale:

Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis. Dysregulation of PGC1α (peroxisome proliferator-activated receptor gamma, coactivator 1α), a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of atherosclerosis, yet its role in atherosclerosis remains controversial.

Objective:

The current study aimed to determine whether and how PGC1α in VSMCs regulates atherosclerosis progression.

Methods and Results:

We generated transgenic rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic atherosclerosis than their nontransgenic littermates after high-cholesterol diet feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the high-cholesterol diet-induced phenotypic switching in the aortic media was largely reversed in transgenic rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, MMPs (matrix metalloproteinases), reactive oxygen species production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of high-cholesterol diet feeding on the association of SRF (serum response factor) with ELK1 (ETS transcription factor ELK1), a TCF (ternary complex factor) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased ERK (extracellular signal-regulated kinase)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR (epidermal growth factor receptor)-ERK1/2 MAPK (mitogen-activated protein kinase) signaling via modulating PPARγ (peroxisome proliferator-activated receptor γ) activity in RVSMCs (rabbit vascular smooth muscle cells). Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings.

Conclusions:

We demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for atherosclerosis.
Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies
Authors: Mäkinen Taija , Boon Laurence M. , Vikkula Miikka , Alitalo Kari
Published: June 2021

Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell–autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.
Cerebral Cavernous Malformation: From Mechanism to Therapy
Authors: Snellings Daniel A. , Hong Courtney C. , Ren Aileen A. , Lopez-Ramirez Miguel A. , Girard Romuald , Srinath Abhinav , Marchuk Douglas A. , Ginsberg Mark H. , Awad Issam A. , Kahn Mark L.
Published: June 2021

Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage. These novel insights are the integrated product of human clinical studies, human genetic studies, studies in mouse and zebrafish genetic models, and basic molecular and cellular studies. This review addresses the genetic and molecular underpinnings of cerebral cavernous malformation disease, the mechanisms that lead to lesion hemorrhage, and emerging biomarkers and therapies for clinical treatment of cerebral cavernous malformation disease. It may also serve as an example for how focused basic and clinical investigation and emerging technologies can rapidly unravel a complex disease mechanism.
Unveiling Complexity and Multipotentiality of Early Heart Fields
Authors: Zhang Qingquan , Carlin Daniel , Zhu Fugui , Cattaneo Paola , Ideker Trey , Evans Sylvia M. , Bloomekatz Joshua , Chi Neil C.
Published: June 2021

Rationale:

Extraembryonic tissues, including the yolk sac and placenta, and the heart within the embryo, work to provide crucial nutrients to the embryo. The association of congenital heart defects with extraembryonic tissue defects further supports the potential developmental relationship between the heart and extraembryonic tissues. Although the development of early cardiac lineages has been well-studied, the developmental relationship between cardiac lineages, including epicardium, and extraembryonic mesoderm remains to be defined.

Objective:

To explore the developmental relationships between cardiac and extraembryonic lineages.

Methods and Results:

Through high-resolution single-cell and genetic lineage/clonal analyses, we show an unsuspected clonal relationship between extraembryonic mesoderm and cardiac lineages. Single-cell transcriptomics and trajectory analyses uncovered 2 mesodermal progenitor sources contributing to left ventricular cardiomyocytes, 1 embryonic and the other with an extraembryonic gene expression signature. Additional lineage-tracing studies revealed that the extraembryonic-related progenitors reside at the embryonic/extraembryonic interface in gastrulating embryos and produce distinct cell types forming the pericardium, septum transversum, epicardium, dorsolateral regions of the left ventricle and atrioventricular canal myocardium, and extraembryonic mesoderm. Clonal analyses demonstrated that these progenitors are multipotent, giving rise to not only cardiomyocytes and serosal mesothelial cell types but also, remarkably, extraembryonic mesoderm.

Conclusions:

Overall, our results reveal the location of previously unknown multipotent cardiovascular progenitors at the embryonic/extraembryonic interface and define the earliest embryonic origins of serosal mesothelial lineages, including the epicardium, which contributes fibroblasts and vascular support cells to the heart. The shared lineage relationship between embryonic cardiovascular lineages and extraembryonic mesoderm revealed by our studies underscores an underappreciated blurring of boundaries between embryonic and extraembryonic mesoderm. Our findings suggest unexpected underpinnings of the association between congenital heart disease and placental insufficiency anomalies and the potential utility of extraembryonic cells for generating cardiovascular cell types for heart repair.
Time to Evacuation and Functional Outcome After Minimally Invasive Endoscopic Intracerebral Hemorrhage Evacuation
Authors: Kellner Christopher P. , Song Rui , Ali Muhammad , Nistal Dominic A. , Samarage Milan , Dangayach Neha S. , Liang John , McNeill Ian , Zhang Xiangnan , Bederson Joshua B. , Mocco J
Published: June 2021

Background and Purpose:

We present a retrospective analysis of patients who underwent minimally invasive endoscopic intracerebral hemorrhage (ICH) evacuation to identify variables that were associated with long-term outcome.

Methods:

Minimally invasive endoscopic ICH evacuation was performed on patients with supratentorial ICH who fit prespecified clinical inclusion and exclusion criteria. Demographic, clinical, and radiographic factors previously demonstrated to impact functional outcome in ICH were included in a univariate analysis to identify factors associated with favorable outcome (modified Rankin Scale score, 0–3) at 6 months. Factors associated with a favorable outcome in the univariate analysis (
P
≤0.20) were included in a multivariate logistic regression analysis with the same dependent variable.

Results:

Ninety patients underwent MIS endoscopic ICH evacuation within 72 hours of ictus. In a multivariate analysis, factors associated with good long-term functional outcome included time to evacuation (per hour; OR, 0.95 [95% CI, 0.92–0.98],
P
=0.004), age (per decade, odds ratio [OR], 0.49 [95% CI, 0.28–0.77],
P
=0.005), presence of intraventricular hemorrhage (OR, 0.15 [95% CI, 0.04–0.47],
P
=0.002), and lobar location (OR, 18.5 [95% CI, 4.5–103],
P
=0.0005). Early evacuation was not associated with an increased risk of rebleeding.

Conclusions:

Young age, lack of intraventricular hemorrhage, lobar location, and time to evacuation were independently associated with good long-term functional outcome in patients undergoing minimally invasive endoscopic ICH evacuation. The OR for time to evacuation suggests that for each additional hour, there was a 5% reduction in the odds of achieving a favorable outcome.
Molecular genetics and phylogeny of Ephippigera species group of genus Saga Charpentier, 1825 (Orthoptera: Ensifera: Saginae) in Anatolia
Authors: BİNİCİ BURCU , ŞİRİN DENİZ , TAYLAN MEHMET SAİT
Published: June 2021

The genus Saga, one of the largest predatory bush crickets and insects in the Palearctic region, is represented by nine species in Anatolia. According to the morphological and bioacoustics evaluations of the Ephippigera species group belonging to the Saga genus, it consists of three species: S. ephippigera, S. syriaca, and S. hakkarica. To the present, however, there is no molecular genetic research on this species group. In our study, by using the 16S rDNA gene sequences, the molecular phylogeny of this species group is revealed and the morphological species hypotheses has been tested. In the study, specimens belonging to S. ephippigera, S. syriaca, and S. hakkarica were collected between the years of 2018 and 2020 with sweep netting; the DNA isolation, polymerase chain reactions, purifications and double-stranded sequencing were performed to obtain 16S rDNA gene sequences. Sequences were evaluated phylogenetically by performing alignment, phylogenetic analysis (Maximum Likelihood and Bayesian Inference), and dating of cladogenetic events, respectively. The monophyletic and species hypotheses of all three species have been supported by molecular data. It has been determined that the S. ephippigera species is the origin lineages of the Ephippigera species group which diverged approximately 0.4 million years ago; it has been also revealed that the climatic changes in the glacial and inter-glacial periods in the Middle Pleistocene period affected greatly the evolution of the species group.
1. The Origins of Autism
Authors: Hens Kristien
Published: June 2021

This chapter describes how at least three meanings of autism have been around from the start. I take a closer look at original texts about autism: the English text from 1943 by Leo Kanner (1894-1981), 'Autistic Disturbances of Affective Contact' and the German book from 1944 by Hans Asperger (1906–1980), 'Die "Autistischen Psychopathen" im Kindesalter'. As child psychiatrist, Leo Kanner viewed autism primarily as a disorder of development. For Hans Asperger, autistic characteristics were lifelong characteristics of one's personality. Hence, from the beginning, autism was conceptualized as a (child) psychiatric disorder, as an innate and lifelong character trait, and as a developmental phenomenon.
3. Cognitive Explanations of Autism: Beyond Theory of Mind
Authors: Hens Kristien
Published: June 2021

This chapters explores explanatory models of autism and their ethical implications. I describe older explanatory models such as deficit in theory of mind, weak central coherence and problems with executive functioning. Focussing on deficit in theory of mind I demonstrate that problematic assumptions about autistic people and their capacity for emotions and empathy have profound implications for how people look at autistic persons. I also discuss how such assumptions have played a role in meta ethical discussions on the nature of morality. I describe more recent models such as models based on atypical information and sensory processing. Such models are sometimes thought of as more representative of the autistic experience.
5. Difference and Disability
Authors: Hens Kristien
Published: June 2021

This chapters introduces the neurodiversity approach and describes different models and approaches of disability, such as the medical model, the social model and crip theory. It argues that we cannot subdivide autistic people based on criteria of functioning alone to draw ethical conclusions. Instead, philosophers and ethicists must re-examen their intuitions regarding concepts of autonomy and what it means to lead a good life. We may define autism, in all its forms, perhaps in analogy with Elizabeth Barnes’ minority body, as a minority brain. In this way, we do not have to deny that some autistic people suffer from some aspects related to autism. Nevertheless, we also acknowledge that this does not necessarily have to be so. Simultaneously, a poststructuralist approach such as ‘Reading Rosie’ demonstrates that people with specific disabilities can always ‘be read’ in different ways, in various stories that can be juxtaposed but do not have to annihilate one another. In short, we can learn from disability studies that we must take first-person perspectives seriously and shy away from quick assumptions about well-being and happiness based on broad categories such as intelligence or autism.
11. Autism and Genetics
Authors: Hens Kristien
Published: June 2021

This chapter describes how autism is often called an innate, genetic and lifelong developmental disorder. Indeed, since the beginning of the history of autism as we know it, people have considered it a biological disorder. As a result, for the last forty years most autism research was on its causes, and autism still is primarily conceived of as a phenomenon rooted in genetics. The chapter explore the link between autism and genetics and the meaning of genetics. I argue that genes convey a certain image of stasis. I describe epigenetic mechanisms and the concept of epigenesis and challenge the idea that biology and genetics are necessarily fixed and argue that the gap between our biology or genetics and our experiences is not that wide. In this way, we may be able to look at autism as a truly developmental phenomenon.
Epilogue
Authors: Hens Kristien
Published: June 2021

This chapter first gives an overview of the arguments developed in the different chapters of the book. Then it describes, using early detection of autism as an example, how dynamic approaches to autism can help providing a framework to think about specific clinical-ethical dilemmas.