bluuebunny/crossref_metadata_2025 huggingface dataset:
Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity
Authors: Auzmendi-Iriarte Jaione , Otaegi-Ugartemendia Maddalen , Carrasco-Garcia Estefania , Azkargorta Mikel , Diaz Antonio , Saenz-Antoñanzas Ander , Andermatten Joaquin Andrés , Garcia-Puga Mikel , Garcia Idoia , Elua-Pinin Alejandro , Ruiz Irune , Sampron Nicolas , Elortza Felix , Cuervo Ana Maria , Matheu Ander
Published: February 2022

Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities. Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels.

Significance:

A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.
Olaparib Maintenance Monotherapy in Asian Patients with Platinum-Sensitive Relapsed Ovarian Cancer: Phase III Trial (L-MOCA)
Authors: Gao Qinglei , Zhu Jianqing , Zhao Weidong , Huang Yi , An Ruifang , Zheng Hong , Qu Pengpeng , Wang Li , Zhou Qi , Wang Danbo , Lou Ge , Wang Jing , Wang Ke , Low John , Kong Beihua , Rozita Abdul Malik , Sen Lim Chun , Yin Rutie , Xie Xing , Liu Jihong , Sun Wei , Su Jingya , Zhang Chunyi , Zang Rongyu , Ma Ding
Published: February 2022

Purpose:

In patients with platinum-sensitive relapsed (PSR) ovarian cancer, olaparib maintenance monotherapy significantly improves progression-free survival (PFS) versus placebo. However, evidence in the Asian population is lacking. This is the first study to evaluate olaparib efficacy and tolerability exclusively in Asian patients with PSR ovarian cancer.

Patients and Methods:

Considering the limited placebo effect and significant clinical benefit of olaparib in previous trials, and the rapid approval of olaparib in China, this phase III study was designed as an open-label, single-arm trial. Patients with high-grade epithelial PSR ovarian cancer were enrolled from country-wide clinical centers across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. Primary endpoint was median PFS (mPFS). Primary analysis of PFS using the Kaplan–Meier method was performed when data reached 60% maturity (clinicaltrials.gov NCT03534453).

Results:

Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received ≥3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval ≤12 months. At primary data cut-off (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively. Adverse events (AE) occurred in 99.1% of patients (grade ≥3, 48.7%); 9.4% discontinued therapy due to treatment-related AEs.

Conclusions:

Olaparib maintenance therapy was highly effective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. This study highlights the promising efficacy of olaparib in this Asian population.

See related commentary by Nicum and Blagden, p. 2201
Feasibility of a Novel ECG Electrode Placement Method in Newborn Infants
Authors: Henry Caroline , Shipley Lara , Morgan Stephen , Crowe John A. , Carpenter James , Hayes-Gill Barrie , Sharkey Don
Published: February 2022

Background: International newborn resuscitation guidelines recommend electrocardiogram (ECG) heart rate (HR) monitoring at birth. We evaluated the application time of pre-set ECG electrodes fixed to a polyethene patch allowing adhesive-free attachment to the wet skin of the newborn chest. Objectives: Using a three-electrode pre-set ECG patch configuration, application success was calculated using video analysis and measured at three time points, the time to (1) apply electrodes; (2) detect recognizable QRS complexes after application; and (3) display a HR after application. Method: A prospective observational study in two UK tertiary maternity units was undertaken with 71 newborns including 23 who required resuscitation. Results: The median (IQR) time for ECG patch application was 8 (6–10) seconds, detection of recognizable QRS complexes 8 (2–12) seconds, and time to output HR was 23 (15–37) seconds. Conclusion: Pre-set ECG chest electrodes allow rapid HR information at birth without electrode detachment or compromising skin integrity.
Comparative Analysis of Guideline Adherence between Germany and Austria by Using the Example of Uncomplicated Urinary Tract Infections
Authors: Kranz Jennifer , Wiesinger Clemens Georg , Nagler Julian , Pfuner Jacob , Steffens Joachim , Hüsch Tanja , Wagenlehner Florian M.E. , Schneidewind Laila
Published: February 2022

Background: Medical guidelines represent the evidence-based state of the art of their scientific field. They aim to guide decisions for physicians and patients about appropriate health care for specific clinical circumstances. However, guideline recommendations are often not adhered to in clinical practice. In particular, a large discrepancy exists regarding the treatment of uncomplicated urinary tract infections. To date, just a few studies addressed the potential reasons for these guideline violations. Objectives: This investigation aimed to identify and complement reasons for the nonadherence to guideline recommendations. Methods: A survey amongst a total of 563 German and Austrian urologists identified physician- and patient-related factors contributing to this current state. Results: The physician’s personal experience, the lack of applicability to individual patients, and shortage of time were identified as crucial barriers for the physician. Patient-related barriers were poor experience with the antibiotic, fear of collateral damage, and inadequate information about the disease and its therapy. Conclusions: We suggest modifying guideline designs by including abstracts and flowcharts appropriate for daily use and separate patient instructions to improve guideline compliance. Furthermore, guideline authors should communicate updates in a timely and accessible manner. Presentations at scientific congresses increase visibility and enhance the dialogue with colleagues.
Association between the Estimated Glomerular Filtration Rate and Brain Atrophy in Older Adults
Authors: Grasing Michael , Sharma Palash , Lepping Rebecca J. , Honea Robyn , Burns Jeffrey M. , Brooks William M. , Gupta Aditi ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2022

End-stage kidney disease has been associated with cognitive impairment and brain atrophy. It remains unclear if mild to moderate kidney dysfunction is associated with brain atrophy, especially in older adults. We used cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), an NIH-funded multicenter longitudinal cohort study, to better understand the association between estimated glomerular filtration rate (eGFR) and brain volumes. We included all ADNI participants with both baseline serum creatinine values and MRI brain volume assessments. We used multiple linear regression modeling to assess cross-sectional associations between eGFR and whole-brain gray matter, hippocampus, entorhinal, fusiform, and middle temporal brain volumes. Participants (n = 1,596) were 74 ± 7 years old with a mean eGFR of 69.4 ± 14.8 mL/min/1.73 m2; 53% had mild cognitive impairment, and 19% had dementia. Unadjusted analysis showed an association between lower eGFR and smaller brain volumes. After adjusting for age, sex, and education, there was no association between eGFR brain volumes (p > 0.05 for all). These results remained consistent after subgroup analysis by age stratification and baseline cognitive status. Age was a confounding variable in the unadjusted association between the eGFR and brain volumes. Thus, a mild to moderately reduced eGFR was not associated with brain atrophy in ADNI participants.
Melatonin Inhibits 17β-Estradiol-Induced Epithelial-Mesenchymal Transition in Endometrial Adenocarcinoma Cells via Upregulating Numb Expression
Authors: Zhang Hui , Qi Shasha , Liu Zhao , Li Chunyan , Li Mingjiang , Zhao Xingbo
Published: February 2022

Objectives: Melatonin (MLT) shows antitumor effects in various tumor types, including endometrial carcinoma. However, the molecular mechanism involved is unclear. In the current study, we investigated the effect of MLT on the estrogen-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells and explored the pathway that might be involved. Design: Laboratory study was via cultured endometrial cancer cells. Design refers only to in vitro experiments. Methods: In cell culture experiments, cell growth was examined using CCK-8 assays. The expression of Numb and EMT markers in Ishikawa cells was examined using Western blot analysis and real-time PCR. Cell invasion was examined using transwell assays. Cell migration was examined using wound-healing assays and transwell assays. Using immunohistochemistry analysis, the expression of Numb in human endometrial cancers was examined. Results: In immunohistochemistry experiments, we found that 15.2% of atypical endometrial hyperplasia and 15.6% of endometrial carcinoma did not express Numb. In cell culture experiments, MLT inhibited cell proliferation, invasion, and migration induced by 17β-estradiol (E2) in endometrial cancer cells. MLT decreased the expression of vimentin and Slug and increased the expression of Numb and E-cadherin in Ishikawa cells. Numb knockdown in cancer cells significantly increased cell proliferation, invasion, and migration. Limitations: No animal experiments were performed. Conclusions: MLT blocked E2-induced cell growth and EMT in endometrial cancer cells via upregulating Numb expression.
Hannah Arendt em quadrinhos
Authors: Amaral Muriel Emídio Pessoa do Amaral
Published: February 2022

O propósito da resenha é de apresentar a obra "As três fugas de Hannah Arendt: uma tirania da verdade" de Ken Krimstein. Em formato em quadrinhos, o autor consegue analisar ideias desenvolvidas por Arendt e aspectos significativos da sua obra.
Reflexões sobre Educação Especial e Inclusiva: das condições estruturais ao papel das Histórias em Quadrinhos no ensino para estudantes dentro do espectro autista
Authors: Giesta Gabriel Valladares
Published: February 2022

Faz um levantamento acerca dos desafios na construção de uma escola que contemple a Educação Especial e Inclusiva, propondo caminhos para enfrentar tais dificuldades através dos quadrinhos, com foco em um público da educação especial: estudantes com transtorno do espectro autista (TEA). Para isto, traz uma revisão bibliográfica e de dados sobre educação inclusiva para, afinal, refletir acerca dos quadrinhos na educação de pessoas com TEA, baseado em pesquisas sobre o tema e vivências pedagógicas dos autores.
Tendências e alterações climáticas no Estado de Sergipe, nordeste do Brasil
Authors: Castelhano Francisco Jablinski , Pinto Josefa Eliane Santana de Siqueira
Published: February 2022

Entendendo a complexidade da atmosfera, em seus componentes sistêmicos, internos e externos e o seu envolver para com a Terra, faz crescer a necessidade de seu conhecimento, em escalas que venham integrar para contribuir em análises geográficas. Partindo deste pressuposto, o objetivo deste artigo é pensar sob uma perspectiva socioambiental, a variabilidade climática no Estado do Sergipe, nordeste do Brasil, com análises das tendências futuras para índices climáticos. Tal avaliação realizou-se a partir de uma análise estatística com base nos vinte e sete índices de mudanças climáticas propostos por Peterson et al., (2001) e recomendados pela Organização Mundial Meteorológica. Os índices utilizam-se de dados climáticos em escala diária, sendo conhecidos como “Índices ETCCDI”. Foi analisada a tendência dos índices previamente gerados através do método de Mann Kendall. Constatou-se tendências a queda nos valores anuais de chuva em todo o estado. Em relação às variáveis térmicas, observou-se uma ampla tendência, ao longo de todo estado, para aumento nos extremos tanto nas temperaturas máximas quanto mínimas. Perdura no estado uma problemática socioambiental regional.
Apropriação do cerrado e pressão nos recursos naturais da terra indígena Avá-Canoeiro e entorno (Goiás)
Authors: Silva Lorranne Gomes da , Silva Izaias de Souza , Souza José Carlos de
Published: February 2022

O povo Avá-Canoeiro pode ser encontrado em dois estados brasileiros, uma família em Goiás com 08 indígenas e outra em Tocantins com aproximadamente 32 indígenas. Esta pesquisa tem como foco de estudo o povo e a Terra Indígena (TI) Avá-Canoeiro de Goiás e que objetivou analisar os aspectos ambientais e pressões no território e recursos naturais da TI e seu entorno, na perspectiva das ameaças à sociobiodiverdade do Cerrado. Para isso foi realizada uma caracterização e avaliação das condições geoambientais da TI, na perspectiva da análise integrada da paisagem, considerando aspectos do meio físico e dinâmica espaço-temporal do uso e cobertura do solo, com aplicações de técnicas de geoprocessamento para geração de matriz de transição e modelagem de previsão. Realizou-se também uma fundamentação teórica acerca da constituição do território e da dinâmica do povo Avá-Canoeiro, no norte do estado. Os resultados das análises evidenciaram que os Avá-Canoeiro vivem em um território permeado por interesses de empreendimentos econômicos de várias ordens. O hidronegócio e a pecuária extensiva que estão promovendo a redução do território, mudanças na paisagem e perda de vegetação de Cerrado e o potencial mineral da região, que tem promovido o desenvolvimento de pesquisas com projeções para futuras explorações. Os dados de uso e cobertura do solo indicam expansão das pastagens plantadas na TI e entorno e projeção para o avanço da agricultura e silvicultura.
Em barcos de papel: poesia na sala de aula
Authors: Andrade Fábio de Souza
Published: February 2022

Esse artigo é um exercício de leitura cerrada de um poema, “O poema e a água”, pensado como primeira aproximação das dificuldades de leitura crítica por leitores iniciantes.
A formação de diretores de arte no Brasil
Authors: Moura Carolina Bassi de
Published: February 2022

A formação em direção de arte no Brasil, atualmente, é tortuosa, intuitiva e fragmentada, dificultando o aprendizado do estudante, o trabalho do profissional no mercado de trabalho e podendo prejudicar a qualidade das produções. Este artigo faz um cruzamento de minha observação como profissional em produções cinematográficas e docente pesquisadora em universidades com a de outros profissionais da área acerca do tema. Serão usadas a minha tese A direção e a direção de arte, (MOURA, 2015), publicações (BRUTUCE; BOUILLET, 2017) (HAMBURGER, 2014) e debates específicos (SEMANA ABC, 2015 e 2018). Desejo com este artigo apontar necessidades desta formação, para que um pensamento possa ser melhor desenvolvido nas universidades, suprindo as carências apontadas.A formação em direção de arte no Brasil, atualmente, é tortuosa, intuitiva e fragmentada, dificultando o aprendizado do estudante, o trabalho do profissional no mercado de trabalho e podendo prejudicar a qualidade das produções. Este artigo faz um cruzamento de minha observação como profissional em produções cinematográficas e docente pesquisadora em universidades com a de outros profissionais da área acerca do tema. Serão usadas a minha tese A direção e a direção de arte, (MOURA, 2015), publicações (BRUTUCE; BOUILLET, 2017) (HAMBURGER, 2014) e debates específicos (SEMANA ABC, 2015 e 2018). Desejo com este artigo apontar necessidades desta formação, para que um pensamento possa ser melhor desenvolvido nas universidades, suprindo as carências apontadas.
Algumas interseções metodológicas no desenvolvimento do traje cênico
Authors: Sobrinho José Isac Nobre
Published: February 2022

Resumo: O artigo revisita metodologias de desenvolvimento para figurino nas áreas cênicas de teatro, dança e cinema e observa suas semelhanças. O estudo faz parte do processo de investigação acerca de metodologias para criação em figurino, desenvolvido pelo autor para a conclusão de curso. Usou-se como método a pesquisa exploratória delineada a partir de material bibliográfico visando descrever as possíveis convergências.
Canteiro de Obras
Authors: Toscano Priscilla
Published: February 2022

Homenagem de Priscilla Toscano para Marcelo Denny
Esse corpo que me veste: o traje de cena como disparador de uma pesquisa acadêmica
Authors: Baena Graziela Ribeiro
Published: February 2022

O artigo aborda uma pesquisa teórica sobre a indumentária da festividade religiosa amazônica do culto ao São Benedito de Bragança (PA), que teve como disparador a construção do traje de cena do espetáculo teatral “Esse corpo que me veste”, realizado pelo grupo Cuíra e apresentado em 2015, em Belém do Pará
A separação dos Poderes e o controle jurisdicional da transparência das Políticas Públicas de Enfretamento ao Coronavírus no Brasil: exame da constitucionalidade do julgamento do Supremo Tribunal Federal, na ar-guição de descumprimento de Preceito Fundamental nº 690-DF, que es-tabeleceu o conteúdo da publicidade das informações sobre a Covid-19
Authors: Sousa Horácio Augusto Mendes de , Fabriz Daury Cesar
Published: February 2022

O presente artigo visa analisar a constitucionalidade do julgamento proferido pelo Supremo Tribunal Federal, na Arguição de Descumprimento de Preceito Fundamental nº 690-DF, que estabeleceu a obrigatoriedade da transparência das informações sobre a Covid-19, à luz do princípio constitucional da separação e independência dos Poderes da República. Neste sentido, o problema da presente pesquisa consiste em analisar se a Suprema Corte pode interferir dessa maneira nas políticas de saúde formuladas pelo Poder Executivo Federal. Neste contexto, é importante identificar a tensão existente entre a deliberação do Poder Executivo Federal e a decisão do Supremo Tribunal Federal, bem como verificar como a Suprema Corte brasileira vem controlando a transparência das políticas públicas federais de enfretamento à Covid-19, visando à proteção direitos fundamentais.
De montes e montanhas à paisagem – reflexões sobre sua abordagem estética
Authors: Conti Camila
Published: February 2022

Montes e montanhas participam diretamente da vida nos lugares, assim como da história das concepções de paisagem. O objetivo deste artigo é levantar a discussão sobre as abordagens da sensibilidade estética na paisagem em relação às formas expressivas de relevo, e de sua pertinência aos problemas que se apresentam no horizonte atual das transformações espaciais. Parte-se da preocupação de não reduzir a questão do estético ao caráter das representações mentais da natureza, que ainda se mantém atreladas a essas formações. Conclui-se pela importância de uma consciência estética como expressão de uma cumplicidade humana com as formas da Terra.
Traduzindo bits, exposições virtuais na pandemia
Authors: Ruggiero Amanda Saba
Published: February 2022

O que são as exposições digitais nas plataformas tecnológicas em realidade pandêmica: uma possibilidade de contato e introspecção por meio da arte, ou apenas uma forma encontrada pelas instituições e pelo mercado de arte em não suspender contato ou consumo de seu público? Em que medida mostras virtuais propiciam espaços de interlocução e conhecimento, ou simples deleite e prazer contemplativo, em que pesem simulacros espaciais revestidos por chancelas de grandes nomes ou instituições? Tais mensagens, adequadas digitalmente, constituem paradigma das novas relações e interações humanas?
A “Mulher Nua ” A representação do feminino no imaginário moderno de Curitiba
Authors: Batista Fábio Domingos
Published: February 2022

Propõe-se neste a reflexão sobre a representação do corpo feminino nas dinâmicas urbanas. Para a análise elegeu-se duas obras de Erbo Stenzel e Humberto Cozzo: a “Justiça” e o “Homem Paranaense”. A “Justiça” seria instalada junto ao Tribunal do Júri, mas por se tratar de uma mulher nua, ela foi recolhida longe da vista do público. O “Homem Paranaense”, também nu, é a figura principal do Memorial do Centenário, inaugurado em 1955. As duas estátuas foram reunidas em 1972.
Camadas de tempo e espaço no painel de azulejaria Kilomètre 47, de Maria Helena Vieira da Silva
Authors: Herbst Helio
Published: February 2022

Nos anos de exílio, em 1943, a artista luso-francesa Maria Helena Vieira da Silva elaborou um painel de azulejaria para o refeitório de um novo campus universitário, situado no quilômetro 47 da rodovia Rio-São Paulo, no antigo distrito de Seropédica. O presente artigo pretende examinar, sob o amparo do conceito benjaminiano de experiência (Erfahrung), as narrativas evocadas pelas temporalidades não-lineares e pelas espacialidades inscritas nesta obra. Sob tal enfoque, o painel Kilomètre 47 pode ser visto como uma homenagem ao trabalho no campo, uma ode à simplicidade, um tributo à mulher, uma deferência às tradições lusitanas. Mas também pode ser interpretado como o reencontro da artista consigo mesma, ou ainda, como uma introjeção pessoal que vislumbra uma dimensão coletiva, a um só tempo poética e potencialmente transformadora.
Common Polymorphism That Protects From Cardiovascular Disease Increases Fibronectin Processing and Secretion
Authors: Soubeyrand Sébastien , Lau Paulina , Nikpay Majid , Dang Anh-Thu , McPherson Ruth
Published: February 2022

Background:

Fibronectin (
FN1
) is an essential regulator of homodynamic processes and tissue remodeling that have been proposed to contribute to atherosclerosis. Moreover, recent large-scale genome-wide association studies (GWAS) have linked common genetic variants within the
FN1
gene to coronary artery disease risk.

Methods:

Public databases were analyzed by 2-Sample Mendelian Randomization. Expression constructs encoding short
FN1
reporter constructs and full-length plasma
FN1
variants were introduced in various cell models. Secreted and cellular levels were then analyzed and quantified by SDS-PAGE and fluorescence microscopy. Mass spectrometry and glycosylation analyses were performed to probe possible posttranscriptional differences.

Results:

Bioinformatic analyses revealed that common coronary artery disease risk single nucleotide polymorphisms in the
FN1
locus associate with circulating levels of FN1 and that higher FN1 (fibronectin 1) protein levels in plasma are linked to lower coronary artery disease risk. The coronary artery disease-associated
FN1
locus encompasses a common polymorphism that translates a L15Q variant situated within the FN1 signal peptide. Introduction of FN1 reporter constructs, differing at position 15, revealed differences in secretion, with the FN1 Q15 variant being less well secreted. Moreover, the L15Q polymorphism was found to alter glycosylation in some cell models but not in human plasma.

Conclusions:

In addition to providing novel functional evidence implicating FN1 in cardioprotection, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.
Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival
Authors: Kudryashova Tatiana V. , Dabral Swati , Nayakanti Sreenath , Ray Arnab , Goncharov Dmitry A. , Avolio Theodore , Shen Yuanjun , Rode Analise , Pena Andressa , Jiang Lifeng , Lin Derek , Baust Jeffrey , Bachman Timothy N. , Graumann Johannes , Ruppert Clemens , Guenther Andreas , Schmoranzer Mario , Grobs Yann , Eve Lemay Sarah , Tremblay Eve , Breuils-Bonnet Sandra , Boucherat Olivier , Mora Ana L. , DeLisser Horace , Zhao Jing , Zhao Yutong , Bonnet Sébastien , Seeger Werner , Pullamsetti Soni S. , Goncharova Elena A.
Published: February 2022

Rationale:

The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown.

Objective:

To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH.

Methods and Results:

Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension.

Conclusions:

Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.
Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial
Authors: MacIntyre Iain M. , Turtle Emma J. , Farrah Tariq E. , Graham Catriona , Dear James W. , Webb David J. , McCallum Morag , Melville Vanessa , Fok Henry , McCrae Jame C. , Sule Ashish , Caparrotta Thomas M. , Kirkby Nicholas S. , Mitchell Jane A.
Published: February 2022

Background:

Acetaminophen is widely used as first-line therapy for chronic pain because of its perceived safety and the assumption that, unlike nonsteroidal anti-inflammatory drugs, it has little or no effect on blood pressure (BP). Although observational studies suggest that acetaminophen may increase BP, clinical trials are lacking. We, therefore, studied the effects of regular acetaminophen dosing on BP in individuals with hypertension.

Methods:

In this double-blind, placebo-controlled, crossover study, 110 individuals were randomized to receive 1 g acetaminophen 4× daily or matched placebo for 2 weeks followed by a 2-week washout period before crossing over to the alternate treatment. At the beginning and end of each treatment period, 24-hour ambulatory BPs were measured. The primary outcome was a comparison of the change in mean daytime systolic BP from baseline to end of treatment between the placebo and acetaminophen arms.

Results:

One-hundred three patients completed both arms of the study. Regular acetaminophen, compared with placebo, resulted in a significant increase in mean daytime systolic BP (132.8±10.5 to 136.5±10.1 mm Hg [acetaminophen] vs 133.9±10.3 to 132.5±9.9 mm Hg [placebo];
P
<0.0001) with a placebo-corrected increase of 4.7 mm Hg (95% CI, 2.9–6.6) and mean daytime diastolic BP (81.2±8.0 to 82.1±7.8 mm Hg [acetaminophen] vs 81.7±7.9 to 80.9±7.8 mm Hg [placebo];
P
=0.005) with a placebo-corrected increase of 1.6 mm Hg (95% CI, 0.5–2.7). Similar findings were seen for 24-hour ambulatory and clinic BPs.

Conclusions:

Regular daily intake of 4 g acetaminophen increases systolic BP in individuals with hypertension by ≈5 mm Hg when compared with placebo; this increases cardiovascular risk and calls into question the safety of regular acetaminophen use in this situation.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01997112. URL:
https://www.clinicaltrialsregister.eu
; Unique identifier: 2013-003204-40.
Acquired Rights in International Administrative Law
Authors: Gulati Rishi
Published: February 2022

The acquired rights doctrine limits the ability of an international organisation (io) to unilaterally amend a staff member’s conditions of employment to his or her detriment. The leading international administrative tribunals, especially the Administrative Tribunal of the International Labour Organisation or the ILOAT refined and developed the doctrine’s meaning and scope over decades. There has been a general consensus that the acquired rights doctrine protects a staff member’s essential terms of employment both retrospectively and prospectively. However, in its recent jurisprudence, the United Nations Appeals Tribunal or the UNAT has rendered the acquired rights doctrine with little work to do by reducing it to the principle of non- retroactivity. As a result, the consensus as to the doctrine’s core meaning is now undermined. International civil servants having access to the ILOAT are much better protected from unilateral adverse amendments to their conditions of employment when compared to those international public officials whose organisations have subscribed to the jurisdiction of the UNAT. This is an unwelcome development for the content of substantive protections is now more dependent on the tribunal approach, as opposed to a coherent development of the law.
Review of the Gargara genistae (Fabricius, 1775) species group (Hemiptera: Membracidae) from Russia and adjacent territories
Authors: TISHECHKIN DMITRI YU.
Published: February 2022

In Russia, Kazakhstan, and Central Asia the Gargara genistae species group includes three species differing from each other in the male calling signal patterns, but almost indistinguishable in external appearance and the male genitalia shape. Illustrated descriptions of morphology and the male calling signals, and data on host plants and distribution for all species are given. Considerations concerning possible modes of species divergence in this group are provided.
The Temperature Anomaly Pattern of the Pacific–North American Teleconnection: Growth and Decay
Authors: Clark Joseph P. , Feldstein Steven B.
Published: February 2022

Applying composite analysis to ERA-Interim data, the surface air temperature (SAT) anomaly pattern of the Pacific–North American (PNA) teleconnection is shown to include both symmetric and asymmetric SAT anomalies with respect to the PNA phase. The symmetric SAT anomalies, overlying the Russian Far East and western and eastern North America, grow through advection of the climatological temperature by the anomalous meridional wind and vertical mixing. The asymmetric SAT anomalies, overlying Siberia during the positive PNA and the subtropical North Pacific during the negative PNA, grow through vertical mixing only. For all SAT anomalies, vertical mixing relocates the temperature anomalies of the PNA teleconnection pattern from higher in the boundary layer downward to the level of the SAT. Above the level of the SAT, temperature anomaly growth is caused by horizontal temperature advection in all locations except for the subtropical North Pacific, where adiabatic cooling dominates. SAT anomaly decay is caused by longwave radiative heating/cooling, except over Siberia, where SAT anomaly decay is caused by vertical mixing. Additionally, temperature anomaly decay higher in the boundary layer due to nonlocal mixing contributes indirectly to SAT anomaly decay by weakening downgradient diffusion. These results highlight a diverse array of mechanisms by which individual anomalies within the PNA pattern grow and decay. Furthermore, with the exception of Siberia, throughout the growth and decay stages, horizontal temperature advection and/or vertical mixing is nearly balanced by longwave radiative heating/cooling, with the former being slightly stronger during the growth stage and the latter during the decay stage.
Spatial and Seasonal Isotope Variability in Precipitation across China: Monthly Isoscapes Based on Regionalized Fuzzy Clustering
Authors: Wang Shengjie , Lei Shijun , Zhang Mingjun , Hughes Catherine , Crawford Jagoda , Liu Zhongfang , Qu Deye
Published: February 2022

The spatial patterns of stable hydrogen and oxygen isotopes in precipitation (precipitation isoscapes) provide a geographic perspective to understand the atmospheric processes in modern environment and paleoclimate records. Here we compiled stable isotope data in modern precipitation at 223 sites across China and 48 in surrounding countries, and used regionalized fuzzy clustering to create monthly precipitation isoscapes for China (C-Isoscape). Based on regressions using spatial and climatic parameters for 12 months, the best-fitting equations were chosen for four climate clusters, and then the four layers were weighted using fuzzy membership. The moisture transportation path, controlled by the westerlies and the monsoon, results in different spatial and seasonal diversity of precipitation isotopes. Based on C-Isoscape, we determined a nationwide meteoric water line asδ2H = 7.4δ18O + 5.5 using least squares regression orδ2H = 8.0δ18O + 10.2 using precipitation weighted reduced major axis regression. Compared with previous global products, the C-Isoscape usually shows precipitation more enriched in18O and2H in summer and more depleted in winter for northwest China, while the C-Isoscape values are more enriched in heavy isotopes in most months for southwest China. The new monthly precipitation isoscapes provide an accurate and high-resolution mapping for Chinese precipitation isotopes, allowing for future intra-annual atmospheric process diagnostics using stable hydrogen and oxygen isotope in precipitation in the region.
Relative Impacts of the Orography and Land–Sea Contrast over the Indochina Peninsula on the Asian Summer Monsoon between Early and Late Summer
Authors: Zhuang Moran , Duan Anmin , Lu Riyu , Li Puxi , Yao Jinglong
Published: February 2022

The Indochina Peninsula (ICP) has a critical effect in shaping the Asian summer monsoon (ASM). However, the seasonal responses of the ASM to the ICP are not fully understood. This study employs a 1° atmospheric general circulation model to examine the different contributions of the ICP’s orography and land–sea contrast to the ASM during the early and late summer. Results indicate that the orographic effect increases South Asian rainfall and reduces the rainfall over the South China Sea (SCS) and North China in early summer, but its influence on monsoonal circulation and rainfall is limited to East Asia in late summer. The impact of the ICP’s land–sea contrast is basically opposite in the two summer stages. With the presence of the ICP, SCS rainfall is enhanced but South Asian rainfall is weakened in early summer. In late summer, however, rainfall from the ICP to the northwestern Pacific is strikingly reduced, accompanied by intensified rainfall over South Asia. Relatively, the orographic effect seems to be more important in modulating the South Asian monsoon in early summer, while the land–sea contrast is dominant in strengthening the SCS monsoon and suppressing the northwest Pacific monsoon via the interaction between the induced local circulation and multilevel ASM subsystems. In late summer, the orographic effect on the ASM is much weaker compared to the land–sea contrast, which plays a critical role by shifting the subtropical high southwestward and through the “thermal adaption” feedback mechanism. Therefore, the orographic impact of the ICP on the ASM differs from that of the land–sea contrast in the two summer stages.
Sex Difference in the Association Between Neutrophil to Lymphocyte Ratio and Severity of Coronary Artery Disease
Authors: Pan Qingrong , Zhang Wenkai , Li Xiaoli , Chen Zhe , Yang Yanna , Wang Guang
Published: February 2022

The neutrophil to lymphocyte ratio (NLR) is a predictor of cardiovascular risk. However, little was known about the influence of sex in this relationship. The present study was designed to evaluate the association between NLR and coronary artery disease (CAD) risk and severity in males and females. A total of 810 patients (478 males and 332 females) who had undergone coronary angiography at the Beijing Chaoyang Hospital were enrolled. CAD severity was evaluated using the Gensini and SYNTAX scores. For males, the NLR was higher in CAD patients than that in non-CAD patients (all P < .001). But there was no significant difference in NLR between female CAD and non-CAD patients ( P = .222). The NLR correlated with the Gensini and SYNTAX scores in male CAD patients (both P < .001), but this correlation was not found in female counterparts (both P > .10). Logistic regression analyses and receiver operator characteristic curve (ROC) analyses showed that the NLR was an independent risk factor and a predictor of CAD in males (both P < .01) but not in females (both P > .10). In conclusion, the NLR was closely related to the presence and severity of CAD in males but not in females.
The drawbacks of drones: The effects of UAVs on escalation and instability in Pakistan
Authors: Gartzke Erik , Walsh James Igoe
Published: February 2022

Growing reliance on Unmanned Aerial Vehicles (UAVs) in the effort to combat militant groups has led to considerable debate about the consequences of this new mode of warfare. While critics have focused on the impact of civilian casualties on militant recruitment and the resulting use of terrorism, evidence suggests that ‘drones’ are paradoxically more effective in limiting civilian deaths compared to other forms of military force. This article demonstrates a different causal pathway connecting militant use of force to terrorist attacks. Drone strikes encourage militants to displace operations to urban centers. Confronted with unfamiliar terrain and greater government capacity, militants emphasize terrorist attacks against civilians. The article explores these dynamics in the longest running drone campaign, in Pakistan. While civilian casualties from drone strikes have no discernible effect on terrorism, strikes that kill militants increase terrorist attacks against civilians in urban settings, while failing to reduce attacks on government targets.
Do Different Devices Perform Equally Well with Different Numbers of Scale Points and Response Formats? A test of measurement invariance and reliability
Authors: Menold Natalja , Toepoel Vera
Published: February 2022

Research on mixed devices in web surveys is in its infancy. Using a randomized experiment, we investigated device effects (desktop PC, tablet and mobile phone) for six response formats and four different numbers of scale points. N = 5,077 members of an online access panel participated in the experiment. An exact test of measurement invariance and Composite Reliability were investigated. The results provided full data comparability for devices and formats, with the exception of continuous Visual Analog Scale (VAS), but limited comparability for different numbers of scale points. There were device effects on reliability when looking at the interactions with formats and number of scale points. VAS, use of mobile phones and five point scales consistently gained lower reliability. We suggest technically less demanding implementations as well as a unified design for mixed-device surveys.
The results of cardiac surgery during the COVID-19 pandemic compared with previous years: a propensity weighted study of outcomes at six months
Authors: Day Emily , Fiorentino Francesca , Abdelkhalek Mohamed , Smail Hassiba , Stock Ulrich A , Bhudia Sunil , De Robertis Fabio , Bahrami Toufan , Raja Shahzad , Gaer Jullien
Published: February 2022

Objectives

In addition to excess mortality due to COVID-19, the pandemic has been characterised by excess mortality due to non-COVID diagnoses and consistent reports of patients delaying seeking medical treatment. This study seeks to compare the outcomes of cardiac surgery during and before the COVID-19 pandemic.

Design

Our institutional database was interrogated retrospectively to identify all patients undergoing one of three index procedures during the first six months of the pandemic and the corresponding epochs of the previous five years.

Setting

A regional cardiothoracic centre.

Participants

All patients undergoing surgery during weeks #13-37, 2015-2020.

Main outcome measures

Propensity score weighted analysis was employed to compare the incidence of major complications (stroke, renal failure, re-ventilation), 30-day mortality, six month survival and length of hospital stay between the two groups.

Results

There was no difference in 30-day mortality (HR = 0.76 [95% CI 0.27-2.20], p = 0.6211), 6-month survival (HR = 0.94 [95% CI 0.44-2.01], p = 0.8809) and duration of stay (SHR = 1.00 (95% CI 0.90-1.12), p = 0.959) between the two eras. There were no differences in the incidence of major complications (weighted chi-square test: renal failure: p = 0.923, stroke: p = 0.991, new respiratory failure: p = 0.856).

Conclusions

Cardiac surgery is as safe now as in the previous five years. Concerns over the transmission of COVID-19 in hospital are understandable but patients should be encouraged not to delay seeking medical attention. All involved in healthcare and the wider public should be reassured by these findings.
What Longitudinal Research and Large-Scale Population Representative Studies Can Tell Us About Gifted Students and Education Policy 50 Years After the Marland Report
Authors: Wai Jonathan , Bardach Lisa , Tran Bich
Published: February 2022

The Marland Report included many correct observations about gifted education. Some findings, for example, were based on Project Talent, a large‐scale population representative longitudinal study of the US high school population. This paper uses the intersection of cognitive aptitudes and gifted education as a framework and synthesizes studies using prospective longitudinal data from numerous sources. Additional retrospective data on US high achievers are reviewed, as are longitudinal findings from other countries. All these sources will be used to reevaluate a selected set of claims made in the Marland Report. Specifically, we explore (a) the definition and understanding of gifted students; (b) the identification of and longitudinal research on gifted students; and (c) we briefly discuss the context of the Marland Report in the wider history of education policy and reform in the US, including how to best support talented students using information from the field of education policy.
Improving healthcare in adult probation services: Learning from Youth Offending Teams
Authors: Brooker Charlie , Collinson Beth , Sirdifield Coral
Published: February 2022

This article reviews the development of the healthcare provision in youth offending teams (YOTs), and the implications of this for improving provision for adults supervised by probation. The Crime and Disorder Act (1998) made healthcare funding a statutory requirement in YOTs, and healthcare presence in most YOTs was significantly boosted by the collaborative commissioning initiative. There is no parallel commissioning initiative in adult probation services. Only a small proportion of NHS clinical commissioning groups make specific investment for this population. Pockets of healthcare provision in probation settings exist, but not consistently. We argue that this represents a major social inequality.
Start-ups’ business model changes during the COVID-19 pandemic: Counteracting adversities and pursuing opportunities
Authors: Guckenbiehl Peter , Corral de Zubielqui Graciela
Published: February 2022

This article investigates how start-ups have been affected by, and have responded to, the COVID-19 pandemic by analysing interview data from 32 Australian start-ups during Australia’s second wave of COVID-19. A framework and visualisation were developed, capturing unexplored heterogeneity within these start-ups, depending whether the emphasis was upon opportunities or adversity, and the type and extent of business model changes. Six start-up types were identified: stable beneficiaries, business-as-usual continuers, digital adjusters, adversity survivors, opportunity graspers and lemonade makers. The findings suggest that most start-ups responded to the crisis through business model changes because of crisis-induced opportunities and crisis-induced adversity The anaysis found that the interplay between firm size and crisis influences whether start-ups focus on business model adaptation or business model innovation or a combination of both We thus contribute to the literature on business models, crisis management and a newly emerging field focusing on the implications of the COVID-19 pandemic for start-ups.
Ambiguous spaces, empirical traces: Accounting for ignorance when researching around the illicit
Authors: Dev Laura , Miller Karly Marie , Lu Juliet , Withey Lauren S , Hruska Tracy
Published: February 2022

Human geographers investigating socio-environmental change in resource frontiers often encounter illicit activities occurring alongside the licit processes they study. These encounters pose logistical challenges to conducting research and moral and analytical dilemmas for researchers. Illicit activities produce what we refer to as spheres of ambiguity, which obscure certain information, relationships, and phenomena surrounding them. We address the dearth of analytical tools for approaching the uncertainty this generates by bringing concepts from agnotology—the study of ignorance—to bear on research conducted amidst illicit activity, offering a framework for systematically evaluating ambiguous field data that is incompletely observed or reported.