bluuebunny/crossref_metadata_2025 huggingface dataset:
AhR Regulates Peptidoglycan-Induced Inflammatory Gene Expression in Human Keratinocytes
Authors: Wang Lanqi , Cheng Binbin , Ju Qiang , Sun Bryan K.
Published: August 2021

Bacterial peptidoglycan (PGN) stimulates toll-like receptor 2 (TLR2) on the surface of keratinocytes (KCs), triggering signaling pathways that promote an innate immune response. However, excessive TLR2 activation can lead to inappropriate inflammation, which contributes to skin conditions such as rosacea. To better treat these conditions, there is a need to understand the molecular mechanisms that regulate the cellular response to TLR2 activation in the skin. Aryl hydrocarbon receptor (AhR) is a transcription factor that modulates the immune response in KCs and is a promising therapeutic target for inflammatory skin diseases. Here, we investigated the role of the AhR in regulating the transcriptional response of human KCs to PGN. We performed whole-transcriptome sequencing in wild-type and AhR-depleted KCs after PGN stimulation. AhR depletion altered the expression of 72 genes in response to PGN, leading to increased expression of 48 genes and repression of 24 genes, including interleukin (IL)-1β. Chromatin immunoprecipitation showed that PGN stimulation resulted in AhR binding the promoters of IL-1β and IL-6 to activate them. More broadly, AhR promoted inflammatory gene expression by increasing JNK/mitogen-activated protein kinase signaling and FosB expression. Finally, we observed that AhR depletion increased TLR2 expression itself, raising the hypothesis that AhR may serve to restrain TLR2-mediated inflammation in KCs through negative feedback. Viewed together, our findings demonstrate a significant and complex role for AhR in modulating the expression of inflammatory genes in KCs in response to PGN.
Influence of Baseline Positron Emission Tomography in Metastatic Gastroesophageal Cancer on Survival and Response to Therapy
Authors: Abdelhakeem Ahmed , Patnana Madhavi , Wang Xuemei , Rogers Jane E. , Murphy Mariela Blum , Sagebiel Tara , Ikoma Naruhiko , Badgwell Brian D. , Trail Allison , Estrella Jeannelyn S. , Lu Yang , Devine Catherine , Ajani Jaffer A.
Published: August 2021

Background: The value of baseline fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) remains uncertain once gastroesophageal cancer is metastatic. We hypothesized that assessment of detailed PET-CT parameters (maximum standardized uptake value [SUVmax] and/or total lesion glycolysis [TLG]), and the extent of metastatic burden could aid prediction of probability of response or prognosticate. Methods: We retrospectively analyzed treatment-naive patients with stage 4 gastroesophageal cancer (December 2002–August 2017) who had initial PET-CT for cancer staging at MD Anderson Cancer Center. SUVmax and TLG were compared with treatment outcomes for the full cohort and subgroups based on metastatic burden (≤2 or >2 metastatic sites). Results: We identified 129 patients with metastatic gastroesophageal cancer who underwent PET-CT before first-line therapy. The median follow-up time was 61 months. The median overall survival (OS) was 18.5 months; the first progression-free survival (PFS) was 5.5 months. SUVmax or TLG of the primary tumor or of all metastases combined had no influence on OS or PFS, whether the number of metastases was ≤2 or >2. Overall response rates (ORRs) to first-line therapy were 48% and 45% for patients with ≤2 and >2 metastases, respectively (nonsignificant). ORR did not differ based on low or high values of SUVmax or TLG. Conclusions: This is the first assessment of a unique set of PET-CT data and its association with outcomes in metastatic gastroesophageal cancer. In our large cohort of patients, detailed analyses of PET-CT (by SUVmax and/or TLG) did not discriminate any parameters examined. Thus, baseline PET-CT in untreated metastatic gastroesophageal cancer patients has limited or no utility.
High-Fat Diet-Induced Obesity Aggravates Food Allergy by Intestinal Barrier Destruction and Inflammation
Authors: Gu Yanjun , Guo Xiaoya , Sun Shanfeng , Che Huilian
Published: August 2021

Introduction: The increase in high-fat diet (HFD)-induced obesity and food allergy leads to an assumption that the 2 are related. This study aims to (1) systematic verification of HFD-induced obesity aggravates food allergy and (2) explore the correlation and molecular mechanisms of HFD-induced obesity promotes food allergy. Methods: Female BALB/c mice are divided into the control group (control), the ovalbumin (OVA)-sensitized group (OVA), the HFD-induced obesity group (HFD), and HFD-induced allergic obesity group (HFD + OVA). Results: In vivo data showed that HFD feed enhance clinical symptoms and intestinal mucosa villi shed on allergic mice. Moreover, we found that HFD and OVA irritation enhanced levels of mast cell degranulation and Th2 humoral response. Additionally, Western blot analysis showed the potentiation of peroxisome proliferator-activated receptor γ (PPAR γ) remarkably reduced on intestinal in HFD and OVA group, thereby inhibiting the expression of nuclear factor kappa B (NF-κB)/PPAR γ signal the phosphorylation of NF-κB P65. Conclusions: Overall, our results suggest that HFD-induced obesity is a potential risk factor for food allergy, which related to intestinal barrier destruction and inflammation through the PPAR γ/NF-κB signaling pathway.
NETest: A Systematic Review Focusing on the Prognostic and Predictive Role
Authors: Puliani Giulia , Di Vito Valentina , Feola Tiziana , Sesti Franz , Centello Roberta , Pandozzi Carla , Tarsitano Maria Grazia , Verrico Monica , Lenzi Andrea , Isidori Andrea M. , Giannetta Elisa , Faggiano Antongiulio
Published: August 2021

The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33–40% could predict tumor progression. Moreover, NETest performed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20–40%), while a higher score (>33–40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies.
Localization Defines Streptozotocin/5-FU Response in Primary Pancreatic Neuroendocrine Tumours
Authors: Reher Dominik , Fehrenbach Uli , Kayser Antonin , Pape Ulrich-Frank , Henes Frank Oliver , Cremer Birgit , Hörsch Dieter , Izbicki Jakob , Lohse Ansgar Wilhelm , Rinke Anja , Schrader Jörg
Published: August 2021

Introduction: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. Methods: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. Results: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. Conclusion: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration.
Hélio Oiticica em Brighton: um conto inédito
Authors: Galeazzi Annelise Estrella
Published: August 2021

Este trabalho apresenta o fac-símile datilografado de um conto sem título, escrito pelo artista brasileiro Hélio Oiticica, que se encontra em seu acervo digital, o Programa HO, financiado pelo Itaú Cultural. Escrito em 1969, quando Oiticica realizava uma residência artística na Universidade de Sussex, em Birghton, na Inlgaterra, o conto narra as angústias de um personagem poeta em busca da felicidade.
A abordagem hermenêutica nos estudos da tradução
Authors: Stefanink Bernd , Bălăcescu Ioana , Fortier Diana
Published: August 2021

Na primeira parte, demonstraremos esta validade, baseados no fato de que a abordagem hermenêutica integra fatores como a subjetividade, a intuição, a corporalidade e a criatividade em sua reflexão teórica, aproximando-se, assim, da realidade do processo tradutor. Na segunda parte, situaremos esta abordagem no contexto do desenvolvimento dos estudos modernos da tradução desde os anos 1950, e mostraremos que este desenvolvimento foi caracterizado por uma tendência determinante, que levou de uma visão atomista da unidade de tradução a uma visão mais holística, legitimando-a, o que é fundamental para a Hermenêutica da Tradução. A terceira parte relata a história da hermenêutica filosófica como fundação legítima da Hermenêutica da Tradução. Na quarta parte, devotada às “perspectivas futuras”, procuraremos demonstrar a legitimidade da abordagem hermenêutica, demonstrando como ela é confirmada por resultados de pesquisa em ciência cognitiva. Para motivar a continuidade dos trabalhos em Hermenêutica da Tradução, também oferecemos uma metodologia para o estudo do processo tradutório baseada nos princípios hermenêuticos. Finalmente, oferecemos um exemplo de legitimação do processo de solução de problemas de tradução, baseado na abordagem hermenêutica e validado pelos resultados da pesquisa cognitiva.
Literatura e edição à luz da sociologia dos textos, de D. F. McKenzie
Authors: Landi Thiago
Published: August 2021

Este artigo busca promover uma articulação entre os campos dos estudos literários e editoriais a partir das contribuições do notável bibliógrafo neozelandês D. F. McKenzie, que ao conceber a noção de sociologia dos textos funda um importante entendimento sobre a influência capital que os aspectos materiais, históricos e sociais do texto têm na sua conformação semântica e na sua transmissão ao longo do tempo e do espaço. A partir daí, busca-se demonstrar a relevância da instância editorial – que é parte dessa cadeia sociológica – para os estudos literários perpassando quatro pontos: primeiramente, apresenta-se o projeto bibliográfico da primeira tradução brasileira de O avarento, de Molière, que é seguido de uma exposição crítica sobre a teoria de McKenzie, de um panorama conceitual sobre a edição e, finalmente, de um estudo de caso sobre as circunstâncias editoriais que envolveram a publicação original do romance 2666 (Barcelona: Anagrama, 2004), do escritor chileno Roberto Bolaño.
"Borges não acreditava na perfeição": entrevista com Daniel Balderston
Authors: Bergonzoni Gisela Anauate
Published: August 2021

Daniel Balderston é um dos mais reconhecidos especialistas da obra do escritor argentino Jorge Luis Borges. Professor do departamento de línguas e literaturas hispânicas da University of Pittsburgh, nos Estados Unidos, é diretor do Borges Center, que abriga em seu site um extenso material sobre a obra do autor e sua fortuna crítica. O trabalho de Balderston impactou os estudos da obra de Borges sob diferentes perspectivas teóricas, das pesquisas de suas fontes históricas até os estudos de gênero. Entre seus livros, destacam-se Out of context: Historical Reference and the Representation of Reality in Borges (1993), Borges, Realidad y simulacros (2000) e Innumerables relaciones: cómo leer con Borges (2010). Nos últimos anos, Balderston tem se dedicado a uma tarefa de grande relevância para os estudos hispânicos contemporâneos: a crítica genética dos manuscritos de Borges, que estão espalhados por países diferentes – Estados Unidos, Argentina, Uruguai, Espanha, Suíça – em bibliotecas e coleções particulares. Grande parte dessa pesquisa está reunida no livro How Borges Wrote (University of Virginia Press, 2018), que Balderston considera seu maior feito nos quarenta anos em que passou destrinchando os escritos do argentino. Trata-se de um estudo incontornável sobre a gênese da obra borgeana: há reproduções facsimilares até então inéditas dos manuscritos de Borges e análises finas de suas anotações, de seus esboços e planos de trabalho, de cadernos preparatórios para cursos, de variantes e de cópias manuscritas de ensaios e contos. Nesta entrevista, concedida à Manuscrítica por videoconferência, Balderston falou sobre a busca detetivesca pelos manuscritos de Borges – digna talvez de um conto que o próprio autor argentino teria escrito –, sobre o árduo processo de composição de How Borges Wrote e sobre o status atual das pesquisas genéticas no mundo anglo-saxão. O livro foi publicado na França em 2019, sob o título La Méthode Borges, com tradução de Sophie Campbell (Presses Universitaires de Vincennes) e deverá ser lançado ainda este ano na Argentina, em uma versão ampliada, como El método Borges, com tradução de Ernesto Montequin (Ampersand).
Hypercholesterolemia Impairs Clearance of Neutrophil Extracellular Traps and Promotes Inflammation and Atherosclerotic Plaque Progression
Authors: Dhawan Umesh Kumar , Bhattacharya Purbasha , Narayanan Sriram , Manickam Vijayprakash , Aggarwal Ayush , Subramanian Manikandan
Published: August 2021

Objective:

Hypercholesterolemia-induced NETosis and accumulation of neutrophil extracellular traps (NETs) in the atherosclerotic lesion exacerbates inflammation and is causally implicated in plaque progression. We investigated whether hypercholesterolemia additionally impairs the clearance of NETs mediated by endonucleases such as DNase1 and DNase1L3 and its implication in advanced atherosclerotic plaque progression.

Approach and Results:

Using a mouse model, we demonstrate that an experimental increase in the systemic level of NETs leads to a rapid increase in serum DNase activity, which is critical for the prompt clearance of NETs and achieving inflammation resolution. Importantly, hypercholesterolemic mice demonstrate an impairment in this critical NET-induced DNase response with consequent delay in the clearance of NETs and defective inflammation resolution. Administration of tauroursodeoxycholic acid, a chemical chaperone that relieves endoplasmic reticulum stress, rescued the hypercholesterolemia-induced impairment in the NET-induced DNase response suggesting a causal role for endoplasmic reticulum stress in this phenomenon. Correction of the defective DNase response with exogenous supplementation of DNase1 in
Apoe

−/−

mice with advanced atherosclerosis resulted in a decrease in plaque NET content and significant plaque remodeling with decreased area of plaque necrosis and increased collagen content. From a translational standpoint, we demonstrate that humans with hypercholesterolemia have elevated systemic extracellular DNA levels and decreased plasma DNase activity.

Conclusions:

These data suggest that hypercholesterolemia impairs the NET-induced DNase response resulting in defective clearance and accumulation of NETs in the atherosclerotic plaque. Therefore, strategies aimed at rescuing this defect could be of potential therapeutic benefit in promoting inflammation resolution and atherosclerotic plaque stabilization.
Anthocyanins Activate Membrane Estrogen Receptors With Nanomolar Potencies to Elicit a Nongenomic Vascular Response Via NO Production
Authors: Calfío Camila , Donoso Francisca , Huidobro‐Toro J. Pablo
Published: August 2021

Background

The vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin‐induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17‐β estradiol‐(E2) induced vasodilatations and NO production.

Methods and Results

The rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3‐O‐glycosides, or E2, to examine rapid concentration‐dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO‐DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G‐36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium‐dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G‐36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2‐induced NO production was antagonized up to 70% by these antagonists. NO‐DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G‐36 addition.

Conclusions

The biomedical effect of anthocyanins or 3‐O‐glycosylates derivatives contained in naturally purple‐colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.
Rheumatic Heart Disease in the United States: Forgotten But Not Gone
Authors: de Loizaga Sarah R. , Arthur Lindsay , Arya Bhawna , Beckman Brian , Belay Wubishet , Brokamp Cole , Hyun Choi Nak , Connolly Sean , Dasgupta Soham , Dibert Tavenner , Dryer Marylou M. , Gokanapudy Hahn Lakshmi R. , Greene Elizabeth Anne , Kernizan Daphney , Khalid Omar , Klein Jennifer , Kobayashi Ryan , Lahiri Subhrajit , Lorenzoni Raymond P. , Otero Luna Andrea , Marshall Jennifer , Millette Theodore , Moore Lily , Muhamed Babu , Murali Meghna , Parikh Kinjal , Sanyahumbi Amy , Shakti Divya , Stein Elizabeth , Shah Sanket , Wilkins Hannah , Windom McAllister , Wirth Scott , Zimmerman Meghan , Beck Andrew F. , Ollberding Nicholas , Sable Craig , Beaton Andrea
Published: August 2021

Background

Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD.

Methods and Results

Twenty‐two US pediatric institutions participated in a 10‐year review (2008–2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract‐based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community deprivation were obtained. Data for 947 cases showed median age at diagnosis of 9 years; 51% and 56% identified as male and non‐White, respectively. Most (89%) had health insurance and were first diagnosed in the United States (82%). Only 13% reported travel to an endemic region before diagnosis. Although 96% of patients were prescribed secondary prophylaxis, only 58% were prescribed intramuscular benzathine penicillin G. Higher deprivation was associated with increasing disease severity (odds ratio, 1.25; 95% CI, 1.08–1.46).

Conclusions

The majority of recent US cases of ARF and RHD are endemic rather than the result of foreign exposure. Children who live in more deprived communities are at risk for more severe disease. This study demonstrates a need to improve guideline‐based treatment for ARF/RHD with respect to secondary prophylaxis and to increase research efforts to better understand ARF and RHD in the United States.
Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia
Authors: Tsuzuki Kazuhito , Shimizu Yuuki , Suzuki Junya , Pu Zhongyue , Yamaguchi Shukuro , Fujikawa Yusuke , Kato Katsuhiro , Ohashi Koji , Takefuji Mikito , Bando Yasuko K. , Ouchi Noriyuki , Calvert John W. , Shibata Rei , Murohara Toyoaki
Published: August 2021

Background

Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia.

Methods and Results

A jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model (
P
<0.05). The jet‐lag condition deteriorated tissue capillary formation (
P
<0.001) and tissue blood perfusion recovery (
P
<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie,
Clock
,
Bmal1
, and
Cry
) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet‐lag condition. Next,
Cry1
and
Cry2
double‐knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis.
Cry1
and
Cry2
double‐knockout mice revealed suppressed capillary density (
P
<0.001) and suppressed tissue blood perfusion recovery (
P
<0.05) in the hind limb ischemia model. Moreover, knockdown of
CRY1/2
in human umbilical vein endothelial cells was accompanied by increased expression of
WEE1
and decreased expression of
HOXC5
. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis.

Conclusions

Our data suggest that circadian rhythm disorder deteriorates reparative ischemia‐induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.
Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction
Authors: Greene Stephen J. , Choi Sujung , Lippmann Steven J. , Mentz Robert J. , Greiner Melissa A. , Hardy N. Chantelle , Hammill Bradley G. , Luo Nancy , Samsky Marc D. , Heidenreich Paul A. , Laskey Warren K. , Yancy Clyde W. , Peterson Pamela N. , Curtis Lesley H. , Hernandez Adrian F. , Fonarow Gregg C. , O'Brien Emily C.
Published: August 2021

Background

Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real‐world US practice is unclear.

Methods and Results

This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines–Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker. Over 12‐month follow‐up, compared with a discharge prescription of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all‐cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72–0.94;
P
=0.004) but not all‐cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89–1.07;
P
=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91–1.18;
P
=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all‐cause mortality (adjusted HR, 0.69; 95% CI, 0.60–0.79;
P
<0.001), all‐cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82–0.98;
P
=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82–1.08;
P
=0.40).

Conclusions

Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all‐cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.
Variational Deep Logic Network for Joint Inference of Entities and Relations
Authors: Wang Wenya , Pan Sinno Jialin
Published: August 2021

Currently, deep learning models have been widely adopted and achieved promising results on various application domains. Despite their intriguing performance, most deep learning models function as black boxes, lacking explicit reasoning capabilities and explanations, which are usually essential for complex problems. Take joint inference in information extraction as an example. This task requires the identification of multiple structured knowledge from texts, which is inter-correlated, including entities, events, and the relationships between them. Various deep neural networks have been proposed to jointly perform entity extraction and relation prediction, which only propagate information implicitly via representation learning. However, they fail to encode the intensive correlations between entity types and relations to enforce their coexistence. On the other hand, some approaches adopt rules to explicitly constrain certain relational facts, although the separation of rules with representation learning usually restrains the approaches with error propagation. Moreover, the predefined rules are inflexible and might result in negative effects when data is noisy. To address these limitations, we propose a variational deep logic network that incorporates both representation learning and relational reasoning via the variational EM algorithm. The model consists of a deep neural network to learn high-level features with implicit interactions via the self-attention mechanism and a relational logic network to explicitly exploit target interactions. These two components are trained interactively to bring the best of both worlds. We conduct extensive experiments ranging from fine-grained sentiment terms extraction, end-to-end relation prediction, to end-to-end event extraction to demonstrate the effectiveness of our proposed method.
Detecting Local Insights from Global Labels: Supervised and Zero-Shot Sequence Labeling via a Convolutional Decomposition
Authors: Schmaltz Allen
Published: August 2021

We propose a new, more actionable view of neural network interpretability and data analysis by leveraging the remarkable matching effectiveness of representations derived from deep networks, guided by an approach for class-conditional feature detection. The decomposition of the filter-n-gram interactions of a convolutional neural network (CNN) and a linear layer over a pre-trained deep network yields a strong binary sequence labeler, with flexibility in producing predictions at—and defining loss functions for—varying label granularities, from the fully supervised sequence labeling setting to the challenging zero-shot sequence labeling setting, in which we seek token-level predictions but only have document-level labels for training. From this sequence-labeling layer we derive dense representations of the input that can then be matched to instances from training, or a support set with known labels. Such introspection with inference-time decision rules provides a means, in some settings, of making local updates to the model by altering the labels or instances in the support set without re-training the full model. Finally, we construct a particular K-nearest neighbors (K-NN) model from matched exemplar representations that approximates the original model’s predictions and is at least as effective a predictor with respect to the ground-truth labels. This additionally yields interpretable heuristics at the token level for determining when predictions are less likely to be reliable, and for screening input dissimilar to the support set. In effect, we show that we can transform the deep network into a simple weighting over exemplars and associated labels, yielding an introspectable—and modestly updatable—version of the original model.
A Test of ‘Utilitarianism for Animals, Kantianism for People’
Authors: Wendler David
Published: August 2021

Many people believe that animals possess moral status, but human beings possess higher moral status than animals. To try to identify a theoretical basis for this view, Robert Nozick proposed Utilitarianism for Animals, Kantianism for People. The present manuscript evaluates Nozick’s proposal by identifying the tradeoffs in welfare that it permits in medical research with animals and assessing whether those tradeoffs are indeed permissible. This analysis suggests that at least some deontological side constraints apply to the treatment of sentient animals, hence, Utilitarianism for Animals, Kantianism for People is mistaken. Because Nozick’s proposal represents a prominent attempt to provide a theoretical basis for the common belief that human beings possess higher moral status than animals, this conclusion is noteworthy in its own right. Moreover, by granting equal moral weight to the interests of animals, but reserving deontological side constraints for human beings, Utilitarianism for Animals, Kantianism for People offers one of the more plausible bases for the claim that there are degrees of moral status among those who matter morally. The manuscript thus ends by considering the implications of the present analysis for the possibility that moral status comes in degrees.
Histrionics of Autism in the Media and the Dangers of False Balance and False Identity on Neurotypical Viewers
Authors: Ressa Theodoto
Published: August 2021

Contemporary US media increasingly portray autism “positively.” Based on critical realism and guided by the Disability Studies in Education (dse) framework, three television shows—Atypical, Touch, and The Good Doctor—with fictitious Autism Spectrum Disorder (asd) character(s) are qualitatively analyzed to understand the impact of the media’s portrayal of autism on the perceptions of neurotypical educators from the perspective of a disabled teacher educator. Autism in the three comedydrama series is portrayed as a savant syndrome of White heterosexual male experience affecting middle-class families. These portrayals of asd are less representative of the autism community and therefore lead to two prominent television strategies of misleading information—false balance and false identity. Since media are not neutral informers, entertainers, educators, and persuaders, it is vital for consumers especially educators to engage in dse informed critical literacy to ensure the consumption of meaningful information about autism.
A new species of Leptobrachella (Anura, Megophryidae) from Mount Pu Ta Leng, northwest Vietnam
Authors: NGUYEN LUAN THANH , TAPLEY BENJAMIN , NGUYEN CHUNG THANH , LUONG HAO VAN , ROWLEY JODI J.L.
Published: August 2021

The Hoang Lien Range in northwest Vietnam is known to harbour five species of Leptobrachella, a specious genus of terrestrial frogs. We collected specimens of Leptobrachella from Mount Pu Ta Leng on the second highest peak in the Hoang Lien Range and use morphological and molecular data to show that this population represents a previously undescribed species which we name Leptobrachella graminicola sp. nov. after the abundance of calling males on sedge-like plants. This new species is closely related to L. bourreti but the new species is distinguished from L. bourreti and other congeneric species by a combination of the following characters: (1) a body size range of 23.1–24.6 mm in six adult males and 28.6–32.9 mm in five adult females; (2) skin on dorsum smooth, with many tubercles and lacking dermal ridges; (3) toes with rudimentary webbing and broad lateral fringes; (4) belly white with brown spots; (5) throat dark brown with light grey-brown flecks and spots; (6) a row of large white spots on the outer edge of the tarsus extending from the heel to the inner metatarsal tubercle, sometimes forming a long white stripe; and (7) a bicoloured iris. The new, high-elevation species is likely to be range-restricted and threatened by habitat loss and the activities of tourists.
Taxonomic study of Mesomeloe coelatus (Reiche & Saulcy, 1857) (Coleoptera: Meloidae: Meloini), with the description of an overlooked new species
Authors: SÁNCHEZ-VIALAS ALBERTO , RUIZ JOSÉ L. , GARCÍA-PARÍS MARIO
Published: August 2021

A new species of the genus Mesomeloe (Meloidae) is described from Qatar on the north-eastern coast of the Arabian Peninsula. Mesomeloe ottomerkli sp. nov., which is currently only known from the type locality, was previously identified as Meloe (Mesomeloe) coelatus. Both the morphological and molecular variability of M. coelatus across its wide distribution range are studied to determine the level of congruence between the morphological and genetic differentiation of M. coelatus and the new species. Mesomeloe ottomerkli is distinguishable from all other congeneric species in various traits: it presents a body tegument and appendages that are black in colour and shiny in appearance; an elytral surface absent of impressed longitudinal shallow ridges; a pronotal surface absent of depressed areas and longitudinal midline; and a pronotal base that is slightly arcuate. In addition, males of M. ottomerkli have antennae that gradually widen towards the apex; protarsomeres with a brush patch of yellowish setae on the ventral surface of the first two segments; genitalia in which the gonostyli, in lateral view, become slenderer towards the apex and an aedeagus that is relatively wide and rounded in the distal portion. The distribution records of M. coelatus are also updated and summarized.
Two new oak gall wasp species (Hymenoptera: Cynipidae, Cynipini) from Quercus pontica (Fagaceae) in Turkey
Authors: AZMAZ MUSA , KATILMIŞ YUSUF
Published: August 2021

Two new species of oak gall wasp, Andricus mammadovi Azmaz &  Katılmış sp. n. sexual generation and Cynips fatihi Azmaz &  Katılmış sp. n. asexual generation (Cynipidae: Cynipini) are described from the eastern Black Sea region in Turkey. These species induce galls on Quercus pontica K.Koch representing the first record of cynipids associated with the natural Q. pontica population in Turkey. SEM images, photos of the host galls, and data on the diagnosis, distribution, and biology of both new species are provided.
On two new species of arboreal crabs from phytotelms in Sarawak, Borneo (Crustacea: Brachyura: Gecarcinucidae: Arachnothelphusa)
Authors: NG PETER K. L.
Published: August 2021

Two new species of the gecarcinucid freshwater crab genus Arachnothelphusa are described from the Malaysian state of Sarawak in Borneo; one from Lanjak-Entimau Wildlife Sanctuary and another from Bako National Park. Arachnothelphusa rimba n. sp. is distinctive in possessing very long legs and a male first gonopod which has a cylindrical proximal part of the terminal segment, with the distal part sharply tapering to an acute tip. Arachnothelphusa bako n. sp. is superficially closest to A. kadamaiana from Sabah, but differs markedly by its narrower epistome, and proportionately shorter third maxillipeds and ambulatory legs.
miRNA-489-3p Improves Sepsis-Induced Lung Injury by Regulating Toll-Like Receptor 4 (TLR4) Signaling Pathway
Authors: He Xiaowei , Shao Longgang , Xu Min , Li Tan , Zheng Namin , Liu Keqin
Published: August 2021

Aim: To discuss miRNA-489-3p in sepsis-induced lung injury. Materials and methods: Using NR-8383 as research cell in our study, and using LPS stimulation to sepsis induced lung injury vitro model. Measuring cell proliferation by MTS assay; using Elisa assay to measure
IL-1β, IL-6 and TNF-α concentration; apoptosis cell number and apoptosis rate were evaluated using TUNEL and flow cytometry; gene and protein were measured by RT-PCR and WB assay; measuring p-NF-κB(p65) nuclear volume by Immunofluorescence (IF); using
Luciferase reporter assay to analysis miRNA-489-3p and TLR4 correlation. Results: Cell proliferation rate significantly down-regulated (P < 0.001), apoptosis cell number and apoptosis rate significantly increased (P < 0.001); IL-1β, IL-6 and TNF-α
concentrations significantly up-regulated (P < 0.001); TLR4 and MyD88 gene and protein significantly increased (P < 0.001), NF-κB(p65) mRNA and p-NF-κB(p65) protein and nuclear volume significantly increased (P < 0.001). However, with
miRNA-489-3p supplement, the cell proliferation rate, apoptosis cell number and apoptosis rate were significantly improved (P < 0.001, respectively) via TLR4, MyD88 and NF-κB(p65) mRNA and protein significantly depressing (P < 0.001, respectively). By LUC assay,
miRNA-489-3p could target to TLR4 in NR-8383 cell. Conclusion: miRNA-489-3p overexpression had effect to improve sepsis induced lung injury via regulation TLR4/MyD88/NF-κB(p65).
Hydroxyl Safflower Yellow Pigment A (HSYA) Improves Vascular Endothelial Injury Induced by Lipopolysaccharide In Vitro Study
Authors: Yan Li , Jingping Ge , Yuanyuan Yin , Xiaomei Li , Boxiang Zhao , Jianping Gu
Published: August 2021

Aim: This research was to investigate the effects and mechanisms of HSYA in vascular endothelial injury by vitro study. Methods: Dividing HUVECs as Normal Control (NC), Model (LPS treated) group, HSYA-L, HSYA-M and HSYA-H groups. Cells in the HSYA treatment groups were
treated with LPS, followed by 40 mg/ml, 80 mg/ml, and 120 mg/ml HSYA intervention (HSYA-L, HSYA-M, and HSYA -H groups), respectively. Measuring the cell proliferation, apoptosis, relative proteins and mRNA (TLR4, MyD88 and NF-κB(p65)) expressions by MTT, Flow cytometry, WB and
RT-qPCR assay. Using cellular immunofluorescence to evaluate NF-κB(p65) nuclear volume of difference groups. Results: With HSYA supplement, the cell proliferation rates were significantly up-regulation with cell apoptosis significantly down-regulation with TLR4 relatived
mRNA and proteins and NF-κB(p65) nuclear significantly depressed with dose-dependent (P <0.05, respectively). Conclusion: HSYA improved vascular endothelial injury induced by LPS via TLR4 pathway In Vitro.
MicroRNA-16-5p Promoted Fibroblast-Like Synoviocyte Proliferation and Suppressed Apoptosis via Targeting Suppressor of Cytokine Signaling 6 (SOCS6) in Human Rheumatoid Arthritis
Authors: Meng Deqian , Pan Wenyou , Li Ju
Published: August 2021

Accumulating evidence have indicated that MicroRNAs (miRNAs) are key regulators in human rheumatoid arthritis (RA). The aim of this study was to explore the functional roles of miR-16-5p in proliferation, inflammation, and apoptosis of fibroblast-like synoviocytes (FLS). The expression
of miR-16-5p and SOCS6 in FLA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry, respectively. Luciferase reporter assay was used to verify the direct target of miR-16-5p. Western blot
analysis was performed to analysis the levels of SOCS6, Bcl-2, Bax and cleaved caspase 3. miR-16-5p expression was significantly upregulated while SOCS6 level was decreased in RA-FLS compared with normal FLS. In addition, luciferase reporter assay confirmed that SOCS6 was the target of miR-16-5p.
Silencing of miR-16-5p inhibited cell proliferation, releases of TNF-α, IL-1β, IL-6 and IL-8, and induced the apoptosis. The effects of miR-16-5p silencing on RA-FLS were reversed by downregulation of SOCS6. In summary, knockdown of miR-16-5p could suppress cell proliferation
and accelerate the apoptosis of RA-FLS through targeting SOCS6, which may provide a potential therapeutic target for patients with RA.
Irisin Attenuates Osteogenic Differentiation of Mouse Mesenchymal Stem Cells via Suppressing Bone Morphogenetic Protein-2 Signaling
Authors: Liang Yongying , Hu Li , Ji Chuanting , Hu Xiaoxue , Dai Hao
Published: August 2021

This study assessed the impact of irisin on mouse mesenchymal stem cells (MSCs) differentiation and the underlying mechanisms. Bone marrow mesenchymal stem cells (BMMSCs) and mesenchymal progenitor cells (KUSA-A1 cells) were isolated from mice and inoculated into petri dishes. Cell
proliferation and apoptosis under different concentrations of irisin were detected by MTT. Irisin (1 μM) with nontoxic dose concentration was selected for subsequent experiments. Cells were exposed to 1 μM irisin, osteogenic differentiation was detected by von kossa stain,
we employed oil red o stain to test adipocyte differentiation, Alcian blue stain to determine chondrocyte differentiation. BMP-2 expression was analyzed by immunocytochemical staining. Finally, signal transduction pathways and expression and transcription levels of osteogenic differentiation
markers in irisin-treated cells were detected by protein imprinting and PCR. BMMSCs and KUSA-A1 cells displayed significantly suppressed osteogenic differentiation and reduced formation of extracellular mineralized matrix, while BMMSCs presented unaffected adipocyte differentiation and chondrocyte
differentiation. 1 μM Irisin did not exert cytotoxicity. Further, irisin treatment abated osteogenic differentiation makers Runx2, Osterix, Osteocalcin, Osteopontin, alkaline phosphatase expression. Finally, BMP-2/Smads signaling related molecules (BMP-2, Smad1, Smad4, Smad5 and
Smad8) levels were reduced after Irisin treatment. Irisin might inhibit osteoblast differentiation by modulating BMP-2/Smads axis.
miR-26b Regulates Osteoactivin (OA)-Induced Bone Marrow Mesenchymal Cells (BMSCs) Osteogenic Differentiation by Targeting Fms-Like Tyrosine Kinase 3 (FLT3)/AXL
Authors: Sun Feng , Huang Tianwen , Shi Jianhui , Wei Tianli , Zhang Haiwei
Published: August 2021

Osteoactivin (OA) plays a key role in osteogenic differentiation. miR-26b is elevated in the bone formation process of BMSCs, but whether it is involved in this process is unclear. Bone formation is regulated by FLT3/AXL signaling pathway, which may be a potential target of miR-26b.
qRT-PCR detected miR-26b mRNA levels and bone formation-related genes or FLT3/AXL signaling pathway-related genes. Bone formation was analyzed by staining and FLT3/AXL signaling was evaluated along with analysis of miR-26b’s relation with LT3/AXL. miR-26b was significantly elevated in
OA-induced bone formation of BMSCs, which can be promoted by miR-26b mimics. When miR-26b was overexpressed, FLT3/AXL signaling pathway was activated. miR-26b can ameliorate Dex-induced osteo-inhibition. miR-26b promotes bone formation of BMSCs by directly targeting FLT3/AXL signaling pathway,
suggesting that miR-26b might be a target for inducing osteogenic differentiation.
Design and Fabrication of Microfluidic-Based 3D Microphysiological Systems for Studying Cell Migration and Invasion Behaviors
Authors: Wang Xi , He Qingling , Li Qianyin , Li Yuan , Suresh Shoma , Krishnan Sasirekha , Ramalingam Murugan , Lv Xiaoyan , Ni Yilu
Published: August 2021

The cell migration and invasion behaviors play pivotal roles in tissue regeneration. For the skin repair process, a directed inflammatory response that regulates fibroblasts is critical for efficient wound healing. In this study, the authors present the design and fabrication of a microfluidic-based
three-dimensional (3D) microphysiological system and how it impacts in controlling fibroblast migration and invasion under the induction of differently polarized macrophages. The microfluidic device had two chambers on opposite sides of a 1 mm micochannel, providing directed induction and
sufficient width for long-term observation. The test cells could be seeded with or without matrix gel, cultured in a 2D or 3D microenvironment according to experiment settings. The microchannel allowed for any sorts of matrix filling and was on-demanding for continuous surveillance. Herein,
our microfluidic device reserved the advantages of traditional methods using transwell chamber or scratch wound healing assay. In addition, it even came with more superiority such as retrievability, dynamic observation, and 3D environment simulation. The migration and invasion pattern of NIH3T3
modulated by RAW264.7 macrophages in different polarization status was demonstrated as an example. The results of the migration assay corresponded with that of the proliferation and gene expression experiments, verifying that our device was fully capable of restoring in vivo microenvironment
and presenting cellular motility behaviors.
Bone Marrow Mesenchymal Stem Cells (BMSC)-Originated miR-133 Impedes Migration and Invasiveness of Glioma Cells While Enhancing Apoptosis via Targeting the Receptor for Activated C Kinase 1 (RACK1)
Authors: Xiong Jiangbo , Liu Sheng , Xiang Bin , Zhang Weibo , Du Jun , Zhou Sheng , Huang Huaizhong , Wang Peng , Luo Li
Published: August 2021

This study aims to dissect the effects of bone marrow mesenchymal stem cells (BMSC) on the in vitro activity of glioma cells and the underlying mechanisms. The glioma cells were transfected with miR-133 mimics, RACK1-Vector, negative control (NC) and miR-133 mimic+RACK1-Vector,
respectively, and then co-cultured with BMSC followed by analysis of miR-133 expression via PCR, apoptosis via flow cytometry, proliferation via CCK-8, invasion and migration via Transwell assay, the expression of proteins involved in apoptosis, anti-apoptosis, invasiveness and RACK1 by western
blot, and the targeting relationship between miR-133 and RACK1 by dual-luciferase reporter gene assay. In comparison with normal glial cells, glioma cells exhibited a significantly diminished miR-133 level. miR-133 was upregulated in glioma cells after co-culture with BMSC, along with significantly
restrained proliferation rate, migration and invasion activities as well as reduced protein levels (MMP-2, Vimentin, N-cadherin and MMP-9). Mechanistic study showed that miR-133 can retard the expression of RACK1, thereby impeding the invasion, migration and proliferation activities of cells
while triggering cell apoptosis. In conclusion, BMSC-originated miR-133 can impede the migration and invasion while enhancing the apoptosis of glioma cells via targeting RACK1.