bluuebunny/crossref_metadata_2025_split huggingface dataset:
New bis(thieno[2,3-b]pyridine) hybrids linked to arene units as potential bacterial biofilm and MRSA inhibitors
Authors: Sanad Sherif M.H. , Mekky Ahmed E.M. 
Published: April 2023

Using sonication and mediated by piperazine, new arene-linked bis(thieno[2,3- b]pyridine) hybrids were efficiently prepared in this study. The target hybrids were prepared by reacting bis(α-haloketone) with two equivalents of the appropriate pyridine-2(1H)-thiones in the presence of 1.4 equivalents of piperazine. The reaction mixture was subjected to sonication at 60 °C for 30–40 min to produce the desired products in 88%–95% yields. When tested against six different ATCC bacterial strains, the new products demonstrated a wide range of antibacterial activity. The 4-(4-methoxyphenyl)-linked hybrids 1i and 1j, attached to 6-(4-methoxyphenyl) and 6-( p-tolyl) units, respectively, had the best efficacy against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa strains. Both hybrids showed more effective potency than the reference ciprofloxacin with MIC and MBC values in the ranges from 2.0 to 2.1, and 4.1 to 4.2 µM, respectively. Additionally, hybrids 1i and 1j demonstrated stronger efficacy than linezolid with MIC values ranging from 2.0 to 4.2 µM, and MBC values ranging from 8.2 to 8.5 µM, respectively, against the MRSA ATCC:33 591 and ATCC:43 300 strains. Furthermore, hybrids 1i and 1j showed inhibitory antibacterial biofilm activity comparable to the standard ciprofloxacin. They had IC50 values ranging from 3.8 to 4.6 µM against S. aureus, E. faecalis, E. coli, and P. aeruginosa strains. The cytotoxicity of hybrids 1i and 1j against the human breast epithelial cell line MCF-10A lends credence to both hybrids’ potential as safe antibacterial agents.
The influence of sociodemographic and environmental factors on wildlife carcass submissions in urban areas: Opportunities for increasing equitable and representative wildlife health surveillance
Authors: Giacinti Jolene A. , Robinson Sarah J. , French Shannon K. , Pearl David L. , Jardine Claire M. 
Published: April 2023

Wildlife health surveillance is important in rapidly expanding urban areas, where wildlife live in close association with humans and face unique health risks. Urban areas are not homogeneous, and social and environmental factors may affect the distribution of surveillance data we receive from these environments. The Canadian Wildlife Health Cooperative (CWHC) operates a national wildlife surveillance programme that receives carcass submissions for diagnostic evaluation. Our objective was to evaluate sociodemographic and environmental factors associated with CWHC submissions within two cities in Ontario, Canada. Submissions were mapped at two geographic scales and linked with census and environmental data. The results of mixed multivariable Poisson and negative binomial regression analyses suggest that natural (e.g., percent parkland) and anthropogenic environmental (e.g., presence of a zoo) and social variables (e.g., low income) are associated with submissions at both administratively relevant scales. Associations that are common across scales may represent robust intervention points and inform surveillance methodology/messaging. Surveillance data may influence public health policy, wildlife management, and other decision-making regarding the benefits/risks associated with coexistence with wildlife. This study highlights gaps in surveillance methodology that may prevent equal opportunity for participation in wildlife health surveillance and enable equal opportunity to benefit from the associated outputs.
ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
Authors: Sun Yan , Zhu Liang , Liu Pian , Zhang Huan , Guo Feng , Jin Xin 
Published: April 2023

Abstract

Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K–AKT–mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2–AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC.

Significance:
ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT–mTOR pathway.
Selective Inhibition of ATM-dependent Double-strand Break Repair and Checkpoint Control Synergistically Enhances the Efficacy of ATR Inhibitors
Authors: Turchick Audrey , Zimmermann Astrid , Chiu Li-Ya , Dahmen Heike , Elenbaas Brian , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T. 
Published: April 2023

Abstract
Ataxia telangiectasia and Rad3-related protein (ATR) kinase regulate a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double-strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell-cycle checkpoints controlled by ataxia telangiectasia–mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1-phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell-cycle checkpoints, and DSB repair lowered the p53 protective barrier and extended the life of ATR inhibitor–induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Furthermore, a combination study in 26 patient-derived xenograft models of triple-negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared with single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.
Risk Factors for Early-onset Sporadic Colorectal Cancer in Male Veterans
Authors: Imperiale Thomas F. , Myers Laura J. , Barker Barry C. , Larson Jason , Stump Timothy E. , Daggy Joanne K. 
Published: April 2023

Abstract

Identifying risk factors for early-onset colorectal cancer (EOCRC) could help reverse its rising incidence through risk factor reduction and/or early screening. We sought to identify EOCRC risk factors that could be used for decisions about early screening. Using electronic databases and medical record review, we compared male veterans ages 35 to 49 years diagnosed with sporadic EOCRC (2008–2015) matched 1:4 to clinic and colonoscopy controls without colorectal cancer, excluding those with established inflammatory bowel disease, high-risk polyposis, and nonpolyposis syndromes, prior bowel resection, and high-risk family history. We ascertained sociodemographic and lifestyle factors, family and personal medical history, physical measures, vital signs, medications, and laboratory values 6 to 18 months prior to case diagnosis. In the derivation cohort (75% of the total sample), univariate and multivariate logistic regression models were used to derive a full model and a more parsimonious model. Both models were tested using a validation cohort. Among 600 cases of sporadic EOCRC [mean (SD) age 45.2 (3.5) years; 66% White], 1,200 primary care clinic controls [43.4 (4.2) years; 68% White], and 1,200 colonoscopy controls [44.7 (3.8) years; 63% White], independent risk factors included age, cohabitation and employment status, body mass index (BMI), comorbidity, colorectal cancer, or other visceral cancer in a first- or second-degree relative (FDR or SDR), alcohol use, exercise, hyperlipidemia, use of statins, NSAIDs, and multivitamins. Validation c-statistics were 0.75–0.76 for the full model and 0.74–0.75 for the parsimonious model, respectively. These independent risk factors for EOCRC may identify veterans for whom colorectal cancer screening prior to age 45 or 50 years should be considered.

Prevention Relevance:
Screening 45- to 49-year-olds for colorectal cancer is relatively new with uncertain uptake thus far. Furthermore, half of EOCRC occurs in persons &lt; 45 years old. Using risk factors may help 45- to 49-year-olds accept screening and may identify younger persons for whom earlier screening should be considered.
See related Spotlight, p. 479
A morte de Edward Gordon Craig: visualidades místicas de um pensamento Über
Authors: Silva Filho Almir Ribeiro da 
Published: April 2023

O apelo à plasticidade é um dos fundamentos da proposta visual da nova arte da encenação inaugurada por Edward Gordon Craig no início do século XX. Esse apelo possui um eixo central inusitado, baseado em uma visão de mundo particular de seu autor: o misticismo. Ao desenvolver sua obra multifacetada, Craig criou um universo místico em que refletia sobre os limites da linguagem teatral, mas também sobre as frestas entre a vida, a não vida e a morte. Duas de suas realizações mais importantes – a montagem de Hamlet e a criação do Übermarionette – oferecem argumentos definitivos em relação ao papel da Morte na obra de Gordon Craig.
BCL6B Contributes to Ocular Vascular Diseases via Notch Signal Silencing
Authors: Tanaka Miruto , Nakamura Shinsuke , Sakaue Tomohisa , Yamamoto Takumi , Maekawa Masashi , Nishinaka Anri , Yasuda Hiroto , Yunoki Kaori , Sato Yuji , Sawa Masaaki , Yoshino Kohichiro , Shimazawa Masamitsu , Hatano Masahiko , Tokuhisa Takeshi , Higashiyama Shigeki , Hara Hideaki 
Published: April 2023

Background:
Endothelial cell activation is tightly controlled by the balance between VEGF (vascular endothelial cell growth factor) and Notch signaling pathway. VEGF destabilizes blood vessels and promotes neovascularization, which are common features of sight-threatening ocular vascular disorders. Here, we show that BCL6B (B-cell CLL/lymphoma 6 member B protein), also known as BAZF, ZBTB28, and ZNF62, plays a pivotal role in the development of retinal edema and neovascularization.

Methods:
The pathophysiological physiological role of BCL6B was investigated in cellular and animal models mimicking 2 pathological conditions: retinal vein occlusion and choroidal neovascularization. An in vitro experimental system was used in which human retinal microvascular endothelial cells were supplemented with VEGF. Choroidal neovascularization cynomolgus monkey model was generated to investigate the involvement of BCL6B in the pathogenesis. Mice lacking BCL6B or treated with BCL6B-targeting small-interfering ribose nucleic acid were examined for histological and molecular phenotypes.

Results:
In retinal endothelial cells, the BCL6B expression level was increased by VEGF. BCL6B-deficient endothelial cells showed Notch signal activation and attenuated cord formation via blockage of the VEGF-VEGFR2 signaling pathway. Optical coherence tomography images showed that choroidal neovascularization lesions were decreased by BCL6B-targeting small-interfering ribose nucleic acid. Although BCL6B mRNA expression was significantly increased in the retina, BCL6B-targeting small-interfering ribose nucleic acid suppressed ocular edema in the neuroretina. The increase in proangiogenic cytokines and breakdown of the inner blood-retinal barrier were abrogated in BCL6B knockout (KO) mice via Notch transcriptional activation by CBF1 (C promotor-binding factor 1) and its activator, the NICD (notch intracellular domain). Immunostaining showed that Müller cell activation, a source of VEGF, was diminished in BCL6B-KO retinas.

Conclusions:
These data indicate that BCL6B may be a novel therapeutic target for ocular vascular diseases characterized by ocular neovascularization and edema.
Religious Family Agreements
Authors: Bix Brian H. 
Published: April 2023

Abstract
The article offers an overview of recent United States court cases on the topic of religious family agreements, focusing in particular on cases seeking to enforce mahr provisions, provisions of ketubahs, and religious upbringing agreements. Overall, the recent cases display the tensions created by an intersection of separate concerns: interpretive, doctrinal, and constitutional. The cases ultimately display a cautious approach, including a general reluctance to enforce provisions where doing so might interfere with religious freedom or override the financial rights of vulnerable parties.
Bias and Uncertainty of the Relationship between AO and Winter Synoptic Temperature Variability over the Northern Hemisphere under Present and Future Climate
Authors: Jian Yuntao , Leung Marco Y. T. , Zhang Ruhua , Zhou Wen , Jian Maoqiu , Yang Song , Feng Yerong , Zhang Banglin 
Published: April 2023

Abstract
In this study, the relationship between AO and winter synoptic temperature variability (STV) over the Northern Hemisphere is examined in 34 CMIP5/CMIP6 model outputs. With significant model bias around the North Pacific and North Atlantic, most models fail to capture the correct AO–STV pattern in historical simulations compared to observations. To investigate the bias of AO–STV relationship simulations, AO-related processes for the connection between AO and winter STV are examined in high pattern score (HPS) models and low pattern score (LPS) models, respectively. Furthermore, the bias of AO impact can be traced back to AO pattern simulations. On the one hand, compared to observations, HPS models can overall capture the intensity in the North Pacific and North Atlantic center of AO. On the other hand, LPS models tend to overestimate the North Pacific center and underestimate the North Atlantic center. In addition, similar to historical simulations, a robust AO–STV relationship can still be found over the Northern Hemisphere in future projections based on HPS models. Meanwhile, the uncertainty of the projected AO–STV relationship in the multimodel ensemble is confined mainly to the North Pacific, consistent with the large diversity of intensity over the North Pacific center of AO, which is related to the uncertainty of the relationship between AO and regional mode variability.
Tail Dependence as a Measure of Teleconnected Warm and Cold Extremes of North American Wintertime Temperatures
Authors: Krock Mitchell L. , Monahan Adam H. , Stein Michael L. 
Published: April 2023

Abstract
Current models for spatial extremes are concerned with the joint upper (or lower) tail of the distribution at two or more locations. Such models cannot account for teleconnection patterns of 2-m surface air temperature (T2m) in North America, where very low temperatures in the contiguous United States may coincide with very high temperatures in Alaska in the wintertime. This dependence between warm and cold extremes motivates the need for a model with opposite-tail dependence in spatial extremes. This work develops a statistical modeling framework that has flexible behavior in all four pairings of high and low extremes at pairs of locations. In particular, we use a mixture of rotations of common Archimedean copulas to capture various combinations of four-corner tail dependence. We study teleconnected T2m extremes using ERA5 of daily average 2-m temperature during the boreal winter. The estimated mixture model quantifies the strength of opposite-tail dependence between warm temperatures in Alaska and cold temperatures in the midlatitudes of North America, as well as the reverse pattern. These dependence patterns are shown to correspond to blocked and zonal patterns of midtropospheric flow. This analysis extends the classical notion of correlation-based teleconnections to considering dependence in higher quantiles.
Challenges in the Description of Sea Ice for a Kilometer-Scale Weather Forecasting System
Authors: Müller Malte , Batrak Yurii , Dinessen Frode , Grote Rafael , Wang Keguang 
Published: April 2023

Abstract
Simulation of atmosphere–ocean–ice interactions in coupled Earth modeling systems with kilometer-scale resolution is a new challenge in operational numerical weather prediction. This study presents an assessment of sensitivity experiments performed with different sea ice products in a convective-scale weather forecasting system for the European Arctic. On kilometer-scale resolution sea ice products are challenged by the large footprint of passive microwave satellite observations and issues with spurious sea ice detection of the higher-resolution retrievals based on synthetic aperture radar instruments. We perform sensitivity experiments with sea ice concentration fields of 1) the global ECMWF-IFS forecast system, 2) a newly developed multisensor product processed through a coupled sea ice–ocean forecasting system, and 3) the AMSR2 product based on passive microwave observations. There are significant differences between the products on O(100) km scales in the northern Barents Sea and along the Marginal Ice Zone north of the Svalbard archipelago and toward the Fram Strait. These differences have a direct impact on the modeled surface skin temperature over ocean and sea ice, the turbulent heat flux, and 2-m air temperature (T2M). An assessment of Arctic weather stations shows a significant improvement of forecasted T2M in the north and east of Svalbard when using the new multisensor product; however, south of Svalbard this product has a negative impact. The different sea ice products are resulting in changes of the surface turbulent heat flux of up to 400 W m−2, which in turn results in T2M variations of up to 5°C. Over a 2-day forecast lead time this can lead to uncertainties in weather forecasts of about 1°C even hundreds of kilometers away from the sea ice.

Significance Statement
Weather forecasting in polar regions requires an accurate description of sea ice properties due to the very important atmosphere–ocean–ice interactions. With the increasing resolution of weather forecasting systems, there is also a need to advance the resolution of the sea ice characteristics in the models. This is, however, not straightforward due to various issues in the sea ice satellite products. This study explores new products and approaches to integrate high-resolution sea ice in a weather prediction system. We find that the model is sensitive to the choice of the sea ice product and that it is still challenging to provide an accurate sea ice field on a kilometer-scale resolution.
Brief Online Intervention Model Promotes Sustained Helping Behavior Across 6 Months Following a Population-Wide Traumatic Event
Authors: Balderas Jessica , Bistricky Steven L. , Gimenez-Zapiola Malena , Pascuzzi Bailey , Millmann Megan , Short Mary B. 
Published: April 2023

Background: Following natural disasters, early helping behavior often dissipates despite remaining disaster-related suffering and affective vulnerability in the community. Interventions that have successfully increased helping behaviors have included components of motivational interviewing (MI) and mindful compassion; however, this research is limited by laboratory-based settings and lengthy training sessions. Brief, portable, and efficient intervention is needed to increase accessibility to large groups simultaneously. Method: The current study piloted a brief, online, self-administered MI and mindful compassion intervention administered 4–10 weeks post-Hurricane Harvey examining if it would sustain helping behaviors over the ensuing year. The study also examined potential moderators of the relationship between compassion for others and internalizing symptoms, and whether helping behaviors predicted post-traumatic stress symptoms. Results: The intervention group sustained the use of helping behaviors more than an active control group after 9–12 months. Also, compassion satisfaction and burnout moderated the relationship between compassion for others and post-traumatic stress and depressive symptoms at follow-up. Conclusions: Results suggest a potentially useful model of how an efficiently distributed intervention might sustain helping behaviors after a natural disaster and provide insight into possible longitudinal risk and protective factors for post-traumatic stress and depressive symptoms among helping volunteers.
Assessment of the relationship between C-reactive protein to albumin ratio and late-term mortality in patients with acute pulmonary embolism
Authors: Artac Inanc , Omar Timor , Karakayali Muammer , Ilis Dogan , Karabag Yavuz , Rencuzogullari Ibrahim 
Published: April 2023

Objective In recent years, an increasing number of evidences suggests that inflammation plays a significant role in the pathophysiology of pulmonary embolism. Although the association between inflammatory markers and pulmonary embolism prognosis has been previously reported, no studies have investigated the ability of the C-reactive protein/albumin ratio, defined as an inflammation-based prognostic score, to predict death in patients experiencing a pulmonary embolism. Materials and methods This retrospective study included 223 patients experiencing a pulmonary embolism. The study population was divided into two groups according to their C-reactive protein/albumin ratio values and analyzed whether the C-reactive protein/albumin ratio was an independent predictor of late-term mortality. Then, the performance of the C-reactive protein/albumin ratio in predicting patients’ outcomes was further compared with its components. Results Out of 223 patients, death was observed in 57 patients (25.60%) during an average follow-up of 18 months (range: 8–26). The average C-reactive protein/albumin ratio was 0.12 (0.06–0.44). The group with a higher C-reactive protein/albumin ratio was older and had a higher troponin level and simplified Pulmonary Embolism Severity Index score. Independent predictors of late-term mortality were found to be C-reactive protein/albumin ratio (hazard ratio: 1.594, 95% CI: 1.003–2.009; p < 0.001), cardiopulmonary disease, simplified Pulmonary Embolism Severity Index score and fibrinolytic therapy. Receiver operating characteristic curve comparisons for both 30-day and late-term mortality demonstrated that the C-reactive protein/albumin ratio was a better predictor than both albumin and C-reactive protein, separately. Conclusion The present study revealed that the C-reactive protein/albumin ratio is an independent predictor of both 30-day and late-term mortality in patients experiencing a pulmonary embolism. As a marker that can be easily obtained, and calculated, and does not require additional costs C-reactive protein/albumin ratio can be an effective parameter used for prognosis estimation of pulmonary embolism.