bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes
Authors: Basagni Filippo , Rosini Michela , Decker Michael 
Published: June 2020

AbstractCannabinoid subtype 2 receptors (CB2Rs) are G protein‐coupled receptors (GPCRs) belonging to the endocannabinoid system, a complex network of signalling pathways leading to the regulation of key physiological processes. Interestingly, CB2Rs are strongly up‐regulated in pathological conditions correlated with the onset of inflammatory events like cancer and neurodegenerative diseases. Therefore, CB2Rs represent an important biological target for therapeutic as well as diagnostic purposes. No CB2R‐selective drugs are yet on the market, thus underlining a that deeper comprehension of CB2Rs’ complex activation pathways and their role in the regulation of diseases is needed. Herein, we report an overview of pharmacological and imaging tools such as fluorescent, positron emission tomography (PET), photochromic and covalent selective CB2R ligands. These molecular probes can be used in vitro as well as in vivo to investigate and explore the unravelled role(s) of CB2Rs, and they can help to design suitable CB2R‐targeted drugs.
Hybrid molecules based on 1,3,5‐triazine as potential therapeutics: A focused review
Authors: Prasher Parteek , Sharma Mousmee , Aljabali Alaa A. A. , Gupta Gaurav , Negi Poonam , Kapoor Deepak N. , Singh Inderbir , Zacconi Flavia C. , de Jesus Andreoli Pinto Terezinha , da Silva Mateus Webba , Bakshi Hamid A. , Chellappan Dinesh Kumar , Tambuwala Murtaza M. , Dua Kamal 
Published: June 2020

AbstractMajority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux‐pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5‐triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5‐triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5‐triazine based hybrid molecules in the development of pharmaceuticals.
Evaluation of longitudinal steroid profiling with the ADAMS adaptive model for detection of transdermal, intramuscular, and subcutaneous testosterone administration
Authors: Nair Vinod S. , Husk Jacob , Miller Geoffrey D. , van Eenoo Peter , Crouch Andre , Eichner Daniel 
Published: June 2020

AbstractThe steroidal module of the Athlete Biological Passport (ABP) has been used since 2014 for the longitudinal monitoring of urinary testosterone and its metabolites in order to identify samples suspicious for the use of synthetic forms of endogenous anabolic androgenic steroids (EAAS). Samples identified by the module may then be confirmed by isotope ratio mass spectrometry (IRMS) to establish clearly the exogenous origin of testosterone and/or metabolites in the sample. To examine the detection capability of the steroidal ABP model, testosterone administration studies were performed with various doses and three routes of administration – transdermal, intramuscular, and subcutaneous with 15 subjects for each route of administration. Urine samples were collected before, during, and after administration and steroid profiles were analyzed using the steroidal ABP module in ADAMS. A subset of samples from each mode of administration was also analyzed by IRMS. The steroidal ABP module was more sensitive to testosterone use than population‐based thresholds and with high dose administrations there was very good agreement between the IRMS results and samples flagged by the module. However, with low dose administration the ABP module was unable to identify samples where testosterone use was still detectable by IRMS analysis. The testosterone/epitestosterone (T/E) ratio was the most diagnostic parameter for longitudinal monitoring with the exception of low testosterone excretors for whom the 5α‐androstane‐3α, 17β‐diol/epitestosterone (5αAdiol/E) ratio may provide more sensitivity.
River food chains lead to riparian bats and birds in two mid‐order rivers
Authors: Jackson Breeanne K. , Stock Sarah L. , Harris Leila S. , Szewczak Joseph M. , Schofield Lynn N. , Desrosiers Michelle A. 
Published: June 2020

AbstractRiver regulation can modify natural flow regimes with deleterious effects on aquatic communities. While the effects of flow manipulation on the physical environment and populations and assemblages of aquatic organisms have been described thoroughly, how and to what extent river regulation influences ecosystem processes like food web architecture is less studied. Emergent aquatic insect prey can provide an important food resource to riparian consumers like birds and bats with concomitant consequences for nutrient cycling through aquatic–terrestrial food webs, thus potentially increasing the spatial influence of river regulation into the riparian zone and beyond. We used naturally abundant stable isotopes of carbon and nitrogen to compare food web architecture (trophic position and reliance on an aquatic nutritional pathway) leading to birds and bats between a regulated river, the Tuolumne River downstream of Hetch Hetchy Reservoir, and an adjacent unregulated river, the Merced River, located in Yosemite National Park on the west slope of the Sierra Nevada, California, USA. We found that both birds and bats derived >50% of their nutrition from food webs originating in photosynthesis by algae. In addition, birds and bats occupied a similar trophic position to predatory fish in other systems. Both birds and bats seemed to rely more strongly on an aquatic nutritional pathway during the dryer year of our study period, underscoring the potential importance of emergent aquatic prey as a water subsidy in dry systems and in dry years. In the Tuolumne River, reservoir managers strive to simulate characteristics of the natural flow regime, including seasonal scouring flows and prolonged floodplain inundation. Although we found no conclusive evidence of an effect of river regulation on food web responses, our study suggests that nutrient cycling through aquatic–terrestrial food webs expands the potential influence of river regulation to organisms and ecosystems typically characterized as terrestrial.
Highly competent native snake hosts extend the range of an introduced parasite beyond its invasive Burmese python host
Authors: Miller Melissa A. , Kinsella John M. , Snow Ray W. , Falk Bryan G. , Reed Robert N. , Goetz Scott M. , Mazzotti Frank J. , Guyer Craig , Romagosa Christina M. 
Published: June 2020

AbstractInvasive Burmese pythons (Python bivittatus) have introduced a nonnative pentastomid parasite (Raillietiella orientalis) to southern Florida that has spilled over to infect native snakes. However, the extent of spillover, regarding prevalence and intensity, is unknown. We examined native snakes (n = 523) and invasive pythons (n = 1003) collected from Florida to determine the degree to which parasite spillover is occurring. We found R. orientalis has infected 13 species of native snakes collected from areas of sympatry with pythons. Prevalence and infection intensity of R. orientalis were significantly higher among native snakes compared with pythons. Moreover, adult female pentastomes achieved larger sizes and represented a greater proportion of the overall parasite population in native snakes vs. pythons, indicating native snakes are more competent hosts of R. orientalis than pythons. We also examined native snakes from regions of allopatry with pythons to determine how far R. orientalis has spread. We found an infected native snake 348 km north of the northernmost infected python. Our data show that native snakes are highly competent hosts of R. orientalis and have facilitated the rapid spread of this nonnative pentastome beyond the range of its invasive host.
Statin intensity and risk for cardiovascular events after heart transplantation
Authors: Golbus Jessica R. , Adie Sarah , Yosef Matheos , Murthy Venkatesh L. , Aaronson Keith D. , Konerman Matthew C. 
Published: June 2020

AbstractAimsStatins improve survival and reduce rejection and cardiac allograft vasculopathy after heart transplantation (HT). The impact of different statin intensities on clinical outcomes has never been assessed. We set out to determine the impact of statin exposure on cardiovascular outcomes after HT.Methods and resultsWe performed a retrospective study of 346 adult patients who underwent HT from 2006 to 2018. Statin intensity was determined longitudinally after HT based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The primary outcome was the time to the first primary event defined as the composite of heart failure hospitalization, myocardial infarction, revascularization, and all‐cause mortality. Secondary outcomes included time to significant rejection and time to moderate–severe cardiac allograft vasculopathy. Adverse events were evaluated for subjects on high‐intensity statin therapy. A Cox proportional hazards model was used to evaluate the relationship between clinical variables, statin intensity, and outcomes. Most subjects were treated with low‐intensity statin therapy although this declined from 89.9% of the population at 1month after HT to 42.8% at 5years after HT. History of ischaemic cardiomyopathy, significant acute rejection, older donor age, and lesser statin intensity (p ≤ 0.001) were associated with reduced time to the primary outcome in a multivariable Cox model. Greater intensity of statin therapy was most beneficial early after HT. There were no statin‐related adverse events for the 14 subjects on high‐intensity statin therapy.ConclusionsGreater statin intensity was associated with a reduction in adverse cardiovascular outcomes after HT.
Mortality and pathophysiology of acute kidney injury according to time of occurrence in acute heart failure
Authors: Diebold Matthias , Kozhuharov Nikola , Wussler Desiree , Strebel Ivo , Sabti Zaid , Flores Dayana , Shrestha Samyut , Martin Jasmin , Staub Daniel , Venge Per , Mueller Christian , Breidthardt Tobias 
Published: June 2020

AbstractAimsAcute kidney injury (AKI) during acute heart failure (AHF) is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanism appears to have prognostic relevance; however, the differentiation of true, structural AKI from hemodynamic pseudo‐AKI remains a clinical challenge.Methods and resultsThe Basics in Acute Shortness of Breath Evaluation Study (NCT01831115) prospectively enrolled adult patients presenting with AHF to the emergency department. Mortality of patients was prospectively assessed. Haemoconcentration, transglomerular pressure gradient (n = 231) and tubular injury patterns (n = 253) were evaluated to investigate pathophysiological mechanisms underlying AKI timing (existing at presentation vs. developing during in‐hospital period). Of 1643 AHF patients, 755 patients (46%) experienced an episode of AKI; 310 patients (19%; 41% of AKI patients) presented with community‐acquired AKI (CA‐AKI), 445 patients (27%; 59% of AKI patients) developed in‐hospital AKI. CA‐AKI but not in‐hospital AKI was associated with higher mortality compared with no‐AKI (adjusted hazard ratio 1.32 [95%‐CI 1.01–1.74]; P = 0.04). Independent of AKI timing, haemoconcentration was associated with a lower two‐year mortality. Transglomerular pressure gradient at presentation was significantly lower in CA‐AKI compared to in‐hospital AKI and no‐AKI (P < 0.01). Urinary NGAL ratio concentrations were significantly higher in CA‐AKI compared to in‐hospital AKI (P < 0.01) or no‐AKI (P < 0.01).ConclusionsCA‐AKI but not in‐hospital AKI is associated with increased long‐term mortality and marked by decreased transglomerular pressure gradient and tubular injury, probably reflecting prolonged tubular ischemia due to reno‐venous congestion. Adequate decongestion, as assessed by haemoconcentration, is associated with lower long‐term mortality independent of AKI timing.
Diagnosis of isolated cardiac sarcoidosis based on new guidelines
Authors: Kawai Hideki , Sarai Masayoshi , Kato Yasuchika , Naruse Hiroyuki , Watanabe Ayumi , Matsuyama Takahiro , Takahashi Hiroshi , Motoyama Sadako , Ishii Junnichi , Morimoto Shin‐ichiro , Toyama Hiroshi , Ozaki Yukio 
Published: June 2020

AbstractAimsIn the updated guidelines for cardiac sarcoidosis (CS) proposed by the Japanese Circulation Society (JCS), the definition of isolated CS (iCS) was established for the first time. This prompted us to examine the characteristics of patients with CS including iCS according to them by reviewing patients undergoing 18F‐fluoro‐2‐deoxyglucose positron‐emission tomography/computerized tomography (FDG‐PET/CT), compared with those with CS determined by the conventional international criteria.Methods and resultsFrom 2013 to 2019, 94 patients (61 ± 15 years, 50 female patients) with suspected CS underwent whole‐body and cardiac FDG‐PET/CT scanning. In contrast to 22 patients with CS based on the international criteria, 34 [27 with systemic sarcoidosis including cardiac involvement (sCS) and 7 with clinical iCS] were diagnosed with CS according to the new JCS guidelines (P = 0.012), and 60 were not (4 suspected iCS, 13 systematic sarcoidosis without cardiac involvement, and 43 no sarcoidosis). In addition to 26 of 34 patients with CS, corticosteroids were also started in 6 of 60 without CS according to clinical need.ConclusionsDiagnostic yield with the new JCS guidelines was higher, with approximately 1.5‐fold of the patients diagnosed with CS compared with the previous international criteria and clinical iCS accounting for approximately 20% of the whole CS cohort. In addition to 75% of the patients with sCS or clinical iCS in the updated guidelines, 10% in whom CS was not documented were also started on corticosteroids for clinical indications such as reduced cardiac function or arrhythmia.
Long‐term impact of new‐onset atrial fibrillation complicating acute myocardial infarction on heart failure
Authors: Luo Jiachen , Xu Siling , Li Hongqiang , Li Zhiqiang , Liu Baoxin , Qin Xiaoming , Gong Mengmeng , Shi Beibei , Wei Yidong 
Published: June 2020

AbstractAimsNew‐onset atrial fibrillation (NOAF) complicating acute myocardial infarction (AMI) has been associated with poor survival, but the clinical implication of NOAF on heart failure (HF) is still not well characterized. We aimed to investigate the relationship between NOAF complicating AMI and HF hospitalization.Methods and resultsAdult AMI patients identified in the New‐Onset Atrial Fibrillation Complicating Acute Myocardial Infarction in Shanghai registry who, discharged alive, had complete echocardiography and follow‐up data from February 2014 to March 2018 were included. Patients were divided according to the presence of NOAF. The outcome measures were HF hospitalization and death during the observational period (until 10 April 2019). Cox proportional hazard models were performed in the whole population and propensity score‐matched (PSM) cohort to assess the adjusted hazard ratio (HR) and 95% confidence interval (CI). Overall, 2075 patients (mean age: 65.2 ± 12.3 years, 77.3% were men) with AMI were analysed, of whom 228 (11.0%) developed NOAF. Advanced age, admission HF (Killip II–IV), impaired renal function, decreased left ventricular ejection fraction, increased heart rate, and left atrial enlargement were independent predictors of NOAF. Over a median observational period of 2.7 years, the annual incidence rates of HF hospitalization were 18.4% and 2.8% for patients with NOAF and sinus rhythm, respectively. After adjustment for confounders, NOAF was significantly associated with HF hospitalization (HR: 3.14, 95% CI: 2.30–4.28, P < 0.001). Similar results were obtained when accounting for the competing risk of all‐cause death (subdistribution HR: 3.06, 95% CI: 2.18–4.30, P < 0.001) or from the PSM cohort (HR: 2.82, 95% CI: 1.99–4.00, P < 0.001). Patients with persistent NOAF (HR: 5.81, 95% CI: 3.59–9.41) were at significantly higher risk of HF hospitalization when compared with those with transient one (HR: 2.61, 95% CI: 1.84–3.70, P interaction = 0.008). Although post‐MI NOAF was significantly related to cardiovascular death (annual incidence rates for NOAF and sinus rhythm were 9.4% and 2.3%, respectively; HR: 1.97, 95% CI: 1.36–2.85, P < 0.001), such an association was attenuated when HF hospitalization (modelled as a time‐varying covariate) and antithrombotic treatment were adjusted (HR: 1.37, 95% CI: 0.92–2.02, P = 0.121).ConclusionsIn patients with AMI, NOAF is strongly associated with an increased long‐term risk of HF hospitalization. Our findings suggest that strengthened secondary prevention of HF should be considered in this high‐risk population.
Subacute cannabidiol alters genome‐wide DNA methylation in adult mouse hippocampus
Authors: Wanner Nicole M , Colwell Mathia , Drown Chelsea , Faulk Christopher 
Published: June 2020

AbstractUse of cannabidiol (CBD), the most abundant non‐psychoactive compound found in cannabis (Cannabis sativa), has recently increased as a result of widespread availability of CBD‐containing products. CBD is FDA‐approved for the treatment of epilepsy and exhibits anxiolytic, antipsychotic, prosocial, and other behavioral effects in animal studies and clinical trials, however, the underlying mechanisms governing these phenotypes are still being elucidated. The epigenome, particularly DNA methylation, is responsive to environmental input and can govern persistent patterns of gene regulation affecting phenotype across the life course. In order to understand the epigenomic activity of cannabidiol exposure in the adult brain, 12‐week‐old male wild‐type a/a Agouti viable yellow (Avy) mice were exposed to either 20 mg/kg CBD or vehicle daily by oral administration for 14 days. Hippocampal tissue was collected and reduced‐representation bisulfite sequencing (RRBS) was performed. Analyses revealed 3,323 differentially methylated loci (DMLs) in CBD‐exposed animals with a small skew toward global hypomethylation. Genes for cell adhesion and migration, dendritic spine development, and excitatory postsynaptic potential were found to be enriched in a gene ontology term analysis of DML‐containing genes, and disease ontology enrichment revealed an overrepresentation of DMLs in gene sets associated with autism spectrum disorder, schizophrenia, and other phenotypes. These results suggest that the epigenome may be a key substrate for CBD's behavioral effects and provides a wealth of gene regulatory information for further study.
Roles of Chk2/CHEK2 in guarding against environmentally induced DNA damage and replication‐stress
Authors: Mustofa Md. Kawsar , Tanoue Yuki , Tateishi Chie , Vaziri Cyrus , Tateishi Satoshi 
Published: June 2020

AbstractCheckpoint kinase 2 (human CHEK2; murine Chk2) is a critical mediator of the DNA damage response and has established roles in DNA double strand break (DSB)‐induced apoptosis and cell cycle arrest. DSBs may be invoked directly by ionizing radiation but may also arise indirectly from environmental exposures such as solar ultraviolet (UV) radiation. The primary forms of DNA damage induced by UV are DNA photolesions (such as cyclobutane pyrimidine dimers CPD and 6‐4 photoproducts) which interfere with DNA synthesis and lead to DNA replication fork stalling. Persistently stalled and unresolved DNA replication forks can “collapse” to generate DSBs that induce signaling via Chk2 and its upstream activator the ataxia telangiectasia‐mutated (ATM) protein kinase. This review focuses on recently defined roles of Chk2 in protecting against DNA replication‐associated genotoxicity. Several DNA damage response factors such as Rad18, Nbs1 and Chk1 suppress stalling and collapse of DNA replication forks. Defects in the primary responders to DNA replication fork stalling lead to generation of DSB and reveal “back‐up” roles for Chk2 in S‐phase progression and genomic stability. In humans, there are numerous variants of the CHEK2 gene, including CHEK2*1100delC. Individuals with the CHEK2*1100delC germline alteration have an increased risk of developing breast cancer and malignant melanoma. DNA replication fork‐stalling at estrogen‐DNA adducts and UV‐induced photolesions are implicated in the etiology of breast cancer and melanoma, respectively. It is likely therefore that the Chk2/CHEK2‐deficiency is associated with elevated risk for tumorigenesis caused by replication‐associated genotoxicities that are exacerbated by environmental genotoxins and intrinsic DNA‐damaging agents.
Fuzzy reliability‐redundancy allocation problem of the overspeed protection system
Authors: Taghiyeh Sajjad , Mahmoudi Morteza , Fadaie Saber , Tohidi Hossein 
Published: June 2020

AbstractSystem reliability is defined as the probability of satisfactory performance of a system under stated conditions for a specified period of time. According to this definition, four parameters, including probability, satisfactory performance, specific conditions, and time should be exactly characterized to evaluate the system reliability accurately. However, due to the uncertainty involved in real situations, it is hardly possible to assess the aforementioned parameters precisely. In this article, two general and distinct approaches, including Zadeh's extension principle and modification of fuzzy parametric programming (FPP), are proposed to take into account such uncertainty in a famous reliability problem called the overspeed protection system. According to Zadeh's extension principle, a pair of nonlinear programming problems is formulated to compute α‐level cuts of fuzzy system reliability. The membership function of fuzzy system reliability can then be constructed analytically by numerating different values of α. This fuzzy system reliability presents flexibility for further system analysis. In the second approach, from a different point of view, a variant of FPP is improved that provides a crisp value as a system reliability measure. The rewarding point of the latter procedure is to handle the problem in a computationally easier way.