Miracle-dz/UniFAR-FTUs huggingface dataset:
FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway

F-box/WD repeat-containing protein 5 (FBXW5) is a member of the FBXW subclass of F-box proteins. Despite its known function as a component of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex, the role of FBXW5 in gastric cancer tumorigenesis and metastasis has not been investigated. The present study investigates the role of FBXW5 in tumorigenesis and metastasis, as well as the regulation of key signaling pathways in gastric cancer; using in-vitro FBXW5 knockdown/overexpression cell line and in-vivo models. In-vitro knockdown of FBXW5 results in a decrease in cell proliferation and cell cycle progression, with a concomitant increase in cell apoptosis and caspase-3 activity. Furthermore, knockdown of FBXW5 also leads to a down regulation in cell migration and adhesion, characterized by a reduction in actin polymerization, focal adhesion turnover and traction forces. This study also delineates the mechanistic role of FBXW5 in oncogenic signaling as its inhibition down regulates RhoA-ROCK 1 (Rho-associated protein kinase 1) and focal adhesion kinase (FAK) signaling cascades. Overexpression of FBXW5 promotes in-vivo tumor growth, whereas its inhibition down regulates in-vivo tumor metastasis. When considered together, our study identifies the novel oncogenic role of FBXW5 in gastric cancer and draws further interest regarding its clinical utility as a potential therapeutic target.
School-wide implementation of positive behavioral interventions and supports in an alternative school setting: A case study.

AIMS The purpose of this 1-year case study was to identify how School-Wide Positive Behavioral Interventions and Supports (SW-PBIS) can be adapted to meet the needs of students in alternative schools and to evaluate the early impact of SW-PBIS on discipline outcomes. METHODS Suggestions for adaptations are provided at each stage of the intervention process with a focus on buy-in, training, data collection, and resource allocation. RESULTS Data from this case study included information about key components of the implementation process as well as initial outcomes. Process data revealed the importance of stakeholder buy-in, training opportunities, and potential adaptations to the framework. Outcome data from the first year of implementation indicated that the number of incident reports did not significantly differ from the baseline; however, there was a reduction in defiance-related behaviors and an increase in on-task behaviors. CONCLUSION This study contributes to the determination of the efficacy of SW-PBIS in a historically more punitive environment. Given the initial positive response and lessons learned, it is believed that, with the support of additional Tier 2 and Tier 3 interventions, SW-PBIS may be an appropriate framework to support students in alternative schools.
A Unified Model of Language Acquisition

This paper presents an extended formulation of the Competition Model. The extended model is designed to account for a larger range of phenomena in first and second language acquisition, including bilingualism. As in the classic version of the Competition Model, competition is at the core of a set of non-modular interacting forces. However, now the various inputs to competition are described in terms of six additional subcomponents: arenas, cues, chunking, storage, codes, and resonance. Learning is viewed as a resonant process that relies on storage, chunking, and support to acquire new mappings.
The Role of Pets in Supporting Cognitive-Behavioral Chronic Pain Self-Management: Perspectives of Older Adults

Cognitive-behavioral self-management strategies are recommended for older adults with chronic pain. The goal of this study was to explore how pet ownership promotes use of these strategies in everyday life. We conducted four focus groups (N = 25) with dog and cat owners aged ≥70 years with persistent pain. Participants described how their pets affect their daily routines and health, including pain and its management. We analyzed transcripts for salient themes, categorizing them according to their alignment with recommended pain self-management strategies: Mood Management (e.g., increases positive affect), Relaxation/Distraction (e.g., soothing presence), Physical Activity (e.g., dog-walking), Behavioral Activation (e.g., motivates activity even when pain present), Social Activation (e.g., facilitates socializing), and Sleep (e.g., encourages routine). Some participants described negative impacts of pet ownership. Having pets can facilitate behaviors and thoughts that may enhance coping with pain. Testing formal ways of leveraging pets’ role may expand nonpharmacological options for chronic pain management.
Diversity and Function of Somatostatin-Expressing Interneurons in the Cerebral Cortex

Inhibitory interneurons make up around 10–20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct and non-overlapping interneuron classes in the mouse neocortex, namely, parvalbumin-expressing, 5-HT3A receptor-expressing and somatostatin-expressing interneuron classes. Each class is, in turn, composed of a multitude of subclasses, resulting in a growing number of interneuron classes and subclasses. In this review, I will focus on the diversity of somatostatin-expressing interneurons (SOM+ INs) in the cerebral cortex and elucidate their function in cortical circuits. I will then discuss pathological consequences of a malfunctioning of SOM+ INs in neurological disorders such as major depressive disorder, and present future avenues in SOM research and brain pathologies.
Association Between Self-reported Prenatal Cannabis Use and Maternal, Perinatal, and Neonatal Outcomes.

Importance Recent evidence suggests that cannabis use during pregnancy is increasing, although population-based data about perinatal outcomes following in utero exposure remain limited. Objective To assess whether there are associations between self-reported prenatal cannabis use and adverse maternal and perinatal outcomes. Design, Setting, and Participants Population-based retrospective cohort study covering live births and stillbirths among women aged 15 years and older in Ontario, Canada, between April 2012 and December 2017. Exposures Self-reported cannabis exposure in pregnancy was ascertained through routine perinatal care. Main Outcomes and Measures The primary outcome was preterm birth before 37 weeks' gestation. Indicators were defined for birth occurring at 34 to 36 6/7 weeks' gestation (late preterm), 32 to 33 6/7 weeks' gestation, 28 to 31 6/7 weeks' gestation, and less than 28 weeks' gestation (very preterm birth). Ten secondary outcomes were examined including small for gestational age, placental abruption, transfer to neonatal intensive care, and 5-minute Apgar score. Coarsened exact matching techniques and Poisson regression models were used to estimate the risk difference (RD) and relative risk (RR) of outcomes associated with cannabis exposure and control for confounding. Results In a cohort of 661 617 women, the mean gestational age was 39.3 weeks and 51% of infants were male. Mothers had a mean age of 30.4 years and 9427 (1.4%) reported cannabis use during pregnancy. Imbalance in measured maternal obstetrical and sociodemographic characteristics between reported cannabis users and nonusers was attenuated using matching, yielding a sample of 5639 reported users and 92 873 nonusers. The crude rate of preterm birth less than 37 weeks' gestation was 6.1% among women who did not report cannabis use and 12.0% among those reporting use in the unmatched cohort (RD, 5.88% [95% CI, 5.22%-6.54%]). In the matched cohort, reported cannabis exposure was significantly associated with an RD of 2.98% (95% CI, 2.63%-3.34%) and an RR of 1.41 (95% CI, 1.36-1.47) for preterm birth. Compared with no reported use, cannabis exposure was significantly associated with greater frequency of small for gestational age (third percentile, 6.1% vs 4.0%; RR, 1.53 [95% CI, 1.45-1.61]), placental abruption (1.6% vs 0.9%; RR, 1.72 [95% CI, 1.54-1.92]), transfer to neonatal intensive care (19.3% vs 13.8%; RR, 1.40 [95% CI, 1.36-1.44]), and 5-minute Apgar score less than 4 (1.1% vs 0.9%; RR, 1.28 [95% CI, 1.13-1.45]). Conclusions and Relevance Among pregnant women in Ontario, Canada, reported cannabis use was significantly associated with an increased risk of preterm birth. Findings may be limited by residual confounding.
Analysis of trends in the prevalence of cannabis use and related metrics in Canada.

BACKGROUND The Canadian federal government legalized non-medical cannabis use by adults in October 2018. Ongoing monitoring of the effects of the change is needed because uncertainty remains about the impact of the legislation on cannabis use behaviours and whether the impact will affect some more than others. DATA AND METHODS Data from the Canadian Tobacco, Alcohol and Drugs Survey and the Canadian Tobacco Use Monitoring Survey were used to examine longer-term (historical) rates of use during 2004 to 2017. Five iterations of the National Cannabis Surveys (NCS) (2018-2019) were used to examine current use (overall, daily or almost daily (DAD), quantities, and types of products) in the months before and after legalization. RESULTS From 2004 through 2017 cannabis use decreased among 15 to 17 year olds, remained stable for 18 to 24 year olds, and increased among adults aged 25 to 64. During 2018 and into 2019, rates of cannabis use increased overall from 14% to 18%; with statistically significant increases also for males generally (16% to 22%) and males aged 18 to 64. Rates of cannabis use remained largely stable for females (13%) and seniors (4%). In 2019, about 60% of consumers reported using one cannabis product; use of dried cannabis (flower/leaf) was the most common (84.2%). The average user consumed 27.5 grams of dried cannabis (flower/leaf) over three months; amounts consumed varied depending on use frequency (e.g. occasional users: 2.6 grams/3 months versus DAD users: 62.6 grams/3 months). DISCUSSION Results highlight the importance of understanding pre-legalization behaviours as changes in use after legalization may have begun prior to the legislation. NCS allows for the early impacts of legalisation to be examined and provides a picture of not only changes in who is using but also what and how much.
Novel insights into the complex pharmacokinetics of voriconazole: a review of its metabolism

Abstract Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have been observed and the therapeutic range for this compound is relatively narrow, the metabolism of voriconazole has not been fully elucidated yet. The available literature data investigating the multiple different pathways and metabolites are extremely unbalanced and thus the absolute or relative contribution of the different pathways and enzymes involved in the metabolism of voriconazole remains uncertain. Furthermore, other factors such as nonlinear pharmacokinetics caused by auto-inhibition or -induction and polymorphisms of the metabolizing enzymes hinder safe and effective voriconazole dosing in clinical practice and have not yet been studied sufficiently. This review aimed at amalgamating the available literature on the pharmacokinetics of voriconazole in vitro and in vivo, with a special focus on metabolism in adults and children, in order to congregate an overall landscape of the current body of knowledge and identify knowledge gaps, opening the way towards further research in order to foster the understanding, towards better therapeutic dosing decisions.
Shared Resource Management for Non-Volatile Asymmetric Memory

Non-volatile memory (NVM), such as Phase-Change Memory (PCM), is a promising energy-efficient candidate to replace DRAM. It is desirable because of its non-volatility, good scalability and low idle power. NVM, nevertheless, faces important challenges. The main problems are: writes are much slower and more power hungry than reads and write bandwidth is much lower than read bandwidth. Hybrid main memory architecture, which consists of a large NVM and a small DRAM, may become a solution for architecting NVM as main memory. Adding an extra layer of cache mitigates the drawbacks of NVM writes. However, writebacks from the last-level cache (LLC) might still (a) overwhelm the limited NVM write bandwidth and stall the application, (b) shorten lifetime and (c) increase energy consumption. Effectively utilizing shared resources, such as the last-level cache and the memory bandwidth, is crucial to achieving high performance for multi-core systems. No existing cache and bandwidth allocation scheme exploits the read/write asymmetry property, which is fundamental in NVM. This thesis tries to consider the asymmetry property in partitioning the cache and memory bandwidth for NVM systems. The thesis proposes three writeback-aware schemes to manage the resources in NVM systems. First, a runtime mechanism, Writeback-aware Cache Partitioning (WCP), is proposed to partition the shared LLC among multiple applications. Unlike past partitioning schemes, WCP considers the reduction in cache misses as well as writebacks. Second, a new runtime mechanism, Writeback-aware Bandwidth Partitioning (WBP), partitions NVM service cycles among applications. WBP uses a bandwidth partitioning weight to reflect the importance of writebacks (in addition to LLC misses) to bandwidth allocation. A companion Dynamic Weight Adjustment scheme dynamically selects the cache partitioning weight to maximize system performance. Third, Unified Writeback-aware Partitioning (UWP) partitions the last-level cache and the memory bandwidth cooperatively. UWP can further improve the system performance by considering the interaction of cache partitioning and bandwidth partitioning. The three proposed schemes improve system performance by considering the unique read/write asymmetry property of NVM.
Impact of Body Mass Index and Pretreatment Hemoglobin Level on Prognosis Following Radical Cystectomy for Bladder Cancer in Males and Females

Objective: To assess the impact of pretreatment hemoglobin (Hb) and body mass index (BMI) on overall survival (OS) following radical cystectomy (RC) for bladder cancer (BCa) in males versus females. Materials and Methods: We retrospectively reviewed 152 patients treated with RC for BCa between 2012 and 2016. Hb was categorized as low Hb or high Hb. BMI was classified as underweight, overweight, or obese. Univariate and multivariate Cox regression models were used to evaluate the association of Hb and BMI with OS both in the entire cohort and in gender subgroups. Results: In these 152 BCa cases, 79 cases (52.0%) were categorized as low Hb, and 67 cases (44.1%) were overweight or obese. Both Hb (p = 0.001) and BMI (p = 0.046) were independent prognostic factors for the entire cohort. In females, only Hb (p = 0.012) and BMI (p = 0.027) were significant prognostic factors. In males, Hb (p = 0.024) was an independent prognostic factor, but BMI (p = 0.142) lost significance in multivariate analysis. Conclusion: Our results found that both higher pretreatment Hb and higher BMI were associated with favorable prognosis for OS in BCa treated with RC. The differing impact of Hb and BMI on prognosis in progression of BCa in males versus females suggests there is involvement of sex hormone pathways.
Efficacy of a Laparoscopic Saline-Coupled Bipolar Sealer in Minimally Invasive Hepatobiliary Surgery

Hepatic resection presents unique surgical challenges to reduce blood loss during parenchymal division. The development of saline-coupled bipolar devices, in which hemostasis is achieved at lower temperatures than electrocautery or other bipolar sealing devices, have been employed for open hepatic resection. Saline-coupled bipolar devices have now become available for minimally invasive use. The goals of this study were to evaluate the feasibility and safety of a laparoscopic saline-coupled bipolar device for minimally invasive hepatectomy. Seventeen patients (median age 66 years, range 36-81) were consented for inclusion and enrolled. Patient demographics, intraoperative data, and surgeon feedback were collected. Seven robot-assisted partial hepatectomies, 9 laparoscopic partial hepatectomies, and 1 laparoscopic cholecystectomy with liver abscess resection were performed. Average operating time was 222 ± 33 minutes (median 188 minutes; range 61-564 minutes) with no difference between robotic versus laparoscopic time. Successful seals were achieved in all cases following application of 150 to 200 J energy (average 179 ± 3 J, average time to achieve a successful seal 9.3 ± 2.7 minutes). Estimated blood loss was 362 ± 74 mL (median 300 mL, range 5-1200 mL) and 3/17 patients received intraoperative blood transfusion. No bile leaks were detected in any of the patients. Median length of stay was 5 days (range 1-20 days), and there were no readmissions within 30 days. Postoperative morbidity occurred in 5/17 patients, all of which were Clavien Grade 1. There was no mortality within 90 days or complications requiring a return to the operating room, and there were no liver-specific morbidities. These data suggest the laparoscopic Aquamantys device represents a useful device for use in minimally invasive liver resection.
PI3K/ Akt/ mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence.

BACKGROUND The Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. OBJECTIVE The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains pre-clinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. METHODS The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. RESULTS PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among these are patented. CONCLUSION Inhibitors of the PI3K/mTOR pathway has been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.
Prenatal developmental sequence of the skull of minke whales and its implications for the evolution of mysticetes and the teeth‐to‐baleen transition

Baleen whales (Mysticeti) have an extraordinary fossil record documenting the transition from toothed raptorial taxa to modern species that bear baleen plates, keratinous bristles employed in filter‐feeding. Remnants of their toothed ancestry can be found in their ontogeny, as they still develop tooth germs in utero. Understanding the developmental transition from teeth to baleen and the associated skull modifications in prenatal specimens of extant species can enhance our understanding of the evolutionary history of this lineage by using ontogeny as a relative proxy of the evolutionary changes observed in the fossil record. Although at present very little information is available on prenatal development of baleen whales, especially regarding tooth resorption and baleen formation, due to a lack of specimens. Here I present the first detailed description of prenatal specimens of minke whales (Balaenoptera acutorostrata and Balaenoptera bonaerensis), focusing on the skull anatomy and tooth germ development, resorption, and baleen growth. The ontogenetic sequence described consists of 10 specimens of both minke whale species, from the earliest fetal stages to full term. The internal skull anatomy of the specimens was visualized using traditional and iodine‐enhanced computed tomography scanning. These high‐quality data allow detailed description of skull development both qualitatively and quantitatively using three‐dimensional landmark analysis. I report distinctive external anatomical changes and the presence of a denser tissue medial to the tooth germs in specimens from the final portion of gestation, which can be interpreted as the first signs of baleen formation (baleen rudiments). Tooth germs are only completely resorbed just before the eruption of the baleen from the gums, and they are still present for a brief period with baleen rudiments. Skull shape development is characterized by progressive elongation of the rostrum relative to the braincase and by the relative anterior movement of the supraoccipital shield, contributing to a defining feature of cetaceans, telescoping. These data aid the interpretation of fossil morphologies, especially of those extinct taxa where there is no direct evidence of presence of baleen, even if caution is needed when comparing prenatal extant specimens with adult fossils. The ontogeny of other mysticete species needs to be analyzed before drawing definitive conclusions about the influence of development on the evolution of this group. Nonetheless, this work is the first step towards a deeper understanding of the most distinctive patterns in prenatal skull development of baleen whales, and of the anatomical changes that accompany the transition from tooth germs to baleen. It also presents comprehensive hypotheses to explain the influence of developmental processes on the evolution of skull morphology and feeding adaptations of mysticetes.
Tea Consumption and Health Outcomes: Umbrella Review of Meta-Analyses of Observational Studies in Humans.

SCOPE We sought to conduct an umbrella review to study the strength and validity of associations between tea consumption and diverse health outcomes. METHODS AND RESULTS Meta-analyses of observational studies examining associations between tea consumption and health outcomes in all human populations and settings were screened. The umbrella review identified 96 meta-analyses with 40 unique health outcomes. Tea consumption showed more benefits than harms to health in this review. Dose-response analyses of tea consumption indicated reduced risks of total mortality, cardiac death, coronary artery disease, stroke and type 2 diabetes mellitus with increment of 2 to 3 cups per day. Beneficial associations were also found for several cancers, skeletal, cognitive, and maternal outcomes. Harmful associations were found for esophageal and gastric cancer when the temperature of intake was more than 55-60°C. CONCLUSION Tea consumption, except for very hot tea, seems generally safe at usual levels of intake, with summary estimates indicating the largest reduction for diverse health outcomes at two to three cups per day. Generally, tea consumption seems more beneficial than harmful in this umbrella review. Randomized controlled trials are further needed to understand whether the observed associations are causal. This article is protected by copyright. All rights reserved.