bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of cellular energy homeostasis modulation through AMPK on regulation of protein translation and response to hypoxia
Authors: Gunaydin Gurcan , Gedik Mustafa Emre 
Published: March 2019

Abstract

Objective
AMP-activated-protein-kinase (AMPK) regulates cellular energy-homeostasis. Eukaryotic-elongation-factor-2-kinase (eEF2K) plays important roles in regulating protein-synthesis, functions similarly to AMPK to protect cancer-cells from metabolic stress. Tumor-hypoxia induces angiogenesis with activation of hypoxia-inducible-factor-1-alpha (HIF-1α). AMPK might be implicated both in regulation of protein-translation and response-to-hypoxia. We aimed to investigate the effects of AMPK modulation on regulation of protein translation and response-to-hypoxia by evaluating eEF2K and HIF-1α proteins in breast and hepatocellular cancers.

Materials and methods
Hepatocellular (Huh-7, HepG2) and breast (SKBR-3, MDA-MB-453) cancer-cells were incubated with AMPK-activator (A769662) or inhibitor (dorsomorphin) for 8/24 h. Alterations in eEF2K/HIF-1α protein expressions were examined.

Results
Cancer-cells slightly increased eEF2K expression after 24-h of AMPK-activation. Significant decreases in eEF2K expressions were observed with AMPK inhibition in all cancer-cells except Huh-7. Slight transient decrease in HIF-1α expression was observed after 8-h of AMPK-activation in all cancer-cells except MDA-MB-453. AMPK-inhibition decreased HIF-1α expression, especially in HepG2-cells.

Conclusion
The effects of AMPK modulation on eEF2K/HIF-1α protein expressions were investigated. Cells with varying molecular-expression-profiles demonstrate different metabolic activities. AMPK-activation may provide adaptive advantage to cancers and such an advantage may be reverted with an AMPK-inhibitor. The current study contributes to the literature in determining the effects of therapeutic strategies targeting AMPK on cancer-cell metabolic-pathway regulation.
Investigation of beta globin gene mutations in Syrian refugee patients with thalassemia major
Authors: Çevirici Hatice , Acıpayam Can , Yenilmez Ebru Dündar , Belen Fatma Burcu , Pekpak Esra , Yaman Yöntem , Tuli Abdullah 
Published: March 2019

Abstract

Objectives
This study, detection of beta globin gene mutations in thalassemia major patients who migrated from Syria to Kahramanmaraş region were planned.

Materials and methods
The study included 35 Syrian national beta thalassemia major patients. Beta globin gene mutations were detected by ARMS (Amplification Refractory Mutation System) method, RFLP (Restriction Fragment Length Polymorphism) method and DNA sequence analysis. Codon 15, codon 9/10, codon 5 and codon 8 mutations, which we could not detect with other methods in our study, were detected by sequence analysis.

Results
In beta thalassemia major patients, 16 types of mutations were detected, the most common being IVS-I-110 (n=8). Other mutations are according to frequency order IVS-II-745 (n=3), codon 44 (n=3), codon 15 (n=3), IVS-I-110/IVS-I-1 (n=3), codon 5 (n=2), IVS-I-1 (n=2), codon 8/IVS-II-1 (n=2), codon 44/codon 15 (n=2), IVS-II-1 (n=1), codon 39 (n=1), IVS-I-6/codon 5 (n=1), codon 9/10 (n=1), IVS-I-110/codon 39 (n=1), IVS-I-5/IVS-II-1 (n=1), codon 39/IVS-II-745 (n=1).

Conclusions
According to the results of our study beta-thalassemia mutations in Syrian immigrant groups show heterogeneity and mutation types of mutation map is similar to Turkey. The conclusion is to prevent families to have a second patient child by genetic counseling.
Exploring the Effect of Electron Withdrawing Groups on Optoelectronic Properties of Pyrazole Derivatives as Efficient Donor and Acceptor Materials for Photovoltaic Devices
Authors: Irfan Ahmad , Pannipara Mehboobali , Al-Sehemi Abdullah G. , Mumtaz Muhammad Waseem , Assiri Mohammed A. , Chaudhry Aijaz Rasool , Muhammad Shabbir 
Published: March 2019

Abstract
Multifunctional pyrazole derivative, i.e. 3-amino-1-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1H-benzo[f]chromene-2-carbonitrile (PBCC) has been synthesized and characterized. To shed light on various properties of interests, the ground state geometry was optimized by adopting Density Functional Theory (PBE/TZ2P). The effect of different functionals on the absorption wavelengths was studied by using Time-Domain DFT (TDDFT), e.g. GGA functional PBE, hybrid functionals B3LYP and PBE0, rang separated functionals CAM-B3LYP, LCY-PBE and CAMY-B3LYP, Dispersion Corrections PBE-D3 and B3LYP-D3. Among all these functionals PBE and PBE-D3 were found to be good choices which reproduced the absorption spectra of the PBCC. With the aim to enhance the electro-optical, charge transfer and photovoltaic properties, five new derivatives were designed by di-substituting the –F, –Cl, –Br, –COOH and –CN at benzochromene moiety. The electron injection barrier, band gap alignment and related calculated photovoltaic parameters revealed that PBCC and its newly designed derivatives would be proficient to be used in photovoltaic devices. These compounds can be used as donor materials in dye-sensitized solar cells (DSSCs) with favorable type-II band alignment. Moreover, PBCC and most of its derivatives might also be good choice as efficient acceptors with poly(dithieno[3,2-b:2,3-d]pyrrole thiophene) (PDTPr-T) and donor materials with Phenyl-C61-butyric acid methyl ester (PC61BM) in organic solar cells.
GIRK Channel Activity in Dopamine Neurons of the Ventral Tegmental Area Bidirectionally Regulates Behavioral Sensitivity to Cocaine
Authors: McCall Nora M. , Marron Fernandez de Velasco Ezequiel , Wickman Kevin 
Published: March 2019

Dopamine (DA) neurons of the VTA have been widely implicated in the cellular and behavioral responses to drugs of abuse. Inhibitory G protein signaling mediated by GABABreceptors (GABABRs) and D2DA receptors (D2Rs) regulates the excitability of VTA DA neurons, DA neurotransmission, and behaviors modulated by DA. Most of the somatodendritic inhibitory effect of GABABR and D2R activation on DA neurons reflects the activation of G protein-gated inwardly rectifying K+(GIRK) channels. Furthermore, GIRK-dependent signaling in VTA DA neurons can be weakened by exposure to psychostimulants and strengthened by phasic DA neuron firing. The objective of this study was to determine how the strength of GIRK channel activity in VTA DA neurons influences sensitivity to cocaine. We used a Cre-dependent viral strategy to overexpress the individual GIRK channel subunits in VTA DA neurons of male and female adult mice, leading to enhancement (GIRK2) or suppression (GIRK3) of GIRK channel activity. Overexpression of GIRK3 decreased somatodendritic GABABR- and D2R-dependent signaling and increased cocaine-induced locomotor activity, whereas overexpression of GIRK2 increased GABABR-dependent signaling and decreased cocaine-induced locomotion. Neither manipulation impacted anxiety- or depression-related behavior, despite the link between such behaviors and DA signaling. Together, these data show that behavioral sensitivity to cocaine in mice is inversely proportional to the strength of GIRK channel activity in VTA DA neurons and suggest that direct activators of the unique VTA DA neuron GIRK channel subtype (GIRK2/GIRK3 heteromer) could represent a promising therapeutic target for treatment of addiction.SIGNIFICANCE STATEMENTInhibitory G protein signaling in dopamine (DA) neurons, including that mediated by G protein-gated inwardly rectifying K+(GIRK) channels, has been implicated in behavioral sensitivity to cocaine. Here, we used a viral approach to bidirectionally manipulate GIRK channel activity in DA neurons of the VTA. We found that decreasing GIRK channel activity in VTA DA neurons increased behavioral sensitivity to cocaine, whereas increasing GIRK channel activity decreased behavioral sensitivity to cocaine. These manipulations did not alter anxiety- or depression-related behaviors. These data highlight the unique GIRK channel subtype in VTA DA neurons as a possible therapeutic target for addiction.
A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma
Authors: Hakami Osamah A , Ioana Julia , Ahmad Shahzad , Tun Tommy Kyaw , Sreenan Seamus , McDermott John H 
Published: March 2019

Summary
Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy and improved outcomes for patients with advanced disease. Pembrolizumab, a monoclonal antibody that acts as a programmed cell death 1 (PD-1(PDCD1)) inhibitor, has been approved for the treatment of advanced melanoma and other solid tumours. Immune-related adverse events (irAEs) including endocrinopathies have been well described with this and other PD-1 inhibitors. While hypothyroidism and hyperthyroidism, and less commonly hypophysitis, are the most common endocrinopathies occurring in patients treated with pembrolizumab, the incidence of type 1 diabetes mellitus (T1DM) was low in clinical trials. We report a case of pembrolizumab-induced primary hypothyroidism and T1DM presenting with severe diabetic ketoacidosis (DKA). A 52-year-old male patient was treated with pembrolizumab for metastatic melanoma. He presented to the emergency department with a 1-day history of nausea and vomiting 2 weeks after his seventh dose of pembrolizumab, having complained of polyuria and polydipsia for 2 months before presentation. He had been diagnosed with thyroid peroxidase (TPO) antibody-negative hypothyroidism, requiring thyroxine replacement, shortly after his fifth dose. Testing revealed a severe DKA (pH: 6.99, glucose: 38.6 mmol/L, capillary ketones: 4.9 and anion gap: 34.7). He was treated in the intensive care unit as per the institutional protocol, and subsequently transitioned to subcutaneous basal-bolus insulin. After his diabetes and thyroid stabilised, pembrolizumab was recommenced to treat his advanced melanoma given his excellent response. This case highlights the importance of blood glucose monitoring as an integral part of cancer treatment protocols composed of pembrolizumab and other ICIs.

Learning points:

The incidence of T1DM with pembrolizumab treatment is being increasingly recognised and reported, and DKA is a common initial presentation.

Physicians should counsel patients about this potential irAE and educate them about the symptoms of hyperglycaemia and DKA.

The ESMO guidelines recommend regular monitoring of blood glucose in patients treated with ICIs, a recommendation needs to be incorporated into cancer treatment protocols for pembrolizumab and other ICIs in order to detect hyperglycaemia early and prevent DKA.
Computational Complexity as an Ultimate Constraint on Evolution
Authors: Kaznatcheev Artem 
Published: March 2019

AbstractExperiments show that evolutionary fitness landscapes can have a rich combinatorial structure due to epistasis. For some landscapes, this structure can produce a computational constraint that prevents evolution from finding local fitness optima—thus overturning the traditional assumption that local fitness peaks can always be reached quickly if no other evolutionary forces challenge natural selection. Here, I introduce a distinction between easy landscapes of traditional theory where local fitness peaks can be found in a moderate number of steps, and hard landscapes where finding local optima requires an infeasible amount of time. Hard examples exist even among landscapes with no reciprocal sign epistasis; on these semismooth fitness landscapes, strong selection weak mutation dynamics cannot find the unique peak in polynomial time. More generally, on hard rugged fitness landscapes that include reciprocal sign epistasis, no evolutionary dynamics—even ones that do not follow adaptive paths—can find a local fitness optimum quickly. Moreover, on hard landscapes, the fitness advantage of nearby mutants cannot drop off exponentially fast but has to follow a power-law that long-term evolution experiments have associated with unbounded growth in fitness. Thus, the constraint of computational complexity enables open-ended evolution on finite landscapes. Knowing this constraint allows us to use the tools of theoretical computer science and combinatorial optimization to characterize the fitness landscapes that we expect to see in nature. I present candidates for hard landscapes at scales from single genes, to microbes, to complex organisms with costly learning (Baldwin effect) or maintained cooperation (Hankshaw effect). Just how ubiquitous hard landscapes (and the corresponding ultimate constraint on evolution) are in nature becomes an open empirical question.
Short Sleep Duration is a Risk of Incident Nonalcoholic Fatty Liver Disease: A Population-based Longitudinal Study
Authors: Okamura Takuro , Hashimoto Yoshitaka , Hamaguchi Masahide , Obora Akihiro , Kojima Takao , Fukui Michiaki 
Published: March 2019

Background & Aims: Previous cross-sectional studies revealed that short sleep duration has a close relationship with the presence of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the association between sleep duration and incident NAFLD.Methods: In this historical cohort study of 12,306 participants (5,848 men and 6,458 women), we investigated the effect of sleep duration on incident NAFLD. NAFLD was defined as having fatty liver diagnosed by abdominal ultrasonography in the participants who consumed ethanol less than 30 g/day for men and 20 g/day for women. We divided the participants into four groups according to sleep duration: >7, >6-7, >5-6, and ≤5h. Cox proportional hazards models were performed to investigate the effect of sleep duration on incident NAFLD, adjusting for age, body mass index categories, alanine aminotransferase, triglycerides, high density lipoprotein-cholesterol, fasting plasma glucose, smoking status, alcohol consumption, systolic blood pressure, exercise.Results: During the median 6.8-year follow-up for men and the 7.0-year follow-up duration for women, 2,280 participants (1,581 men and 699 women) developed NAFLD. In Cox proportional hazards models, sleep duration of ≤5 h in both men and women were revealed to be a significant risk for incident NAFLD, compared to men and women with a sleep duration of >7 h (men: hazard ratio 1.39, 95% confidence interval 1.13-1.72, p=0.002; women; 1.46, 1.05-2.04, p=0.023).Conclusion: This is the first study showing that short sleep duration was a risk factor for incident NAFLD.
Validation of the Traumatic Events Screening Inventory for ACEs
Authors: Choi Kristen R. , McCreary Michael , Ford Julian D. , Rahmanian Koushkaki Sara , Kenan Kristen N. , Zima Bonnie T. 
Published: March 2019

OBJECTIVES:
Our purpose in this study was to adapt and validate the Traumatic Events Screening Inventory (TESI) as a primary-care childhood adversity screening tool for children living in vulnerable neighborhoods using a community-partnered approach.

METHODS:
In this cross-sectional, descriptive study, we used a sample of 261 children (3–16 years old) who were seeking services at a Federally Qualified Health Center with colocated behavioral health services in Chicago and had a positive Pediatric Symptom Checklist screen result or received a referral for behavioral health evaluation. The TESI was adapted as a screening tool to be sensitive to adverse childhood experiences (ACEs) unique to the clinic communities. ACEs were mapped by zip code with objective neighborhood crime data, and latent class analysis was performed to identify ACE subgroups.

RESULTS:
The mapping validation suggested face validity for geographic overlap between participant ACEs and objective violent-crime occurrence. With latent class analysis, we identified 3 ACE subgroups: (1) high ACE (18.0% of the sample; polyvictimization and/or maltreatment), (2) moderate ACE (52.1%; violent environments), and (3) low ACE (29.9%; few adverse experiences). Membership in the high-ACE subgroup was associated with higher odds of a clinically significant Pediatric Symptom Checklist score (odds ratio = 3.83) and clinical-level attention problems (odds ratio = 3.58) even after accounting for child resilience and parent depression.

CONCLUSIONS:
ACEs play a significant role in predicting a need for behavioral health services among children seeking primary-care services. The community-adapted TESI is a valid ACE screening tool.
Risk of refeeding syndrome. Case report
Authors: Villa Adriana Giraldo 
Published: March 2019

Introduction: Refeeding syndrome is an acute metabolic disorder that occurs during nutritional repletion. Although it has been known for years, the early detection of risk factors for its onset and the implementation of measures to prevent it are not common in nutritional care.Case presentation: 48-year-old male patient, in critical care for 6 days, with suspected Wernicke-Korsakoff encephalopathy and high risk of refeeding syndrome according to criteria of the National Institute of Health and Clinical Excellence. The subject received enteral nutrition with 14 kcal/kg for the first 3 days, with subsequent increases aiming to achieve a nutritional goal of 25 kcal/kg on day 5. He also received daily supplementation of thiamine 600mg, folic acid 5mg and pyridoxine 50mg. Blood phosphorus decreased from 3 mg/dL to 2 mg/dL the day after initiating the nutritional plan and normalized by day 3.Discussion: The patient did not present severe hypophosphatemia or clinical manifestations of refeeding syndrome. Hypophosphatemia was resolved by maintaining a stable caloric restriction during the first days. Some professionals consider this restriction as very conservative, and others think that it may lead to achieve significant improvements in mortality reduction.Conclusions: The strategy for assessing the risk of refeeding syndrome, nutritional management and implemented follow-up were successful in preventing the patient from developing a refeeding syndrome.
Zollinger-Ellison syndrome. Case report
Authors: Rivillas-Reyes Juan Felipe , Castro-Avendaño Juan Leonel , Martínez-Muñoz Héctor Fabián 
Published: March 2019

Introduction: The Zollinger-Ellison syndrome (ZES) is a pathology caused by a neuroendocrine tumor, usually located in the pancreas or the duodenum, which is characterized by elevated levels of gastrin, resulting in an excessive production of gastric acid.Case presentation: A 42-year-old female patient with a history of longstanding peptic ulcer disease, who consulted due to persistent epigastric pain, melena and signs of peritoneal irritation. Perforated peptic ulcer was suspected, requiring emergency surgical intervention. Subsequently, a tumor lesion in the head of the pancreas was documented and managed with Whipple procedure. The pathology results reported a tumor suggestive of neuroendocrine neoplasm.Discussion: The Zollinger-Ellison syndrome occurs in 0.1 to 3 people per 1 000 000 inhabitants worldwide and is predominant in women between 20 and 50 years of age. It usually appears as a refractory acid-peptic disease or as a complication of gastric acid hypersecretion. Medical therapy is the standard management, being proton pump inhibitors (PPI) the most effective option. Surgery is recommended for sporadic ZES.Conclusions: ZES has a low incidence rate. It is rarely considered in the differential diagnosis of chronic epigastric pain and high clinical suspicion is required to achieve adequate management. This article is highly relevant as it presents a confirmed clinical case of ZES in Colombia, highlighting the importance of producing local scientific literature to improve the diagnosis and treatment of this pathology.
THE EFFECTS OF SELF-REGULATED LEARNING STRATEGIES ON PRESCHOOL CHILDREN’S SELF-EFFICACY AND PERFORMANCE IN EARLY WRITING
Authors: Kim Siew Siew , Nor Mariani Md. 
Published: March 2019

To enhance the will and the skills to express thoughts explicitly and effectively in early writing among preschool children, self-regulated learning (SRL) was suggested for preschool children as one of the effective learning approaches. This quasi-experimental study involved seventy-five preschool children (5-6 years old) from two public preschools in Selangor, Malaysia. This study investigated the effects of SRL strategies on early writing self-efficacy and early writing performance among preschool children. Interview data was engaged and supported the quantitative result to obtain a deep insight of the findings. Two-way Repeated Measure ANCOVA was employed and confirmed the effectiveness of self-regulated learning intervention with an interaction effect between the test and group for early writing self-efficacy being statistically significant (F(1, 72) = 12.665; p = 0.001, 2= 0.150), with Cohen’s d = 0.84; and early writing performance statistically significant (F(1, 72) = 110.801; p < 0.001, 2= 0.606), with Cohen’s d = 2.84. The result also confirmed that self-monitoring and controlling (F (5, 69) = 17.934, p < 0.001), with an adjusted R² = 0.534, was a strong predictor for early writing self-efficacy, and planning and goal setting (F(5, 69) = 12.706, p< 0.001), with an adjusted R² = 0.442, were a strong predictor for early writing performance. Eleven self-regulated learning strategies used emerged from the interviews’ data pertaining to different contexts. According to the participant children, planning and goal setting, self-monitoring, and self-evaluation were the strategies that will assure their writing quality. These responses supported the results produced by the quantitative data. The findings of this research provide a useful insight into early writing and self-regulated learning instructions in the Malaysian preschool context.