Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynamin 2 mediates fluid-phase micropinocytosis in epithelial cells

It is well-known that dynamin 2 (Dyn2) participates in clathrin- and caveolae-mediated endocytosis; however, the role of Dyn2 in coat-independent endocytic processes remains controversial. Here we demonstrate a role for specific spliced variants of Dyn2 in the micropinocytosis of fluid in epithelial cells, independent of coat-mediated endocytic pathways. A general inhibition of Dyn2 was first performed using either microinjection of anti-dynamin antibodies or Dyn2-siRNA treatment. Both of these methods resulted in reduced uptake of transferrin, a marker for clathrin-mediated endocytosis, and, under unstimulated conditions, reduced the uptake of the fluid-phase markers dextran and horseradish peroxidase (HRP). By contrast, cells treated similarly but stimulated with serum or EGF internalized substantial amounts of dextran or HRP, indicating that Dyn2 is not required for stimulated fluid uptake via macropinocytosis. We next tested whether a specific spliced variant might selectively affect fluid-phase endocytosis. Mutation of specific Dyn2 spliced variants resulted in a differential attenuation of transferrin and dextran internalization. Furthermore, the reduction in fluid uptake in Dyn2-siRNA-treated cells was only rescued upon re-expression of select spliced variants. These findings suggest that Dyn2 function is required for the coat-independent internalization of fluid through endocytic pathways distinct from macropinocytosis and, in addition, implicate different Dyn2 spliced variants in specific endocytic functions.
The emotion: A crucial component in the care of critically ill patients

Background: The acquisition of experience is a major concern for nurses in intensive care units. Although the emotional component of the clinical practice of these nurses has been widely studied, greater examination is required to determine how this component influences their learning and practical experience. Objective: To discover the relationships between emotion, memory and learning and the impacts on nursing clinical practice. Research design: This is a qualitative phenomenological study. The data were collected from open, in-depth interviews. A total of 22 intensive care unit nurses participated in this research between January 2012 and December 2014. Ethical considerations: The School of Nursing Ethics Committee approved the study, which complied with ethical principles and required informed consent. Findings: We found a clear relationship between emotion, memory and the acquisition of experience. This relationship grouped three dimensions: (1) satisfaction, to relieve the patient’s pain or discomfort, give confidence and a sense of security to the patient, enable the presence of family members into the intensive care unit and provide family members with a realistic view of the patient’s situation; (2) error experience, which nurses feel when a patient dies, when they fail to accompany a patient in his or her decision to abandon the struggle to live or when they fail to lend support to the patient’s family; and (3) the feel bad–feel good paradox, which occurs when a mistake in the patient’s care or handling of his or her family is repaired. Conclusion: Emotion is a capacity that impacts on nurses’ experience and influences improvements in clinical practice. Recalling stories of satisfaction helps to reinforce good practice, while recalling stories of errors helps to identify difficulties in the profession and recognise new forms of action. The articulation of emotional competencies may support the development of nursing ethics in the intensive care unit to protect and defend their patients and improve their relationships with families in order to maximise the potential for patient care.
Staphylococcus aureus penicillin-binding protein 4 and intrinsic beta-lactam resistance

Increased levels of production of penicillin-binding protein PBP 4 correlated with in vitro acquired intrinsic beta-lactam resistance in a mutant derived from a susceptible strain of Staphylococcus aureus, strain SG511 Berlin. Truncation of the PBP 4 C-terminal membrane anchor abolished the PBP 4 content of cell membrane preparations as well as the resistance phenotype. A single nucleotide change and a 90-nucleotide deletion, comprising a 14-nucleotide inverted repeat in the noncoding pbp4 gene promoter proximal region, were the only sequence differences between the resistant mutant and the susceptible parent. These mutations were thought to be responsible for the observed overproduction of PBP 4 in the intrinsically beta-lactam-resistant mutant. The pbp4 gene was flanked upstream by the open reading frame abcA, coding for an ATP-binding cassette transporter-like protein showing similarities to eukaryotic multidrug transporters and downstream by a glycerol 3-phosphate cytidyltransferase (tagD)-like open reading frame presumably involved in teichoic acid synthesis. The abcA-pbp4-tagD gene cluster was located in the SmaI-D fragment in the S. aureus 8325 chromosome in close proximity to the RNA polymerase gene rpoB.
Hyponatremic natriuretic syndrome in tuberculous meningitis: the probable role of atrial natriuretic peptide.

Hyponatremia has been reported in up to one third of patients with intracranial disease and has frequently been associated with tuberculous meningitis, often complicated by hydrocephalus. The lowered plasma sodium levels were previously attributed to the syndrome of inappropriate secretion of antidiuretic hormone. A controlled prospective study of 24 patients with tuberculous meningitis and hydrocephalus was carried out. Analyses of serum electrolytes and cerebrospinal fluid were performed. Plasma and cerebrospinal fluid levels of atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) were measured by radioimmunoassay. Fifteen patients were found to be hyponatremic (plasma sodium < 130 mmol/L) and ANP levels of 12 to 1,488 pg/ml were present (median, 26 pg/ml). The remaining 9 patients had normal plasma sodium values between 130 and 145 mmol/L, and in these, plasma ANP values varied between 12 and 21.7 pg/ml (median, 12 pg/ml). The difference between these two groups was not statistically significant. (Control values from patients undergoing myelography were established to range between 12 and 40 pg/ml; median, 14.4 pg/ml.) ANP levels were undetectable in the cerebrospinal fluid in all. Plasma ADH levels in the hyponatremic group were between 7 and 159 pg/ml (median, 40 pg/ml). In the normonatremic group, plasma ADH levels of 25 to 250 pg/ml (median, 29 pg/ml) were obtained. (The controls ranged between 3.6 and 35 pg/ml; median, 10.4 pg/ml). In the hyponatremic group, there was a moderate negative correlation (r = -0.683) between plasma ANP and plasma sodium (P = 0.02). No correlation between plasma ADH and plasma sodium was found (r = -0.168; P = 0.62). (ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC.
Fatty acid‐induced cholecystokinin secretion and changes in intracellular Ca2+ in two enteroendocrine cell lines, STC‐1 and GLUTag

1 Fatty acid‐induced cholecystokinin (CCK) secretion in humans and from the enteroendocrine cell line STC‐1 depends critically on acyl chain length. 2 Therefore we have characterized the relationship between acyl chain length and the potency of the fatty acid to induce CCK secretion and changes in intracellular Ca2+ concentration ([Ca2+]i) in two enteroendocrine cell lines (STC‐1 and GLUTag). We found that the potency of the fatty acid was directly proportional to its chain length and therefore inversely proportional to its solubility. 3 In both cell types, the fatty acid‐induced rise in [Ca2+]i in response to decanoic acid (C10), dodecanoic acid (C12) and tetradecanoic acid (C14) was significantly reduced in Ca2+‐free medium and largely blocked by nicardipine. Intracellular stores also contributed to the overall shape of the [Ca2+]i peak. Thus all the fatty acids tested caused the release of Ca2+ from stores and influx of extracellular Ca2+, presumably through L‐type calcium channels. 4 To probe the site of fatty acid action, we studied the distribution of 14C‐labelled dodecanoic acid. This label was rapidly and irreversibly accumulated by both cell types, where it became concentrated about 20‐fold. Confocal microscopy of a fluorescent analogue of dodecanoic acid clearly demonstrated that it entered the cytosol and was not merely partitioning in the cell membrane. These data indicate that an intracellular action for fatty acid‐induced CCK secretion cannot be eliminated. 5 Dodecanoic acid itself, and not a metabolite, is the agent responsible for triggering Ca2+ entry since a non‐metabolizable form of dodecanoic acid (2‐bromododecanoic acid) was also capable of inducing a rise in [Ca2+]i in both cell types. 6 In conclusion, the rise in [Ca2+]i in STC‐1 and GLUTag cells evoked by medium‐ to long‐chain fatty acids results from the triggering of a specific signalling pathway. Whether triggering occurs through activation of a membrane‐bound receptor or at an intracellular site remains to be clarified.
25 Years of Real Option Empirical Research in Management

For several decades, management scholars have extolled the virtues of using real option logic when making decisions under uncertainty. Real option logic suggests that in such situations, firms might be better off deferring or staging investments, reducing potential financial losses, while at the same time securing an option to grow (or abandon) the investment when uncertainty abates. Our analysis of the empirical research published in leading management journals over the past 25 years suggests that while some progress has been made, much more work needs to be done. We still do not have the answers to critical questions such as: Which entrepreneurial/managerial traits impact the identification or exploitation of real options? Do multiple types of uncertainties interact with each other and influence real option decisions? Addressing these and other issues identified in our study can help improve our understanding of the usefulness of real option logic in management.
Pro-Apoptotic Activities of Polyphenolics From Açai (Euterpe oleracea Martius) in Human SW-480 Colon Cancer Cells

This study aimed to evaluate the cell growth inhibition activity of açai (Euterpe oleracea Mart.) polyphenolic extract against colon cancer HT-29 and SW-480 cells and the nonmalignant CCD-18Co colon fibroblast cells. Results showed that açai polyphenolic extract (5–20 mg/L) inhibited preferentially the growth of SW-480 cells with no toxicity in CCD-18Co cells, and this was accompanied by reduction of H2O2-induced reactive oxygen species (ROS) generation. The mechanisms involved in SW-480 cell growth-inhibition by açai polyphenolic extract included the downregulation of NF-κB proinflammatory transcription factor and the nuclear factor-kappa B targets intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Furthermore, prooncogenic specificity proteins (Sp) were downregulated as well as Sp-targets Bcl-2, vascular endothelial growth factor, and survivin. This was accompanied by activation of mitochondrial proapoptotic pathway involving increase of cytochrome c, cleavage of caspase-3, and decrease of PARP-1. Results strongly suggest that açai polyphenolic extract has antiinflammatory and cytotoxic activities in colon cancer cells and can be effective as natural colon cancer chemopreventive agents.
Age‐at‐onset subsets of bipolar I disorders: A critical insight into admixture analyses

Gaussian mixture analysis is frequently used to model the age‐at‐onset (AAO) in bipolar I disorder and identify homogeneous subsets of patients. This study aimed to examine whether, using admixture analysis of AAO, cross‐sectional designs (which cause right truncation), unreliable diagnosis for individuals younger than 10 years old (which causes left truncation) and the selection criterion used for admixture analysis impact the number of identified subsets. A simulation study was performed. Different criteria – the likelihood ratio test (LRT), the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) – were compared using no, left and/or right truncation simulated data. The error rate of each criterion (percentage of erroneous number of detected subsets) was estimated. An application to two real databases, including 2,876 and 1,393 patients, is provided. Without data truncation and regardless of the distribution of AAO, the LRT and the AIC had much higher error rates (12% and 33%, respectively) than the BIC (1%). For a homogeneous population, the error rate increased with the introduction of left truncation. This study shows that the number of subsets identified using admixture analysis may depend on the sample size, the selection criterion, and the study design.
Heterogeneity in dementia of the Alzheimer type

We reviewed records of 121 consecutive patients with dementia of the Alzheimer type. Patients with myoclonus or extrapyramidal signs had greater intellectual decline and functional impairment in daily activities. Among patients studied over 4 years, there were four groups: benign—little to no progression; myoclonic—severe intellectual decline and frequent mutism after younger onset; extrapyramidal—severe intellectual and functional decline and frequent psychotic symptoms; typical—a gradual progression of intellectual and functional decline, but without other distinguishing features. Except for the group with myoclonus, no subgroup was segregated by age at onset or other demographic variables. This study suggests that dementia of the Alzheimer type is heterogeneous, and that certain clinical manifestations may be useful in predicting outcome.
Doing Better but Feeling Worse

Expanding upon Simon's (1955) seminal theory, this investigation compared the choice-making strategies of maximizers and satisficers, finding that maximizing tendencies, although positively correlated with objectively better decision outcomes, are also associated with more negative subjective evaluations of these decision outcomes. Specifically, in the fall of their final year in school, students were administered a scale that measured maximizing tendencies and were then followed over the course of the year as they searched for jobs. Students with high maximizing tendencies secured jobs with 20% higher starting salaries than did students with low maximizing tendencies. However, maximizers were less satisfied than satisficers with the jobs they obtained, and experienced more negative affect throughout the job-search process. These effects were mediated by maximizers' greater reliance on external sources of information and their fixation on realized and unrealized options during the search and selection process.
TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma.

BACKGROUND TGFβ1 and Smad3 play an important role in the process of EMT. TGFβ1 regulates the expression of Jagged1 by modulating Notch signaling. Jagged1 is related to tumor invasion, metastasis, chemotherapy resistance, and tumor immune escape. The aims of this study are to examine deregulation of TGFβ1-Smad3-Jagged1-Notch1-Slug signaling in TSCC and to investigate its roles in TSCC progression. MATERIALS AND METHODS Notch1, Smad3, Jagged1 and Slug proteins and mRNA expression were detected in specimens from 89 cases of patients. We analyzed the correlation between their expressions and histological grade, clinical stage and lymph node metastasis. RESULTS Notch1, Smad3, Jagged1 and Slug mRNA expressions in TSCC were higher than normal tissue (P <0.05). The protein expression of Notch1 and Smad3 in TSCC were higher (χ(2) =7.30, P <0.01 and χ(2) = 5.84, P <0.05). Notch1 and Smad3 expressions were correlated with clinical stage (χ(2) =18.81, P<0.01; χ(2) =22.29, P<0.01), but not Jagged1 (χ(2) =0.53, P>0.05). The Slug protein expression was correlated with clinical stage. The positive rate of Notch1 was higher in lymph node metastases positive cases (χ(2) =7.30, P<0.01). Moreover, higher expression of Jagged1 was found in lymph node positive cases (χ(2) =10.82, P<0.01). CONCLUSIONS The key protein expression in TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway significantly correlated with the clinicopathological features of TSCC patients. It's potential as a biomarker and a novel therapeutic target for TSCC patients at risk of metastasis. It may play an irreplaceable role in TSCC progression which may attribute to promoting EMT which enhances cell migration, invasion and metastasis.
Electroencephalogram reactivity to verbal command after dexmedetomidine, propofol and sevoflurane‐induced unresponsiveness

Although electroencephalogram reactivity (i.e. transient changes in electrical brain activity following external stimulus) might be useful in depth‐of‐anaesthesia monitoring, it has not been systematically examined with different anaesthetics at doses titrated to unresponsiveness. Three 10‐subject groups of healthy volunteers received dexmedetomidine, propofol or sevoflurane in escalating pseudo‐steady‐state concentrations at 10‐min intervals until they did not open their eyes to command. The electroencephalogram was continuously recorded and spectral variables were calculated with short‐time Fourier transform and time‐varying autoregressive modelling. Electroencephalogram reactivity was most prominent in the midfrontal derivations (termed F3 and F4). During drug‐induced unresponsiveness, electroencephalogram reactivity was still present in all drug groups. Dexmedetomidine, propofol and sevoflurane induced distinct suppression patterns on the electroencephalogram reactivity at the same clinical endpoint (unresponsiveness). Reactivity was best maintained with propofol, while only minimally preserved with dexmedetomidine and sevoflurane. Thus, it may be difficult to harness reactivity for depth‐of‐anaesthesia monitoring.
Impact of common polymorphisms in candidate genes for insulin resistance and obesity on weight loss of morbidly obese subjects after laparoscopic adjustable gastric banding and hypocaloric diet.

CONTEXT It is unknown whether genetic factors that play an important role in body weight homeostasis influence the response to laparoscopic adjustable gastric banding (LAGB). OBJECTIVE We investigated the impact of common polymorphisms in four candidate genes for insulin resistance on weight loss after LAGB. DESIGN The design was a 6-month follow-up study. SETTING The study setting was hospitalized care. PATIENTS A total of 167 unrelated morbidly obese subjects were recruited according to the following criteria: age, 18-66 yr inclusive; and body mass index greater than 40 kg/m2 or greater than 35.0 kg/m2 in the presence of comorbidities. INTERVENTION LAGB was used as an intervention. MAIN OUTCOME MEASURE Measure of correlation between weight loss and common polymorphisms in candidate genes for insulin resistance and obesity was the main outcome measure. RESULTS The following single nucleotide polymorphisms were detected by digestion of PCR products with appropriate restriction enzymes: Gly972Arg of the insulin receptor substrate-1 gene, Pro12Ala of the proliferator-activated receptor-gamma gene, C-174G in the promoter of IL-6 gene, and G-866A in the promoter of uncoupling protein 2 gene. Baseline characteristics including body mass index did not differ between the genotypes. At the 6-month follow-up after LAGB, carriers of G-174G IL-6 genotype had lost more weight than G-174C or C-174C genotype (P = 0.037), and carriers of A-866A uncoupling protein 2 genotype had lost more weight as compared with G-866G (P = 0.018) and G-866A (P = 0.035) genotype, respectively. Weight loss was lower in carriers of Gly972Arg insulin receptor substrate-1 genotype than Gly972Gly carriers, but not statistically significant (P = 0.06). No difference between carriers of Pro12Ala and Pro12Pro proliferator-activated receptor-gamma genotype was observed. CONCLUSIONS These data demonstrate that genetic factors, which play an important role in the regulation of body weight, may account for differences in the therapeutic response to LAGB.
Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant‐Driven Prostate Cancer Model

Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next‐generation androgen‐AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration‐resistant prostate cancer (CRPC) model, designated JDCaP‐hr (hormone refractory).