Miracle-dz/UniFAR-FTUs huggingface dataset:
A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.
Children's Health Status: Examining the Associations among Income Poverty, Material Hardship, and Parental Factors

Background We examined a model of multiple mediating pathways of income poverty, material hardship, parenting factors, and child health status to understand how material hardship and parental factors mediate the effects of poverty on child health. We hypothesized that: (a) poverty will be directly associated with material hardship, parental depression, and health status, and indirectly with parenting behaviors through its effects on parental depression and material hardship; (b) material hardship will be associated with parental depression, parenting behaviors, and health status; and (c) parental depression will be correlated with parenting behaviors, and that both parental depression and parenting behaviors will predict child health. Methods and Results We used data from the 2002 National Survey of American Families for a sample of 9,645 6-to-11 year-olds to examine a 4-step structural equation model. The baseline model included covariates and income poverty. In the hardship model, food insufficiency and medical need were added to the baseline model. The parental model included parental depression and parenting behavior and baseline model. In the full model, all the constructs were included. First, income poverty had a direct effect on health status, and an indirect effect through its association with material hardship, parental depressive affect, and parenting behaviors. Medical need and food insufficiency had negative effects on child health, and indirect effects on health through their association with parental depression and parenting behaviors. Finally, parental depression and parenting behaviors were associated with child health, and part of the effect of parental depression on health was explained by its association with parenting behaviors. Conclusions Poverty has an independent effect on health, however, its effects are partially explained by material hardship, parental depression and parental behaviors. To improve children's health would require a multi-pronged approach involving income transfers, health insurance coverage, food and nutrition assistance, and parenting interventions.
Combining Quantitative Genetic Footprinting and Trait Enrichment Analysis to Identify Fitness Determinants of a Bacterial Pathogen

Strains of Extraintestinal Pathogenic Escherichia c oli (ExPEC) exhibit an array of virulence strategies and are a major cause of urinary tract infections, sepsis and meningitis. Efforts to understand ExPEC pathogenesis are challenged by the high degree of genetic and phenotypic variation that exists among isolates. Determining which virulence traits are widespread and which are strain-specific will greatly benefit the design of more effective therapies. Towards this goal, we utilized a quantitative genetic footprinting technique known as transposon insertion sequencing (Tn-seq) in conjunction with comparative pathogenomics to functionally dissect the genetic repertoire of a reference ExPEC isolate. Using Tn-seq and high-throughput zebrafish infection models, we tracked changes in the abundance of ExPEC variants within saturated transposon mutant libraries following selection within distinct host niches. Nine hundred and seventy bacterial genes (18% of the genome) were found to promote pathogen fitness in either a niche-dependent or independent manner. To identify genes with the highest therapeutic and diagnostic potential, a novel Trait Enrichment Analysis (TEA) algorithm was developed to ascertain the phylogenetic distribution of candidate genes. TEA revealed that a significant portion of the 970 genes identified by Tn-seq have homologues more often contained within the genomes of ExPEC and other known pathogens, which, as suggested by the first axiom of molecular Koch's postulates, is considered to be a key feature of true virulence determinants. Three of these Tn-seq-derived pathogen-associated genes—a transcriptional repressor, a putative metalloendopeptidase toxin and a hypothetical DNA binding protein—were deleted and shown to independently affect ExPEC fitness in zebrafish and mouse models of infection. Together, the approaches and observations reported herein provide a resource for future pathogenomics-based research and highlight the diversity of factors required by a single ExPEC isolate to survive within varying host environments.
Impact of HR Practices on Employee Satisfaction and Employee Loyalty: An Empirical Study of Government Owned Public Sector Banks of Pakistan

Employee satisfaction and loyalty is one of the most important challenges that banking sector is facing in current competitive market. A lot of studies have been conducted to determine predictors of employee satisfaction but these studies focused only on developed countries. Therefore, the main purpose of study is to find the relationship between three HR practices i.e. compensation, empowerment and appraisal system and employee satisfaction & loyalty in government owned public sector banks of Pakistan. For this purpose, data has been collected from the employees of govt. owned public banks. Statistical software SPSS 17 has been used for validity, reliability, correlation and regression analysis. Employee compensation is found to be most important factor for creating satisfaction among employee while employee empowerment is found to be significant factor for developing employee loyalty. Theoretical and managerial implications along with limitations for future research have also been discussed.
Proteasomal Degradation of Glutamine Synthetase Regulates Schwann Cell Differentiation

Rapid saltatory nerve conduction is facilitated by myelin structure, which is composed of Schwann cells in the peripheral nervous system. Schwann cells drastically change their phenotype following peripheral nerve injury. These phenotypic changes are required for efficient degeneration/regeneration. We previously identified ZNRF1 as an E3 ubiquitin ligase containing a RING finger motif, whose expression is upregulated in the Schwann cells following nerve injury. This suggested that posttranscriptional regulation of protein expression in Schwann cells may be involved in their phenotypic changes during nerve degeneration/regeneration. Here we report the identification of glutamine synthetase (GS), an enzyme that synthesizes glutamine using glutamate and ammonia, as a substrate for E3 activity of ZNRF1 in Schwann cells. GS is known to be highly expressed in differentiated Schwann cells, but its functional significance has remained unclear. We found that during nerve degeneration/regeneration, GS expression is controlled mostly by ZNRF1-dependent proteasomal degradation. We also found that Schwann cells increase oxidative stress upon initiation of nerve degeneration, which promotes carbonylation and subsequent degradation of GS. Surprisingly, we discovered that GS expression regulates Schwann cell differentiation; i.e., increased GS expression promotes myelination via its enzymatic activity. Among the substrates and products of GS, increased glutamate concentration inhibited myelination and yet promoted Schwann cell proliferation by activating metabotropic glutamate receptor signaling. This would suggest that GS may exert its effect on Schwann cell differentiation by regulating glutamate concentration. These results indicate that the ZNRF1-GS system may play an important role in correlating Schwann cell metabolism with its differentiation.
Polo-like Kinase-1 Is Required for Bipolar Spindle Formation but Is Dispensable for Anaphase Promoting Complex/Cdc20 Activation and Initiation of Cytokinesis*

Polo-like kinase-1 (Plk1) performs multiple essential functions during the cell cycle. Here we show that human Plk1-deficient cells are unable to separate their centrosomes, fail to form a bipolar spindle, and undergo a Mad2/BubR1-dependent prometaphase arrest. However, electron microscopy demonstrates that kinetochore-microtubule interactions can be established in cells lacking Plk1. In addition, co-depletion of Plk1 and survivin allows mitotic exit. This indicates that Plk1 depletion does not prevent microtubule attachment, but specifically interferes with the generation of tension, as a consequence of a failure to form a bipolar spindle. Moreover, we find that after silencing of the spindle assembly checkpoint, degradation of cyclin B1 is unaffected in cells lacking Plk1. These data indicate that activation of the anaphase promoting complex or cyclosome (APC/C)-Cdc20 complex that is under control of the spindle assembly checkpoint does not require Plk1 activity. Finally, we find that translocation of chromosome passengers and initiation of cleavage furrow ingression is unaffected in cells depleted of Plk1. Thus, our data confirm an important role of Plk1 in bipolar spindle formation, and also demonstrate that Plk1 is dispensable for APC/C-Cdc20 activation and the initiation of cytokinesis.
Elevated Preoperative Serum Alanine Aminotransferase/Aspartate Aminotransferase (ALT/AST) Ratio Is Associated with Better Prognosis in Patients Undergoing Curative Treatment for Gastric Adenocarcinoma

The level of anine aminotransferase/aspartate aminotransferase (ALT/AST) ratio in the serum was often used to assess liver injury. Whether the ALT/AST ratio (LSR) was associated with prognosis for gastric adenocarcinoma (GA) has not been reported in the literature. Our aim was to investigate the prognostic value of the preoperative LSR in patients with GA. A retrospective study was performed in 231 patients with GA undergoing curative resection. The medical records collected include clinical information and laboratory results. We investigated the correlations between the preoperative LSR and overall survival (OS). Survival analysis was conducted with the Kaplan–Meier method, and Cox regression analysis was used to determine significant independent prognostic factors for predicting survival. A p value of <0.05 was considered to be statistically significant. A total of 231 patients were finally enrolled. The median overall survival was 47 months. Multivariate analysis indicated that preoperative LSR was an independent prognostic factor in GA. Patients with LSR ≤ 0.80 had a greater risk of death than those with LSR > 0.80. The LSR was independently associated with OS in patients with GA (hazard ratio: 0.610; 95% confidence interval: 0.388–0.958; p = 0.032), along with tumor stages (hazard ratio: 3.118; 95% confidence interval: 2.044–4.756; p < 0.001) and distant metastases (hazard ratio: 1.957; 95% confidence interval: 1.119–3.422; p = 0.019). Our study first established a connection between the preoperative LSR and patients undergoing curative resection for GA, suggesting that LSR was a simple, inexpensive, and easily measurable marker as a prognostic factor, and may help to identify high-risk patients for treatment decisions.
Integrated garnet and zircon–titanite geochronology constrains the evolution of ultra‐high–pressure terranes: An example from the Sulu orogen

Dating ultra‐high–pressure (UHP) metamorphic rocks provides important timing constraints on deep subduction zone processes. Eclogites, deeply subducted rocks now exposed at the surface, undergo a wide range of metamorphic conditions (i.e. deep subduction and exhumation) and their mineralogy can preserve a detailed record of chronologic information of these dynamic processes. Here, we present an approach that integrates multiple radiogenic isotope systems in the same sample to provide a more complete timeline for the subduction–collision–exhumation processes, based on eclogites from the Dabie–Sulu orogenic belt in eastern China, one of the largest UHP terranes on Earth. In this study, we integrate garnet Lu–Hf and Sm–Nd ages with zircon and titanite U–Pb ages for three eclogite samples from the Sulu UHP terrane. We combine this age information with Zr‐in‐rutile temperature estimates, and relate these multiple chronometers to different P–T conditions. Two types of rutile, one present as inclusions in garnet and the other in the matrix, record the temperatures of UHP conditions and a hotter stage, subsequent to the peak pressure (‘hot exhumation') respectively. Garnet Lu–Hf ages (c. 238–235 Ma) record the initial prograde growth of garnet, while coupled Sm–Nd ages (c. 219–213 Ma) reflect cooling following hot exhumation. The maximum duration of UHP conditions is constrained by the age difference of these two systems in garnet (c. 235–220 Ma). Complementary zircon and titanite U–Pb ages of c. 235–230 Ma and c. 216–206 Ma provide further constraints on the timing of prograde metamorphism and the ‘cold exhumation' respectively. We demonstrate that timing of various metamorphic stages can thus be determined by employing complementary chronometers from the same samples. These age results, combined with published data from adjacent areas, show lateral diachroneity in the Dabie–Sulu orogeny. Three sub‐blocks are thus defined by progressively younger garnet ages: western Dabie (243–238 Ma), eastern Dabie–northern Sulu (238–235 Ma) and southern Sulu terranes (225–220 Ma), which possibly correlate to different crustal slices in the recently proposed subduction channel model. These observed lateral chronologic variations in a large UHP terrane can possibly be extended to other suture zones.
Role of parents in adolescent sexual activity and contraceptive use in four African countries.

CONTEXT Parents have an influence on the sexual and reproductive health of adolescents, but evidence from Sub- Saharan Africa is limited. A better understanding of the relationship between different dimensions of parenting and recent sexual activity and contraceptive use is needed in the region. METHODS Data were collected in 2004 in nationally representative surveys of 12-19-year-olds in Burkina Faso, Ghana, Malawi and Uganda. Bivariate analysis compared gender differences for two outcomes among unmarried 15-19-year-olds-having had sexual intercourse in the last 12 months and, among those who had had sex in this period, contraceptive use at last sex. Multivariate logistic regression analysis identified associations between these outcomes and coresidence with parents or parent figures, parental monitoring and parent-child communication. RESULTS Unmarried adolescents reported moderate to high levels of parental monitoring and low levels of parent-child communication about sexual matters. In all countries, adolescent males who reported low monitoring were at elevated risk of having had sex in the last year (odds ratios, 2.4-5.4), as were their female counterparts in three of the countries (6.9-7.7). Communication with parents was positively associated with sexual activity among Malawian males and Ugandan females (2.2 and 1.5, respectively). Parental monitoring was not associated with contraceptive use at last sex, whereas parent-child communication was associated with such use among Ghanaian females (3.0) and among Ugandan adolescents of both genders (1.9-2.0). CONCLUSIONS Programs to improve adolescent sexual and reproductive health should include dimensions of parental involvement that can strengthen the program's specific behavior change goals.
What Can Genome-Wide Association Studies Tell Us about the Genetics of Common Disease

The success of genome-wide association studies relies on much of the risk of common diseases being due to common genetic variants; but evidence for this is inconclusive. The results of published genome-wide association studies are examined to see what can be learnt about the distribution of disease-associated variants and how this might influence future study design. Although replicated disease-associated variants tend to be very common and frequency is inversely correlated with estimated effect size, our simulations suggest that such observations are the result of power. We find that for studies conducted to date, the frequency and effect size of significantly associated alleles are likely to be similar to those of the underlying disease alleles that they represent. Little of the genetic variation of disease has been explained so far, but current studies are only adequately powered to detect very common alleles unless they greatly increase disease risk. Thus, although the truth of the common disease / common variant hypothesis remains undecided, recent successes suggest that there are many more common genetic disease-associated variants, requiring larger studies to be identified.
Review on Cell Mechanics: Experimental and Modeling Approaches

The interplay between the mechanical properties of cells and the forces that they produce internally or that are externally applied to them play an important role in maintaining the normal function of cells. These forces also have a significant effect on the progression of mechanically related diseases. To study the mechanics of cells, a wide variety of tools have been adapted from the physical sciences. These tools have helped to elucidate the mechanical properties of cells, the nature of cellular forces, and mechanoresponses that cells have to external forces, i.e., mechanotransduction. Information gained from these studies has been utilized in computational models that address cell mechanics as a collection of biomechanical and biochemical processes. These models have been advantageous in explaining experimental observations by providing a framework of underlying cellular mechanisms. They have also enabled predictive, in silico studies, which would otherwise be difficult or impossible to perform with current experimental approaches. In this review, we discuss these novel, experimental approaches and accompanying computational models. We also outline future directions to advance the field of cell mechanics. In particular, we devote our attention to the use of microposts for experiments with cells and a bio-chemical-mechanical model for capturing their unique mechanobiological properties. [DOI: 10.1115/1.4025355]
Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors

Whole-cell patch-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) were made from granule cells of the rat dentate gyrus in vitro. Tetanic stimulation in control media evoked a statistically identical long-term potentiation (LTP) of both the AMPA and NMDA receptor-mediated components of the dual component EPSC (AM-PAR and NMDAR EPSCs), as shown by a similar percentage increase in both components when measured at a holding potential of -30 mV, and also by an identical time course of the pre- and post-LTP induced EPSC at -30 mV and -70 mV. Application of the selective metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD induced a transient depression followed by a rapid onset LTP of both the AMPAR and the NMDAR components of the dual component EPSC. The ACPD- and tetanically induced LTP of the AMPAR EPSC was NMDAR dependent, being abolished by the NMDAR antagonist AP5. Tetanic stimulation, and application of ACPD, also induced a relatively rapid onset LTP of the pharmacologically isolated NMDAR EPSC. Such tetanically and ACPD-induced LTP of the isolated NMDAR EPSC was also dependent on NMDAR activation, being strongly inhibited by AP5. The tetanically and the ACPD-induced LTP of the NMDAR EPSC were dependent on protein kinase C (PKC) stimulation, being strongly inhibited by the PKC inhibitor PKCI (19–31). The studies suggest that coactivation of the mGluR and NMDAR are required for induction of LTP of both the AMPAR- and NMDAR-mediated synaptic transmission. Moreover, LTP of the NMDAR-mediated synaptic transmission appears to be dependent on coincident activation of the NMDAR and mGluR.
The clinical differentiation of bacterial and fungal keratitis: a photographic survey.

PURPOSE The purpose of this study was to determine whether clinical signs of infectious keratitis can be used to identify the causative organism. METHODS Eighty photographs of eyes with culture-proven bacterial keratitis or smear-proven fungal keratitis were randomly selected from 2 clinical trials. Fifteen cornea specialists from the F. I. Proctor Foundation and the Aravind Eye Care System assessed the photographs for prespecified clinical signs of keratitis, and they identified the most likely causative organism. RESULTS Clinicians were able to correctly distinguish bacterial from fungal etiology 66% of the time (P < 0.001). The Gram stain, genus, and species were accurately predicted 46%, 25%, and 10% of the time, respectively. The presence of an irregular/feathery border was associated with fungal keratitis, whereas a wreath infiltrate or an epithelial plaque was associated with bacterial keratitis. CONCLUSIONS Cornea specialists correctly differentiated bacterial from fungal keratitis more often than chance, but in fewer than 70% of cases. More specific categorization led to less successful clinical distinction. Although certain clinical signs of infectious keratitis may be associated with a bacterial or fungal etiology, this study highlights the importance of obtaining appropriate microbiological testing during the initial clinical encounter.
Confirmatory Factor Analysis of the End-User Computing Satisfaction Instrument: Replication within an ERP Domain

Over the past decade, organizations have made significant investments in enterprise resource planning (ERP) systems. The realization of benefits from these investments depends on supporting effective use of information technology (IT) and satisfying IT users. User satisfaction with information systems is one of the most important determinants of the success of those systems. Drawing upon a sample of 407 end users of ERP systems and working within the framework of confirmatory factor analysis (CFA), this study examines the structure and dimensionality, and reliability and validity of the end-user computing satisfaction (EUCS) instrument posited by Doll and Torkzadeh (1988). In response to Klenke's (1992) motion to cross-validate management information system (MIS) instruments and to retest the end user computing satisfaction instrument using new data, this study's results, consistent with previous findings, confirm that the EUCS instrument maintains its psychometric stability when applied to users of enterprise resource planning application software. Implications of these results for practice and research are provided.