Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of Stimulation of AMP-activated Protein Kinase on Insulin-like Growth Factor 1- and Epidermal Growth Factor-dependent Extracellular Signal-regulated Kinase Pathway*

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis. Previously, AMPK was reported to phosphorylate serine 621 of Raf-1 in vitro. In the present study, we investigated a possible role of AMPK in extracellular signal-regulated kinase (Erk) cascades, using 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a cell-permeable activator of AMPK and antisense RNA experiments. Activation of AMPK by AICAR in NIH-3T3 cells resulted in drastic inhibitions of Ras, Raf-1, and Erk activation induced by insulin-like growth factor 1 (IGF-1). Expression of an antisense RNA for the AMPK catalytic subunit decreased the AMPK activity and significantly diminished the AICAR effect on IGF-1-induced Ras activation and the subsequent Erk activation, indicating that its effect is indeed mediated by AMPK. Phosphorylation of Raf-1 serine 621, however, was not involved in AMPK-mediated inhibition of Erk cascades. In contrast to IGF-1, AICAR did not block epidermal growth factor (EGF)-dependent Raf-1 and Erk activation, but our results demonstrated that multiple Raf-1 upstream pathways induced by EGF were differentially affected by AICAR: inhibition of Ras activation and simultaneous induction of Ras-independent Raf activation. The activities of IGF-1 and EGF receptor were not affected by AICAR. Taken together, our results suggest that AMPK differentially regulate Erk cascades by inhibiting Ras activation or stimulating the Ras-independent pathway in response to the varying energy status of the cell.
Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration‐resistant prostate cancer

ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggest that ERG IHC may be less sensitive for ERG rearrangements in castration‐resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC).
A validated ultra high-pressure liquid chromatography method for separation of candesartan cilexetil impurities and its degradents in drug product

Introduction: A selective, specific, and sensitive “Ultra High-Pressure Liquid Chromatography” (UPLC) method was developed for determination of candesartan cilexetil impurities as well asits degradent in tablet formulation. Materials and Methods: The chromatographic separation was performed on Waters Acquity UPLC system and BEH Shield RP18 column using gradient elution of mobile phase A and B. 0.01 M phosphate buffer adjusted pH 3.0 with Orthophosphoric acid was used as mobile phase A and 95% acetonitrile with 5% Milli Q Water was used as mobile phase B. Ultraviolet (UV) detection was performed at 254 nm and 210 nm, where (CDS-6), (CDS-5), (CDS-7), (Ethyl Candesartan), (Desethyl CCX), (N-Ethyl), (CCX-1), (1 N Ethyl Oxo CCX), (2 N Ethyl Oxo CCX), (2 N Ethyl) and any unknown impurity were monitored at 254 nm wavelength, and two process-related impurities, trityl alcohol and MTE impurity, were estimated at 210 nm. Candesartan cilexetil andimpurities were chromatographed with a total run time of 20 min. Results: Calibration showed that the response of impurity was a linear function of concentration over the range limit of quantification to 2 μg/mL (r2≥0.999) and the method was validated over this range for precision, intermediate precision, accuracy, linearity, and specificity. For the precision study, percentage relative standard deviation of each impurity was <15% (n=6). Conclusion: The method was found to be precise, accurate, linear, and specific. The proposed method was successfully employed for estimation of candesartan cilexetil impurities in pharmaceutical preparations.
Optimal low switching frequency pulse width modulation of current-fed five-level inverter for solar integration

Current fed multilevel converters have several advantages in terms of high power capability, transformer less operation, short circuit protection and excellent quality of waveforms. For high power applications, these converters are required to be operated under low device switching frequency to necessitate thermal constraints of the semiconductor devices. However, the converter output currents under low device switching frequency results in higher total harmonic (THD) distortion. Synchronous optimal pulse-width modulation (SOP) technique is an emerging low device frequency modulation technique which has been successfully implemented for voltage source multilevel inverters without compromising on total harmonic distortion. This paper proposes and implements a modified SOP technique for five level current source inverter topology. The experimental results obtained from a low power prototype demonstrated its effectiveness.
Building native protein conformation from NMR backbone chemical shifts using Monte Carlo fragment assembly

We have been analyzing the extent to which protein secondary structure determines protein tertiary structure in simple protein folds. An earlier paper demonstrated that three‐dimensional structure can be obtained successfully using only highly approximate backbone torsion angles for every residue. Here, the initial information is further diluted by introducing a realistic degree of experimental uncertainty into this process. In particular, we tackle the practical problem of determining three‐dimensional structure solely from backbone chemical shifts, which can be measured directly by NMR and are known to be correlated with a protein's backbone torsion angles. Extending our previous algorithm to incorporate these experimentally determined data, clusters of structures compatible with the experimentally determined chemical shifts were generated by fragment assembly Monte Carlo. The cluster that corresponds to the native conformation was then identified based on four energy terms: steric clash, solvent‐squeezing, hydrogen‐bonding, and hydrophobic contact. Currently, the method has been applied successfully to five small proteins with simple topology. Although still under development, this approach offers promise for high‐throughput NMR structure determination.
Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury.

BACKGROUND Nitric oxide (NO) seems to play an important role during renal ischemia/reperfusion (I/R) injury. We investigated whether rutin inhibits inducible nitric oxide synthase (iNOS) and reduces 3-nitrotyrosine (3-NT) formation in the kidneys of rats during I/R. METHODS Wistar albino rats were nephrectomized unilaterally and, 2 weeks later, subjected to 45 minutes of left renal pedicle occlusion followed by 3 hours of reperfusion. We intraperitoneally administered L-N6-(1-iminoethyl)lysine (L-NIL; 3 mg/kg) for 30 minutes or rutin (1 g/kg) for 60 minutes before I/R. After reperfusion, kidney samples were taken for immunohistochemical analysis of iNOS and 3-NT. We measured plasma nitrite/nitrate and cyclic guanosine monophosphate (cGMP) to evaluate NO levels. RESULTS Ischemia/reperfusion caused plasma cGMP to increase significantly. Similarly, plasma nitrite/nitrate was elevated in the I/R group compared with the control group. Histochemical staining was positive for iNOS and 3-NT in the I/R group. Pretreatment with L-NIL or rutin significantly mitigated the elevation of plasma cGMP and nitrite/nitrate. These changes in biochemical parameters were also associated with changes in immunohistochemical appearance. Pretreatment with L-NIL or rutin significantly decreased the incidence and severity of iNOS and 3-NT formation in the kidney tissues. CONCLUSION Our findings suggest that high activity of iNOS causes renal I/R injury, and that rutin exerts protective effects, probably by inhibiting iNOS.
Humoral Immune Response to Flagellin Requires T Cells and Activation of Innate Immunity1

Bacterial flagellin, the primary structural component of flagella, is a dominant target of humoral immunity upon infection by enteric pathogens and in Crohn’s disease. To better understand how such responses may be regulated, we sought to define, in mice, basic mechanisms that regulate generation of flagellin-specific Igs. We observed that, in response to i.p. injection with flagellin, generation of flagellin-specific Ig required activation of innate immunity in that these responses were ablated in MyD88-deficient mice and that flagellin from Helicobacter pylori, which is known not to activate TLR5, also did not elicit Abs. Mice lacking αβ T cells (TCRβnull) were completely deficient in their ability to make flagellin Abs in various contexts indicating that, in contrast to common belief, generation of flagellin-specific Ig is absolutely T cell dependent. In contrast to Ab responses to whole flagella (H serotyping), responses to flagellin monomers displayed only moderate serospecificity. Whereas neither oral nor rectal administration of flagellin elicited a strong serum Ab response, induction of colitis with dextran sodium sulfate resulted in a MyD88-dependent serum Ab response to endogenous flagellin, suggesting that, in an inflammatory milieu, TLR signaling promotes acquisition of Abs to intestinal flagellin. Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine.
Machine learning algorithms for the prediction of hERG and CYP450 binding in drug development

Importance of the field: The cost of developing new drugs is estimated at ∼ $1 billion; the withdrawal of a marketed compound due to toxicity can result in serious financial loss for a pharmaceutical company. There has been a greater interest in the development of in silico tools that can identify compounds with metabolic liabilities before they are brought to market. Areas covered in this review: The two largest classes of machine learning (ML) models, which will be discussed in this review, have been developed to predict binding to the human ether-a-go-go related gene (hERG) ion channel protein and the various CYP isoforms. Being able to identify potentially toxic compounds before they are made would greatly reduce the number of compound failures and the costs associated with drug development. What the reader will gain: This review summarizes the state of modeling hERG and CYP binding towards this goal since 2003 using ML algorithms. Take home message: A wide variety of ML algorithms that are comparable in their overall performance are available. These ML methods may be applied regularly in discovery projects to flag compounds with potential metabolic liabilities.
Readmission after hospitalization for congestive heart failure among Medicare beneficiaries.

BACKGROUND Congestive heart failure is the most common discharge diagnosis for Medicare beneficiaries. While several single-center studies have suggested that these patients are particularly vulnerable to readmission, no recent study, to our knowledge, has reported the readmission rates for a large number of elderly patients with congestive heart failure across a diverse spectrum of hospitals. OBJECTIVES To define the readmission rate for elderly patients discharged after an episode of congestive heart failure. To determine the spectrum of diagnoses that are responsible for readmissions among patients with congestive heart failure. To identify patient and hospital characteristics associated with a higher likelihood of readmission. METHODS This observational study, using Medicare administrative files, evaluated readmission and death among all survivors of a hospitalization in Connecticut for congestive heart failure from fiscal year 1991 through fiscal year 1994. RESULTS There were 17448 survivors of a hospitalization for congestive heart failure during the study period. In the 6 months following the index admission, 7596 patients (44%) were readmitted to a hospital at least once. Congestive heart failure was the most frequent reason for readmission among study patients, accounting for 18% of all readmissions. In the multivariable analysis, significant predictors of readmission included male sex (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.05-1.20), at least 1 prior admission within 6 months of the index admission (OR, 1.64; 95% CI, 1.53-1.77), Deyo comorbidity score of more than 1 (OR, 1.56; 95% CI, 1.45-1.68), and length of stay in the index hospitalization of more than 7 days (OR, 1.32; 95% CI, 1.24-1.41). While age was not a significant predictor of readmission, it became significant in a model with the combined outcome of readmission or death as the dependent variable. CONCLUSION Readmission after a hospitalization for congestive heart failure is common among Medicare beneficiaries, with almost half of the patients readmitted within 6 months. This striking rate of readmission in a common diagnosis demands efforts to further clarify the determinants of readmission and develop strategies to prevent this adverse outcome.
No association between cigarette smoking and incidence of plasma cell myeloma: A meta‐analysis of 17 observational studies

Plasma cell myeloma (PCM) is a lymphoproliferative disorder characterized by the malignant growth of monoclonal plasma cells within the bone marrow. Although risk factors for the development of PCM have been identified, the etiology on the majority of patients with PCM remains unclear. Cigarette smoking has been postulated as a potential risk factor for lymphoid malignancies; however, the association with PCM is inconclusive. We have carried out a meta-analysis of observational studies to assess the relationship, if any, between cigarette smoking and PCM. A literature search through December 2011 rendered 4 prospective cohort and 13 case–control studies evaluating such association. Our categorical meta-analysis showed that there is no association between ever, current, and former smokers and PCM.This lack of association was maintained when analyzing by study design, study quality, and geographical area of report. Similarly, meta regression analysis showed no association with the number of cigarettes smoked per day. In conclusion, our meta-analysis shows that there is no relationship between cigarette smoking and an increased incidence of PCM. Future studies should focus on other potential risk factors for PCM.
PYPAF3, a PYRIN-containing APAF-1-like Protein, Is a Feedback Regulator of Caspase-1-dependent Interleukin-1β Secretion*

PYPAF3 is a member of the PYRIN-containing apoptotic protease-activating factor-1-like proteins (PYPAFs, also called NALPs). Among the members of this family, PYPAF1, PYPAF5, PYPAF7, and NALP1 have been shown to induce caspase-1-dependent interleukin-1β secretion and NF-κB activation in the presence of the adaptor molecule ASC. On the other hand, we recently discovered that PYNOD, another member of this family, is a suppressor of these responses. Here, we show that PYPAF3 is the second member that inhibits caspase-1-dependent interleukin-1β secretion. In contrast, PYPAF2/NALP2 does not inhibit this response but rather inhibits the NF-κB activation that is induced by the combined expression of PYPAF1 and ASC. Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain. They are also expressed in many cell lines of both hematopoietic and non-hematopoietic lineages. Stimulation of monocytic THP-1 cells with lipopolysaccharide or interleukin-1β induced PYPAF3 mRNA expression. Furthermore, the stable expression of PYPAF3 in THP-1 cells abrogated the ability of the cells to produce interleukin-1β in response to lipopolysaccharide. These results suggest that PYPAF3 is a feedback regulator of interleukin-1β secretion. Thus, PYPAF2 and PYPAF3, together with PYNOD, constitute an anti-inflammatory subgroup of PYPAFs.
Throughput analysis of channel surfing in jammed single-hop wireless networks

We develop a theoretical approach to derive system throughput for single-hop wireless networks where U users share a spectrum set θU of n independent channels, and J jammers attack the system by selecting channels from a spectrum set θJ of N independent channels while θU ⊆θJ. Users and jammers follow the given policies to randomly select channels at each time slot. The whole system can be modeled as a Markov chain. The key point is to derive the transition probability matrix and obtain the stationary distribution. Then, the theoretical system throughput can be computed straightforwardly. Another interesting problem is to study the system failure probability for the scenario where each user pair has multiple links. The network model is modified as: m user pairs share a spectrum set θU and each user pair has c links. System failure happens when at least one user pair fails all of its links. A two-step approach is developed to compute the system failure probability for the modified model. Numerical experiments are used to validate theoretical results.
Social vulnerability and prefrontal cortical function in elderly people: a report from the Canadian Study of Health and Aging

ABSTRACT Background: Prefrontal cortical lobe function is related to social behavior in humans. We investigated whether performance on tests of prefrontal cortical function was associated with social vulnerability. Associations with non-frontal cognitive function were investigated for comparison. Methods: 1216 participants aged 70+ of the Canadian Study of Health and Aging-2 screening examination, who also underwent detailed neuropsychological testing, comprised the study sample. Performance on WAIS-R abstraction, WAIS-R comprehension, Trails B, FAS and category verbal fluency, Block construction, Token Test and Wechsler Memory Scale Information Subset was tested in relation to the participant's level of social vulnerability using regression models adjusted for age, education, sex, frailty, MMSE score, diagnosis of depression, and use of psychoactive medications. Social vulnerability was measured by an index comprising many social problems or “deficits”. Results: The most socially vulnerable group had worse performance on FAS verbal fluency, generating 4.1 fewer words (95% CI: 1.8–6.4, p<0.001) than those in the least socially vulnerable group; those with intermediate social vulnerability generated 2.6 fewer words (95% CI: 0.4–4.8, p = 0.02). Social vulnerability was also associated, though less strongly, with category verbal fluency. The most socially vulnerable people had impaired performance on the Trails B, taking 37 seconds longer (95% CI: 11–63, p = 0.005). These results were independent of age, education, sex, frailty, MMSE score, depression, and psychoactive medications. Social vulnerability was not associated with performance on WAIS-R abstraction, WAIS-R comprehension, Block Design, Token Test or Wechsler Memory Scale tests Conclusions: High social vulnerability was associated with impaired performance on verbal fluency and set shifting but not with common sense judgment, abstraction, long-term memory, constructional ability, or language comprehension. The association between social functioning and the cognitive functions subserved by prefrontal cortex warrants further study.
Phase Resetting in Duper Hamsters

The duper mutation in Syrian hamsters shortens the free-running period of locomotor activity (τDD) to about 23 h and results in a type 0 phase-response curve (PRC) to 15-min light pulses. To determine whether exaggerated phase shifts are specific to photic cues and/or restricted to subjective night, we subjected hamsters to novel wheel confinements and dark pulses during subjective day. Small phase shifts elicited by the nonphotic cue were comparable in mutant and wild-type (WT) hamsters, but dark pulses triggered larger shifts in dupers. To assess further the effects of the duper mutation on light-dark transitions, we transferred hamsters between constant light (LL) and constant dark (DD) or between DD and LL at various circadian phases. Duper hamsters displayed significantly larger phase shifts than WT hamsters when transferred from LL to DD during subjective day and from DD to LL during subjective night. The variability of phase shifts in response to all light/dark transitions was significantly greater in duper hamsters at all time points. In addition, most duper hamsters, but none of the WTs, displayed transient ultradian wheel-running patterns for 5 to 12 days when transferred from light to dark at CT 18. The χ2 periodogram and autocorrelation analyses indicate that these ultradian patterns differ from the disruption of rhythmicity by SCN lesions or exposure to constant bright light. We conclude that the duper mutation specifically amplifies phase shifts to photic cues and may destabilize coupling of circadian organization upon photic challenge due to weakened coupling among components of the circadian pacemaker. Mathematical modeling of the circadian pacemaker supports this hypothesis.
The influence of squat depth on maximal vertical jump performance

Abstract An increase in the period over which a muscle generates force can lead to the generation of greater force and, therefore, for example in jumping, to greater jump height. The aim of this study was to examine the effect of squat depth on maximum vertical jump performance. We hypothesized that jump height would increase with increasing depth of squat due to the greater time available for the generation of muscular force. Ten participants performed jumps from preferred and deep squat positions. A computer model simulated jumps from the different starting postures. The participants showed no difference in jump height in jumps from deep and preferred positions. Simulated jumps produced similar kinematics to the participants' jumps. The optimal squat depth for the simulated jumps was the lowest position the model was able to jump from. Because jumping from a deep squat is rarely practised, it is unlikely that these jumps were optimally coordinated by the participants. Differences in experimental vertical ground reaction force patterns also suggest that jumps from a deep squat are not optimally coordinated. These results suggest there is the potential for athletes to increase jump performance by exploiting a greater range of motion.
Normalized Energy Density-Based Forensic Detection of Resampled Images

We propose a new method to detect resampled imagery. The method is based on examining the normalized energy density present within windows of varying size in the second derivative of the image in the frequency domain, and exploiting this characteristic to derive a 19-D feature vector that is used to train a SVM classifier. Experimental results are reported on 7500 raw images from the BOSS database. Comparison with prior work reveals that the proposed algorithm performs similarly for resampling rates greater than 1, and is superior to prior work for resampling rates less than 1. Experiments are performed for both bilinear and bicubic interpolations, and qualitatively similar results are observed for each. Results are also provided for the detection of resampled imagery with noise corruption and JPEG compression. As expected, some degradation in performance is observed as the noise increases or the JPEG quality factor declines.