Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial Protein UCP2 Controls Pancreas Development

The mitochondrial carrier uncoupling protein (UCP) 2 belongs to the family of the UCPs. Despite its name, it is now accepted that UCP2 is rather a metabolite transporter than a UCP. UCP2 can regulate oxidative stress and/or energetic metabolism. In rodents, UCP2 is involved in the control of α- and β-cell mass as well as insulin and glucagon secretion. Our aim was to determine whether the effects of UCP2 observed on β-cell mass have an embryonic origin. Thus, we used Ucp2 knockout mice. We found an increased size of the pancreas in Ucp2−/− fetuses at embryonic day 16.5, associated with a higher number of α- and β-cells. This phenotype was caused by an increase of PDX1+ progenitor cells. Perinatally, an increase in the proliferation of endocrine cells also participates in their expansion. Next, we analyzed the oxidative stress in the pancreata. We quantified an increased nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2) in the mutant, suggesting an increased production of reactive oxygen species (ROS). Phosphorylation of AKT, an ROS target, was also activated in the Ucp2−/− pancreata. Finally, administration of the antioxidant N-acetyl-l-cysteine to Ucp2−/− pregnant mice alleviated the effect of knocking out UCP2 on pancreas development. Together, these data demonstrate that UCP2 controls pancreas development through the ROS-AKT signaling pathway.
Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite “normal” glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF.
Skill Balance and Entrepreneurship Evidence from Online Career Histories

Lazear's jack–of–all–trades theory suggests that individuals with balanced skills are more likely to become entrepreneurs, and that balanced skills can be accumulated by studying a varied curriculum, working in a variety of functions, and working for a variety of employers. We reexamine the theory using a matched case–control sample, constructed from a professional networking website that controls for unobserved heterogeneity in employer and job characteristics. We find evidence that variety predicts entry into entrepreneurship, largely through its positive association with the likelihood of having certain specific skills. However, our analysis also demonstrates that attempts to identify the effects of skill variety on entrepreneurship are likely to be highly sensitive to sample construction and regression specification.
Treatment of Pancreatic Cancer Patient–Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors. Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin. Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTEN. Conclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639–47. ©2017 AACR.
SUMOylation determines the voltage required to activate cardiac IKs channels

Significance The slow delayed rectifier K+ current (IKs) determines the length of each human heartbeat because it activates after myocytes are excited and depolarize. This sensitivity to voltage, as well as dynamic regulation by hormones and second messengers, underlies the essential role of IKs in determining the duration and rhythm of cardiac action potentials. Here, we demonstrate the unexpected mechanism that establishes the voltage-dependent operation of IKs channels: SUMOylation. When native IKs channels are resident in the plasma membranes of neonatal mouse ventricular myocytes, or human channels are reconstituted in CHO cells, each of the four KCNQ1 pore-forming subunits is subject to monoSUMOylation in a manner that depends on KCNE1 accessory subunits, leading to stepwise depolarizing shifts in the activation voltage. IKs channels open in response to depolarization of the membrane voltage during the cardiac action potential, passing potassium ions outward to repolarize ventricular myocytes and end each beat. Here, we show that the voltage required to activate IKs channels depends on their covalent modification by small ubiquitin-like modifier (SUMO) proteins. IKs channels are comprised of four KCNQ1 pore-forming subunits, two KCNE1 accessory subunits, and up to four SUMOs, one on Lys424 of each KCNQ1 subunit. Each SUMO shifts the half-maximal activation voltage (V1/2) of IKs ∼ +8 mV, producing a maximal +34-mV shift in neonatal mouse cardiac myocytes or Chinese hamster ovary (CHO) cells expressing the mouse or human subunits. Unexpectedly, channels formed without KCNE1 carry at most two SUMOs despite having four available KCNQ1-Lys424 sites. SUMOylation of KCNQ1 is KCNE1 dependent and determines the native attributes of cardiac IKs in vivo.
Predictability in International Financial Markets

Cochrane and Piazzesi (2005) use forward rates to forecast future bond returns. We extend their approach by applying their model to international bond markets. Our results indicate that the unrestricted Cochrane and Piazzesi (2005) model has a reasonable forecasting power for future bond returns. The restricted model, however, does not perform as well on an international level. Our results do not confirm the systematic tent-shape of the estimated parameters found by Cochrane and Piazzesi (2005). The forecasting models are used to implement various trading strategies. These strategies exhibit high information ratios when implemented in individual countries or on an international level. We also introduce an alternative specification to forecast future bond returns. This alternative specification delivers superior risk-adjusted returns in our trading strategy.
Development and Validation of an Overreporting Scale for the Personality Inventory for DSM–5 (PID-5)

Our aim in the current study was to develop a validity scale for the Personality Inventory for DSM–5 (PID-5) to detect noncredible overreported responding. To this end, we used a rare symptoms approach and identified extreme response options on PID-5 items that were infrequently endorsed by students in 3 different university samples (N = 1,370) and in a psychiatric patient sample (N = 194). The resulting 10-item scale (the PID-5-ORS) produced adequate-to-good estimates of internal reliability and was significantly correlated with the Minnesota Multiphasic Personality Inventory-2 Restructued Form (MMPI-2-RF) overreporting validity scales, providing evidence of concurrent validity. The criterion validity of the PID-5-ORS was demonstrated in an analog simulation design study. More specifically, university students instructed to overreport (n = 80) scored substantially higher on the PID-5-ORS relative to both a group of genuine psychiatric patients and students instructed to complete the PID-5 under standard (honest) instructions (n = 161); the effect size magnitudes associated with these differences were large. Classification accuracy analyses further revealed that high scores on the PID-5-ORS were associated with high specificity (and thus, low rates of false positive classifications) in differentiating overreporters from genuine patients, with sensitivity being somewhat weaker.
Selective Oxidation of 1,2-Propanediol to Lactic Acid over Different Supported Au, Pt and Pd Catalysts

1,2-Propanediol selective oxidation with molecular oxygen in presence of heterogeneous catalyst is one of the most nature friendly 1,2-propanediol conversion methods. This work demonstrates Au, Pt and Pd containing catalysts’ activity and selectivity in a 1,2-propanediol oxidation process. The main product of the 1,2-propanediol catalytic oxidation was lactic acid, by-products were acetic and formic acids. It was found that Au based catalysts are best for 1,2-propanediol oxidation in alkaline water solutions. The best result was achieved using the 4.8wt%Au/Al2O3 catalyst: selectivity by lactic acid was 94% with 1,2-propanediol conversion 100% (c0(1,2-propanediol) = 0.3 mol/L, P(O2) = 6 atm, n (1,2-propanediol)/n (Au) = 500, t = 60°C, c0(NaOH) = 1.5 mol/L).
Longitudinal Analysis of the Associations between Antiretroviral Therapy, Viraemia and Immunosuppression with Lipid Levels: The D:A:D Study

Background Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. Methods Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. Results Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/ stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. Conclusions TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.
Complete mitochondrial genome sequence of Indian medium carp, Labeo gonius (Hamilton, 1822) and its comparison with other related carp species

Abstract In the present study, the complete mitochondrial genome sequence of Labeo gonius is reported using PGM sequencer (Ion Torrent). The complete mitogenome of L. gonius is obtained by the de novo sequences assembly of genomic reads using the Torrent Mapping Alignment Program (TMAP) which is 16 614 bp in length. The mitogenome of L. gonius comprised of 13 protein-coding genes, 22 tRNAs, 2 rRNA genes, and D-loop as control region along with gene order and organization, being similar to most of other fish mitogenomes of NCBI databases. The mitogenome in the present study has 99% similarity to the complete mitogenome sequence of Labeo fimbriatus, as reported earlier. The phylogenetic analysis of Cypriniformes depicted that their mitogenomes are closely related to each other. The complete mitogenome sequence of L. gonius would be helpful in understanding the population genetics, phylogenetics, and evolution of Indian Carps.
Using a Cloud Computing System to Reduce Door-to-Balloon Time in Acute ST-Elevation Myocardial Infarction Patients Transferred for Percutaneous Coronary Intervention

Background This study evaluated the impact on clinical outcomes using a cloud computing system to reduce percutaneous coronary intervention hospital door-to-balloon (DTB) time for ST segment elevation myocardial infarction (STEMI). Methods A total of 369 patients before and after implementation of the transfer protocol were enrolled. Of these patients, 262 were transferred through protocol while the other 107 patients were transferred through the traditional referral process. Results There were no significant differences in DTB time, pain to door of STEMI receiving center arrival time, and pain to balloon time between the two groups. Pain to electrocardiography time in patients with Killip I/II and catheterization laboratory to balloon time in patients with Killip III/IV were significantly reduced in transferred through protocol group compared to in traditional referral process group (both p < 0.05). There were also no remarkable differences in the complication rate and 30-day mortality between two groups. The multivariate analysis revealed that the independent predictors of 30-day mortality were elderly patients, advanced Killip score, and higher level of troponin-I. Conclusions This study showed that patients transferred through our present protocol could reduce pain to electrocardiography and catheterization laboratory to balloon time in Killip I/II and III/IV patients separately. However, this study showed that using a cloud computing system in our present protocol did not reduce DTB time.
The structure and function of Mycobacterium tuberculosis MazF-mt6 toxin provide insights into conserved features of MazF endonucleases

Toxin-antitoxin systems are ubiquitous in prokaryotic and archaeal genomes and regulate growth in response to stress. Escherichia coli contains at least 36 putative toxin-antitoxin gene pairs, and some pathogens such as Mycobacterium tuberculosis have over 90 toxin-antitoxin operons. E. coli MazF cleaves free mRNA after encountering stress, and nine M. tuberculosis MazF family members cleave mRNA, tRNA, or rRNA. Moreover, M. tuberculosis MazF-mt6 cleaves 23S rRNA Helix 70 to inhibit protein synthesis. The overall tertiary folds of these MazFs are predicted to be similar, and therefore, it is unclear how they recognize structurally distinct RNAs. Here we report the 2.7-Å X-ray crystal structure of MazF-mt6. MazF-mt6 adopts a PemK-like fold but lacks an elongated β1-β2 linker, a region that typically acts as a gate to direct RNA or antitoxin binding. In the absence of an elongated β1-β2 linker, MazF-mt6 is unable to transition between open and closed states, suggesting that the regulation of RNA or antitoxin selection may be distinct from other canonical MazFs. Additionally, a shortened β1-β2 linker allows for the formation of a deep, solvent-accessible, active-site pocket, which may allow recognition of specific, structured RNAs like Helix 70. Structure-based mutagenesis and bacterial growth assays demonstrate that MazF-mt6 residues Asp-10, Arg-13, and Thr-36 are critical for RNase activity and likely catalyze the proton-relay mechanism for RNA cleavage. These results provide further critical insights into how MazF secondary structural elements adapt to recognize diverse RNA substrates.
Prospective Evaluation of the Relationship Between Mechanical Stability and Response to Palliative Radiotherapy for Symptomatic Spinal Metastases.

BACKGROUND A substantial number of patients with spinal metastases experience no treatment effect from palliative radiotherapy. Mechanical spinal instability, due to metastatic disease, could be associated with failed pain control following radiotherapy. This study investigates the relationship between the degree of spinal instability, as defined by the Spinal Instability Neoplastic Score (SINS), and response to radiotherapy in patients with symptomatic spinal metastases in a multi-institutional cohort. METHODS AND MATERIALS The SINS of 155 patients with painful thoracic, lumbar, or lumbosacral metastases from two tertiary hospitals was calculated using images from radiotherapy planning CT scans. Patient-reported pain response, available for 124 patients, was prospectively assessed. Pain response was categorized, according to international guidelines, as complete, partial, indeterminate, or progression of pain. The association between SINS and pain response was estimated by multivariable logistic regression analysis, correcting for predetermined clinical variables. RESULTS Of the 124 patients, 16 patients experienced a complete response and 65 patients experienced a partial response. Spinal Instability Neoplastic Score was associated with a complete pain response (adjusted odds-radio [ORadj] 0.78; 95% confidence interval [CI] 0.62-0.98), but not with an overall pain response (ORadj 0.94; 95% CI 0.81-1.10). CONCLUSIONS A lower SINS, indicating spinal stability, is associated with a complete pain response to radiotherapy. This supports the hypothesis that pain resulting from mechanical spinal instability responds less well to radiotherapy compared with pain from local tumor activity. No association could be determined between SINS and an overall pain response, which might indicate that this referral tool is not yet optimal for prediction of treatment outcome. IMPLICATIONS FOR PRACTICE Patients with stable painful spinal metastases, as indicated by a Spinal Instability Neoplastic Score (SINS) of 6 or lower, can effectively be treated with palliative external beam radiotherapy. The majority of patients with (impending) spinal instability, as indicated by a SINS score of 7 or higher, will achieve a (partial) response after palliative radiotherapy; however, some patients might require surgical intervention. Therefore, it is recommended to refer patients with a SINS score of 7 or higher to a spine surgeon to evaluate the need for surgical intervention.
Harmonic Brain Modes: A Unifying Framework for Linking Space and Time in Brain Dynamics

A fundamental characteristic of spontaneous brain activity is coherent oscillations covering a wide range of frequencies. Interestingly, these temporal oscillations are highly correlated among spatially distributed cortical areas forming structured correlation patterns known as the resting state networks, although the brain is never truly at “rest. ” Here, we introduce the concept of harmonic brain modes—fundamental building blocks of complex spatiotemporal patterns of neural activity. We define these elementary harmonic brain modes as harmonic modes of structural connectivity; that is, connectome harmonics, yielding fully synchronous neural activity patterns with different frequency oscillations emerging on and constrained by the particular structure of the brain. Hence, this particular definition implicitly links the hitherto poorly understood dimensions of space and time in brain dynamics and its underlying anatomy. Further we show how harmonic brain modes can explain the relationship between neurophysiological, temporal, and network-level changes in the brain across different mental states (wakefulness, sleep, anesthesia, psychedelic). Notably, when decoded as activation of connectome harmonics, spatial and temporal characteristics of neural activity naturally emerge from the interplay between excitation and inhibition and this critical relation fits the spatial, temporal, and neurophysiological changes associated with different mental states. Thus, the introduced framework of harmonic brain modes not only establishes a relation between the spatial structure of correlation patterns and temporal oscillations (linking space and time in brain dynamics), but also enables a new dimension of tools for understanding fundamental principles underlying brain dynamics in different states of consciousness.
Prefetch-Based Energy Optimization on Smartphones

Cellular network enables pervasive data access, but it also increases the power consumption of smartphones due to the long tail problem, where the cellular interface has to stay in the high-power state for some time after each data transmission. To reduce the tail energy, data that will be used in the future can be prefetched. However, prefetching unnecessary data may waste energy, and this problem becomes worse when the network quality is poor. In this paper, we generalize and formulate the prefetch-based energy optimization problem, where the goal is to find a prefetching schedule that minimizes the energy consumption of the data transmissions under the current network condition. To solve this nonlinear optimization problem, we first propose a greedy algorithm, and then propose a discrete algorithm with better performance. We have implemented and evaluated the proposed algorithms in two apps: in-app advertising and mobile video streaming. Evaluation results show that the proposed algorithms can significantly reduce the energy consumption.