Miracle-dz/UniFAR-FTUs huggingface dataset:
Monotropein promotes angiogenesis and inhibits oxidative stress‐induced autophagy in endothelial progenitor cells to accelerate wound healing

Attenuating oxidative stress‐induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress‐induced mitochondrial dysfunction and stimulate bone marrow‐derived EPC (BM‐EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM‐EPCs and prevented tert‐butyl hydroperoxide (TBHP)‐induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM‐EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury‐related wounds.
Financial Incentives Differentially Regulate Neural Processing of Positive and Negative Emotions during Value-Based Decision-Making

Emotional and economic incentives often conflict in decision environments. To make economically desirable decisions then, deliberative neural processes must be engaged to regulate automatic emotional reactions. In this functional magnetic resonance imaging (fMRI) study, we evaluated how fixed wage (FW) incentives and performance-based (PB) financial incentives, in which pay is proportional to outcome, differentially regulate positive and negative emotional reactions to hypothetical colleagues that conflicted with the economics of available alternatives. Neural activity from FW to PB incentive contexts decreased for positive emotional stimuli but increased for negative stimuli in middle temporal, insula, and medial prefrontal regions. In addition, PB incentives further induced greater responses to negative than positive emotional decisions in the frontal and anterior cingulate regions involved in emotion regulation. Greater response to positive than negative emotional features in these regions also correlated with lower frequencies of economically desirable choices. Our findings suggest that whereas positive emotion regulation involves a reduction of responses in valence representation regions, negative emotion regulation additionally engages brain regions for deliberative processing and signaling of incongruous events.
Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support

Objective Skin-to-skin care (SSC) has proven benefits in preterm infants, but increased hypoxic and bradycardic events have been reported. This may make clinicians hesitant to recommend SSC as standard care. We hypothesised that regional cerebral oxygenation (rStO2) measured with near infrared spectroscopy is not worse during SSC compared with standard incubator care. Design Prospective, observational, non-inferiority study. Setting Single tertiary perinatal centre in Australia. Patients Forty preterm infants (median (IQR) 30.6 (29.1–31.7) weeks' gestation) not receiving respiratory support were studied on day 14 (8–38). Interventions Recordings during 90 min of incubator care, followed by 90 min of SSC. Each infant acted as their own control and caregivers were blinded to the rStO2 measurements. Main outcome measures The primary outcome was the mean difference in rStO2 between SSC and incubator care. The prespecified margin of non-inferiority was −1.5%. Secondary outcomes included heart rate (HR), peripheral oxygen saturation (SpO2), time in quiet sleep, temperature and hypoxic (SpO2 <80% for >5 s) or bradycardic events (HR <80 bpm for >5 s) and time spent in cerebral hypoxia (rStO2<55%) and hyperoxia (rStO2>85%). Results Mean (SD) rStO2 was lower during SSC compared with incubator care: 73.6 (6.0)% vs 74.8 (4.6)%, mean difference (95% CI) 1.3 (2.2 to 0.4)%. HR was 5 bpm higher, SpO2 1% lower and time in quiet sleep 24% longer during SSC. Little evidence of a difference was observed in temperature. The number of hypoxic or bradycardic events as well as the proportion of time spent in cerebral hypoxia and hyperoxia was very low in both periods. Conclusions Mean rStO2 was marginally lower during SSC without observed differences in hypoxic or bardycardic events but an increase in time spent in quiet sleep. Trial registration number This trial is linked to Australian New Zealand Clinical Trials Registry: identifier 12616000240448. It was registered pre-results.
Stronger generalization bounds for deep nets via a compression approach

Deep nets generalize well despite having more parameters than the number of training samples. Recent works try to give an explanation using PAC-Bayes and Margin-based analyses, but do not as yet result in sample complexity bounds better than naive parameter counting. The current paper shows generalization bounds that're orders of magnitude better in practice. These rely upon new succinct reparametrizations of the trained net --- a compression that is explicit and efficient. These yield generalization bounds via a simple compression-based framework introduced here. Our results also provide some theoretical justification for widespread empirical success in compressing deep nets. Analysis of correctness of our compression relies upon some newly identified \textquotedblleft noise stability\textquotedblright properties of trained deep nets, which are also experimentally verified. The study of these properties and resulting generalization bounds are also extended to convolutional nets, which had eluded earlier attempts on proving generalization.
Apigenin inhibits cell proliferation, migration, and invasion by targeting Akt in the A549 human lung cancer cell line

Apigenin (APG), a widely distributed flavonoid in vegetables and fruits, with low toxicity, and a nonmutagenic characteristic, has been reported to have many targets. Evidence indicates that APG can inhibit the proliferation, migration, invasion, and metastasis of some tumor cells, but the mechanism, specifically in lung cancer, is unclear. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway regulates a diverse set of cellular functions relevant to the growth and progression of lung cancer, including proliferation, survival, migration, and invasion. Our results showed that APG exerted anti-proliferation, anti-migration, and anti-invasion effects in A549 human lung cancer cells by targeting the PI3K/Akt signaling pathway. 3-(4, 5-dimethylthiszol-2-yl)-2, 5-diphenytetrazolium bromide assay and colony formation assay showed that APG suppressed cell proliferation in a dose-dependent and time-dependent manner. Cell motility and invasiveness were assayed using a wound healing and Transwell assay, suggesting that APG inhibited the migration and invasion of A549 cells. Western blot analyses were carried out to examine the Akt signaling pathways. The results confirmed that APG decreased Akt expression and its activation. Then, cells were transfected with Akt-active and Akt-DN plasmids separately. The migration and invasion of A549 cells were significantly changed, constitutively activating Akt or knocking down Akt, indicating that APG can suppress the migration and invasion of lung cancer cells by modulating the PI3K/Akt signaling pathway. Furthermore, the results indicated that APG not only suppressed phosphorylation of Akt, thereby preventing its activation, but also inhibited its downstream gene expression of matrix metalloproteinases-9, glycogen synthase kinase-3&bgr;, and HEF1. Together, APG is a new inhibitor of Akt in lung cancer and a potential natural compound for cancer chemoprevention.
Association of cancer-related mortality, age and gonadectomy in golden retriever dogs at a veterinary academic center (1989-2016)

Golden retriever dogs have been reported to have an increased prevalence of cancer compared to other breeds. There is also controversy over the effect spay or neuter status might have on longevity and the risk for developing cancer. The electronic medical records system at an academic center was searched for all dogs who had a necropsy exam from 1989–2016. 9,677 canine necropsy examinations were completed of which 655 were golden retrievers. Age was known for 652 with a median age of death 9.15 years. 424 of the 652 (65.0%) were determined to have died because of cancer. The median age for dying of a cause other than cancer was 6.93 years while those dying of cancer had a median age of 9.83 years (p<0.0001). There was no significant difference in the proportion of intact males and castrated males dying of cancer (p = 0.43) but a greater proportion of spayed females died of cancer compared to intact females (p = 0.001). Intact female dogs had shorter life spans than spayed female dogs (p<0.0001), but there were no differences between intact and castrated males. Intriguingly, being spayed or neutered did not affect the risk of a cancer related death but increasing age did. The most common histologic diagnosis found in golden retrievers dying of cancer was hemangiosarcoma (22.64%) followed by lymphoid neoplasia (18.40%). Overall golden retriever dogs have a substantial risk of cancer related mortality in a referral population and age appears to have a larger effect on cancer related mortality than reproductive status.
Efficient bioconversion of oleuropein from olive leaf extract to antioxidant hydroxytyrosol by enzymatic hydrolysis and high‐temperature degradation

Hydroxytyrosol (HT), a powerful antioxidant, clears free radicals and exhibits many biological activities. Because contents of HT are low in natural sources, bioconversion of oleuropein (OLE) to HT is of increasing interest. A biotechnological process was investigated to produce HT from OLE presented in olive leaf extract. Enzymatic hydrolysis using two cellulases with high β‐glucosidase activity, Novozymes CTec2 and commercial cellulase KDN (Qingdao, People's Republic of China) was carried out at 50 °C for 12 H followed by raising the temperature to 90 °C for chemical hydrolysis. After 48 H of hydrolysis, an OLE degradation rate of 100% and a HT yield of 86–88% were achieved. These cellulases degrade OLE and release a glucose molecule. Chemical hydrolysis at a high temperature promotes the cleavage of ester bond and the formation of HT. This process has a promising alternative for production of HT comparing with acid hydrolysis which not only causes significant pollution to the environment but also makes difficult to the subsequent separation.
Differential microRNA expression profiles in tamoxifen-resistant human breast cancer cell lines induced by two methods

Tamoxifen (TAM) resistance has become a severe problem for endocrine therapy of breast cancer. The present study investigated the association between microRNA (miRNA) expression and TAM resistance in breast cancer. The TAM-resistant breast cancer MCF-7C and MCF-7T cell lines were established using the human breast cancer cell line MCF-7 as the parental cell line and 4-hydroxytamoxifen (OHT) as the screening drug in vitro. The MCF-7C cell line was established by dose stepwise induction beginning with a low concentration of OHT; the MCF-7T cell line was established by temporal stepwise induction beginning with a high concentration of OHT. Differential miRNA expression profiles between TAM-sensitive (MCF-7) and TAM-resistant (MCF-7C and MCF-7T) breast cancer cell lines were detected and analyzed using RNA sequencing technology. The results of western blot analysis indicated that the level of ERα protein expression in drug-resistant cells was significantly increased. A total of 1,646 miRNAs were detected in all samples, including 1,376 known miRNAs and 270 predicted miRNAs. There were 118 miRNAs expressed at significantly different levels between MCF-7C and MCF-7 cells (P<0.05); among them, 67 miRNAs were upregulated (P<0.05) and 51 miRNA were downregulated (P<0.05). There were 42 miRNAs expressed at significantly different levels between MCF-7T and MCF-7 (P<0.05); among them, 23 miRNAs were upregulated (P<0.05) and 19 miRNAs were downregulated (P<0.05). There were 126 miRNAs with significant differences between MCF-7C and MCF-7T (P<0.05); among them, 76 miRNAs were upregulated (P<0.05) and 50 miRNAs were downregulated. On the basis of the results of the present study, we hypothesize that miR-21, miR-146a, miR-148a, miR-34a and miR-27a may serve important roles in mediating TAM resistance in breast cancer, and have potential as therapeutic targets for TAM-resistant breast cancer.
Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses

Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF–prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.
Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study

Abstract Aims An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM. Methods and results In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died. Conclusion Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group. Clinical trial registration ClinicalTrials.gov, study number: NCT00998556.
Microbial dynamics during harmful dinoflagellate Ostreopsis cf. ovata growth: Bacterial succession and viral abundance pattern

Algal–bacterial interactions play a major role in shaping diversity of algal associated bacterial communities. Temporal variation in bacterial phylogenetic composition reflects changes of these complex interactions which occur during the algal growth cycle as well as throughout the lifetime of algal blooms. Viruses are also known to cause shifts in bacterial community diversity which could affect algal bloom phases. This study investigated on changes of bacterial and viral abundances, bacterial physiological status, and on bacterial successional pattern associated with the harmful benthic dinoflagellate Ostreopsis cf. ovata in batch cultures over the algal growth cycle. Bacterial community phylogenetic structure was assessed by 16S rRNA gene ION torrent sequencing. A comparison between bacterial community retrieved in cultures and that one co‐occurring in situ during the development of the O. cf. ovata bloom from where the algal strain was isolated was also reported. Bacterial community growth was characterized by a biphasic pattern with the highest contributions (~60%) of highly active bacteria found at the two bacterial exponential growth steps. An alphaproteobacterial consortium composed by the Rhodobacteraceae Dinoroseobacter (22.2%–35.4%) and Roseovarius (5.7%–18.3%), together with Oceanicaulis (14.2‐40.3%), was strongly associated with O. cf. ovata over the algal growth. The Rhodobacteraceae members encompassed phylotypes with an assessed mutualistic‐pathogenic bimodal behavior. Fabibacter (0.7%–25.2%), Labrenzia (5.6%–24.3%), and Dietzia (0.04%–1.7%) were relevant at the stationary phase. Overall, the successional pattern and the metabolic and functional traits of the bacterial community retrieved in culture mirror those ones underpinning O. cf. ovata bloom dynamics in field. Viral abundances increased synoptically with bacterial abundances during the first bacterial exponential growth step while being stationary during the second step. Microbial trends also suggest that viruses induced some shifts in bacterial community composition.
Resynchronization Therapy for the Treatment of Heart Failure

Heart failure remains a major cardiovascular health problem, afflicting 22 million individuals worldwide and approximately 5 million persons in the United States alone. Management of patients with this problem represents the largest single expense to Medicare. A common feature predictive of adverse clinical outcomes in patients with congestive heart failure is prolongation of the QRS duration. Several different types of studies suggested QRS delay was an independent risk factor for adverse outcome, particularly in patients with left ventricular dysfunction.1,2 These data were derived from both longitudinal population studies and retrospective studies performed in heart failure patients with pacemakers and “acquired” left bundle branch block (LBBB). 1,2 The significance of QRS delay in heart failure patients is that this common finding may be observed in up to 30% of patients with moderate to severe heart failure. Acute studies performed with hemodynamic measurements and nuclear imaging phase analysis demonstrate that QRS delay, particularly LBBB, creates electrical and mechanical dyssynchrony in patients with depressed left ventricular function. Delayed and inhomogeneous left ventricular activation reduces stroke volume, left ventricular ejection fraction, and time for aortic ejection. Reductions in left ventricular dP/dT, increased left ventricular end-systolic and diastolic volumes, and abnormal patterns of wall stretch are also seen.3–5 Additionally, ventricular dyssynchrony promotes functional mitral regurgitation. Acutely pacing the right and left ventricle simultaneously or pacing the left ventricle alone results in marked improvements and restoration of a more homogeneous contraction pattern (Figure 1 and Figure 2⇓). Figure 1. The upper panels represent phase images obtained during normal sinus rhythm with LBBB and during atrial sensed CRT. The contraction sequence is indicated by the color bar from early (green) to late (yellow). The histograms below each image illustrate the dispersion of the phase angle O, computed for the RV and LV blood pools. …
Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Cystic fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution electron microscopy (EM) structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another, and both correspond to the inward-facing, nucleotide binding domains (NBDs) separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel. Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to an NBD associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet is one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data. Moreover, despite different starting points, the final models share many common features. Finally, we propose that the combination of high resolution cryo-EM maps, which are currently emerging from multiple laboratories, and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators.