Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessment of Neurotrophins and Inflammatory Mediators in Vitreous of Patients With Diabetic Retinopathy

Purpose To assess vitreous levels of inflammatory cytokines and neurotrophins (NTs) in diabetic retinopathy (DR) and elucidate their potential roles. Methods A prospective study was performed on 50 vitreous samples obtained from patients with DR (n = 22) and the nondiabetic controls (n = 28). All patients were candidates for vitrectomy. Inflammatory cytokine and NT levels were determined with ELISA. Potential source and role of NTs was determined by using human retinal Müller glia and mouse photoreceptor cells and challenging them with TNF-α or IL-1β, followed by detection of NTs and cell death. Results Vitreous NT levels of all DR patients were significantly higher than those of nondiabetic controls (nerve growth factor [NGF, P = 0.0001], brain-derived neurotrophic factor [BDNF, P = 0.009], neurotrophin-3 [NT-3, P < 0.0001], neurotrophin-4 [NT-4, P = 0.0001], ciliary neurotrophic factor [CNTF, P = 0.0001], and glial cell–derived neurotrophic factor [GDNF, P = 0.008]). Similarly, the levels of inflammatory mediators IL-1β (P < 0.0001), IL-6 (P = 0.0005), IL-8 (P < 0.0001), and TNF-α (P < 0.0001) were also higher in eyes with DR. Interestingly, inflammatory cytokine and NT levels, particularly TNF-α (P < 0.05), IL-8 (P < 0.004), NT-3 (P = 0.012), NGF (P = 0.04), GDNF (P = 0.005), and CNTF (P = 0.002), were higher in eyes with nonproliferative diabetic retinopathy (NPDR) than in eyes with active proliferative diabetic retinopathy (PDR). Cytokine stimulation of Müller glia resulted in production of NTs, and GDNF treatment reduced photoreceptor cell death in response to inflammation and oxidative stress. Conclusions Together, our study demonstrated that patients with DR have higher levels of both inflammatory cytokines and NTs in their vitreous. Müller glia could be the potential source of NTs under inflammatory conditions to exert neuroprotection.
An Optimal Energy Efficiency Investment and Product Pricing Strategy in a Two-Market Framework

Energy efficiency (EE) level has become an essential environmental index of products and can be improved by EE innovation. With consideration of EE level evolution and market differentiation, an optimal control model under a two-market framework is proposed to investigate EE innovation and two-stage pricing strategies. Impacts of consumer environmental awareness (CEA) and EE standard on optimal investment and pricing strategies are discussed. Results indicate that environmental awareness and standard result in strategy shift. As environmental awareness increases, the EE level driven by investment strategy may switch from staying in traditional market, to expanding markets by entering the green market and remaining at the standard, till capturing the green market and keeping above that standard. Impacts of standard on strategy shift exhibit a tricky trend. For loose and appropriate standards, the producer prefers to invest more to expand market by entering the green market with the increase of standard. However, a stringent standard may prevent the producer from entering the green market. In addition, optimal prices in both stages are positively impacted by the CEA and the standard.
Insulin‐Mediated Downregulation of Apolipoprotein A‐I Gene in Human Hepatoma Cell Line HepG2: The Role of Interaction Between FOXO1 and LXRβ Transcription Factors

Apolipoprotein A‐I (ApoA‐I) is a key component of high density lipoproteins which possess anti‐atherosclerotic and anti‐inflammatory properties. Insulin is a crucial mediator of the glucose and lipid metabolism that has been implicated in atherosclerotic and inflammatory processes. Important mediators of insulin signaling such as Liver X Receptors (LXRs) and Forkhead Box A2 (FOXA2) are known to regulate apoA‐I expression in liver. Forkhead Box O1 (FOXO1) is a well‐known target of insulin signaling and a key mediator of oxidative stress response. Low doses of insulin were shown to activate apoA‐I expression in human hepatoma HepG2 cells. However, the detailed mechanisms for these processes are still unknown. We studied the possible involvement of FOXO1, FOXA2, LXRα, and LXRβ transcription factors in the insulin‐mediated regulation of apoA‐I expression. Treatment of HepG2 cells with high doses of insulin (48 h, 100 nM) suppresses apoA‐I gene expression. siRNAs against FOXO1, FOXA2, LXRβ, or LXRα abrogated this effect. FOXO1 forms a complex with LXRβ and insulin treatment impairs FOXO1/LXRβ complex binding to hepatic enhancer and triggers its nuclear export. Insulin as well as LXR ligand TO901317 enhance the interaction between FOXA2, LXRα, and hepatic enhancer. These data suggest that high doses of insulin downregulate apoA‐I gene expression in HepG2 cells through redistribution of FOXO1/LXRβ complex, FOXA2, and LXRα on hepatic enhancer of apoA‐I gene. J. Cell. Biochem. 118: 382–396, 2017. © 2016 Wiley Periodicals, Inc.
Evidence of the preferential use of disease prototypes over case exemplars among early year one medical students prior to and following diagnostic training

Abstract Background: Two core dual processing theory (DPT) System I constructs (Exemplars and Prototypes) were used to: 1) formulate a training exercise designed to improve diagnostic performance in year one medical students, and 2) explore whether any observed performance improvements were associated with preferential use of exemplars or prototypes. Methods: With IRB approval, 117 year one medical students participated in an acute chest pain diagnostic training exercise. A pre- and post-training test containing the same 27 case vignettes was used to determine if the subjects’ diagnostic performance improved via training in both exemplars and prototypes. Exemplar and Prototype theory was also used to generate a unique typicality estimate for each case vignette. Because these estimates produce different performance predictions, differences in the subjects’ observed performance would make it possible to infer whether subjects were preferentially using Exemplars or Prototypes. Results: Pre- vs. post-training comparison revealed a significant performance improvement; t=14.04, p<0.001, Cohen’s d=1.32. Pre-training, paired t-testing demonstrated that performance against the most typical vignettes>mid typical vignettes: t=4.94, p<0.001; and mid typical>least typical: t=5.16, p<0.001. Post-training, paired t-testing again demonstrated that performance against the most typical vignettes>mid typical: t=2.94, p<0.01; and mid typical>least typical: t=6.64, p<0.001. These findings are more consistent with the performance predictions generated via Prototype theory than Exemplar theory. Conclusions: DPT is useful in designing and evaluating the utility of new approaches to diagnostic training, and, investigating the cognitive factors driving diagnostic capabilities among early medical students.
Capacity Analysis of NOMA With mmWave Massive MIMO Systems

Non-orthogonal multiple access (NOMA), millimeter wave (mmWave), and massive multiple-input-multiple-output (MIMO) have been emerging as key technologies for fifth generation mobile communications. However, less studies have been done on combining the three technologies into the converged systems. In addition, how many capacity improvements can be achieved via this combination remains unclear. In this paper, we provide an in-depth capacity analysis for the integrated NOMA-mmWave-massive-MIMO systems. First, a simplified mmWave channel model is introduced by extending the uniform random single-path model with angle of arrival. Afterward, we divide the capacity analysis into the low signal to noise ratio (SNR) and high-SNR regimes based on the dominant factors of signal to interference plus noise ratio. In the noise-dominated low-SNR regime, the capacity analysis is derived by the deterministic equivalent method with the Stieltjes–Shannon transform. In contrast, the statistic and eigenvalue distribution tools are invoked for the capacity analysis in the interference-dominated high-SNR regime. The exact capacity expression and the low-complexity asymptotic capacity expression are derived based on the probability distribution function of the channel eigenvalue. Finally, simulation results validate the theoretical analysis and demonstrate that significant capacity improvements can be achieved by the integrated NOMA-mmWave-massive-MIMO systems.
Improving the tracking and erosion resistance performance of alumina trihydrate-free addition-cure liquid silicone rubber

Aiming to improve tracking and erosion resistance performance of addition-cure liquid silicone rubber (ALSR) without alumina trihydrate, A- and B-series ALSR samples with different fumed silica mass fraction and platinum catalyst concentration were prepared respectively. The tracking and erosion resistance performance of all the samples were evaluated. Also, the thermal decomposition products were detected. Basing on the comparative analysis of thermal decomposition characteristics, morphology, crystal structure, the improvement mechanism was discussed. Results showed that increasing the concentration of platinum catalyst and the mass fraction of fumed silica both can improve the tracking and erosion resistance performance, whereas the former was more effectively. Further analysis considered that platinum catalyst played a very important role in thermal decomposition process of ALSR, increasing the platinum catalyst content can not only promote the crosslinking reaction between the methyl groups, but also suppress backbone decomposition.
Water Transparency Drives Intra-Population Divergence in Eurasian Perch (Perca fluviatilis)

Trait combinations that lead to a higher efficiency in resource utilization are important drivers of divergent natural selection and adaptive radiation. However, variation in environmental features might constrain foraging in complex ways and therefore impede the exploitation of critical resources. We tested the effect of water transparency on intra-population divergence in morphology of Eurasian perch (Perca fluviatilis) across seven lakes in central Sweden. Morphological divergence between near-shore littoral and open-water pelagic perch substantially increased with increasing water transparency. Reliance on littoral resources increased strongly with increasing water transparency in littoral populations, whereas littoral reliance was not affected by water transparency in pelagic populations. Despite the similar reliance on pelagic resources in pelagic populations along the water transparency gradient, the utilization of particular pelagic prey items differed with variation in water transparency in pelagic populations. Pelagic perch utilized cladocerans in lakes with high water transparency and copepods in lakes with low water transparency. We suggest that under impaired visual conditions low utilization of littoral resources by littoral perch and utilization of evasive copepods by pelagic perch may lead to changes in morphology. Our findings indicate that visual conditions can affect population divergence in predator populations through their effects on resource utilization.
Isolation and Characterization of Pseudomonas Strain That Inhibit Growth of Indigenous and Clinical Isolate

The use of microorganisms for biological purpose has become an effective alternative to control pathogens. Bacteria from marine environment are an underutilized source of novel antibiotics. A total of 100 bacteria were isolated from marine samples (Fish, Water and Crustaceans) of Baluchistan coast and screened for antagonistic interaction. Out of these 15 strains showed antibacterial activity. One strain designated as CMG1030 identified as Pseudomonas aeruginosa gave excellent antibacterial activity, capable of inhibiting growth of clinical isolates such as methicillin resistant Staphylococcus aureus. Escherichia coli, Salmonella typhi, Shigella flexnerie, Staphylococcus epidermidis, as well as indeginous marine bacteria such as Staphylococcus aureus, Shewanella putrifacians, Vibrio alginolyticus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis. Inhibition did not involve living cells, which has suggested that at least a substantial portion of the anti microbial activity was due to the excretion of extra cellular compound but did not give activity against Streptococcus (group G), Candida albicans, Aspergillus niger Thin layer chromatography of crude extract of cells of Pseudomonas aeruginosa revealed one UV active fraction with biological activity. Microscopic examination of exponentially growing cells of S.aureus treated with crude extract of P.aeruginosa suggests cell lysis and some ghost cells and big cells were also observed.
Lactate-mediated mitoribosomal defects impair mitochondrial oxidative phosphorylation and promote hepatoma cell invasiveness

Impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity, accompanied by enhanced glycolysis, is a key metabolic feature of cancer cells, but its underlying mechanism remains unclear. Previously, we reported that human hepatoma cells that harbor OXPHOS defects exhibit high tumor cell invasiveness via elevated claudin-1 (CLN1). In the present study, we show that OXPHOS-defective hepatoma cells (SNU354 and SNU423 cell lines) exhibit reduced expression of mitochondrial ribosomal protein L13 (MRPL13), a mitochondrial ribosome (mitoribosome) subunit, suggesting a ribosomal defect. Specific inhibition of mitoribosomal translation by doxycycline, chloramphenicol, or siRNA-mediated MRPL13 knockdown decreased mitochondrial protein expression, reduced oxygen consumption rate, and increased CLN1-mediated tumor cell invasiveness in SNU387 cells, which have active mitochondria. Interestingly, we also found that exogenous lactate treatment suppressed MRPL13 expression and oxygen consumption rate and induced CLN1 expression. A bioinformatic analysis of the open RNA-Seq database from The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) cohort revealed a significant negative correlation between MRPL13 and CLN1 expression. Moreover, in patients with low MRPL13 expression, two oxidative metabolic indicators, pyruvate dehydrogenase B expression and the ratio of lactate dehydrogenase type B to type A, significantly and negatively correlated with CLN1 expression, indicating that the combination of elevated glycolysis and deficient MRPL13 activity was closely linked to CLN1-mediated tumor activity in LIHC. These results suggest that OXPHOS defects may be initiated and propagated by lactate-mediated mitoribosomal deficiencies and that these deficiencies are critically involved in LIHC development.
The Roles of Featural and Configural Face Processing in Snap Judgments of Sexual Orientation

Research has shown that people are able to judge sexual orientation from faces with above-chance accuracy, but little is known about how these judgments are formed. Here, we investigated the importance of well-established face processing mechanisms in such judgments: featural processing (e.g., an eye) and configural processing (e.g., spatial distance between eyes). Participants judged sexual orientation from faces presented for 50 milliseconds either upright, which recruits both configural and featural processing, or upside-down, when configural processing is strongly impaired and featural processing remains relatively intact. Although participants judged women’s and men’s sexual orientation with above-chance accuracy for upright faces and for upside-down faces, accuracy for upside-down faces was significantly reduced. The reduced judgment accuracy for upside-down faces indicates that configural face processing significantly contributes to accurate snap judgments of sexual orientation.
Transcriptional Profiling of Plasmodium falciparum Parasites from Patients with Severe Malaria Identifies Distinct Low vs. High Parasitemic Clusters

Background In the past decade, estimates of malaria infections have dropped from 500 million to 225 million per year; likewise, mortality rates have dropped from 3 million to 791,000 per year. However, approximately 90% of these deaths continue to occur in sub-Saharan Africa, and 85% involve children less than 5 years of age. Malaria mortality in children generally results from one or more of the following clinical syndromes: severe anemia, acidosis, and cerebral malaria. Although much is known about the clinical and pathological manifestations of CM, insights into the biology of the malaria parasite, specifically transcription during this manifestation of severe infection, are lacking. Methods and Findings We collected peripheral blood from children meeting the clinical case definition of cerebral malaria from a cohort in Malawi, examined the patients for the presence or absence of malaria retinopathy, and performed whole genome transcriptional profiling for Plasmodium falciparum using a custom designed Affymetrix array. We identified two distinct physiological states that showed highly significant association with the level of parasitemia. We compared both groups of Malawi expression profiles with our previously acquired ex vivo expression profiles of parasites derived from infected patients with mild disease; a large collection of in vitro Plasmodium falciparum life cycle gene expression profiles; and an extensively annotated compendium of expression data from Saccharomyces cerevisiae. The high parasitemia patient group demonstrated a unique biology with elevated expression of Hrd1, a member of endoplasmic reticulum-associated protein degradation system. Conclusions The presence of a unique high parasitemia state may be indicative of the parasite biology of the clinically recognized hyperparasitemic severe disease syndrome.
Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Significance Proteasome inhibitors show remarkable anti-multiple myeloma (MM) activity in preclinical and clinical studies. However, resistance develops in the majority of patients, and novel treatments are urgently needed. Histone deacetylase 6 (HDAC6) has been shown to mediate aggresomal protein degradation and could be a potential target for combination treatment to overcome drug resistance. Here we designed and developed an HDAC6-selective small molecule inhibitor, WT161, and used this compound to define mechanisms of anti-MM activity, both alone and in combination with proteasome inhibitors in in vitro and in vivo studies. This study has established the framework for combination treatment of HDAC6 inhibitors with proteasome inhibitors in MM and validates an in vivo quality chemical probe for broad use by the research community. Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.
Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients.

BACKGROUND Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. RESULTS Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. CONCLUSION Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.
A Conserved Non-Reproductive GnRH System in Chordates

Gonadotropin-releasing hormone (GnRH) is a neuroendocrine peptide that plays a central role in the vertebrate hypothalamo-pituitary axis. The roles of GnRH in the control of vertebrate reproductive functions have been established, while its non-reproductive function has been suggested but less well understood. Here we show that the tunicate Ciona intestinalis has in its non-reproductive larval stage a prominent GnRH system spanning the entire length of the nervous system. Tunicate GnRH receptors are phylogenetically closest to vertebrate GnRH receptors, yet functional analysis of the receptors revealed that these simple chordates have evolved a unique GnRH system with multiple ligands and receptor heterodimerization enabling complex regulation. One of the gnrh genes is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord of vertebrates. Correspondingly, GnRH receptor genes were found to be expressed in the tail muscle and notochord of embryos, both of which are phylotypic axial structures along the nerve cord. Our findings suggest a novel non-reproductive role of GnRH in tunicates. Furthermore, we present evidence that GnRH-producing cells are present in the hindbrain and spinal cord of the medaka, Oryzias latipes, thereby suggesting the deep evolutionary origin of a non-reproductive GnRH system in chordates.