Miracle-dz/UniFAR-FTUs huggingface dataset:
Metabolic Syndrome and Obesity : Targets and Therapy SGLT-2 inhibitors and their potential in the treatment of diabetes

Correspondence: Rebecca F Rosenwasser East Coast Institute for Research, 3550 University Blvd, Suite #101, Jacksonville, FL 32216, USA Tel +1 813 220 5217 Fax +1 904 854 1355 Email rebecca.rosenwasser@ecirmed.com Abstract: Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules’ attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol – an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A 1c (HbA 1c ), body weight, and blood pressure of −0.34% to −1.03%, −2.0 to −3.4 kg, and −1.7 to −6.4 mmHg/−0.3 to −2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk–benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action.
Low Triiodothyronine Alters Flow-Mediated Vasodilatation in Advanced Nondiabetic Kidney Disease

Background/Aims: Subclinical or frank hypothyroidism is causally implicated in endothelial dysfunction. Since the plasma concentration of the active form of thyroid hormone, triiodothyronine (T3), is reduced in chronic kidney disease (CKD), where endothelial function is frequently altered, low T3 may be a factor implicated in this disturbance in CKD patients. Methods: We investigated the relationship between flow-mediated vasodilatation (FMD) and thyroid hormones in a series of 217 nondiabetic patients with stage 3–4 CKD. Results: The plasma concentration of free T3 (fT3) was closely associated with FMD (r = 0.38; p < 0.001). fT3 was also inversely associated with hemoglobin (r = –0.41; p < 0.001), systolic pressure (r = –0.28; p < 0.001) and the plasma concentration of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA; r = –0.18; p = 0.007). However, adjustment for ADMA markedly attenuated the fT3-FMD link, a phenomenon suggesting that raised plasma ADMA, possibly driven by low fT3, at least in part mediates the adverse effects of low T3 on endothelial function in CKD. Conclusions: Low T3 in patients with moderate-to-severe CKD is a marker of endothelial dysfunction. This study sets a solid rationale for designing specific intervention studies aimed at clarifying the nature (causal or not causal) of the endothelial function-T3 link in CKD.
Extraction of microsporidial DNA from modified trichrome-stained clinical slides and subsequent species identification using PCR sequencing

SUMMARY Molecular techniques involving polymerase chain reaction (PCR) and sequencing provide a relatively simple and objective means of identifying microsporidia to species level. We modified previously described methods of DNA extraction and PCR conditions for identification of microsporidia from museum slides, clinical specimens and environmental samples and successfully identified Vittaforma corneae in 11 out of 13 cases of microsporidial infection from used trichrome-stained slides of corneal scrapings from HIV-negative patients with keratoconjunctivitis.
Single-molecule Force Spectroscopy Predicts a Misfolded, Domain-swapped Conformation in human γD-Crystallin Protein*

Cataract is a protein misfolding disease where the size of the aggregate is directly related to the severity of the disorder. However, the molecular mechanisms that trigger the onset of aggregation remain unknown. Here we use a combination of protein engineering techniques and single-molecule force spectroscopy using atomic force microscopy to study the individual unfolding pathways of the human γD-crystallin, a multidomain protein that must remain correctly folded during the entire lifetime to guarantee lens transparency. When stretching individual polyproteins containing two neighboring HγD-crystallin monomers, we captured an anomalous misfolded conformation in which the β1 and β2 strands of the N terminus domain of two adjacent monomers swap. This experimentally elusive domain-swapped conformation is likely to be responsible for the increase in molecular aggregation that we measure in vitro. Our results demonstrate the power of force spectroscopy at capturing rare misfolded conformations with potential implications for the understanding of the molecular onset of protein aggregation.
The Tumor Suppressor Role of miR-124 in Osteosarcoma

MicroRNAs have crucial roles in development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-124 was down-regulated in many cancers; however, the role of miR-124 in osteosarcoma development is unkonwn. In this study, we demonstrate that expression of miR-124 is significantly downregulated in osteosarcoma tissues and cell lines, compared to the adjacent tissues. The expression of miR-124 in the metastases osteosarcoma tissues was lower than that in non- metastases tissues. We identified and confirmed Rac1 as a novel, direct target of miR-124 using prdiction algorithms and luciferase reporter gene assays. Overexpression of miR-124 suppressed Rac1 protein expression and attenuated cell proliferation, migration, and invasion and induced apotosis in MG-63 and U2OS in vitro. Moreover, overexpression of Rac1 in miR-124-transfected osteosarcoma cells effectively rescued the inhibition of cell invasion caused by miR-124. Therefore, our results demonstrate that miR-124 is a tumor suppressor miRNA and suggest that this miRNA could be a potential target for the treatment of osteosarcoma in future.
Moraxella catarrhalis Might Be More Common than Expected in Acute Otitis Media in Young Finnish Children

ABSTRACT According to studies based on bacterial cultures of middle ear fluids, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been the most common pathogens in acute otitis media. However, bacterial culture can be affected by reduced viability or suboptimal growth of bacteria. PCR detects bacterial DNA from samples with greater sensitivity than culture. In the present study, we analyzed the middle ear pathogens with both conventional culture and semiquantitative real-time PCR in 90 middle ear fluid samples obtained from children aged 5 to 42 months during acute otitis media episodes. Samples were tested for the presence of S. pneumoniae, H. influenzae, M. catarrhalis, Alloiococcus otitidis, Staphylococcus aureus, and Pseudomonas aeruginosa. One or more bacterial pathogens were detected in 42 (47%) samples with culture and in 69 (77%) samples with PCR. According to PCR analysis, M. catarrhalis results were positive in 42 (47%) samples, H. influenzae in 30 (33%), S. pneumoniae in 27 (30%), A. otitidis in 6 (6.7%), S. aureus in 5 (5.6%), and P. aeruginosa in 1 (1.1%). Multibacterial etiology was seen in 34 (38%) samples, and M. catarrhalis was detected in most (85%) of those cases. Fifteen signals for M. catarrhalis were strong, suggesting a highly probable etiological role of the pathogen. In conclusion, even though M. catarrhalis is often a part of mixed flora in acute otitis media, a considerable proportion of cases may be primarily attributable to this pathogen.
Geographic body size variation in the periodical cicadas Magicicada: implications for life cycle divergence and local adaptation

Seven species in three species groups (Decim, Cassini and Decula) of periodical cicadas (Magicicada) occupy a wide latitudinal range in the eastern United States. To clarify how adult body size, a key trait affecting fitness, varies geographically with climate conditions and life cycle, we analysed the relationships of population mean head width to geographic variables (latitude, longitude, altitude), habitat annual mean temperature (AMT), life cycle and species differences. Within species, body size was larger in females than males and decreased with increasing latitude (and decreasing habitat AMT), following the converse Bergmann's rule. For the pair of recently diverged 13‐ and 17‐year species in each group, 13‐year cicadas were equal in size or slightly smaller on average than their 17‐year counterparts despite their shorter developmental time. This fact suggests that, under the same climatic conditions, 17‐year cicadas have lowered growth rates compared to their 13‐years counterparts, allowing 13‐year cicadas with faster growth rates to achieve body sizes equivalent to those of their 17‐year counterparts at the same locations. However, in the Decim group, which includes two 13‐year species, the more southerly, anciently diverged 13‐year species (Magicicada tredecim) was characterized by a larger body size than the other, more northerly 13‐ and 17‐year species, suggesting that local adaptation in warmer habitats may ultimately lead to evolution of larger body sizes. Our results demonstrate how geographic clines in body size may be maintained in sister species possessing different life cycles.
Biosynthetic energy cost of potentially highly expressed proteins vary with niche in selected actinobacteria

Amino acid and protein biosynthesis requires a number of high energy phosphate bonds and includes a dual energy cost for the synthesis of chemical intermediates during the fueling reactions and the conversion of precursor molecules to final products. One popular hypothesis is that the proteins encoded by putative highly expressed genes (hence called PHXPs) generally utilize low energy consuming amino acids to reduce the biosynthetic cost of the essential proteins. In our study, we found that this idea was not supported in the case of actinobacteria. With the actinobacteria, the energy costs of PHXPs varied in relation to their niche. Free‐living, including aquatic, soil and extremophilic, and plant‐associated actinobacteria were found to use energetically expensive amino acids in their PHXPs. An exception occurred with some animal‐host‐associated actinobacteria that used energy efficient amino acids. One explanation for these results may be due to the diverse metabolic patterns exhibited by actinobacteria under varied niches influenced by nutritional availability and physical environment.
QPTAS for Weighted Geometric Set Cover on Pseudodisks and Halfspaces

Weighted geometric set-cover problems arise naturally in several geometric and non-geometric settings (e.g. the breakthrough of Bansal and Pruhs (FOCS 2010) reduces a wide class of machine scheduling problems to weighted geometric set-cover). More than two decades of research has succeeded in settling the (1 + status for most geometric set-cover problems, except for some basic scenarios which are still lacking. One is that of weighted disks in the plane for which, after a series of papers, Varadarajan (STOC 2010) presented a clever quasi-sampling technique, which together with improvements by Chan et al. (SODA 2012), yielded an O(1)-approximation algorithm. Even for the unweighted case, a PTAS for a fundamental class of objects called pseudodisks (which includes half-spaces, disks, unit-height rectangles, translates of convex sets etc.) is currently unknown. Another fundamental case is weighted halfspaces in R 3 , for which a PTAS is currently lacking. In this paper, we present a QPTAS for all of these remaining problems. Our results are based on the separator framework of Adamaszek and Wiese (FOCS 2013, SODA 2014), who recently obtained a QPTAS for weighted independent set of polygonal regions. This rules out the possibility that these problems are APX-hard, assuming NP DTIME(2 polylog(n)). Together with the recent work of Chan and Grant (CGTA 2014), this settles the APX-hardness status for all natural geometric set-cover problems.
Comparison of two lipid extraction methods produced by yeast in cheese whey

This work aimed to evaluate nine strains of yeast, previously identified as good producers of lipids in honey medium, for selecting the most suitable strain for the production of lipids in cheese whey medium and compared two well known extraction methods of lipids from the culture medium. The highest yield of total lipids was 1.27 g.L-1 produced by Cryptococcus laurentii 11. A comparison was made between the two culture media: cheese whey and liquid YEPG, and two lipid extraction methods: Bligh and Dyer and Folch et al. for C. laurentii. The experiments were performed with 22 full factorial design using two factors and two levels. Lipid content was higher in cheese whey and there was no difference in the extraction methods statistically. The method of Bligh and Dyer was used in preference to Folch et al. as it resulted in larger mean of total lipids.
Development of an Antigen Capture Immunoassay Based on Monoclonal Antibodies Specific for Dengue Virus Serotype 2 Nonstructural Protein 1 for Early and Rapid Identification of Dengue Virus Serotype 2 Infections

ABSTRACT The dengue virus (DENV) has four distinct serotypes (DENV1, DENV2, DENV3, and DENV4) that require differentiation for effective prevention of morbid diseases. The recently developed DENV1-specific NS1 antigen capture enzyme-linked immunosorbent assay (ELISA) based on the monoclonal antibodies (MAbs) that recognize distinct epitopes on nonstructural protein 1 (NS1) of a specific DENV serotype is convenient and cost-effective, but assays have not yet been developed for DENV serotypes 2 to 4. This paper describes the development and validation of a DENV2-specific NS1 antigen capture ELISA by selection and optimization of the pair of well-characterized MAbs that recognized epitopes specific for DENV2 NS1 from a large panel of MAbs. The DENV2 NS1 ELISA displayed exclusive sensitivity with the DENV2 serotype and did not cross-react with the other three DENV serotypes. The sensitivity and specificity of the DENV2 NS1 ELISA were 83.3% (25/30) and 100% (504/504) when used to test 30 acute-phase serum samples from patients infected with DENV2 identified by virus isolation or reverse transcription-PCR serotyping and 504 serum samples from healthy individuals, respectively. The specificity of this assay was also evaluated using a panel of serum samples which were positive for DENV1, other flaviviruses, and nonflaviviruses; no cross-reactions were observed in these clinical samples. The DENV2 NS1 ELISA was eightfold more sensitive than a commercially available serotype-cross-reactive NS1 ELISA (Panbio Diagnostics, Brisbane, Australia) when the two assays were used to test the DENV2-infected cell culture supernatants in parallel. The Panbio NS1 ELISA displayed variation in sensitivity between DENV serotypes. The DENV2-specific NS1 antigen capture ELISA can be used as a tool for the rapid identification of DENV2 infections.
MAPKKK-independent Regulation of the Hog1 Stress-activated Protein Kinase in Candida albicans

The Hog1 stress-activated protein kinase regulates both stress responses and morphogenesis in Candida albicans and is essential for the virulence of this major human pathogen. Stress-induced Hog1 phosphorylation is regulated by the upstream MAPKK, Pbs2, which in turn is regulated by the MAPKKK, Ssk2. Here, we have investigated the role of phosphorylation of Hog1 and Pbs2 in Hog1-mediated processes in C. albicans. Mutation of the consensus regulatory phosphorylation sites of Hog1 (Thr-174/Tyr-176) and Pbs2 (Ser-355/Thr-359), to nonphosphorylatable residues, resulted in strains that phenocopied hog1Δ and pbs2Δ cells. Consistent with this, stress-induced phosphorylation of Hog1 was abolished in cells expressing nonphosphorylatable Pbs2 (Pbs2AA). However, mutation of the consensus sites of Pbs2 to phosphomimetic residues (Pbs2DD) failed to constitutively activate Hog1. Furthermore, Ssk2-independent stress-induced Hog1 activation was observed in Pbs2DD cells. Collectively, these data reveal a previously uncharacterized MAPKKK-independent mechanism of Hog1 activation in response to stress. Although Pbs2DD cells did not exhibit high basal levels of Hog1 phosphorylation, overexpression of an N-terminal truncated form of Ssk2 did result in constitutive Hog1 activation, which was further increased upon stress. Significantly, both Pbs2AA and Pbs2DD cells displayed impaired stress resistance and attenuated virulence in a mouse model of disease, whereas only Pbs2AA cells exhibited the morphological defects associated with loss of Hog1 function. This indicates that Hog1 mediates C. albicans virulence by conferring stress resistance rather than regulating morphogenesis.
Suppression of EEG visual-evoked potentials in rats through neuromodulatory focused ultrasound

We investigated the use of pulsed low-intensity focused ultrasound (FUS) to suppress the visual neural response induced by light stimulation in rodents. FUS was administered transcranially to the rat visual cortex using different acoustic intensities and pulsing duty cycles. The visual-evoked potentials (VEPs) generated by an external strobe light stimulation were measured three times before, once during, and five times after the sonication. The VEP magnitude was suppressed during the sonication using a 5% duty cycle (pulse-repetition frequency of 100 Hz) and a spatial-peak pulse-average acoustic intensity of 3 W/cm2; however, this suppressive effect was not present when a lower acoustic intensity and duty cycle were used. The application of a higher intensity and duty cycle resulted in a slight elevation in VEP magnitude, which suggested excitatory neuromodulation. Our findings demonstrate that the application of pulsed FUS to the region-specific brain area not only suppresses its excitability, but can also enhance the excitability depending on the acoustic intensity and the rate of energy deposition. This bimodal feature of FUS-mediated neuromodulation, which has been predicted by numerical models on neural membrane capacitance change by the external acoustic pressure waves, suggests its versatility for neurotherapeutic applications.
Effect of cracks on chloride-induced corrosion of steel in concrete - a review: Etatsprogrammet Varige konstruksjoner 2012-2015

This report reviews literature studies about the effect of concrete cracks on reinforcement steel corrosion in chloride exposure environments. While there is general agreement that cracks can lead to earlier corrosion initiation, the current state-of-the-art suggests that the effect of cracks on corrosion diminishes with time and may on the long-term even be negligible. Nevertheless, the vast majority of literature results are from short-term studies (< 2 y); well-documented long-term studies (> 10 y) under realistic field exposure are scarce. A further major lack of knowledge was identified with respect to crack frequency. According to current understanding of the working mechanism of corrosion in cracked concrete, it is expected that the corrosion rate at the local anodic site at the crack should decrease with increasing crack frequency. There is, however, very little experimental data confirming this suggested effect of the crack frequency. The current state-of-knowledge does not permit general recommendations for critical crack widths, neither for corrosion initiation nor for corrosion propagation. This clearly illustrates the urgent need for more research.
Raman studies of bovine serum albumin

The Raman Spectra of bovine serum albumin have been obtained in the solute state, in alkaline and acidic solutions, and in the gel. The reversible denaturations of bovine serum albumin solutions by heat, acid's, and alkali were studied and a new mechanism for heat denaturation has been proposed based on a continuous unfolding of the α‐helices.
The Relationship between Unemployment and Risk-Aversion

In this paper we use a direct measure of individual risk-aversion to examine the relationship between risk-aversion and unemployment. The traditional search model predicts that more risk-averse individuals have lower reservation wages and thus are less likely to be observed in unemployment. Our findings, however, do not support this prediction: on the contrary our data suggest that more risk-averse individuals are more likely to be unemployed.
Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD.

BACKGROUND AND OBJECTIVES CD14 plays a key role in the innate immunity as pattern-recognition receptor of endotoxin. Higher levels of soluble CD14 (sCD14) are associated with overall mortality in hemodialysis patients. The influence of kidney function on plasma sCD14 levels and its relationship with adverse outcomes in patients with CKD not yet on dialysis is unknown. This study examines the associations between plasma levels of sCD14 and endotoxin with adverse outcomes in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We measured plasma levels of sCD14 and endotoxin in 495 Leuven Mild-to-Moderate CKD Study participants. Mild-to-moderate CKD was defined as presence of kidney damage or eGFR<60 ml/min per 1.73 m(2) for ≥3 months, with exclusion of patients on RRT. Study participants were enrolled between November 2005 and September 2006. RESULTS Plasma sCD14 was negatively associated with eGFR (ρ=-0.34, P<0.001). During a median follow-up of 54 (interquartile range, 23-58) months, 53 patients died. Plasma sCD14 was predictive of mortality, even after adjustment for renal function, Framingham risk factors, markers of mineral bone metabolism, and nutritional and inflammatory parameters (hazard ratio [HR] per SD higher of 1.90; 95% confidence interval [95% CI],1.32 to 2.74; P<0.001). After adjustment for the same risk factors, plasma sCD14 was also a predictor of cardiovascular disease (HR, 1.30; 95% CI, 1.00 to 1.69; P=0.05). Although plasma sCD14 was associated with progression of CKD, defined as reaching ESRD or doubling of serum creatinine in models adjusted for CKD-specific risk factors (HR, 1.24; 95% CI, 1.01 to 1.52; P=0.04), significance was lost when adjusted for proteinuria (HR, 1.19; 95% CI, 0.96 to 1.48; P=0.11). There was neither correlation between plasma endotoxin and sCD14 (ρ=-0.06, P=0.20) nor was endotoxin independently associated with adverse outcome during follow-up. CONCLUSIONS Plasma sCD14 is elevated in patients with decreased kidney function and associated with mortality and cardiovascular disease in patients with CKD not yet on dialysis.