Miracle-dz/UniFAR-FTUs huggingface dataset:
Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes

OBJECTIVE Insulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium–glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DM to dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg ⋅ min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg ⋅ min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.
A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against Leishmania major

We present an approach for detecting enzymes that are specific of Leishmania major compared with Homo sapiens and provide targets that may assist research in drug development. This approach is based on traditional techniques of sequence homology comparison by similarity search and Markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. From 67 enzymes represented by 42 enzymatic activities classified by AnEnPi (Analogous Enzymes Pipeline) as specific for L major compared with H sapiens, only 40 (23 Enzyme Commission [EC] numbers) could actually be considered as strictly specific of L major and 27 enzymes (19 EC numbers) were disregarded for having ambiguous homologies or analogies with H sapiens. Among the 40 strictly specific enzymes, we identified sterol 24-C-methyltransferase, pyruvate phosphate dikinase, trypanothione synthetase, and RNA-editing ligase as 4 essential enzymes for L major that may serve as targets for drug development.
THE ACTION OF SODIUM DODECYL SULFATE ON THE CHLOROPHYLL-PROTEIN COMPOUND OF THE SPINACH LEAF

1. Sodium dodecyl sulfate (SDS) attacks the chlorophyll-protein compound modifying its protein properties and absorption spectrum. 2. In the presence of SDS, chlorophyll is quantitatively converted to phaeophytin; i.e., magnesium is removed from the molecule. This reaction, measured spectrophotometrically, proceeds at a rate directly proportional to the hydrogen ion concentration. At constant pH, the rate is proportional to the SDS concentration until a maximum rate is achieved. 3. The chlorophyll or phaeophytin (depending on the pH) remains attached to the protein, since the prosthetic group cannot be separated by ultrafiltration, dialysis, or fractional precipitation. 4. This suggests that the magnesium plays no part in binding chlorophyll to the split protein fragments, but may be concerned in binding the larger units, since the metal becomes extremely labile when the protein is split.
Inhibition of Na+,K+‐ATPase from rat brain cortex by propionic acid

BUFFERED propionic acid was injected s.c. into rats twice a day at 8 h intervals from the 6 to 21 days of age. Control rats received saline in the same volumes. The animals were weighed and killed by decapitation at 23 days. Whole brain and cerebral cortex were weighed and synaptic plasma membranes were prepared from cortex for the determination of Na+,K+-ATPase and Mg2+-ATPase activities. Body, whole brain and cortical weights were similar in the two groups, suggesting that propionic acid does not cause malnutrition in rats. Na+,K+-ATPase activity was significantly reduced by 30% in membranes from the propionate-treated group, whereas Mg2+-ATPase activity was not. In another set of experiments, synaptic plasma membranes were prepared from cerebral cortex of 23-day-old rats and incubated with propionic acid at final concentrations ranging from 0.1 to 2.0 mM. Na+,K+-ATPase activity, but not Mg2+-ATPase activity, was inhibited by 22–32%. Since propionic acid concentrations in plasma of chronically treated rats and of propionic acidaemic children are of the same order of magnitude as those tested in vitro, the results suggest that the inhibition of Na+,K+-ATPase activity may be related to the neurological dysfunction of patients affected by propionic acidaemia.
Design of Glycoconjugate Vaccines against Invasive African Salmonella enterica Serovar Typhimurium

ABSTRACT Nontyphoidal salmonellae, particularly Salmonella enterica serovar Typhimurium, are a major cause of invasive disease in Africa, affecting mainly young children and HIV-infected individuals. Glycoconjugate vaccines provide a safe and reliable strategy against invasive polysaccharide-encapsulated pathogens, and lipopolysaccharide (LPS) is a target of protective immune responses. With the aim of designing an effective vaccine against S. Typhimurium, we have synthesized different glycoconjugates, by linking O-antigen and core sugars (OAg) of LPS to the nontoxic mutant of diphtheria toxin (CRM197). The OAg-CRM197 conjugates varied in (i) OAg source, with three S. Typhimurium strains used for OAg extraction, producing OAg with differences in structural specificities, (ii) OAg chain length, and (iii) OAg/CRM197 ratio. All glycoconjugates were compared for immunogenicity and ability to induce serum bactericidal activity in mice. In vivo enhancement of bacterial clearance was assessed for a selected S. Typhimurium glycoconjugate by challenge with live Salmonella. We found that the largest anti-OAg antibody responses were elicited by (i) vaccines synthesized from OAg with the highest glucosylation levels, (ii) OAg composed of mixed- or medium-molecular-weight populations, and (iii) a lower OAg/CRM197 ratio. In addition, we found that bactericidal activity can be influenced by S. Typhimurium OAg strain, most likely as a result of differences in OAg O-acetylation and glucosylation. Finally, we confirmed that mice immunized with the selected OAg-conjugate were protected against S. Typhimurium colonization of the spleen and liver. In conclusion, our findings indicate that differences in the design of OAg-based glycoconjugate vaccines against invasive African S. Typhimurium can have profound effects on immunogenicity and therefore optimal vaccine design requires careful consideration.
Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice

Background: Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation. Methods: Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-&bgr;, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed. Results: Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-&bgr;-dependent, but IL-10 and iFoxp3+ Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP+ and Foxp3+ Tregs in the colon. Conclusions: This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.
DISEASE COMPLEXITY IN A DECLINING ALASKAN MUSKOX (OVIBOS MOSCHATUS) POPULATION

Abstract The muskox (Ovibos moschatus) population inhabiting the eastern North Slope (ENS) of Alaska, US declined dramatically during 1999–2006, whereas populations in western Alaska (WA) were stable or increasing. To understand morbidity and mortality factors contributing to the decline, Alaska Department of Fish and Game conducted pathologic investigations of carcasses from 2005 until 2008. Additionally, archived sera from both ENS and WA muskoxen collected during 1984–92, before the documented beginning of the ENS decline; sera collected during 2000, near the beginning of the decline; and contemporary sera (from live capture–release, adult females) collected during 2006, 2007, and 2008 were analyzed to determine whether prevalence of antibody to potential pathogens differed in the two areas or changed over time. The pathogens investigated were those that were believed could cause lameness or poor reproduction or adversely affect general health. Furthermore, trace mineral levels, hemograms, and gastrointestinal parasites were evaluated in live adult females captured 2006–08. Pathologic investigations identified several comorbid conditions, including predation, polyarthritis caused by or consistent with Chlamydophila spp. infection, hoof lesions, copper deficiency, contagious ecthyma, verminous pneumonia, hepatic lipidosis suggestive of negative energy balance, and bacterial bronchopneumonia due to Trueperella pyogenes and Bibersteinia trehalosi. Pathogens suspected to be newly introduced in the ENS muskox population on the basis of serologic detection include bovine viral diarrhea, respiratory syncytial virus, Chlamydophila spp. , Brucella spp. , Coxiella burnetii, and Leptospira spp. , whereas parainfluenza virus-3 antibody prevalence has increased in the WA population. Although multiple disease syndromes were identified that contributed to mortality and, in combination, likely limited the ENS muskox population, further holistic investigations of disease agents, trace mineral status, and nutritional factors in conjunction with intensive demographic and environmental analyses would provide a better understanding of factors that influence Alaskan muskox populations.
Three-dimensional measurement of bone loss at implants in patients with periodontal disease.

BACKGROUND The aim of this prospective study is to evaluate the three-dimensional marginal bone level around implants 5 to 15 years after loading in partially edentulous patients treated for generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP). METHODS Seventeen patients with GCP and 17 patients with GAgP were treated with a total of 119 implants. Patients were examined clinically on a 3-month recall schedule after insertion of the superstructure, and radiographs were taken at fixed intervals. At the end of the observation period, cone-beam computed tomography was used for the analysis of the circumferential three-dimensional bone level (mesial, distal, buccal, and lingual/palatal) and determination of keratinized mucosa thickness (KMT). RESULTS In both groups, a significant bone loss at implants was observed buccally (GAgP group: 4.49 ± 2.93 mm; GCP group: 3.57 ± 2.94 mm) with significantly more average bone loss in patients with GAgP (3.00 ± 1.67 mm) compared to in patients with GCP (2.45 ± 1.08 mm). The lowest values for KMT in both groups were found in the anterior mandible (GAgP group: 0.99 ± 1.13 mm; GCP group: 0.82 ± 0.91 mm). There were significant correlations between clinical parameters and bone loss in mandibles of patients with GAgP. CONCLUSIONS The lowest value for KMT in both groups was found in the mandible. Bone loss was observed buccally and was more pronounced in patients with GAgP, with a significant correlation with keratinized mucosa and increased inflammation.
Neural Mechanisms for Adaptive Learned Avoidance of Mental Effort

Humans tend to avoid mental effort. Previous studies have demonstrated this tendency using various demand-selection tasks; participants generally avoid options associated with higher cognitive demand. However, it remains unclear whether humans avoid mental effort adaptively in uncertain and nonstationary environments. If so, it also remains unclear what neural mechanisms underlie such learned avoidance and whether they remain the same regardless of cognitive-demand types. We addressed these issues by developing novel demand-selection tasks where associations between choice options and cognitive-demand levels change over time, with two variations using mental arithmetic and spatial reasoning problems (males/females: 29:4 and 18:2). Most participants showed avoidance, and their choices depended on the demand experienced on multiple preceding trials. We assumed that participants updated the expected cost of mental effort through experience, and fitted their choices by reinforcement learning models, comparing several possibilities. Model-based fMRI analyses revealed that activity in the dorsomedial and lateral frontal cortices was positively correlated with the trial-by-trial expected cost for the chosen option commonly across the different types of cognitive demand. Analyses also revealed a trend of negative correlation in the ventromedial prefrontal cortex. We further identified correlates of cost-prediction error at time of problem presentation or answering the problem, the latter of which partially overlapped with or were proximal to the correlates of expected cost at time of choice cue in the dorsomedial frontal cortex. These results suggest that humans adaptively learn to avoid mental effort, having neural mechanisms to represent expected cost and cost-prediction error, and the same mechanisms operate for various types of cognitive demand. SIGNIFICANCE STATEMENT In daily life, humans encounter various cognitive demands and tend to avoid high-demand options. However, it remains unclear whether humans avoid mental effort adaptively under dynamically changing environments. If so, it also remains unclear what the underlying neural mechanisms are and whether they operate regardless of cognitive-demand types. To address these issues, we developed novel tasks where participants could learn to avoid high-demand options under uncertain and nonstationary environments. Through model-based fMRI analyses, we found regions whose activity was correlated with the expected mental effort cost, or cost-prediction error, regardless of demand type. These regions overlap, or are adjacent with each other, in the dorsomedial frontal cortex. This finding helps clarify the mechanisms for cognitive-demand avoidance, and provides empirical building blocks for the emerging computational theory of mental effort.
Studies of cardiovascular disease and cause-specific mortality trends in Japanese-American men living in Hawaii and risk factor comparisons with other Japanese populations in the Pacific region: a review.

The Honolulu Heart Program (HHP) is a long-term prospective epidemiologic study of cardiovascular disease (CVD) in male descendants of Japanese migrants to Hawaii. The article is a review of data from recent and past HHP studies relevant to the Seventeenth Pacific Science Congress symposium "Changes in Disease Patterns in the Western Pacific and Southeast Asia. " The Ni-Hon-San Study, which compared CVD rates and risk factors in Japanese men living in Japan, Hawaii (HHP), and California, showed that coronary heart disease (CHD) and stroke mortality rates in Hawaii were intermediate between rates in Japan and California. Gradients in CVD risk factors were similar to the gradients in disease rates. From 1966 to 1984 trends in incidence rates for CHD, stroke, and cause-specific mortality were compared for the 8006 participants and 3130 non-participants in the HHP. CHD and stroke rates declined by about 40% for the total HHP cohort. There was a larger decline for CHD mortality (over 60%) in the nonparticipants. There was also a much greater decline in total mortality and cancer mortality rates in the nonparticipants. The results of the reviewed studies show that the subjects, although sharing a common ethnic background, experience different rates of disease when living in diverse geographic and cultural locales. This finding supports evidence that environmental and behavioral factors influence chronic disease rates and provides a basis for intervention and prevention. The finding that nonparticipants in epidemiologic studies can show different incidence trends suggests that caution should be used in interpreting trends limited only to participants.
Big Data Mining and Adverse Event Pattern Analysis in Clinical Drug Trials

Abstract Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov (https://clinicaltrials.gov/), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov. Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs.
Removal of Chlorpyrifos by Water Lettuce (Pistia stratiotes L.) and Duckweed (Lemna minor L.)

The potential of water lettuce (Pistia stratiotes L.) and duckweed (Lemna minor L.) to remove chlorpyrifos in water was investigated under laboratory greenhouse conditions. At initial chlorpyrifos concentrations of 0.0, 0.1 and 0.5 mg/L, the relative growth rates (RGR) of L. minor and P. stratiotes were not significantly different. In contrast, in the presence of 1 mg/L chlorpyrifos the RGR was significantly inhibited, giving an observed fresh weight based RGRFW for P. stratiotes and L. minor from day 0 to 7 of −0.036 and −0.023 mg/g/day, respectively. The maximum removal of chlorpyrifos by P. stratiotes and L. minor, when chlorpyrifos was at an initial culture concentration of 0.5 mg/L, was 82% and 87%, respectively, with disappearance rate constants under these conditions of 2.94, 10.21 and 12.14 μg h−1 for the control (no plants), and with P. stratiotes and L. minor, respectively, giving actual corrected plant removal rate constants of 7.27 and 9.20 μg h−1 for P. stratiotes and L. minor, respectively. The bioconcentration factor (BCF) of L. minor was significantly greater than that for P. stratiotes and therefore, at least under these greenhouse-based conditions, L. minor was more efficient than P. stratiotes for the accelerated removal of chlorpyrifos from water.
Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma.

BACKGROUND This analysis was performed to identify prognostic factors that are predictive of sentinel lymph node (SLN) metastasis in melanoma. METHODS Analysis was performed of a multi-institutional, prospective, randomized trial of SLN biopsy for melanoma. Eligibility criteria included age 18 to 70 years, Breslow thickness of 1.0 mm or more, and clinically negative regional lymph nodes. SLNs were evaluated by serial sectioning and immunohistochemistry for S100. Univariate chi-square and multivariate logistic regression analyses were performed to assess factors predictive of the presence of a positive SLN. Probability values of less than.05 were considered significant. RESULTS SLNs were identified in 99.7% of patients. A total of 1058 patients were evaluated; 961 patients had complete data and were included in the statistical analysis. SLNs were positive for tumor in 208 of 961 patients (22%). Breslow thickness, Clark level, ulceration, and patient age were factors that were found to be independently predictive of the presence of SLN metastasis. CONCLUSIONS Increasing Breslow thickness, Clark level of more than III, the presence of ulceration, and patient age of 60 years or less are the most important independent prognostic factors associated with the finding of positive SLN in patients with melanoma.
Fluidity of the Neural Epithelium During Forebrain Formation in Rat Embryos

SUMMARY During neurulation in rat embryos, the forebrain grows more rapidly than can be accounted for by intrinsic cell division alone, while the adjacent midbrain/rostral hindbrain maintains a constant cell number despite a high mitotic index (the cell cycle time is 6 h throughout the neural epithelium). We have proposed that neuroepithelial cells flow in a rostral direction within the midbrain/rostral hindbrain region, towards and into the rapidly expanding forebrain. Evidence in support of this hypothesis is provided by cell-labelling studies: labelled neuroepithelial cells were injected into specific sites in the midbrain or rostral hindbrain neuroepithelium of unlabelled embryos; after culture of these embryos for 24 h, the labelled cells were found in positions rostral to the injection sites. In the midbrain/rostral hindbrain region, mitotic spindles were found to be predominantly orientated parallel with the long axis of the embryo; transversely orientated spindles were more frequently observed close to the lateral edges than more medially. Neural crest cells emigrate from the lateral edges during neurulation. These observations suggest that mitotic spindle orientation reflects the direction of cell movement: in the lateral region movement towards the lateral edge would maintain cell number in the transverse plane as neural crest cells emigrate; elsewhere, cells are moving mainly in the longitudinal plane, towards the forebrain. The possible causal relationship between cell movement and mitotic spindle orientation is discussed. Cell flow within the intact neural epithelium is compared with cell flow in the intestinal villus epithelium. Other types of epithelial cell movement observed in the cranial neural epithelium during neurulation include expansion and shrinkage of the epithelial surface associated with change of cell shape and microfilament-mediated curvature. Cell rearrangement involving exchange of neighbours and cell movement towards and into a site of epithelio–mesenchymal conversion are also implicated.