Miracle-dz/UniFAR-FTUs huggingface dataset:
An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus

Purpose of review Sodium-glucose co-transporter-2 (SGLT2) inhibitors are the newest class of oral antihyperglycemic agents that have been approved for the treatment of diabetes mellitus. Over the past year, there have been significant developments in both the safety and efficacy of this class of medications that are presented in this review. Recent findings Apart from data on the glucose-lowering effect of SGLT2 inhibitors, other metabolic benefits have been demonstrated for this class of medications. Moreover, there have been three Food and Drug Administration Drug Safety Communications issued in 2015 that have led to additional drug labeling. The basic mechanism of action, indications, glucose-lowering benefits, other metabolic benefits, and adverse side-effects of SGLT2 inhibitors are presented in this review. Summary SGLT2 inhibitors are medications that have a unique mechanism of action and that lower glucose independent of insulin. Given the recent findings on efficacy and benefits, these agents are rapidly establishing their role in the treatment of diabetes. Especially in patients with type 2 diabetes not willing or not ready to start insulin, SGLT2 inhibitors may be another option in those patients requiring additional glucose lowering and in those with acceptable risk factor profiles. Although there appears to be some positive benefits in cardiovascular endpoints, more research on the long-term outcomes in people taking SGLT2 inhibitors is warranted.
Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

Significance Insulin and glucagon are key hormones controlling blood glucose levels. Insulin binding to its receptor promotes glucose disposal in peripheral tissues and suppresses hepatic glucose output. Patients with inactivating mutations in their insulin receptors experience severe insulin resistance and uncontrolled diabetes. No effective therapy is available. Here we demonstrate that glucagon receptor (GCGR) blockade with monoclonal antibody normalized blood glucose in a mouse model of extreme insulin resistance and hyperglycemia. A surprising finding was that compensatory expansions of α- and β-cell masses in settings of inhibited glucagon and insulin signaling occurred at normal glucose levels. The data show that GCGR antibody inhibition represents a potential therapeutic option for patients with extreme insulin-resistance syndromes. Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled β-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.
Electric Conduction Mechanisms Study within Zr Doped Mn3O4 Hausmannite Thin Films through an Oxidation Process in Air

The electrical conductivity spectroscopy is a powerful technique for the investigation of the ion transport processes. Currently, the frequency dependence of the conductivity can be controlled in a frequency range from mHz up to infrared frequencies. No other experimental method provides a comparable dynamics resolution. In transition metal oxides and their mixed systems, the electrical conduction has been studied extensively due to its incompletely filled 3d shell (Alonso-Domínguez et al., 2016; Baghizadeh et al., 2015; Biju & Khadar, 2003; Boukhachem et al., 2016; Dridi et al., 2015; Khumpaitool & Khemprasit, 2014; Rouahi et al., 2016; Wypych et al., 2014). Among these metal oxides family, hausmannite Mn3O4 has attracted much interest due to its typical intrinsic p-type conductivity (Bose & Biju, 2015a, 2015b; Larbi et al., 2014; Ulutas et al., 2016). It is worth noting that in Mn3O4, Mn exhibits different oxidation states including divalent Mn and trivalent Mn ions located at the tetrahedral and octahedral sites, respectively, which makes it one of the most stable manganese oxide. In addition to its stability, the study of the electrical transport phenomena in Mn3O4 seems so far in demand for various applications such as: lithium-ion batteries (Zhen et al., 2016), supercapacitors
Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection

Introduction In 2012 a large epidemic of pertussis occurred in the Netherlands. We assessed pertussis toxin (PT) antibody levels in longitudinal serum samples from Dutch 10–18 year-olds, encompassing the epidemic, to investigate pertussis infection incidence. Methods: Blood was sampled in October 2011 (n = 239 adolescents), then 1 year (2012; n = 228) and 3 years (2014; n = 167) later. PT-IgG concentrations were measured by immunoassay and concentrations ≥50 IU/mL (seropositive) assumed indicative of an infection within the preceding year. Results: During the 2012 epidemic, 10% of participants became seropositive, while this was just 3% after the epidemic. The pertussis acquisition rate proved to be sixfold higher during the epidemic (97 per 1,000 person-years) compared with 2012–2014 (16 per 1,000 person-years). In 2012, pertussis notifications among adolescents nationwide were 228/100,000 (0.23%), which is at least 40 times lower than the seropositivity percentage. Remarkably, 17 of the 22 seropositive participants in 2011, were still seropositive in 2012 and nine remained seropositive for at least 3 years. Discussion: Longitudinal studies allow a better estimation of pertussis infections in the population. A PT-IgG concentration ≥50 IU/mL as indication of recent infection may overestimate these numbers in cross-sectional serosurveillance and should be used carefully.
Identifying High-Cost, High-Risk Patients Using Administrative Databases in Tuscany, Italy

Objective (1) Assessing the performance of the algorithm in terms of sensitivity and positive predictive value, considering General Practitioners' (GPs) judgement as benchmark, and (2) describing adverse events (hospitalisation, death, and health services' consumption) of complex patients compared to the general population. Data Sources (i) Tuscany administrative database containing health data (2013-5); (ii) lists of complex patients indicated by GPs; and (iii) annual health registry of Tuscany. Study Design The present study is a validation study. It compares a list of complex patients extracted through an administrative algorithm (criteria of high health consumption) to a gold standard list of patients indicated by GPs. GPs' decision was subjective but fairly well reasoned. The study compares also adverse outcomes (Emergency Room visits, hospitalisation, and death) between identified complex patients and general population. Principal Findings Considering GPs' judgement, the algorithm showed a sensitivity of 72.8% and a positive predictive value of 64.4%. The complex cases presented here have higher incidence rates/100,000 (death 46.8; ER visits 223.2, hospitalisations 110.87, laboratory tests 1284.01, and specialist examinations 870.37) compared to the general population. Conclusions The final validated algorithm showed acceptable sensitivity and positive predictive value.
Learning From Errors in Super-Resolution

A novel framework of learning-based superresolution is proposed by employing the process of learning from the estimation errors. The estimation errors generated by different learning-based super-resolution algorithms are statistically shown to be sparse and uncertain. The sparsity of the estimation errors means most of estimation errors are small enough. The uncertainty of the estimation errors means the location of the pixel with larger estimation error is random. Noticing the prior information about the estimation errors, a nonlinear boosting process of learning from these estimation errors is introduced into the general framework of the learning-based super-resolution. Within the novel framework of super-resolution, a low-rank decomposition technique is used to share the information of different super-resolution estimations and to remove the sparse estimation errors from different learning algorithms or training samples. The experimental results show the effectiveness and the efficiency of the proposed framework in enhancing the performance of different learning-based algorithms.
Arthropod Distribution in a Tropical Rainforest: Tackling a Four Dimensional Puzzle

Quantifying the spatio-temporal distribution of arthropods in tropical rainforests represents a first step towards scrutinizing the global distribution of biodiversity on Earth. To date most studies have focused on narrow taxonomic groups or lack a design that allows partitioning of the components of diversity. Here, we consider an exceptionally large dataset (113,952 individuals representing 5,858 species), obtained from the San Lorenzo forest in Panama, where the phylogenetic breadth of arthropod taxa was surveyed using 14 protocols targeting the soil, litter, understory, lower and upper canopy habitats, replicated across seasons in 2003 and 2004. This dataset is used to explore the relative influence of horizontal, vertical and seasonal drivers of arthropod distribution in this forest. We considered arthropod abundance, observed and estimated species richness, additive decomposition of species richness, multiplicative partitioning of species diversity, variation in species composition, species turnover and guild structure as components of diversity. At the scale of our study (2km of distance, 40m in height and 400 days), the effects related to the vertical and seasonal dimensions were most important. Most adult arthropods were collected from the soil/litter or the upper canopy and species richness was highest in the canopy. We compared the distribution of arthropods and trees within our study system. Effects related to the seasonal dimension were stronger for arthropods than for trees. We conclude that: (1) models of beta diversity developed for tropical trees are unlikely to be applicable to tropical arthropods; (2) it is imperative that estimates of global biodiversity derived from mass collecting of arthropods in tropical rainforests embrace the strong vertical and seasonal partitioning observed here; and (3) given the high species turnover observed between seasons, global climate change may have severe consequences for rainforest arthropods.
The Pseudouridine Synthases Proceed through a Glycal Intermediate

The pseudouridine synthases isomerize (U) in RNA to pseudouridine (Ψ), and the mechanism that they follow has long been a question of interest. The recent elucidation of a product of the mechanistic probe 5-fluorouridine that had been epimerized to the arabino isomer suggested that the Ψ synthases might operate through a glycal intermediate formed by deprotonation of C2′. When that position in substrate U is deuterated, a primary kinetic isotope effect is observed, which indisputably indicates that the proposed deprotonation occurs during the isomerization of U to Ψ and establishes the mechanism followed by the Ψ synthases.
Protein kinase N1 critically regulates cerebellar development and long-term function

Increasing evidence suggests that synapse dysfunctions are a major determinant of several neurodevelopmental and neurodegenerative diseases. Here we identify protein kinase N1 (PKN1) as a novel key player in fine-tuning the balance between axonal outgrowth and presynaptic differentiation in the parallel fiber–forming (PF-forming) cerebellar granule cells (Cgcs). Postnatal Pkn1–/– animals showed a defective PF–Purkinje cell (PF-PC) synapse formation. In vitro, Pkn1–/– Cgcs exhibited deregulated axonal outgrowth, elevated AKT phosphorylation, and higher levels of neuronal differentiation-2 (NeuroD2), a transcription factor preventing presynaptic maturation. Concomitantly, Pkn1–/– Cgcs had a reduced density of presynaptic sites. By inhibiting AKT with MK-2206 and siRNA-mediated knockdown, we found that AKT hyperactivation is responsible for the elongated axons, higher NeuroD2 levels, and reduced density of presynaptic specifications in Pkn1–/– Cgcs. In line with our in vitro data, Pkn1–/– mice showed AKT hyperactivation, elevated NeuroD2 levels, and reduced expression of PF-PC synaptic markers during stages of PF maturation in vivo. The long-term effect of Pkn1 knockout was further seen in cerebellar atrophy and mild ataxia. In summary, our results demonstrate that PKN1 functions as a developmentally active gatekeeper of AKT activity, thereby fine-tuning axonal outgrowth and presynaptic differentiation of Cgcs and subsequently the correct PF-PC synapse formation.
Replication status and histological features of patients with triple (B, C, D) and dual (B, C) hepatic infections

In patients with multiple hepatotropic viral infections (B and C, or B, C and D), the reciprocal influence of each virus remains controversial. The aims of this study were twofold: first, to determine the impact of multiple infection on the replication status of B, C and D viruses and on histological features; and second, to compare patients with multiple infection to patients infected only with the hepatitis C virus (HCV). We retrospectively included 50 patients with multiple infection and 50 control HCV patients, who were matched on independent factors associated with fibrosis, such as age, gender, alcohol consumption and duration of infection. The replication status of hepatitis B virus (HBV), HCV and hepatitis D virus (HDV), and histological lesions, were determined. In patients with multiple infection, HCV RNA was present less frequently (44% vs 98%, P < 0.001) and the prevalence of cirrhosis was higher (35% vs 8%, P < 0.001). Among patients with triple infection (n = 16), HBV replication was observed in 25%, HCV RNA was detectable in only two (P < 0.0001) and HCV viremia was significantly lower than in the matched HCV patients (0 vs 54.7, P < 0.0001). Among patients with dual infection (n = 34), HCV RNA was present less frequently in those with serological markers of active HBV infection than in those without (30% vs 79%, P = 0.01). Hence, multiple infection is associated with a decrease of HCV replication. Cirrhosis seems to be more frequently observed in patients with multiple infection. In patients with triple infection, serum HCV RNA and markers of HBV replication were absent in 80%, suggesting that HDV acts as a dominant virus. In patients with dual infection, HBV and HCV exert an alternative, dominant replication.
Hardware Trojan Detection Through Chip-Free Electromagnetic Side-Channel Statistical Analysis

The hardware Trojan (HT) has become a major threat for the integrated circuit (IC) industry and supply chain, and has motivated numerous developments of Trojan detection schemes. Although the side-channel method is the most promising one, nearly all of the side-channel methods require fabricated golden chips, which are very difficult to obtain in reality. In this paper, we propose a novel strategy for HT detection using electromagnetic side-channel-based spectrum modeling and analyzing. We utilize the design data at early stage of the IC lifecycle, and the generated spectrum can serve as the golden reference, and thus we do not need the fabricated golden chips anymore. Another very important feature is that our method is immune to the process variation theoretically. Experimental results on selected Advanced Encryption Standard benchmark circuits on FPGA show that our proposed method can effectively detect Trojans even with very small traces.
Impulsivity and Stress Response in Nondependent Smokers (Tobacco Chippers) in Comparison to Heavy Smokers and Nonsmokers.

INTRODUCTION Tobacco chippers are light smokers with stable patterns of smoking that exhibit lower nicotine dependence severity than heavy smokers. Chippers may provide valuable information about the factors influencing drug dependence. Impulsivity and stress are two factors known to influence smoking. By comparing nondependent smokers (tobacco chippers, n = 25) to dependent smokers (heavy smokers, n = 23) and nonsmokers (n = 25), this study examines the relationship between nicotine dependence, impulsivity, chronic stress, and stress reactivity. METHODS A total of 73 adult participants completed a study visit that included questionnaires to measure nicotine dependence, chronic stress, personality, affect, withdrawal, and craving. Impulsivity was measured with the delay discounting task and the flanker task. Stress reactivity was assessed by monitoring respiration, heart rate, and salivary cortisol during performance of a titrated Stroop task. Effects of acute stress on affect and craving were examined. RESULTS Tobacco chippers were as impulsive as heavy smokers on the delay discounting task but no different from nonsmokers on the flanker task. Heavy smokers reported higher perceived stress than chippers and nonsmokers. Perceived stress was a significant predictor of discounting only in heavy smokers. Acute stress induced changes in respiration, heart rate, and heart rate variability. Craving and negative affect increased after stress in both smoking groups, but craving was associated with affect only in chippers. CONCLUSIONS Tobacco chippers do not differ from heavy smokers in impulsivity, but do differ in perceived stress. One's perception and experience of stress might be associated to nicotine dependence resistance and could inform smoking cessation treatments. IMPLICATIONS By examining impulsivity, chronic stress, and stress reactivity in nondependent smokers (tobacco chippers) compared to dependent smokers and nonsmokers, this study contributes to the understanding of nicotine addiction and informs smoking cessation programs.
AID-ing Signaling in Toxoplasma gondii

ABSTRACT The cyclic GMP-dependent protein kinase (PKG) of apicomplexan parasites is essential for secretion of micronemes and host cell invasion and egress. Both kinase specificity and localization can determine which substrates are phosphorylated. The functions of plasma membrane and cytosolic PKG isoforms of Toxoplasma gondii were unknown because of difficulties precisely manipulating expression of essential genes. Brown et al. (K. M. Brown, S. Long, and L. D. Sibley, mBio 8:e00375-17, https://doi.org/10.1128/mBio.00375-17 ) adapted the auxin-inducible degron (AID) system for conditional expression of T. gondii proteins. AID, in combination with clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 gene editing, facilitated creation of a panel of PKG mutants to demonstrate that the membrane association via acylation of PKG is critical for its essential functions in tachyzoites. The cytosolic form of PKG is not sufficient for viability and is dispensable. These studies illuminate a critical role for targeting of kinase complexes for parasite viability. The AID system enables rapid, conditional regulation of protein expression that expands the molecular toolbox of T. gondii.
Positive School and Classroom Environment: Precursors of Successful Implementation of Positive Youth Development Programs

This case study was based on a school where the Tier 1 Program of the Project P.A. T.H. S. was integrated into the formal curriculum. In this case study, an interview with the school principal, vice-principal, and social worker was conducted in order to understand their perceptions of administrative arrangements and issues in the school, implementation characteristics, program effectiveness, program success, and overall impression. Results showed that several positive school and classroom attributes were conducive to program success, including positive school culture and belief in students' potentials, an inviting school environment, an encouraging classroom environment, high involvement of school administrative personnel, and systematic program arrangement.
Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice

Multidrug resistance protein 1 (MDR1), a phase III drug transporter that exports substrates out of cells, has been discovered in both cancerous and normal tissues. The over expression of MDR1 in cancer cells contributes to multiple drug resistance, whereas the MDR1 in normal tissues protects them from chemical-induced toxicity. Currently, the role of MDR1 in the ovary has not been entirely understood. Our objective is to determine the function of MDR1 in protecting against chemotherapy-induced ovarian toxicity. Using both the in vivo transgenic mouse model and in vitro follicle culture model, we investigated the expression of MDR1 in the ovary, the effect of MDR1 deficiency on doxorubicin (DOX)-induced ovarian toxicity, and the ovarian steroid hormonal regulation of MDR1. Results showed that the MDR1 was expressed in the ovarian epithelial cells, stroma cells, theca cell layers, endothelial cells, and luteal cells. The lack of MDR1 did not affect female ovarian function and fertility; however, its deficiency significantly exacerbated the DOX-induced ovarian toxicity in both in vivo and in vitro models. The MDR1 showed significantly higher expression levels in the ovaries at estrus and metestrus stages than those at proestrus and diestrus stages. However, this dynamic expression pattern was not regulated by the ovarian steroid hormones of estrogen (E2) and progesterone (P4) but correlated to the number and status of corpus luteum. In conclusion, our study demonstrates that the lack of MDR1 promotes DOX-induced ovarian toxicity, suggesting the critical role of MDR1 in protecting female ovarian functions during chemotherapy.