Miracle-dz/UniFAR-FTUs huggingface dataset:
Recent Updates on Glucokinase Activators and Glucokinase Regulatory Protein Disrupters for the Treatment of Type 2 Diabetes Mellitus.

INTRODUCTION The impairment of glucose metabolism leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase enzyme is the key regulator of glucose homeostasis that catalyzes the conversion of glucose to glucose-6-phosphate in liver and pancreatic cells. In hepatocytes, GK controls the glucose uptake and glycogen synthesis. The action of liver GK is controlled by Glucokinase Regulatory Protein (GKRP) partially. In fasting conditions the GKRP binds with GK and inactivate it from carbohydrate metabolism and serve as new target for treatment of diabetes mellitus. However, the GK activators as potential antidiabetic agents but results in increased risks of hypoglycemia. CONCLUSION The allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents that can mitigate the risk associated with GK activators. This review discusses the recent advances and current status of potential molecules targeted to GK activators and GK-GKRP disrupters.
When Ovarian Cancer Is Not: Characterizing Nonovarian Cancer Pathology in a Laparoscopy-Based Triage System

Objective Establishing an accurate histologic diagnosis is essential for determining the appropriate course of therapy for ovarian cancer. This study sought to investigate and describe nonovarian cancer pathologies discovered during the systematic laparoscopic workup of presumed advanced ovarian cancer. Methods A retrospective cohort of patients with presumed advanced ovarian cancer (based on elevated CA125 and/or imaging) presenting to our center without confirmed pathologic diagnosis were identified and characterized. Patients without ovarian cancer on final pathology were described and compared with those with confirmed epithelial ovarian cancer using standard statistical methods. Results Nonovarian cancer was found in 26 (7.1%) of 365 cases over 3.5 years of study, and included benign ovarian pathology, and metastatic uterine, breast, and gastrointestinal cancers. Most nonovarian cancer cases could not be diagnosed with percutaneous biopsy, and instead used diagnostic laparoscopy or assessment at the time of laparotomy for diagnosis (58%). No patient received inappropriate treatment. Nonovarian cancer cases were more likely to be nonwhite (P = 0.003), have a better Eastern Cooperative Oncology Group performance status (P < 0.001), and have a lower CA125 value (P < 0.001), and were less likely to have pleural effusions (P = 0.04). Conclusions A systematic laparoscopic triage approach to advanced-stage ovarian cancer eliminates incorrect neoadjuvant chemotherapy administration and inappropriate laparotomy. This algorithm identified a population of women who are more likely to have nonovarian cancer pathology. Increasing screening efforts should be focused on conclusive diagnosis with the least invasive testing possible.
Staphylococcus aureus virulence attenuation and immune clearance mediated by a phage lysin‐derived protein

New anti‐infective approaches are much needed to control multi‐drug‐resistant (MDR) pathogens, such as methicillin‐resistant Staphylococcus aureus (MRSA). Here, we found for the first time that a recombinant protein derived from the cell wall binding domain (CBD) of the bacteriophage lysin PlyV12, designated as V12CBD, could attenuate S. aureus virulence and enhance host immune defenses via multiple manners. After binding with V12CBD, S. aureus became less invasive to epithelial cells and more susceptible to macrophage killing. The expressions of multiple important virulence genes of S. aureus were reduced 2.4‐ to 23.4‐fold as response to V12CBD. More significantly, V12CBD could activate macrophages through NF‐κB pathway and enhance phagocytosis against S. aureus. As a result, good protections of the mice from MRSA infections were achieved in therapeutic and prophylactic models. These unique functions of V12CBD would render it a novel alternative molecule to control MDRS. aureus infections.
Asthma diagnosis using integrated analysis of eosinophil microRNAs

Asthma is a syndrome characterized by airway inflammation and obstruction. Due to its heterogeneity, the difficulties in asthma diagnosis and treatment make the discovery of new biomarkers a focus of research. So, we determined the differential miRNA expression of eosinophils between healthy and asthmatic patients and to establish a differentially expressed miRNA profile detectable in sera for use as biomarker.
Sodium fluoride induces splenocyte autophagy via the mammalian targets of rapamycin (mTOR) signaling pathway in growing mice

Fluoride is known to impair organism’s development and function via adverse effects, and autophagy plays a regulation role in human or animal health and disease. At present, there are no reports focused on fluoride-induced autophagy in the animal and human spleen. The objective of this study was to investigate sodium fluoride (NaF)-induced splenocyte autophagy and the potential mechanism via regulation of p-mTOR in growing mice by using the methods of transmission electron microscopy (TEM), immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. A total of 240 ICR mice were equally allocated into four groups with intragastric administration of distilled water in the control group and 12, 24, 48 mg/kg NaF solution in the experimental groups for 42 days. Results revealed that NaF increased autophagosomes or autolysosomes in spleen. Simultaneously, the autophagy marker LC3 brown punctate staining was increased with NaF dosage increase. On the other hand, NaF caused inhibition of mTOR activity, which was characterized by down-regulation of PI3K, Akt and mTOR mRNA and protein expression levels. And the suppression of mTOR activity in turn resulted in the significantly increased of ULK1 and Atg13 expression levels. Concurrently, NaF increased the levels of mRNA and protein expression of autophagy markers LC3, Beclin1, Atg16L1, Atg12, Atg5 and decreased the mRNA and protein expression levels of p62. The above-mentioned findings verify that NaF induces autophagy via mTOR signaling pathway. The inhibition of mTOR activity and alteration of autophagy-related genes and proteins are the potential molecular mechanism of NaF-induced splenocyte autophagy.
In Vivo and In Vitro Methods to Identify DNA Sequence Variants that Alter RNA Splicing

Identification of sequence variants that create or eliminate splice sites has proven to be a significant challenge and represents one of many roadblocks in the clinical interpretation of rare genetic variation. Current methods of identifying splice‐altering sequence variants are limited by an imperfect understanding of splice signals and the need for cumbersome functional assays. We have recently developed a computational tool that prioritizes putative splice‐altering sequence variants and a moderate‐throughput minigene assay that confirms the variants that alter splicing. This bioinformatic strategy represents a substantial increase in accuracy and efficiency with respect to historical in vitro splicing assays. In this article, we give detailed instructions on how to organize, run, and interpret various features of this procedure. We expect that splice‐altering variants revealed through this protocol can be reliably carried forward for further clinical and biological analyses. © 2018 by John Wiley & Sons, Inc.
MALDI Mass Spectrometry Imaging Reveals Heterogeneous Distribution of Tenofovir and Tenofovir Diphosphate in Colorectal Tissue of Subjects Receiving a Tenofovir-Containing Enema

Efforts to prevent human immunodeficiency virus (HIV) infection via pre-exposure prophylaxis (PrEP) include the development of anti-HIV drugs as microbicides for topical application to the mucosal sites of infection; however, although understanding the distribution profiles of these drugs in target mucosal tissues is of critical importance to guiding their optimization, data in this regard are largely lacking. With this in mind, we developed a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) approach to visualize tenofovir (TFV), an HIV nucleotide analog reverse-transcriptase inhibitor under investigation for use as a topical microbicide, and its active metabolite TFV-diphosphate (TFV-DP) in colorectal biopsies obtained from healthy volunteers who received TFV-containing enemas. Application of MALDI MSI resulted in sufficient spatial resolution to visualize both TFV and TFV-DP and revealed heterogeneity in the distribution profiles of both analytes, including the presence of regions in which TFV and TFV-DP were undetectable, in colorectal tissue at two different time points and concentrations. Cell-specific staining for CD4 T and CD11c dendritic cells, which are important to the establishment of HIV infection, demonstrated that the TFV and TFV-DP distributions were independent of these cell types. MALDI MSI of endogenous lipids demonstrated that the heterogeneity observed for TFV and TFV-DP was not a function of tissue composition or processing. These data provide unique insight into the spatial distribution of TFV and TFV-DP in human colorectal tissue. In addition, this work establishes an approach that can be leveraged to directly detect and visualize these clinically important analytes more broadly in tissue.
Quasiperiodic granular chains and Hofstadter butterflies

We study quasiperiodicity-induced localization of waves in strongly precompressed granular chains. We propose three different set-ups, inspired by the Aubry–André (AA) model, of quasiperiodic chains; and we use these models to compare the effects of on-site and off-site quasiperiodicity in nonlinear lattices. When there is purely on-site quasiperiodicity, which we implement in two different ways, we show for a chain of spherical particles that there is a localization transition (as in the original AA model). However, we observe no localization transition in a chain of cylindrical particles in which we incorporate quasiperiodicity in the distribution of contact angles between adjacent cylinders by making the angle periodicity incommensurate with that of the chain. For each of our three models, we compute the Hofstadter spectrum and the associated Minkowski–Bouligand fractal dimension, and we demonstrate that the fractal dimension decreases as one approaches the localization transition (when it exists). We also show, using the chain of cylinders as an example, how to recover the Hofstadter spectrum from the system dynamics. Finally, in a suite of numerical computations, we demonstrate localization and also that there exist regimes of ballistic, superdiffusive, diffusive and subdiffusive transport. Our models provide a flexible set of systems to study quasiperiodicity-induced analogues of Anderson phenomena in granular chains that one can tune controllably from weakly to strongly nonlinear regimes. This article is part of the theme issue ‘Nonlinear energy transfer in dynamical and acoustical systems’.
Live‐Cell Imaging and Analysis with Multiple Genetically Encoded Reporters

Genetically encoded live‐cell reporters measure signaling pathway activity at the cellular level with high temporal resolution, often revealing a high degree of cell‐to‐cell heterogeneity. By using multiple spectrally distinct reporters within the same cell, signal transmission from one node to another within a signaling pathway can be analyzed to quantify factors such as signaling efficiency and delay. With other reporter configurations, correlation between different signaling pathways can be quantified. Such analyses can be used to establish the mechanisms and consequences of cell‐to‐cell heterogeneity and can inform new models of the functional properties of signaling pathways. In this unit, we describe an approach for designing and executing live‐cell multiplexed reporter experiments. We also describe approaches for analyzing the resulting time‐course data to quantify correlations and trends between the measured parameters at the single‐cell level. © 2018 by John Wiley & Sons, Inc.
Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells

The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.
Oculomotor Assessment in Children

Abstract Oculomotor evaluation as part of videonystagmography is an integral tool in the assessment of vestibular function providing a global assessment of the neurological pathways associated with oculomotor function. The value of an oculomotor evaluation for pediatric evaluation is well established; however, many questions can also arise with the application to the pediatric population. Oculomotor function is age dependent which can have a significant effect on the test results obtain in children. The underlying neural substrates and age effects are discussed across the literature with specific results from recent research using clinical oculomotor equipment and protocols. The evidence suggests there are several key differences in the pediatric population compared with adults. These include longer saccade latencies, reduced smooth pursuit gain, increased optokinetic asymmetry, increased variability in all responses, and increased artifact in saccade and smooth pursuit testing.
Evidence for involvement of a transformer paralogue in sex determination of the wasp Leptopilina clavipes

Transformer (tra) is the central gear in many insect sex determination pathways and transduces a wide range of primary signals. Mediated by transformer‐2 (tra2) it directs sexual development into the female or male mode. Duplications of tra have been detected in numerous Hymenoptera, but a function in sex determination has been confirmed only in Apis mellifera. We identified a tra2 orthologue (Lc‐tra2), a tra orthologue (Lc‐tra) and a tra paralogue (Lc‐traB) in the genome of Leptopilina clavipes (Hymenoptera: Cynipidae). We compared the sequence and structural conservation of these genes between sexual (arrhenotokous) and asexual all‐female producing (thelytokous) individuals. Lc‐tra is sex‐specifically spliced in adults consistent with its orthologous function. The male‐specific regions of Lc‐tra are conserved in both reproductive modes. The paralogue Lc‐traB lacks the genomic region coding for male‐specific exons and can only be translated into a full‐length TRA‐like peptide sequence. Furthermore, unlike LC‐TRA, the LC‐TRAB interstrain sequence variation is not differentiated into a sexual and an asexual haplotype. The LC‐TRAB protein interacts with LC‐TRA as well as LC‐TRA2. This suggests that Lc‐traB functions as a conserved element in sex determination of sexual and asexual individuals.
Does the amplitude of biceps brachii M waves increase similarly in both limbs during staircase, electrically elicited contractions?

Objective: Humans usually tend to control more finely muscle force production in dominant than non-dominant upper limbs. It is well established that motor unit recruitment is a key mechanism by which muscle force is controlled, and we hypothesized that a relatively smaller number of motor units may be recruited in muscles of dominant than non-dominant limbs for any given increase in synaptic input. Hence, we investigated peripheral properties of dominant and non-dominant biceps brachii through the analysis of M-wave responses to incremental electrical stimulation. Approach: Current pulses at progressively greater intensities were applied in the proximal region of biceps brachii of 16 subjects while surface electromyograms were recorded with a grid of electrodes in the distal region. M-wave amplitude was averaged across channels and normalized with respect to the maximum amplitude value, separately for each stimulation intensity and limb. Amplitude–current intensity curves were interpolated to provide an equal number of stimulation levels between limbs. Differences between dominant and non-dominant arms were assessed through the average increase in M-wave amplitude for consecutive stimulation intensities (increments). Main results: Wilcoxon’s signed-rank test showed that increments in the M-wave amplitude were significantly smaller (p = 0.017) in dominant than non-dominant biceps brachii. Significance: The results suggest that there was a more gradual recruitment of motor units in biceps brachii of dominant than non-dominant arms. This is in agreement with the hypothesis of a broader spectrum of motor unit recruitment thresholds in the dominant arm, which may contribute to a finer regulation of force production.
Identifying Asthma Exacerbation-Related Emergency Department Visit Using Electronic Medical Record and Claims Data

Abstract Background Asthma exacerbation leading to emergency department (ED) visit is prevalent, an indicator of poor control of asthma, and is a potentially preventable clinical outcome. Objective We propose to utilize multiple data elements available in electronic medical records (EMRs) and claims database to create separate algorithms with high validity for clinical and research purposes to identify asthma exacerbation-related ED visit among the general population. Methods We performed a retrospective study with inclusion criteria of patients aged 4 to 40 years, a visit to Geisinger ED from January 1, 2006, to October 28, 2013, with asthma on their problem list. Different electronic data elements including chief complaints, vitals, season, smoking, medication use, and discharge diagnoses were obtained to create the algorithm. A stratified random sample was generated to select the charts for review. Chart review was performed to classify patients with asthma-related ED visit, that is, the gold standard. Two reviewers performed the chart review and validation was done on a small subset. Results There were 966 eligible ED visits in the EMR sample and 731 in the claims sample. Agreement between reviewers was 95.45% and kappa statistic was 0.91. Mean age of the EMR sample was 22 years, and mostly white (93%). Multiple models conventionally used in studies were evaluated and the final model chosen included principal diagnosis, bronchodilator, and steroid use for both algorithms, chief complaints for EMR, and secondary diagnosis for claims. Area under the curve was 0.93 (95% confidence interval: 0.91–0.94) and 0.94 (0.93–0.96), respectively, for EMR and claims data, with positive predictive value of > 94%. The algorithms are visually presented using nomograms. Conclusion We were able to develop two separate algorithms for EMR and claims to identify asthma exacerbation-related ED visit with excellent diagnostic ability and varying discrimination threshold for clinical and research purposes.
A Potential Way to Decrease the Know-Do Gap in Hospital Infection Control in Vietnam: “Providing Specific Figures on Healthcare-Associated Infections to the Hospital Staff Can ‘Wake Them Up’ to Change Their Behaviour”

Adequate infection control plays a key role in preventing healthcare-associated infections (HAIs). This study aimed to explore staff perceptions of hospital infection control in a rural and an urban hospital in Vietnam. Individual interviews were conducted with hospital managers, and focus group discussions were conducted with doctors, nurses and cleaning workers separately. Content analysis was applied. An interview guide including discussion points on HAIs, hand hygiene and healthcare waste management was used. Generally, the staff were knowledgeable of hospital infection control, but they were not aware of the situation in their own hospital, and infection control practices in the hospitals remained poor. Reported difficulties in infection control included lack of resources, poor awareness and patient overload. A main theme emerged: ‘Making data on HAIs available for health workers can improve their awareness and motivate them to put their existing knowledge into practice, thus decreasing the know-do gap in infection control’. This could be a feasible intervention to improve infection control practice in the hospitals with limited resources, high workload and patient overload.
Development of a shake tube‐based scale‐down model for perfusion cultures

The use of benchtop bioreactors (BRs) for the development of mammalian cell perfusion cultures is expensive and time consuming, given its complexity in equipment and operation. Scale‐down models, going from liter to milliliter scale, are needed to support the rapid determination of suitable operating conditions in terms of viable cell density (VCD), perfusion rate, and medium composition. In this study, we compare the performance of steady‐state perfusion cultures in orbitally shaken tube and BR systems for a given Chinese hamster ovary cell line. The developed scale‐down model relied on a daily workflow designed to keep the VCD constant at specific target values. This includes: cell count, removal of excessive cells (bleeding), spin down of remaining cells, harvest of cell‐free supernatant, and resuspension in fresh medium. Steady‐state cultures at different VCD values, medium exchange rates and working volumes were evaluated. Shake‐tube perfusion cultures allowed the prediction of cell‐specific growth, glucose consumption, ammonia, and monoclonal antibody production rates for much larger BRs, but not lactate (LAC) production rates. Although charge variant profiles remained comparable, different glycosylation patterns were obtained. The differences in LAC production and glycosylation probably resulted from the discontinuous medium exchange, the poor carbon dioxide removal, and the deficient pH control. Therefore, if requested by the specific process to be developed, product quality has to be fine‐tuned directly in the BR system. Altogether, the developed strategy provides a useful scale‐down model for the design and optimization of perfusion cultures with strong savings in time and media consumption.