Hernandezkramer1632

Activity-based protein profiling (ABPP) is recognized as a powerful and versatile chemoproteomic technology in drug discovery. Central to ABPP is the use of activity-based probes to report the activity of specific enzymes or reactivity of amino acid types in complex biological systems. Over the last two decades, ABPP has facilitated the identification of new drug targets and discovery of lead compounds in human and infectious disease. Furthermore, as part of a sustained global effort to illuminate the druggable proteome, the repertoire of target classes addressable with activity-based probes has vastly expanded in recent years. Here, we provide an overview of ABPP and summarise the major technological advances with an emphasis on probe development.Post-translational modifications, complex formation, subcellular localization, and cell-type-specific expression create functionally distinct protein subpopulations that enable living systems to execute rapid and precise responses to changing conditions. Systems-level analysis of these subproteomes remains challenging, requiring preservation of spatial information or enrichment of species that are transient and present at low abundance. Engineered proteins have emerged as important tools for selective proteomics based on their capacity for highly specific molecular recognition and their genetic targetability. Here, we focus on new developments in protein engineering for selective proteomics of post-translational modifications, protein complexes, subcellular compartments, and cell types. We also address remaining challenges and future opportunities to integrate engineered protein tools across different subproteome scales to map the proteome with unprecedented depth and detail.In the present study, an accurate, simple and fast bioanalytical method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for simultaneous quantification of plasma selexipag and its main metabolite ACT-333679 concentrations in rats was optimized and established. The purpose of chromatographic separation of selexipag, ACT-333679 and the internal standard (IS, diazepam) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column. The mobile phase was consisted of acetonitrile (solution A) and 0.1 % formic acid in water (solution B) in a linear gradient elution procedure with a flow rate of 0.40 mL/min. The measurement of the analytes and IS was explored using a XEVO TQ-S triple quadrupole tandem mass spectrometer, which was comprised with electrospray ionization (ESI) source in positive ion mode. Selected multiple reaction monitoring (MRM) mode was employed to detect the parent-to-daughter ion transitions as follows m/z 497.4 → 302.2 for selexipag, m/z 420.1 → 378.2 for ACT-333679, and m/z 285.0 → 154.0 for diazepam (IS), respectively. The new UPLC-MS/MS method showed good linearity respectively at the calibration curve range of 0.05-50 ng/mL for selexipag, and 0.05-250 ng/mL for ACT-333679. The intra- and inter-day of accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery and matrix effect were also met the requirements. The newly developed UPLC-MS/MS assay was forward successfully used to describe the pharmacokinetic profiles of selexipag and ACT-333679 in rats after oral treatment with 6.0 mg/kg selexipag.

Determine if the pancreatic necrosis volume (PNV) in computed tomography scan (CT) is a useful marker to predict the severity of acute pancreatitis (AP) comparing its predictive value with current clinical scoring systems.

This retrospective study was conducted in a tertiary hospital, including patients hospitalized with AP during the period of 24 months. Demographic, clinical data, length of hospital stay and analytical parameters were collected from the hospital clinical information digital systems. Other information on the severity of the disease was also reviewed, including BISAP score, organ failure (OF) or admission to the ICU, as well as, complications during hospitalization as infected necrotic collections, surgical procedure or death. The quantification of the necrosis volume, CT severity index and Balthazar score were assessed in the CT studies. ROC curves were carried to compare the correlation between different scoring systems and the acute complications.

This study included 163 patients with AP. The calculated average value of PNV in the CT studies was 242 cc (0-1575 cc). PNV showed lineal correlation with hospital stay (Pearson 0.696) and statistically significant association with acute complications as OF, multiple organ failure, infection, need of treatment or hospitalization at ICU (P < 0.05). The optimal cut-off value for predicting complications of necrosis as infections or need of surgery treatments was 75 cc. Sensibility and specificity were 100 % and 78 %, respectively. ROC curves showed that PNV was the best radiological finding correlated with AP complications.

Necrosis volume is a radiological biomarker highly correlated with AP complications.

Necrosis volume is a radiological biomarker highly correlated with AP complications.In this study, tritiated water (HTO) and organically bound tritium (OBT) activity concentration at different depth soil layers (0-5 cm, 5-10 cm, 10-15 cm, 15-20 cm, and 20-25 cm) were measured in uncultivated and cultivated soil samples collected in the vicinity of the Qinshan nuclear power plant (QNPP) in July, September, and December 2018. The concentration difference, the spatial and temporal distribution, the seasonal variation, and the OBT/HTO ratios were investigated. The average ratios of HTO concentration between uncultivated and cultivated soil moisture were 1.20 ± 0.24, 1.39 ± 0.46 and 0.95 ± 0.14 in July, September and December, respectively, the corresponding values for OBT were 1.17 ± 0.31, 1.22 ± 0.49 and 1.08 ± 0.28. In generally, the highest HTO concentration in uncultivated soil was found for the topsoil (0-5 cm) in July and September and for the deeper soil layer (20-25 cm) in December, while for cultivated soil, the highest levels were found for the middle layer soil in July, for the topsoil (0-5 cm) in September, and for the deeper layer soil (20-25 cm) in December. Both soils, the vertical profile distribution of OBT concentration showed no consistent tendency, and there were no significant differences in the HTO and OBT concentrations between different soil layers, except for the highest concentration. Whether uncultivated soil or cultivated soil, HTO activity concentrations showed an apparent spatial distribution and seasonal variability, decreasing with the distance to the release sources and with sampling time, while OBT concentrations showed lower spatial and seasonal variability than HTO. In most cases, the OBT/HTO ratios were less than 1, with average values of 1.01 ± 0.48 and 1.06 ± 0.86 for cultivated soil and cultivated soil samples, respectively. The results of this work suggest that farming may affect tritium behavior in soil, while the spatial and temporal distribution of tritium is only slightly impacted.

The present study analyzed different protocols of administration of boronophenylalanine (BPA) and sodium butyrate (NaB) to increase the BNCT efficacy for poorly differentiated thyroid cancer (PDTC).

Nude mice implanted with human PDTC cells (WRO) were distributed into four protocols 1) BPA; 2) BPA+ip NaB; 3) BPA+oral NaB; 4) Control. Biodistribution and histologic studies were performed. LAT (BPA transporter) isoforms gene expression was assessed by RT-PCR.

Tumor growth delay was observed in animals of the Protocol #3 (p<0.05). NaB (Protocol #2) increased tumor boron uptake 2-h post BPA injection (p < 0.05). On the other hand, NaB upregulated the expression of all the isoforms of the LAT transporter in vitro. Histologic studies showed a significant decrease of mitotic activity and an increase of vacuoles in tumors of Protocol #3. Neutrons alone or combined with NaB caused some tumor growth delay (p<0.05), while in the BNCT and BNCT+NaB groups, there was a halt in tumor growth in 70 and 80% of the animals, respectively.

Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.

Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.Behavioral learning is driven by adaptive changes in the activation of behaviorally relevant neuronal ensembles. This learning-specific reorganization of neuronal circuits is correlated with activity-dependent modifications of synaptic dynamics. However, a definitive causal link remains to be established. How is synaptic plasticity distributed among circuits to eventually shape behavioral learning? A multi-scale understanding of the progressive plasticity is hindered by the lack of techniques for monitoring and manipulating these events. The current rise of synaptic optogenetics, especially combined with brain-wide circuit imaging, opens an entirely new avenue for studying causality at multiple scales. In this review, we summarize these technical achievements and discuss challenges in linking the plasticity across levels to elucidate the multi-scale mechanisms of learning.Honey and its phenolic compounds specifically chrysin are focused as nutritional supplements and likewise as valued phytochemicals, nutraceuticals, and phytopharmaceuticals alone, or adjuvant with some conventional medications to cause synergistic therapeutic or cytotoxic effects. Through the verified beneficial strategies combat several disturbances, phenolic compounds play fundamental functions in the avoidance and treatment of disorders. Oxidative stress, inflammation, and apoptosis are the three most imperative physiological reactions in the prevalence of numerous ailments. Honey, chrysin, and other phenolic compounds detected in honey can modify clinical conditions via modulation of these contrivances and correlated signaling pathways. The current study desires to review the therapeutic effects of honey and its allied molecular mechanisms. Evidenced-base studies show that honey would represent therapeutic potential against various types of cancer and tumor proliferation (colorectal cancer, breast cancer, bladder cancer, leukemia, glioma, hepatocellular cancer, pancreatic cancer, and melanoma), wounds, diabetes mellitus, neurological (depression, Parkinson disease, and Alzheimer's disease), respiratory, gastrointestinal (peptic ulcer and ulcerative colitis), cardiovascular disorders, renal injuries, liver diseases and many other kinds of physiological dysfunctionalities through various molecular mechanisms contributed with oxidative stress, inflammatory process, and apoptosis.Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor impairments. Most PD drugs act by improving motor impairments, whereas very few drugs that efficiently recover PD-related neuropathological features, particularly α-synuclein-related toxicity, have been developed. In this study, we found that papaverine (PAP) attenuated behavioral deficits and protected against nigrostriatal dopaminergic degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) mouse model of PD. Histological analysis of tissue dissected from mice sacrificed nearly 3 weeks after the completion of treatment revealed that PAP significantly ameliorated microglia/astrocyte activation in the striatum and substantia nigra of MPTP/P-treated mice. In addition, PAP diminished α-synuclein expression and aggregation in this model. Furthermore, PAP inhibited the phosphorylation of α-synuclein at serine 129, which may underlie the observed reduction in α-synuclein aggregation. PAP also reduced the expression of matrix metalloproteinase-3 (MMP-3), and the MMP3-positive area co-labeled with thioflavin-S.