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Targeting the protein-protein interaction (PPI) between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its repressor, Kelch-like ECH-associated protein 1 (Keap1), constitutes a promising strategy for treating diseases involving oxidative stress and inflammation. Here, a fragment-based drug discovery (FBDD) campaign resulted in novel, high-affinity ( K i = 280 nM), and cell-active noncovalent small-molecule Keap1-Nrf2 PPI inhibitors. We screened 2500 fragments using orthogonal assays─fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)─and validated the hits by saturation transfer difference (STD) NMR, leading to 28 high-priority hits. Thirteen co-structures showed fragments binding mainly in the P4 and P5 subpockets of Keap1's Kelch domain, and three fluorenone-based fragments featuring a novel binding mode were optimized by structure-based drug discovery. We thereby disclose several fragment hits, including their binding modes, and show how FBDD can be performed to find new small-molecule Keap1-Nrf2 PPI inhibitors.

The Vam Nao River is located Vietnamese Mekong Delta’s upstream, plays the role of transferring flow from the Tien River to the Hau River and balances the discharge for two of these main branches. Hence, the hydrodynamic regime is very complicated. In 2017, there was a severe riverbank failure, resulting in the loss of many houses and negative impacts on the local people. So, in this research, the TELEMAC model was applied to simulate flow and bed change, combined with field surveys, thereby analyzing the hydrodynamic regime of this river. The model was calibrated using the water level, discharge and suspended load data. The simulation results show that the flow has only one direction from the Tien River to Hau. The maximum velocity in the flood season is 1.66 m/s, the discharge is 8298 m3/s (in 2017), the flow after the confluence appears the vortex. Moreover, the confluence area has a rather high erosion rate, up to 1.2 m/year. According to data collected nearly 30 years, the Vam Nao River’s topographic data signify the riverbed is growing to expand and deepen, over 43 m after the confluence and distributed near the riverbank. With this development trend, it is necessary to continuously monitor to provide early warnings to minimize damages due to the risks of riverbank failure.

The present study assessed the effect of different feed ingredients on nutrient apparent digestibility coefficients (ADC), nitrogen/energy balance and morphology changes in the intestine of Nile tilapia; using a control diet and six test diets, in which the following six ingredients were included at 30%: hydrolysed feather meal (HFM), soybean meal (SBM), rice bran (RB), rapeseed meal (RM), sunflower meal (SFM) and dried distillers grains with solubles (DDGS). The proximal, middle and distal intestine was processed for quantitative histology counting the number of goblet cells (GC), and measuring the thickness of lamina propria (LP) and submucosa (SM). The study showed that the ADC of protein in raw materials were highest in SBM (92.2%), followed by SFM (90.2%), DDGS (89.2%), RM (87.8%), HFM (86.9%) and RB (84.0%). The nutrient ADCs had no correlation with intestinal morphology changes. Only the SBM diet caused noticeable changes in intestinal morphology such as an increase the thickness of SM and LP and the number of GC. The diet composition, however, altered the protein efficiency and the maintenance energy requirement. Protein retention efficiency was the lowest in fish fed HFM and the highest in RB. The highest maintenance energy requirements were observed in HFM and SBM treatments.

The impact of two dietary organic acids (OAs) on nutrient digestibility and intestinal morphology was determined in Nile tilapia under conditions of dissolved oxygen in the water: normoxia and hypoxia. Four diets designated as control (0 g/kg organic acid salt), KDF (2 g/kg potassium diformate), CAB (2 g/kg calcium butyrate) and their combination (4 g/kg of a mixture of KDF and CAB, ration 1:1) were formulated with 520 g/kg of soybean meal in order to produce soybean meal enteritis-like symptoms. The four diets were tested first under normoxic conditions (6 mg/L) for a period of 5 weeks, followed by a test period under hypoxic conditions (3 mg/L). The results showed that OAs were unable to significantly improve growth and nutrient digestibility under normoxic conditions but under hypoxic conditions, there was a significant enhancement of the growth and nutrient digestibility. Fish fed OA-supplemented diets showed improvements in the intestinal morphology under the normoxic conditions, and these effects were more pronounced under the hypoxic conditions. Experimental findings suggest that OAs can improve the nutrient digestibility and intestinal morphology under hypoxic conditions. A synergistic effect by the combination of formic and butyric acid on growth, digestibility and intestinal morphology was not found.

Targeting the protein–protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1–Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220–380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04–0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand–protein interactions, and identify new potent inhibitors of the Keap1–Nrf2 PPI. Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

Pain-related stoicism and cautiousness are theorized to be more prevalent in older than younger patients and to lead to greater pain under-reporting and consequently inadequate pain management in older patients. The Pain Attitudes Questionnaire-Revised (PAQ-R), which measures 5 pain-related stoicism (fortitude, concealment, superiority) and cautiousness (self-doubt, reluctance) factors in chronic pain, can help test this hypothesis in advanced cancer but requires validation. We conducted a psychometric evaluation of the PAQ-R in 155 younger (younger than 60 years) and 114 older (aged 60 years and older) patients with advanced cancer. Participants showed disagreement with self-doubt items and floor effects with the subscale. Confirmatory factor analyses revealed good fit of the PAQ-R's 5 factors to younger and older groups' data but collinearity between fortitude and concealment. Multisample confirmatory factor analyses supported partial scalar invariance between age groups. Few hypothesized age-related differences were observed. Younger patients reported higher superiority scores than older patients. Whereas older patients showed greater fortitude and superiority with lower average pain intensity, younger patients showed greater concealment or fortitude with greater worst and average pain intensity. Furthermore, whereas older patients displayed greater superiority with lower interference in relations with others, younger patients displayed greater concealment and superiority with greater interference in walking ability and greater concealment and self-doubt with more interference in relations with others. Cross-validation of the PAQ-R's factor structure and identification of pathways to the factors and effect on pain-related outcomes using multivariate approaches are warranted. Perspective This article presents the psychometric properties of a measure of 2 particular pain-related attitudes. The measure can help clarify whether these attitudes adversely influence pain reporting in older patients with advanced cancer as hypothesized and, in turn, explain the inadequate pain management frequently reported with this clinical group.

The present study was undertaken to evaluate the individual and combined effects of oxygen concentration and diet composition on the growth, nutrient utilization and intestinal morphology of Nile tilapia (Oreochromis niloticus). Two recirculating aquaculture systems were used to create the difference in oxygen concentration: normoxia (6.9 mg·L− 1) and hypoxia (3.5 mg·L− 1). Two diets were formulated using a different soybean meal (SBM) content to create a contrast in the potential to affect the gut barrier function. Triplicate groups of 35 fish with initial mean body weight of 23 g were fed “Control” diet containing 20% fish meal and “Test” diet containing only plant protein source at normoxia and hypoxia for 8 weeks. Six fish per treatment were sampled for intestinal morphological analysis at the end of week 1, 4 and 8. The proximal, middle and distal intestine were processed for quantitative histology, in order to count goblet cells (GC) and eosinophilic granulocytes (EG); and to measure the thickness of lamina propria (LP) and sub-epithelial mucosa (SM). The study showed that growth was best in the “Control” diet under normoxia, while no interaction between oxygen and diet composition was found. Hypoxia reduced nutrient digestibility significantly (p < 0.05). For the “Test” diet, the decline in digestibility was larger than for “Control” diet over time. Both diet composition and oxygen level induced changes in intestinal morphology of Nile tilapia. We observed a thickening of the LP and SM caused by an increased infiltration of inflammatory cells, and an increased number of GC and EG among the enterocytes. The negative effect of increased soybean meal on intestinal morphology was enhanced at low oxygen level and aggravated in time. The SBM enteritis-like symptoms were more pronounced in the proximal than in the distal intestine of Nile tilapia.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has a protective effect against oxidative stress and plays a major role in inflammation and central nervous system (CNS) diseases. Inhibition of the protein-protein interaction (PPI) between Nrf2 and its repressor protein, Kelch-like ECH-associated protein 1 (Keap1), leads to translocation of Nrf2 from the cytosol to the nucleus and expression of detoxifying antioxidant enzymes. To date, several non-covalent small-molecule Keap1-Nrf2 inhibitors have been identified; however, many of them contain carboxylic acids and are rather large in size, which likely prevents or decreases CNS permeability. This Perspective describes current small-molecule Keap1-Nrf2 inhibitors with experimental evidence for the ability to inhibit the Keap1-Nrf2 interaction by binding to Keap1 in a non-covalent manner. Binding data, biostructural studies, and biological activity are summarized for the inhibitors, and their potential as CNS tool compounds is discussed by analyzing physicochemical properties, including CNS multiparameter optimization (MPO) scoring algorithms. Finally, several strategies for identifying CNS-targeting Keap1 inhibitors are described.

Age differences are not evident in pain-related stoicism and cautiousness in people with cancer pain. Little is known about the factors associated with these pain-related attitudes or age-related patterns in these associations. The present cross-sectional study investigated the biopsychosocial correlates of the attitudes in younger and older patients with advanced cancer. Pain-related stoicism (fortitude, concealment, superiority) and cautiousness (self-doubt, reluctance) were assessed using the Pain Attitudes Questionnaire-Revised (PAQ-R). Participants, 155 younger (younger than 60 years old) and 114 older (60 years old or older) patients with advanced cancer completed the PAQ-R and measures of sociodemographic and medical characteristics, pain intensity, cognitive-affective pain-related responses, physical functioning, psychological distress and well-being, and psychosocial functioning. Backwards regression analyses identified correlates for each PAQ-R factor separately for younger and older patients. Activity engagement was a frequent correlate, but its relationship with concealment was the only association common to both age groups. Younger and older patients exhibited different avoidance-related constructs suggesting relational challenges in the former group (avoidant attachment) and intrapersonal fear in the latter (cognitive avoidance). Medical correlates also showed age differences: younger patients showed symptom-focused correlates, whereas older patients showed aging-related correlates. Findings support a biopsychosocial framework of cancer-pain adaptation incorporating a lifespan-developmental perspective. Perspective To our knowledge, this article is the first to identify biopsychosocial correlates of stoic and cautious attitudes toward cancer pain in younger and older patients with advanced cancer. Findings highlight possible age-related motivations for greater pain-related stoicism or cautiousness and can potentially inform interventions addressing challenges in cancer-pain adaptation in advanced cancer.

An increase in salinity of the aquatic habitat can be an environmental stress factor for fresh aquatic organism, including fish. The present study investigated the impact of salinity and diet composition on digestibility and intestinal morphology of Nile tilapia. Triplicate groups of 35 fish weighing 35 g were fed a “Control” and “Test” diet and kept at salinity of 0‰ and 15‰ for 8 weeks. The diets were formulated using a different soybean meal content to create a contrast in alterations in intestinal morphology. Six fish per treatment were sampled for intestinal morphology analysis at the end of weeks 1, 4 and 8. The proximal, middle and distal intestine were processed for quantitative histology, in order to count the number of goblet cells and eosinophilic granulocytes; and to measure the thickness of lamina propria and sub-epithelia mucosa. The study showed that a salinity of 15‰ increased the nutrient digestibility; however this enhanced digestibility diminished over time. The intestinal morphology was influenced by both the salinity as well as the dietary soybean meal content. For soybean meal, the impact on morphology was largest in the proximal region of the intestine, whereas for salinity the largest impact was in the distal region. The negative effect of increased soybean meal on the lamina propria thickness was enhanced at a salinity of 15‰ and aggravated in time. Difference in nutrient digestibility induced by the salinity seemed not to be related to alterations in the intestinal morphology.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Gentamicin pharmacokinetics show wide inter-individual variability across all age groups and impaired gentamicin clearance is associated with impaired creatinine clearance in older people. • Changes in body composition and renal function with old age and frailty are likely to affect the pharmacokinetics of gentamicin. • There is current debate on whether the Modification of Diet in Renal Disease (MDRD) equation estimate of glomerular filtration rate (GFR) should replace the Cockcroft Gault equation estimate of creatinine clearance for calculation of doses of renally excreted drugs. WHAT THIS STUDY ADDS • The volume of distribution of gentamicin is not significantly lower in frail than in non frail older people. • The correlation between volume of distribution of gentamicin and actual bodyweight is poor in frail and moderate in non frail older people. • Gentamicin clearance is significantly lower in frail than in non frail older people. • The Cockcroft Gault calculation of creatinine clearance, calculated using ideal bodyweight, gave the best estimate of gentamicin clearance in this population of frail and non frail older people. • The MDRD estimate of GFR and Cockcroft Gault estimate of creatinine clearance, calculated using actual bodyweight, overestimate gentamicin clearance in frail and non frail older people. AIMS Frailty, a syndrome of decreased physiological reserve that is prevalent in old age, impacts on clinical pharmacology. The aims of the study were to (1) determine whether frailty affects the pharmacokinetics of gentamicin and (2) assess the accuracy of different estimates of body size and renal clearance as estimates of gentamicin pharmacokinetics in older inpatients. METHODS This was an observational study of gentamicin pharmacokinetics in a cohort of Australian hospital inpatients aged ≥65 years, who were administered prophylactic intravenous gentamicin. RESULTS Of the 31 participants, 14 were frail and 17 non frail on the Reported Edmonton Frail Scale. The mean volume of distribution of gentamicin was 14.8 ± 1.4 l in frail participants and 15.3 ± 2.2 l in non frail (NS). Volume of distribution correlated best with lean bodyweight. Gentamicin clearance was significantly lower in frail participants (46.6 ± 10.7 ml min−1) than in non frail (58.2 ± 12.4 ml min−1, P= 0.01). The Cockcroft Gault estimate of creatinine clearance calculated using ideal bodyweight gave the best estimate of gentamicin clearance (mean error – 0.15 ml min−1, 95% CI −2.67, 2.39). The Cockcroft Gault creatinine clearance calculated using actual bodyweight and the estimated glomerular filtration rate from the modified diet in renal disease equation overestimated gentamicin clearance, with mean errors of −10.15 ml min−1 (95%CI −13.60, −6.71) and −18.86 ml min−1 (95% CI −22.45, −15.27), respectively. The Cockcroft Gault creatinine clearance calculated using lean bodyweight underestimated gentamicin clearance (mean error 6.54 ml min−1, 95% CI 4.18, 8.90). CONCLUSIONS Frail older people have significantly lower gentamicin clearance than non frail. The best estimate of gentamicin clearance is obtained from the Cockcroft Gault creatinine clearance calculated using ideal bodyweight.

The world’s highest incidence of thyroid cancer has been reported among females in New Caledonia, a French overseas territory in the Pacific located between Australia and Fiji. To date, no molecular genetic studies in this population are available. Over the past few years, the oncogenic rearrangement of the ret protooncogene (ret/ptc) has been studied in papillary carcinomas in different populations. In this study, we investigated the prevalence and distribution of ret/ptc1, 2, and 3 in papillary thyroid carcinoma from the New Caledonian population and compared the pattern with that of an Australian population. Fresh-frozen and paraffin-embedded papillary carcinomas from 27 New Caledonian and 20 Australian patients were examined for ret rearrangements by means of RT-PCR with primers flanking the chimeric region, followed by hybridization with radioactive probes. ret/ptc was present in 70% of the New Caledonian and in 85% of the Australian samples. Multiple rearrangements were detected and confirmed by sequencing in 19 cases, 4 of which had 3 types of rearrangements in the same tumor. This study demonstrates a high prevalence of ret/ptc in New Caledonian and Australian papillary carcinoma. The findings of multiple ret/ptc in the same tumor suggest that some thyroid neoplasms may indeed be polyclonal.

A variety of lasers are used for many oral soft tissue procedures. Each dental laser has specific parameters giving a wide range of operation. Lasers such as the carbon dioxide, argon and diode operate in continuous wave, while Nd:YAG, Er:YAG, Ho:YAG, and Er,Cr:YSGG are free-running pulsed lasers with high peak power and very short pulse duration. Laser tissue interaction is basically a photothermal effect and the biologic effect is dependent on the laser operating parameters, such as emission wavelength, power, emission mode, pulse duration, energy/pulse, energy density, duration of exposure, total energy and tissue characteristics. This article reviews current knowledge of laser parameters, laser-tissue interaction and applied preclinical and clinical safety and effectiveness scientific support.