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Background: Further exploration of the possible effects of vegetable intake on kidney function is warranted.Objective: We aimed to study the causality of the association between vegetable intake and kidney function by implementing Mendelian randomization (MR) analysis.Methods: This study comprised a cross-sectional dietary investigation using UK Biobank data and MR analysis. For the cross-sectional investigation, 432,732 participants aged 40-69 y from the UK Biobank cohort were included. Self-reported vegetable intake was the exposure, and the outcomes were the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Next, we included 337,138 participants of white British ancestry in the UK Biobank, and a genome-wide association study (GWAS) was performed to generate a genetic instrument. For MR, we first performed polygenic score (PGS)-based 1-sample MR. In addition, 2-sample MR was performed with CKDGen GWAS for kidney function traits, and the inverse variance weighted method was the main MR method.Results: Higher vegetable intake was cross-sectionally associated with a higher eGFR (per heaped tablespoon increase; β: 0.154; 95% CI: 0.144, 0.165) and lower odds of CKD (OR: 0.975; 95% CI: 0.968, 0.982). A PGS for vegetable intake was significantly associated with a higher eGFR [per ordinal category increase (0, 1-3, 4-6, ≥7 tablespoons per day); β: 4.435; 95% CI: 2.337, 6.533], but the association with CKD remained nonsignificant (OR: 0.468; 95% CI: 0.143, 1.535). In the 2-sample MR, the causal estimates indicated that a higher genetically predicted vegetable intake was associated with a higher eGFR (percent change; β: 3.071; 95% CI: 0.602, 0.560) but nonsignificantly associated with the risk of CKD (OR: 0.560; 95% CI: 0.289, 1.083) in the European ancestry data from the CKDGen.Conclusions: This study suggests that higher vegetable intake may have a causal effect on higher eGFRs in the European population. [ABSTRACT FROM AUTHOR]

Background The effects of specific macronutrients on kidney function independent of total calorie intake have rarely been studied, although the composition of macronutrient intake has been reported to affect health outcomes. Objectives We aimed to investigate the effects of macronutrient intake ratios on the risk of chronic kidney disease (CKD) by Mendelian randomization (MR) analysis. Methods The study was an observational cohort study mainly based on the UK Biobank and including MR analysis. First, we evaluated the relative baseline macronutrient composition—that is, the number of calories from each macronutrient divided by total calorie intake—of the diets of UK Biobank participants, and we used Cox regression to assess the incidence of end-stage kidney disease (ESKD) in 65,164 participants with normal kidney function [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2]. We implemented a genetic instrument for relative fat, protein, and carbohydrate intake developed by a previous genome-wide association study (GWAS) and performed MR analysis. Two-sample MR was performed with the summary statistics from independent CKDGen GWAS for kidney function traits (n  = 567,460), including CKD (eGFR <60 mL/min/1.73 m2) and log-transformed eGFR. Results The median relative macronutrient intake composition at baseline was 35% fats, 15% protein, and 50% carbohydrates. Higher relative protein intake in subjects with normal kidney function was significantly associated with a lower risk of incident ESKD (HR: 0.54; 95% CI: 0.30, 0.95) in the observational investigation. Two-sample MR indicated that increased relative fat intake causally increased the risk of kidney function impairment [CKD (OR: 1.94; 95% CI: 1.39, 2.71); log eGFR (β: −0.036; 95% CI: −0.048, −0.024)] and that higher relative protein intake was causally linked to a lower CKD risk [CKD (OR: 0.50; 95% CI: 0.35, 0.72); log eGFR (β: 0.044; 95% CI: 0.030, 0.058)]. Conclusions A desirable macronutrient composition, including high relative protein intake and low relative fat intake, may causally reduce the risk of CKD in the general population. [ABSTRACT FROM AUTHOR]

Tornadoes are generally defined as rotating columns of air characterized by small size, axisymmetry and short duration. Thus, the nature of tornadic wind load is basically different from that of synoptic wind. As direct measurements of velocities are very difficult and limited, lots of empirical and theoretical expressions of tornadic wind have been proposed. In the present study, characteristics of several numerical expressions were investigated, and it was found that the characteristics of velocity fields vary widely from model to model, making it difficult to choose one that is generally applicable. [ABSTRACT FROM AUTHOR]

This paper investigates the effect of the single and multiple aerodynamic modification mechanisms on the dynamic behavior of the principal building that is interfered by a very closely located building. For the study, aeroelastic vibration tests and high-frequency force balance tests are conducted to compare responses and wind forces in a well-simulated turbulent boundary layer flow. The principal building is manufactured with three different building configurations to represent the single and multiple aerodynamic modification treatments; the neighboring building which produces interference effects is made into a square prism model. Results show that the multiple modification treatment is efficient in reducing wind forces in all interference location series. However, it is also found that in certain critical conditions, such treatment is sensitive to reduced velocity, and may amplify the interference effect and result in larger displacements. [ABSTRACT FROM AUTHOR]

Summary Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-β (TGF-β). TGF-β-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-β-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-β led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-β. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions. [ABSTRACT FROM AUTHOR]

This paper addresses the interference effects of high-rise building caused by either an upstream or downstream adjacent building. During the study, aeroelastic vibration tests and high-frequency force balance tests are conducted for two identical square prism models of buildings with an aspect ratio of 8 in a turbulent boundary layer flow. Later, critical locations for interfering buildings are identified by examining interfered force spectral characteristics and various patterns of response trajectories. Finally, an idealized 2D numerical simulation of CFD is tried for the simulations of some critical cases. Although the absolute values from CFD results cannot be perfectly compared with the experimental results, the simulated vorticity movement generated from the existence of both buildings provides an intuitive way for the enhancement of the downstream interference mechanism. [ABSTRACT FROM AUTHOR]

The recharge fractions of injection water in combined abstraction-injection wells (AIW) were determined using continuous radon monitoring and radon mass balance model. The recharge system consists of three combined abstraction-injection wells, an observation well, a collection tank, an injection tank, and tubing for heating and transferring used groundwater. Groundwater was abstracted from an AIW and sprayed on the water-curtain heating facility and then the used groundwater was injected into the same AIW well by the recharge system. Radon concentrations of fresh groundwater in the AIWs and of used groundwater in the injection tank were measured continuously using a continuous radon monitoring system. Radon concentrations of fresh groundwater in the AIWs and used groundwater in the injection tank were in the ranges of 10,830–13,530 Bq/m 3 and 1500–5600 Bq/m 3 , respectively. A simple radon mass balance model was developed to estimate the recharge fraction of used groundwater in the AIWs. The recharge fraction in the 3 AIWs was in the range of 0.595–0.798. The time series recharge fraction could be obtained using the continuous radon monitoring system with a simple radon mass balance model. The results revealed that the radon mass balance model using continuous radon monitoring was effective for determining the time series recharge fractions in AIWs as well as for characterizing the recharge system. [ABSTRACT FROM AUTHOR]

Purpose Calmare therapy (CT) has been suggested as a novel treatment for managing chronic pain. Recently, it was reported to show a positive therapeutic outcome for managing neuropathic pain condition. We performed an exploratory prospective study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). Method We performed an open-labeled, single-arm, exploratory study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). The primary endpoint was a comparison of the 11-point Numerical Rating Scale (NRS) pain score at one month with the baseline score in each patient. Brief Pain Inventory (BPI) and consumption of opioid were also evaluated during follow-up period. Results CT significantly decreased NRS pain score at one month from baseline (p < 0.001) in 20 patients with chemotherapy-induced peripheral neuropathy (n = 6), metastatic bone pain (n = 7), and post-surgical neuropathic pain (n = 7). It also improved overall BPI scores, decreased consumption of rescue opioid (p = 0.050), and was found satisfactory by a half of patients (n = 10, 50.0%). Conclusions Our preliminary results suggest that CT may be considered for cancer patients with various types of CNP. Large studies are necessary to confirm our findings and ascertain which additional CNP show positive response to CT. [ABSTRACT FROM AUTHOR]

Wind pressures on a low-rise building in a large group were measured to investigate the proximity effects of surrounding buildings. Five area densities and a long upstream distance were considered under a suburban flow. Results show that variations of pressure coefficients within one area density are relatively small, and that local pressure coefficients increase significantly because of a rapid decrease in local velocity pressures at the model position. Focusing on the peak pressure coefficients, sensitivity study of area density and building distance were conducted for two area densities. The effect of an upstream building is the largest, and the effect of modified arrangement of all buildings is similar to that of the upstream building. The effects of side and downstream buildings are smaller than that of area density. [ABSTRACT FROM AUTHOR]

Few studies have examined the involvement of specific subregions of the prefrontal cortex in complex regional pain syndrome (CRPS). We analyzed cortical thickness to identify morphologic differences in local brain structures between patients with CRPS and healthy control subjects (HCs). Furthermore, we evaluated the correlation between cortical thickness and neurocognitive function. Cortical thickness was measured in 25 patients with CRPS and 25 HCs using the FreeSurfer method. Pain severity and psychiatric symptoms were assessed using the Short Form McGill Pain Questionnaire and the Beck Depression and Anxiety Inventories, respectively. Neurocognitive function was assessed via the Wisconsin Card Sorting Test and the stop-signal task. The right dorsolateral prefrontal cortex and left ventromedial prefrontal cortex were significantly thinner in CRPS patients than in HCs. CRPS patients made more perseveration errors on the Wisconsin Card Sorting Test and had longer stop-signal task reaction times than HCs. Although the Beck Depression Inventory and the Beck Anxiety Inventory differ significantly between the groups, they were not correlated with cortical thickness. Our study suggests that the pathophysiology of CRPS may be related to reduced cortical thickness in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex. The structural alterations in dorsolateral prefrontal cortex may explain executive dysfunction and disinhibited pain perception in CRPS. Perspective The present study reports decreased cortical thickness in the prefrontal cortex and neurocognitive dysfunctions in patients with CRPS. These findings may contribute to the understanding of pain-related impairments in cognitive function and could help explain the symptoms or progression of CRPS. [ABSTRACT FROM AUTHOR]

Abstract: This paper summarizes the findings from extensive wind tunnel tests carried out by the authors' group for the evaluation of wind load combination effects for various types of building models. Characteristics of correlations of wind force components are examined using the absolute ratio of wind forces, phase–plane trajectories and (absolute) cross-correlation, and then wind load combinations are examined. The necessity to consider wind load combinations is inferred from the instantaneous pressure distributions, and the cross-correlation coefficients of the absolute values of wind force components are found to be more important when examining wind force combinations. Wind load combination effects are directly examined using frame models. Based on the peak normal stresses in columns under various loading conditions, combination factors for low-, middle- and high-rise buildings are proposed. Lastly, effects of wind direction on wind load combinations are discussed. [Copyright &y& Elsevier]

Abstract: For high-rise buildings, the storey height is an important factor influencing the economic efficiency of buildings. The structural system consisting of concrete filled tube columns and flat plate slabs is relatively new. However, the structural behavior of the connection between the concrete filled tube column and the flat plate slab has not yet been fully explored. The finite element analysis is therefore used to examine the stress concentration, load flow, and excessive deformation acting on the connection. Three types of connection details were compared. The analytical parameters are width, thickness of steel tube, length, thickness of wing plate, strength of steel, and eccentricity of rebar. 84 models were analyzed to find the appropriate design equation of the final connection detail. The corresponding proposed design equation showed a good agreement with the finite element analysis results. [Copyright &y& Elsevier]

Abstract: Multiple brain areas involved in nociceptive, autonomic, and social-emotional processing are disproportionally changed in patients with complex regional pain syndrome (CRPS). Little empirical evidence is available involving social cognitive functioning in patients with chronic pain conditions. We investigated the ability of patients with CRPS to recognize the mental/emotional states of other people. Forty-three patients with CRPS and 30 healthy controls performed the Reading Mind in the Eyes Test, which consists of photos in which human eyes express various emotional and mental states. Neuropsychological tests, including the Wisconsin Card Sorting Test, the stop-signal test, and the reaction time test, were administered to evaluate other cognitive functions. Patients with CRPS were significantly less accurate at recognizing emotional states in other persons, but not on other cognitive tests, compared with control subjects. We found a significant association between the deficit in social-emotion recognition and the affective dimension of pain, whereas this deficit was not related to the sensory dimension of pain. Our findings suggest a disrupted ability to recognize others' mental/emotional states in patients with CRPS. Perspective: This article demonstrated a deficit in inferring mental/emotional states of others in patients with CRPS that was related to pain affect. Our study suggests that additional interventions directed toward reducing distressful affective pain may be helpful to restore social cognitive processing in patients with CRPS. [Copyright &y& Elsevier]

Abstract: Systematic wind pressure measurements were conducted in order to investigate the effect of a large group of surrounding buildings on wind pressures on a typical low-rise building. The primary purpose of the present work was to understand the characteristics of wind force correlations and quasi-static wind load combinations of a target model in a large group. Fluctuating pressures were integrated over the surfaces and results were obtained of along-wind force, across-wind force, uplift force, along-wind overturning moment, across-wind overturning moment and torsional moment. First, the characteristics of wind force correlations including the force coefficients, phase-plane expression and cross-correlation coefficients were investigated for an isolated model and for a target model in a large group. Then, in order to directly check the wind load combination effects, peak normal stresses in columns of a simple frame model were examined. Next, a shielding factor of a combination factor was proposed in the form of an exponential function. [Copyright &y& Elsevier]

Abstract: Systematic wind pressure measurements were conducted in order to investigate the effect of a large group of surrounding buildings on wind pressures on a typical low-rise building. The primary purpose of this work was to understand and quantify the effects of nearby structures for engineers/designers, especially with regard to maximum and minimum values. Various ranges of area densities and measurement points were considered under a turbulent boundary layer representing a suburban area. Results show that although the mean pressure coefficient decreases as the area density increases and when the measurement points are located at the downstream side, the fluctuating component increases significantly, giving larger maximum and minimum coefficients than those for an isolated building. [Copyright &y& Elsevier]

Abstract: One characteristic of many tall buildings is that their building shapes vary with height, implying that the distribution of their structural components may also vary with height. Response analyses have been conducted for tall buildings with square plans with height variations using high-frequency force balance data, focusing on comparing the total accelerations of the various building shapes based on the shapes themselves, and not on different natural frequencies. The variation trends of total accelerations are different between mass and rigidity center eccentricity, and the acceleration of the square model is the largest, and the differences among models increase with eccentricity. For the setback and tapered models, although the across-wind acceleration is larger than that of the square model, the along-wind and torsional accelerations are smaller than those of the square model, resulting in smaller total rms acceleration response. However, the increase in torsional response for the tapered and setback buildings when the offsets lie in the windward diagonal direction may enhance building occupants'' awareness of the motion even if the total rms accelerations become small. [Copyright &y& Elsevier]

Abstract: We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5′-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing Gα16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5′-alkyl phosphonate analogues were synthesized and tested. A 6-benzyl-5′-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage. The highest antagonistic potency was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5′-phosphate. The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100nM)-induced inositol trisphosphate (IP3) formation with pIC50 values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA2 value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30nM 2-methylthio-ADP in human P2Y1 receptor-mediated 1321N1 astrocytoma cells with IC50 values of >10 and 0.245μM, respectively. Both analogues were inactive (IC50 >10μM) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells. Thus, MRS2211 displayed >20-fold selectivity as antagonist of the P2Y13 receptor in comparison to P2Y1 and P2Y12 receptors, while MRS2603 antagonized both P2Y1 and P2Y13 receptors. [Copyright &y& Elsevier]

Nonpeptide compounds that mimic bioactive peptides are desirable for a number of clinical indications. We report a new practical method for the design of scaffolds exhibiting drug-like properties that are suitable for the display of peptide pharmacophores. The synthesis of various synthons of 7′-hydroxy-2′,3′-dihydro-1′H,2H,5H-spiro[imidazolidine-4,4′-quinoline]-2,5-dione (1) and methods for the introduction of several mimics of amino acid side-chains are described. This method is exemplified by derivatives that show agonist activity for the somatostatin type 2 receptor. [Copyright &y& Elsevier]

Weather conditions due to climate change affect the health directly and indirectly. Previous studies have shown associations with temperature, heat wave, and cold spell, and these do not only result in mortality from cardiovascular disease, respiratory disease, etc., but also in morbidity. This study aimed to quantify the relative risk for hospital admissions related to ambient temperature for genitourinary system diseases, which are representative of metabolic disease. We conducted a nationwide retrospective cohort study using claims data generated by medical services for diseases of the urinary system. The data was based on medical claims data from 16 districts in South Korea, to the nationwide level between 2003 and 2013. A total of 1,255,671 hospital admissions through the emergency department because of diseases of the genitourinary system were reported within the study period. The overall cumulative relative risk at the 99th percentile vs. the minimum morbidity percentile for renal diseases was 1.252 (95% confidence interval 1.211 to 1.294) in Seoul, 1.252 (1.21 to 1.296) in Busan, 1.236 (1.196 to 1.276) in Daegu, 1.237(1.197 to 1.279) in Gwangju, and 1.258 (1.218 to 1.299) in Gyeonggi-do, 1.278 (1.211 to 1.349) in Chungcheongbuk-do, 1.291 (1.235 to 1.35) in Gyeongsangnam-do. In the group of men over 65 years, the overall cumulative RR was high and statistically significant in acute kidney injury (AKI). But we could not find the effect of high temperature for chronic kidney disease (CKD). The association were rather opposite, but not statistically significant. Our nationwide study not only demonstrates relative risk considering lag effects associated with ambient temperature and trends in hospital admissions through the emergency department for genitourinary disorders but also observed differences among disease groups. [ABSTRACT FROM AUTHOR]

[Display omitted] Drug discovery programs targeting P2X3 receptors (P2X3R), an extracellular adenosine 5′-triphosphate (ATP) gated cation channel family, have been actively investigated for several CNS-related diseases. The current unmet need in the field of P2X3R targeted drugs is to avoid a side effect, the loss of taste, that could be reduced by increase of the P2X3R selectivity vs P2X2/3R. In this study, 5-methyl-1 H -benzo[ d ]imidazole derivatives were designed and synthesized from the analysis of key pharmacophores of current antagonists. In the structure–activity relationship study, the most potent compounds 17a - b was discovered as potent P2X3R antagonists with IC 50 values of 145 and 206 nM, and selectivity index of 60 and 41, respectively. In addition, 17a - b showed the not-competitive antagonism, but poor binding score in the docking study at the known allosteric binding site of Gefapixant binding site, indicating that another allosteric binding site might be existing for the novel P2X3R antagonists. [ABSTRACT FROM AUTHOR]

Recent studies have shown that high levels of serum alkaline phosphatase (ALP) are associated with all-cause and cardiovascular death among patients undergoing hemodialysis. However, there is limited knowledge on the effect of ALP level in kidney transplant recipients (KTRs). The aim of this study was to evaluate if serum ALP levels before and after transplant and the changes in ALP levels are associated with graft failure and mortality. Between January 1997 and December 2012, 3029 KTRs were enrolled in a multicenter cohort. We examined the association of pre- and posttransplant serum ALP levels and long-term outcomes in KTRs. Pretransplant serum ALP level >80 IU/L was associated with a hazard ratio (HR) for graft failure of 1.571 in a fully adjusted model. The graft failure rate gradually increased with ALP level increments of 20 IU/L in KTRs with ALP levels >60 IU/L. An increase in serum ALP level by 40 IU/L during the first 3 months after kidney transplant was associated with higher rates of graft failure (HR, 2.353) and higher rates of mortality (HR, 2.733). Elevated pre-and posttransplant serum ALP levels and increases in the serum ALP levels after kidney transplant increase the risk of graft failure and mortality among KTRs. [ABSTRACT FROM AUTHOR]

This study compared the efficacy and safety of controlled-release pregabalin (GLA5PR GLARS-NF1 tablets) with those of an immediate-release pregabalin capsule after 12 weeks' administration to patients with peripheral neuropathic pain. In this multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III study, the primary outcome was to confirm that a single treatment with the study drug (after the evening meal) is clinically noninferior to the control drug (BID regimen) at improving the mean Daily Pain Rating Scale score for treating peripheral neuropathic pain. Secondary outcomes were the Daily Sleep Interference Scale, Medical Outcomes Study Sleep Scale, Hospital Anxiety and Depression scale, and frequency of rescue medication use. The safety and tolerability of GLA5PR GLARS-NF1 tablets were also evaluated. The total daily dose of pregabalin is 150–600 mg. Of the 352 randomized subjects, 261 (n = 130, study group; n = 131, control group) were analyzed. The difference in adjusted mean Daily Pain Rating Scale scores between the groups was −0.11 (95% confidence interval, −0.05 to 0.30), indicating that the study group is noninferior to the control group. There was no statistically significant difference in Daily Sleep Interference Scale, Medical Outcomes Study Sleep Scale, and Hospital Anxiety and Depression scale scores between the groups at treatment termination. Logistic regression analysis revealed no significant difference in the use of rescue medication between the groups (P = 0.217). The overall adverse event profile of the groups was similar, and no serious adverse drug reactions were observed. GLA5PR GLARS-NF1 tablets can be effectively and safely administered to patients with peripheral neuropathic pain. Furthermore, we found that sleep, anxiety, and depression were improved with pain control. Owing to the once-daily administration, treatment effects can be maximized by improved treatment compliance. ClinicalTrials.gov identifier: NCT03221907. • Pregabalin as a first-line therapy for peripheral neuropathic pain. • Lyrica Capsule administered as 2 doses per day (150-600 mg/day). • GLA5PR GLARS-NF1 Tab. (150 mg and 300 mg) as an extended-release pregabalin formulation for once-daily intake. • The effectiveness and safety of GLA5PR GLARS-NF1 Tab. for peripheral neuropathic pain. • Once-daily administration, treatment effect by improved treatment compliance. [ABSTRACT FROM AUTHOR]

Abstract: Based on the β-catenin-drived Wnt activator of bromoindirubin-3′-oxime (BIO), indirubin analogs were evaluated for β-catenin-mediated gene expression. A novel indirubin analog, indirubin-5-nitro-3′-oxime (INO), was considered a potential activator, and structure–activity studies were conducted with indirubins. These data suggest that INO might be a novel Wnt activator and has a potential of signaling regulator in β-catenin-mediated signaling pathways. [Copyright &y& Elsevier]

This paper investigates the variation of root-mean-square values of acceleration responses and corresponding aerodynamic dampings of two square cross-sectional high-rise buildings with low Scruton numbers due to interference effects caused by neighboring identical buildings. Aero-elastic vibration test is adopted for displacement and acceleration measurements of a rigid, base-pivoted aero-elastic principal building model by a two-directional sway gimbal system. The principal building is manufactured in the shape of a square prism model with an aspect ratio of eight. Twenty close interference locations are of interest, with a special focus on the across-wind responses. Results show that the variations of interfered acceleration responses and estimated damping ratios exhibit different tendencies for different interference locations at different reduced velocities. For the typical upstream interfered effect, the interfering building located at the oblique-upwind locations in this study, the acceleration response with lower Scruton number is suppressed at lower reduced velocities and is amplified at higher reduced velocities. On the other hand, for the secondary downstream interference effect, i.e., the interfering building located at downwind locations, the amplification or reduction in acceleration response is less sensitive to Scruton number but is related to the gap between two buildings. The corresponding response spectra and resultant damping ratios are then calculated to enhance the understanding of different interference mechanisms. Finally, an idealized two-dimensional CFD simulation technique is adopted to further explain the differences between the upstream and downstream interference mechanisms from the viewpoint of the vortex movement between two buildings. • The interfering building is manufactured to be rigid and pivot-based aero-elastic to examine the vibrating effect. • Displacement and acceleration signals are simultaneously recorded at the rooftop of high-rise building under interference effects. • Two Scruton numbers of 1.8 and 4.5 are investigated at various reduced velocities to show the different interference mechanisms. • CFD simulation technology is adopted to intuitively explain the downstream interference effect at two typical reduced velocities: 7.94 for reduction in vibration and 14.44 for amplification in vibration, regardless of Scruton number change. [ABSTRACT FROM AUTHOR]

Lung cancer represents a significant global health concern and stands as the leading cause of cancer-related mortality worldwide. The identification of specific genomic alterations such as EGFR and KRAS in lung cancer has paved the way for the development of targeted therapies. While targeted therapies for lung cancer exhibiting EGFR , MET and ALK mutations have been well-established, the options for RET mutations remain limited. Importantly, RET mutations have been found to be mutually exclusive from other genomic mutations and to be related with high incidences of brain metastasis. Given these facts, it is imperative to explore the development of RET-targeting therapies and to elucidate the mechanisms underlying metastasis in RET-expressing lung cancer cells. In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer. [Display omitted] • The CCDC6-RET gene contributes to the growth and survival of lung cancer cells by activating the PI3K and RAS pathways. • YES1 regulates Cortactin activity to facilitate actin polymerization-dependent cancer cell metastasis. • PLM-101, a novel RET/YES1 dual-target inhibitor, effectively suppresses primary and metastatic secondary lung cancer. [ABSTRACT FROM AUTHOR]

The FMS-like tyrosine kinase 3 (FLT3) gene encodes a class III receptor tyrosine kinase that is expressed in hematopoietic stem cells. The mutations of FLT3 gene found in 30% of acute myeloid leukemia (AML), leads to an abnormal constitutive activation of FLT3 kinase of the receptor and results in immature myeloblast cell proliferation. Although small molecule drugs targeting the FLT3 kinase have been approved, new FLT3 inhibitors are needed owing to the side effects and drug resistances arising from kinase domain mutations, such as D835Y and F691L. In this study, we have developed benzimidazole-indazole based novel inhibitors targeting mutant FLT3 kinases through the optimization of diverse chemical moieties substituted around the core skeleton. The most optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, with IC 50 values of 0.941 and 0.199 nM, respectively. Furthermore, 22f exhibited strong antiproliferative activity against an AML cell line, MV4-11 cells with a GI 50 of 0.26 nM. More importantly, 22f showed single-digit nanomolar GI 50 values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI 50 = 0.29 nM) and FLT3-F691L (GI 50 = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase. [Display omitted] • Benzimidazole-indazole based novel FLT3 inhibitors were designed and synthesized. • The optimized compound 22f showed sub-nanomolar IC 50 values at FLT3 and FLT3/D835Y. • Compound 22f displayed nanomolar GI 50 values against FLT3-TKD-mutated AML cell lines. • The predicted binding mode of 22f at the FLT3 ATP-binding pocket was investigated. [ABSTRACT FROM AUTHOR]

Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z,3E)-5-hydroxy-5′-nitro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) has been targeted for the development of anti-SARS-CoV-2 agents against COVID-19 infection because Mpro processes essential viral polyproteins and plays a key role in SARS-CoV-2 replication. In this study, we report the development of novel SARS-CoV-2 Mpro inhibitors derived from carmofur, a previously identified compound that has shown moderate potency as a covalent inhibitor of SARS-CoV-2 Mpro. To employ a structure-guided drug design strategy, a putative intact binding mode of carmofur at catalytic active site of Mpro was initially predicted by docking simulation. Based on the predicted binding mode, a series of carmofur derivatives aiming to occupy the Mpro substrate binding regions were investigated for structure-activity relationship analysis. As a result, an indole-based derivative, speculated to interact with the S4 binding pocket, 21b (IC 50 = 1.5 ± 0.1 μM) was discovered. Its structure was further modified and evaluated in silico by combining docking simulation, free energy perturbation calculation and subpocket interaction analysis to optimize the interactions at the S2 and S4 binding pockets. Among the newly designed novel derivatives, 21h and 21i showed the best inhibitory potencies against Mpro with IC 50 values of 0.35 and 0.37 μM, respectively. Moreover, their antiviral activities were confirmed with EC 50 values of 20–30 μM in the SARS-CoV-2-infected cell-based assay, suggesting that these novel Mpro inhibitors could be applied as potential lead compounds for the development of substantial anti-SARS-CoV-2 agents. [Display omitted] • Novel potent SARS-CoV-2 Mpro inhibitors were derived from carmofur. • The intact binding mode of carmofur was predicted for in silico design. • The inhibitors were optimized aiming to target S2 and S4 subpockets of Mpro. • The antiviral activity was confirmed in SARS-CoV-2-infected cells. [ABSTRACT FROM AUTHOR]

Due to the low natural frequency and low damping of slender structures, the crosswind aero-elastic effect become dominant around the vortex-resonance wind speed and can lead to undesired crosswind responses. For understanding and describing the aero-elastic effect of slender structures, aerodynamic damping is usually adopted. This study suggested an identification procedure for crosswind aerodynamic damping of slender structures by curve-fitting the probability density function (PDF) of the crosswind response. Firstly, the aerodynamic damping is described by a generalized Van der Pol (GVDP) model, and the analytical solution of response PDF, which is a function of the parameters of GVDP model, is derived by the equivalent nonlinear equation method. Next, the proposed identification method was validated by stochastic simulation of a crosswind-excited tall building. Finally, free-vibration wind tunnel test of a slender structure with slenderness ratio equal to 12 and 20 at open flat terrain was conducted and aerodynamic damping was then quantified by the present method. It is found that the present method provides a robust and accurate identification of crosswind aerodynamic damping of slender structures in atmospheric boundary flow. • Analytical relationship between probability density function (PDF) of crosswind response and nonlinear amplitude-dependent aerodynamic damping was derived. • Aerodynamic damping of slender structures was identified by curve-fitting the response PDF, and verified by the stochastic simulation. • Free-vibration wind tunnel test of a particular slender structure was conducted and aerodynamic damping was quantified. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML. [Display omitted] • The novel FLT3/RET dual-targeting drug, PLM-101, exhibits anti-cancer activity by inducing RET-dependent autophagy activity. • PLM-101 compound synthesized from indirubin with improved solubility and bioavailability, and reduced side effects. • pH-dependent solubility of PLM-101 is responsible for the low toxicity. [ABSTRACT FROM AUTHOR]

Background Percutaneous cervical nucleoplasty (PCN) is an effective treatment for cervical herniated intervertebral disc (C-HIVD). In this retrospective study, we evaluated clinical predictors that affect the successful outcome of PCN. Methods Fluoroscopically guided PCN was conducted for C-HIVD by one pain physician. Successful outcome was defined as a combination of greater than 50% pain relief on the numerical rating scale pain score, no increase in analgesics, and no cervical epidural steroid injection during the 3-month follow-up period. The relationship between outcomes and independent variables, including patient demographics, comorbid diseases, pain duration, type of disc herniation, presence of spinal stenosis, pain location, analgesics, and shape of the PCN needle tip, were investigated using multivariable analyses. Results Of 201 patients, 134 experienced a successful outcome after PCN. In the positive outcome group, shorter pain durations, rarer central canal stenosis, increased unilateral radiculopathy versus axial pain, and more frequent use of the curved tip technique, were reported. Multivariable analyses revealed that unilateral radiculopathy ( P = 0.013) and use of the curved-tip technique ( P = 0.027) were independent positive predictors of successful PCN outcomes; conversely, longer pain duration ( P = 0.014) and concurrent spinal stenosis ( P < 0.001) were negative predictors. No serious complications related to PCN occurred. Conclusions In this study, the success rate of PCN was 66.7% in patients with C-HIVD. Shorter pain duration, the absence of cervical central canal stenosis, pain location (i.e., unilateral radiculopathy vs. axial pain), and the use of the curved-tip technique were positive predictors of successful PCN. [ABSTRACT FROM AUTHOR]

Based on the potent anticancer activity of 6′-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6′-fluorocyclopentenyl-pyrimidines 3a - i and -purines 3j - o to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug 3p of adenine derivative 1b to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of S -adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity in vitro than the cytosine derivative 2b , acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative 1b and N 6 -methyladenine derivative 3k showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A ( 1a ) or Ara-C. However, the phosphoramidate prodrug 3p showed less anticancer activity than 1b , indicating that it did not act as a RNA and/or DNA polymerase inhibitor like 2b . This result also demonstrates that the anticancer activity of 1b largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the N 6 -amino group, the addition of the bulky alkyl group at the N 6 -amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity. [ABSTRACT FROM AUTHOR]

Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R 1 , R 2 and R 3 , of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R 1 position, an adamantyl carboxamide group at R 2 and a 4-methoxy substitution at the R 3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative ( 16c ) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative ( 17k ), with IC 50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds ( 16c and 17k ) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC 50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy (MN) is the most common glomerulonephritis in elderly patients showing nephrotic syndrome. However, little is known about its treatment options and outcomes in elderly MN patients at long term follow-up. We retrospectively enrolled patients with biopsy-proven MN between April 1990 and December 2015 from eight tertiary hospitals in Korea. Among them, we excluded patients who had secondary causes of MN and subnephrotic-range proteinuria. We evaluated the presenting features and clinical outcomes and analyzed the all-cause mortality, renal outcomes, infection, and remission with respect to age. During the median follow-up at 77.2 months, 198 younger patients (<65 years) and 133 elderly patients (≥65 years) were enrolled. Age was an independent risk factor for all-cause mortality, renal outcome, and infection (for all P <  0.05) except remission. In elderly patients, there was no significant factor associated with mortality rate. The use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) was significantly associated with renal outcome and infection (renal outcome, hazard ration [HR] 0.06, 95% confidence intervals [CI] 0.01–0.36, P  = 0.003; infection, HR 0.20, 95% CI 0.04–0.94, P  = 0.041). Immunosuppressant therapy significantly increased renal outcome ( P  = 0.045) and infection ( P  = 0.029) compared with conservative therapy. In conclusion, old age is one of the clinically important predictors for MN patients. Among the treatment of elderly MN patients, only ACEI or ARB was associated with beneficial effects on renal outcome and infection. Elderly MN patients need a more tailored regimen considering their comorbidities and condition. [ABSTRACT FROM AUTHOR]

The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists. [ABSTRACT FROM AUTHOR]

• This study aimed to quantify the effects of greenness on the development of kidney disease. • This study constructed a longitudinal population-based cohort study including all fee-for-service Medicare Part A beneficiaries (aged 65 years or older) in Massachusetts for the period 2000–2016. • We collected annual average Enhanced Vegetation Index (EVI) based on ZIP codes of beneficiaries and used Cox-equivalent Poisson models to estimate the association between EVI and first hospital admission for kidney diseases. • For total kidney disease, hazard ratios (HRs) was 0.95 (95% CI: 0.93 to 0.97) for a 0.1 increase in EVI. For AKI , HR was 0.94 (0.92 to 0.97) for a 0.1 increase in EVI. • To the best of our knowledge, this is the first and largest epidemiological study that investigates the association between greenness and the development of kidney diseases. Recent studies have identified the association of environmental stressors with reduced kidney function and the development of kidney disease. While residential greenness has been linked to many health benefits, the association between residential greenness and the development of kidney disease is not clear. We aimed to investigate the association between residential greenness and the development of kidney disease. We performed a longitudinal population-based cohort study including all fee-for-service Medicare Part A beneficiaries (aged 65 years or older) in Massachusetts (2000–2016). We assessed greenness with the annual average Enhanced Vegetation Index (EVI) based on residential ZIP codes of beneficiaries. We applied Cox-equivalent Poisson models to estimate the association between EVI and first hospital admission for total kidney disease, chronic kidney disease (CKD), and acute kidney injury (AKI), separately. Data for 1,462,949 beneficiaries who resided in a total of 644 ZIP codes were analyzed. The total person-years of follow-up for total kidney disease, CKD, and AKI were 9.8, 10.9, and 10.8 million person-years, respectively. For a 0.1 increase in annual EVI, the hazard ratios (HRs) were 0.95 (95% CI: 0.93 to 0.97) for the first hospital admission for total kidney disease, and the association was more prominent for AKI (HR: 0.94 with 95% CI: 0.92 to 0.97) than CKD (HR: 0.98 with 95% CI: 0.95–1.01]). The estimated effects of EVI on kidney disease were generally more evident in White beneficiaries and those residing in metropolitan areas compared to the overall population. This study found that higher levels of annual residential greenness were associated with a lower risk of the first hospital admission for kidney diseases. Results are consistent with the hypothesis that higher residential greenness benefits kidney patients. [ABSTRACT FROM AUTHOR]