Self-Regulatory Development in Children from Chinese Immigrant Families: Evidence for Commonality and Specificity.

A central theme of acculturative specificity is the heterogeneity of the immigrant experience. This study integrated this application of the Specificity Principle with intergenerational transmission models of self-regulation and identified both common and specific pathways in the self-regulatory development of Chinese American children in immigrant families (N = 169, Mage = 9.2 years). Consistent with intergenerational transmission models, results indicated associations between parents' and children's effortful control, with the mediation of these associations via authoritarian parenting. Parental education, family income, and children's bilingual proficiency were also uniquely associated with children's executive function and effortful control. Together, findings provide new directions for research with ethnic minority immigrant families, and underscore the utility of within-group approaches in advancing research on ethnic minority children's development.

Depressive symptoms in Chinese immigrant mothers: Relations with perceptions of social status and interpersonal support.

OBJECTIVES: The present study examined how English proficiency, aspects of social status (education, income, and shifts in subjective social status), and interpersonal support were directly and indirectly associated with variations in depressive symptoms among Chinese immigrant mothers. METHOD: Individual semistructured interviews and questionnaires were administered to 257 first-generation Chinese immigrant mothers in the United States (Mage = 37.87 years). Participants reported on their English proficiency, perceived shifts in subjective social status, income, education, and levels of interpersonal support. Depressive symptoms were assessed through semistructured individual interviews using a measure previously developed and validated with Chinese American immigrant adults. RESULTS: Path analyses indicated that participants' perceived upward shifts in subjective social status, higher levels of interpersonal support, and higher annual household income were associated with fewer depressive symptoms. Associations between English proficiency and participants' depressive symptoms were mediated by shifts in subjective social status, income, and interpersonal support. CONCLUSION: Chinese immigrant mothers' perceptions of postmigration changes in subjective social status and the availability of interpersonal support play important roles in their mental health, even accounting for objective indicators of socioeconomic status. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Establishing a Parenting Program for Transnationally Separated Chinese Immigrant Families: Community-Based Pilot Program.

Children who experience transnational separation (TS) from their parents, often referred to as "satellite babies," endure a relatively common but underdiscussed experience. To date, no evaluations of clinical interventions to specifically support transnationally separated families have been described. This column describes implementation of a group therapy pilot program for parents to address parenting and emotional concerns related to TS at a social services agency in Boston's Chinatown. Parent and therapist interviews indicated increased skills in negotiating parental feelings of guilt, shame, and regret caused by TS. These insights can guide practitioners and researchers who wish to address family separation in their communities.

Effects of high-protein diet on glycemic control, insulin resistance and blood pressure in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Obesity is a well-known risk factor of type 2 diabetes mellitus (T2DM), and it is commonly accompanied by T2DM. It is estimated that almost two thirds of the population with T2DM is also affected by hypertension. Elevated arterial blood pressure would increase the risk for diabetes development. Recently some studies indicated that a high-protein diet was effective for weight loss, and therefore we hypothesized that a high-protein diet could help control blood glucose, mitigate insulin resistance (IR) and improve blood pressure by weight management in T2DM patients. AIM: The study aimed to systematically review the effects of a high-protein diet on glycemic control, IR and blood pressure in T2DM patients. METHODS: We searched four electronic databases until May 1st 2018 and included all randomized clinical trials comparing a high-protein diet with other diets. Two reviewers independently identified the trials for inclusion and independently extracted data. Either a fixed- or a random-effects model was used to combine the changes in each outcome from baseline to the end of the intervention. The meta-analysis was performed with RevMan 5.3 software. RESULTS: Twelve articles (thirteen studies) including 1138 T2DM patients met our inclusion criteria. Glycemic control was not significantly different between the high-protein diet and control group, with the changes in fasting plasma glucose (FPG) (-0.13 (95% CI (-0.46, 0.19), p = 0.43) mmol/L) and HbA1c% (-0.05 (95% CI (-0.18, 0.08, p = 0.92))) from baseline to the end of intervention. However, the difference in IR between the two groups was statistically significant. Most changes in lipids profiles were favorable. The changes in HDL, LDL, TC, and TG were +0.03 (95% CI (-0.04,0.11), p = 0.35) mmol/L, -0.10 (95% CI (-0.18, -0.02), p = 0.02) mmol/L, -0.21 (95% CI (-0.31, -0.12), p < 0.01) mmol/L and -0.19 (95% CI (-0.33, -0.05), p < 0.01) mmol/L, respectively. The result of HOMA-IR was -0.27 (95% CI (-0.47, -0.06), p < 0.01). Additionally, the difference in blood pressure in terms of systolic blood pressure (-0.57 (95% CI (-2.45, 1.32), p = 0.55)) and diastolic blood pressure (-0.73 (95% CI (-2.48, 1.02), p = 0.41)) was not significant. CONCLUSION: This review showed that a high-protein diet does not significantly improve glycemic control and blood pressure, but can lower LDL, TC, TG and HOMA-IR levels in T2DM patients. Further studies are needed to clarify the effects of a high-protein diet on glycemic control, IR and blood pressure control in T2DM patients.

Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor.

GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers. Plasma clearance was low in monkeys and dogs (9.14 mL min-1 kg-1 and 4.62 mL min-1 kg-1, respectively) and moderate in mice and rats (36.4 mL min-1 kg-1 and 19.3 mL min-1 kg-1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively. Allometric scaling predicted a low clearance of 3.3 mL min-1 kg-1 and a volume of distribution of 1.3 L kg-1 in human. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h). Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP. Simcyp® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.

Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 µM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 µM, A2780 cell culture IC50 = 0.000 49 µM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.

Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.

Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors.

Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

Evaluation of time-dependent cytochrome p450 inhibition in a high-throughput, automated assay: introducing a novel area under the curve shift approach.

Early in the drug discovery process, the identification of cytochrome P450 (CYP) time-dependent inhibition (TDI) is an important step for compound optimization. Here we describe a high-throughput, automated method for the evaluation of TDI utilizing human liver microsomes and conventional CYP-specific mass spectrometer-based probes in a 384-well format. One of the key differences from other published TDI assays is the use of a shift in area the under curve of the percent activity remaining versus inhibitor concentration plot (AUC shift) rather than the traditional fold-shift in IC50, to determine the magnitude of TDI. An AUC shift of < 15% suggests negative TDI and > 15% suggests potential TDI. This AUC shift was used to achieve quantitative data reporting, even in the case of weak inhibitors for which IC50 values cannot be quantified. An Agilent Technologies BioCel 1200 System was programmed such that the TDI liability of up to 77 test compounds, incubated at four test concentrations, with and without NADPH in the pre-incubation, can be analyzed in a single run. The detailed automated methodology, assay validation, data reporting and the novel TDI AUC shift approach to describe magnitude of TDI are presented.

High-Throughput, 384-Well, LC-MS/MS CYP Inhibition Assay Using Automation, Cassette-Analysis Technique, and Streamlined Data Analysi.

Here we describe a high capacity and high-throughput, automated, 384-well CYP inhibition assay using well-known HLM-based MS probes. We provide consistently robust IC(50) values at the lead optimization stage of the drug discovery process. Our method uses the Agilent Technologies/Velocity11 BioCel 1200 system, timesaving techniques for sample analysis, and streamlined data processing steps. For each experiment, we generate IC(50) values for up to 344 compounds and positive controls for five major CYP isoforms (probe substrate): CYP1A2 (phenacetin), CYP2C9 ((S)-warfarin), CYP2C19 ((S)-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4/5 (testosterone and midazolam). Each compound is incubated separately at four concentrations with each CYP probe substrate under the optimized incubation condition. Each incubation is quenched with acetonitrile containing the deuterated internal standard of the respective metabolite for each probe substrate. To minimize the number of samples to be analyzed by LC-MS/MS and reduce the amount of valuable MS runtime, we utilize timesaving techniques of cassette analysis (pooling the incubation samples at the end of each CYP probe incubation into one) and column switching (reducing the amount of MS runtime). Here we also report on the comparison of IC(50) results for five major CYP isoforms using our method compared to values reported in the literature.

High-throughput, 384-well, LC-MS/MS CYP inhibition assay using automation, cassette-analysis technique, and streamlined data analysis.

Here we describe a high capacity and high-throughput, automated, 384-well CYP inhibition assay using well-known HLM-based MS probes. We provide consistently robust IC(50) values at the lead optimization stage of the drug discovery process. Our method uses the Agilent Technologies/Velocity11 BioCel 1200 system, timesaving techniques for sample analysis, and streamlined data processing steps. For each experiment, we generate IC(50) values for up to 344 compounds and positive controls for five major CYP isoforms (probe substrate): CYP1A2 (phenacetin), CYP2C9 ((S)-warfarin), CYP2C19 ((S)-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4/5 (testosterone and midazolam). Each compound is incubated separately at four concentrations with each CYP probe substrate under the optimized incubation condition. Each incubation is quenched with acetonitrile containing the deuterated internal standard of the respective metabolite for each probe substrate. To minimize the number of samples to be analyzed by LC-MS/MS and reduce the amount of valuable MS runtime, we utilize timesaving techniques of cassette analysis (pooling the incubation samples at the end of each CYP probe incubation into one) and column switching (reducing the amount of MS runtime). Here we also report on the comparison of IC(50) results for five major CYP isoforms using our method compared to values reported in the literature.

An automated homogeneous method for quantifying polysorbate using fluorescence polarization.

An automated fluorescence polarization (FP) assay has been developed for the quantitation of polysorbate in bioprocess samples. Using the lipophilic probe 5-dodecanoylaminofluorescein (DAF), polysorbate concentrations above the critical micelle concentration can be quantified by the FP increase that results when DAF inserts into the detergent micelles. The specificity, accuracy, and precision of this assay were defined for samples obtained from vaccine purification processes. Spike recoveries were 98-106% for purified products and 110-120% for crude process intermediates. The coefficients of variation for intra- and interassay precision were less than 9 and 14%, respectively. Because of the operational simplicity of the assay, all of the assay steps from sample preparation to data reduction were automated on a Tecan liquid-handling workstation. The combination of a rapid assay and an automated format makes this method well suited to the routine analysis of samples from trial purification processes which are carried out during the development of a vaccine or therapeutic protein. This method should be adaptable for the quantitation of other detergents into which DAF will insert.