Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects.

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease.

Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.

Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes.

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling. Turnover number (kcat) of CYP2C9 values were optimized to capture the observed profiles in different CYP2C9 genotypes. In the simulation, predicted fraction metabolized by CYP2C9, fraction excreted to urine, bioavailability, and volume of distribution were similar to previously reported values. Predicted plasma concentration-time profiles in different CYP2C9 genotypes were visually similar to the observed profiles. Predicted AUCinf in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.44-, 2.05-, and 3.67-fold higher than the CYP2C9*1/*1 genotype. The ranges of fold errors for AUCinf, Cmax, and t1/2 were 0.84-1.00, 0.61-1.22, and 0.74-0.94 in development and 0.59-0.98, 0.52-0.97, and 0.61-1.52 in validation, respectively, which were within the acceptance criterion. Thus, the PBPK model was successfully established and described the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups. The present model could guide the decision-making of tailored drug administration strategy by predicting the pharmacokinetics of flurbiprofen in various clinical scenarios.

Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.

A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.

Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes.

Metoprolol, a selective ß1-adrenoreceptor blocking agent used in the treatment of hypertension, angina, and heart failure, is primarily metabolized by the CYP2D6 enzyme, which catalyzes α-hydroxylation and O-desmethylation. As CYP2D6 is genetically highly polymorphic and the enzymatic activity differs greatly depending on the presence of the mutant allele(s), the pharmacokinetic profile of metoprolol is highly variable depending on the genotype of CYP2D6. The aim of study was to develop the physiologically based pharmacokinetic (PBPK) model of metoprolol related to CYP2D6 genetic polymorphism for personalized therapy with metoprolol. For PBPK modelling, our previous pharmacogenomic data were used. To obtain kinetic parameters (Km, Vmax, and CLint) of each genotype, the recombinant CYP enzyme of each genotype was incubated with metoprolol and metabolic rates were assayed. Based on these data, the PBPK model of metoprolol was developed and validated in different CYP2D6 genotypes using PK-Sim® software. As a result, the input values for various parameters for the PBPK model were presented and the PBPK model successfully described the pharmacokinetics of metoprolol in each genotype group. The simulated values were within the acceptance criterion (99.998% confidence intervals) compared with observed values. The PBPK model developed in this study can be used for personalized pharmacotherapy with metoprolol in individuals of various races, ages, and CYP2D6 genotypes.

Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 genetic polymorphism.

Piroxicam is a non-steroidal anti-inflammatory drug used to alleviate symptoms of osteoarthritis and rheumatoid arthritis. CYP2C9 genetic polymorphism significantly influences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate the piroxicam physiologically based pharmacokinetic (PBPK) model related to CYP2C9 genetic polymorphism. PK-Sim® version 10.0 was used for the PBPK modeling. The PBPK model was evaluated by predicted and observed plasma concentration-time profiles, fold errors of predicted to observed pharmacokinetic parameters, and a goodness-of-fit plot. The turnover number (kcat) of CYP2C9 was adjusted to capture the pharmacokinetics of piroxicam in different CYP2C9 genotypes. The population PBPK model overall accurately described and predicted the plasma concentration-time profiles in different CYP2C9 genotypes. In our simulations, predicted AUCinf in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.83-, 2.07-, and 6.43-fold higher than CYP2C9*1/*1 genotype, respectively. All fold error values for AUC, Cmax, and t1/2 were included in the acceptance criterion with the ranges of 0.57-1.59, 0.63-1.39, and 0.65-1.51, respectively. The range of fold error values for predicted versus observed plasma concentrations was 0.11-3.13. 93.9% of fold error values were within the two-fold range. Average fold error, absolute average fold error, and root mean square error were 0.93, 1.27, and 0.72, respectively. Our model accurately captured the pharmacokinetic alterations of piroxicam according to CYP2C9 genetic polymorphism.

A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal ß-galactosylceramidase (GALC) activity and formation of neurotoxic ß-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.

Association between the presence of delirium during intensive care unit admission and cognitive impairment or psychiatric problems: the Korean ICU National Data Study.

OBJECTIVE: Delirium in the intensive care unit (ICU) may be a preventable risk factor for cognitive impairment or psychiatric problems. We aimed to evaluate the association between the presence of delirium during hospitalization involving ICU care and post-discharge cognitive impairment or psychiatric problems. DESIGN: A retrospective cohort study. SETTING: A database of nationwide insurance claims data. PATIENTS: All adult patients aged 18 years or older who were admitted to an ICU between January 1, 2008, and May 31, 2015, and had no history of previous cognitive impairment or psychiatric problems were included in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 306,011 patients who met the inclusion criteria, the proportion of those who experienced delirium during hospitalization was 55.0% (n = 168,190). The patients with delirium during hospitalization had significantly increased odds for cognitive impairment (adjusted hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.05-1.29) and psychiatric problems (adjusted HR 1.78; 95% CI 1.67-1.90) after discharge compared with patients without delirium. In patients who had delirium, the incidence of cognitive impairment was 210.8 per 1000 person-years. In 19,496 patients who were diagnosed with cognitive impairment, depression (n = 3233, 16.5%), sleep disorder (n = 1791, 9.2%), and anxiety (n = 1683, 8.6%) were commonly co-diagnosed. The most common psychiatric problem was sleep disorder (148.7 per 1000 person-years), followed by depression (133.3 per 1000 person-years). CONCLUSIONS: Among patients received ICU care, those who experienced delirium during hospitalization had an increased risk of developing cognitive impairment or psychiatric problems post-discharge. Many patients showed multiple cognitive impairment and psychiatric problems during the follow-up period. Efforts to decrease these problems should be made to increase the quality of life of these ICU survivors.

The multiplicative effect of stress and sleep on academic cognitions in Latino college students.

Latino students are increasingly represented in higher education within the United States, but remain one of the groups least likely to graduate from a four-year institution. Stress and sleep are factors that have been implicated in students' academic success. This study examined concurrent and longitudinal interactive effects of stress and sleep on academic cognitions in a sample of 196 Latino students (Mage = 18.95; 64.4% female) in their second and third semester of college. Stress and actigraphy-measured sleep (duration, efficiency, midpoint, midpoint-variability) were measured in the second semester and academic cognitions (engagement, motivation, self-efficacy) were measured in the second and third semesters. Structural equation modeling revealed that higher stress was concurrently related to lower academic cognitions for students with consistently delayed sleep timings (e.g., later average midpoints) and longitudinally related to reduced academic functioning for students with lower sleep efficiency. These findings can inform programs that target stress-reduction and sleep hygiene among incoming college students.

Effects of CYP2C9*3 and *13 alleles on the pharmacokinetics and pharmacodynamics of glipizide in healthy Korean subjects.

Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C9*1/*1, 8 subjects with CYP2C9*1/*3, and 5 subjects with CYP2C9*1/*13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C9*3 and *13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C9*1/*3 and CYP2C9*1/*13 genotypes, the mean AUC0-∞ were increased by 44.8% and 58.2%, respectively (both P < 0.001), compared to those of subjects with CYP2C9*1/*1 genotype, while effects of glipizide on plasma glucose and insulin levels were not significantly different between CYP2C9 genotype groups. In conclusion, individuals carrying the defective CYP2C9*3 and CYP2C9*13 alleles have markedly elevated plasma concentrations of glipizide compared with CYP2C9*1/*1 wild-type.

Long-Term Prognosis of Asthma-Bronchiectasis Overlapped Patients: A Nationwide Population-Based Cohort Study.

PURPOSE: Asthma and bronchiectasis are common chronic respiratory diseases, and their coexistence is frequently observed but not well investigated. Our aim was to study the effect of comorbid bronchiectasis on asthma. METHODS: A propensity score-matched cohort study was conducted using the National Health Insurance Service-Health Screening Cohort database. From 2005 to 2008, 8,034 participants with asthma were weighted based on propensity scores in a 1:3 ratio with 24,099 participants without asthma. From the asthma group, 141 participants with overlapped bronchiectasis were identified, and 7,892 participants had only asthma. Clinical outcomes of acute asthma exacerbation(s) and mortality rates were compared among the study groups. RESULTS: The prevalence of bronchiectasis (1.7%) was 3 times higher in asthmatics than in the general population of Korea. Patients who had asthma comorbid with bronchiectasis experienced acute exacerbation(s) more frequently than non-comorbid patients (11.3% vs. 5.8%, P = 0.007). Time to the first acute exacerbation was also shorter in the asthmatics with bronchiectasis group (1,970.9 days vs. 2,479.7 days, P = 0.005). Although bronchiectasis was identified as a risk factor for acute exacerbation (adjusted odds ratio, 1.73; 95% confidence interval [CI], 1.05-2.86), there was no significant relationship between bronchiectasis and all-cause or respiratory mortality (adjusted hazard ratio [aHR], 1.17; 95% CI, 0.67-2.04 and aHR, 0.81; 95% CI, 0.11-6.08). CONCLUSIONS: Comorbid bronchiectasis increases asthma-related acute exacerbation, but it does not-raise the risk of all-cause or respiratory mortality. Close monitoring and accurate diagnosis of bronchiectasis are required for patients with frequent exacerbations of asthma.

Physiologically based pharmacokinetic (PBPK) modelling of tamsulosin related to CYP2D6*10 allele.

Tamsulosin, a selective [Formula: see text]-adrenoceptor blocker, is commonly used for alleviation of lower urinary tract symptoms related to benign prostatic hyperplasia. Tamsulosin is predominantly metabolized by CYP3A4 and CYP2D6 enzymes, and several studies reported the effects of CYP2D6 genetic polymorphism on the pharmacokinetics of tamsulosin. This study aims to develop and validate the physiologically based pharmacokinetic (PBPK) model of tamsulosin in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 genotypes, using Simcyp® simulator. Physicochemical, and formulation properties and data for absorption, distribution, metabolism and excretion were collected from previous publications, predicted in the simulator, or optimized in different CYP2D6 genotypes. The tamsulosin PBPK model in CYP2D6*wt/*wt and CYP2D6*wt/*10 genotypes were developed based on the clinical pharmacokinetic study where a single oral dose of 0.2 mg tamsulosin was administered to 25 healthy Korean male volunteers with CYP2D6*wt/*wt and CYP2D6*wt/*10 genotypes. A previous pharmacokinetic study was used to develop the model in CYP2D6*10/*10 genotype. The developed model was validated using other clinical pharmacokinetic studies not used in development. The predicted exposures via the PBPK model in CYP2D6*wt/*10 and CYP2D6*10/*10 genotype was 1.23- and 1.76-fold higher than CYP2D6*wt/*wt genotype, respectively. The simulation profiles were visually similar to the observed profiles, and fold errors of all development and validation datasets were included within the criteria. Therefore, the tamsulosin PBPK model in different CYP2D6 genotypes with regards to CYP2D6*10 alleles was appropriately established. Our model can contribute to the implementation of personalized pharmacotherapy of patients, appropriately predicting the pharmacokinetics of tamsulosin reflecting their demographic and CYP2D6 genotype characteristics without unnecessary drug exposure.

Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes.

Meloxicam, a non-steroidal anti-inflammatory drug, is used for the treatment of rheumatoid arthritis and osteoarthritis. Cytochrome P450 (CYP) 2C9 and CYP3A4 are major and minor enzymes involved in the metabolism of meloxicam. Impaired enzyme activity of CYP2C9 variants increases the plasma exposures of meloxicam and the risk of adverse events. The objective of our study is to develop and validate the physiologically based pharmacokinetic (PBPK) model of meloxicam related to CYP2C9 genetic polymorphism using the PK-Sim® software. In vitro kcat of CYP2C9 was optimized in different CYP2C9 genotypes. The demographic and pharmacokinetic dataset for the development of the PBPK model was extracted from two previous clinical pharmacokinetic studies. Thirty-one clinical datasets, representing different dose regimens and demographic characteristics, were utilized to validate the PBPK model. The shapes of simulated plasma concentration-time profiles in each CYP2C9 genotype were visually similar to observed profiles. The predicted exposures (AUCinf) of meloxicam in CYP2C9*1/*3, CYP2C9*1/*13, and CYP2C9*3/*3 genotypes were increased by 1.77-, 2.91-, and 8.35-fold compared to CYP2C9*1/*1 genotype, respectively. In all datasets for the development and validations, fold errors between predicted and observed pharmacokinetic parameters were within the two-fold error criteria. As a result, the PBPK model was appropriately established and properly described the pharmacokinetics of meloxicam in different CYP2C9 genotypes. This study is expected to contribute to reducing the risk of adverse events of meloxicam through optimization of meloxicam dosing in different CYP2C9 genotypes.

Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson's disease enrolled in PPMI.

Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson's disease (PD). GBA encodes the ß-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson's Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.

Physiologically based pharmacokinetic modeling of candesartan related to CYP2C9 genetic polymorphism in adult and pediatric patients.

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.

Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.

Latino Adolescents' Academic Trajectories over the Transition to Higher Education: Variation by School and Neighborhood Contexts and Familism.

Latino college graduation rates continue to fall behind rates of other racial/ethnic groups, highlighting the importance of understanding risk and protective processes across the transition into higher education. The current study examined changes in socio-cultural contexts (i.e., campus and neighborhood co-ethnic composition) and academic achievement across the college transition for Latino adolescents and investigated whether familism values moderated associations. Participants were 188 Latino late-adolescents (Mage = 18.12; SD = 0.40; 62.9% female). Greater campus incongruency (i.e., decrease in co-ethnic composition) was associated with lower achievement for adolescents with low familism values, but not those with average or high levels. Change in neighborhood co-ethnic composition was not associated with achievement. Moving to incongruent campus contexts may be risky for Latino youth who report low levels of familism values, underscoring the importance of sociocultural protective processes in person-context transitions.

Forecasting the Walking Assistance Rehabilitation Level of Stroke Patients Using Artificial Intelligence.

Cerebrovascular accidents (CVA) cause a range of impairments in coordination, such as a spectrum of walking impairments ranging from mild gait imbalance to complete loss of mobility. Patients with CVA need personalized approaches tailored to their degree of walking impairment for effective rehabilitation. This paper aims to evaluate the validity of using various machine learning (ML) and deep learning (DL) classification models (support vector machine, Decision Tree, Perceptron, Light Gradient Boosting Machine, AutoGluon, SuperTML, and TabNet) for automated classification of walking assistant devices for CVA patients. We reviewed a total of 383 CVA patients' (1623 observations) prescription data for eight different walking assistant devices from five hospitals. Among the classification models, the advanced tree-based classification models (LightGBM and tree models in AutoGluon) achieved classification results of over 90% accuracy, recall, precision, and F1-score. In particular, AutoGluon not only presented the highest predictive performance (almost 92% in accuracy, recall, precision, and F1-score, and 86.8% in balanced accuracy) but also demonstrated that the classification performances of the tree-based models were higher than that of the other models on its leaderboard. Therefore, we believe that tree-based classification models have potential as practical diagnosis tools for medical rehabilitation.

Promoter engineering-mediated Tuning of esterase and transaminase expression for the chemoenzymatic synthesis of sitagliptin phosphate at the kilogram-scale.

Here, we report a bienzymatic cascade to produce ß-amino acids as an intermediate for the synthesis of the leading oral antidiabetic drug, sitagliptin. A whole-cell biotransformation using recombinant Escherichia coli coexpressing a esterase and transaminase were developed, wherein the desired expression level of each enzyme was achieved by promotor engineering. The small-scale reactions (30 ml) performed under optimized conditions at varying amounts of substrate (100-300 mM) resulted in excellent conversions of 82%-95% for the desired product. Finally, a kilogram-scale enzymatic reaction (250 mM substrate, 220 L) was carried out to produce ß-amino acid (229 mM). Sitagliptin phosphate was chemically synthesized from ß-amino acids with 82% yield and > 99% purity.

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA.

BACKGROUND: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement. OBJECTIVE: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI). METHODS: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PDGBA patients compared to PDGBA_wildtype patients. RESULTS: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PDGBA_severe . INTERPRETATION: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.