Nguyen TA

References (9)

Title : C-Terminal beta8-alpha9 Interaction Modulates Thermal Stability and Enzymatic Activity Differently in Hyperthermophilic Esterase EstE1 and Mesophilic Esterase rPPE - Nguyen_2023_Appl.Environ.Microbiol__e0066223
Author(s) : Nguyen TA , Jang SH , Lee C
Ref : Applied Environmental Microbiology , :e0066223 , 2023
Abstract : Hydrophobic interactions and hydrogen bonds are 2 types of noncovalent interactions that play distinct roles in the folding and structural stability of proteins. However, the specific roles of these interactions in hydrophobic or hydrophilic environments in alpha/beta-hydrolases are not fully understood. A hyperthermophilic esterase EstE1 in a dimer maintains the C-terminal beta8-alpha9 strand-helix via hydrophobic interactions (Phe276 and Leu299), constituting a closed dimer interface. Moreover, a mesophilic esterase rPPE in a monomer maintains the same strand-helix via a hydrogen bond (Tyr281 and Gln306). Unpaired polar residues (F276Y in EstE1 and Y281A/F and Q306A in rPPE) or reduced hydrophobic interactions (F276A/L299A in EstE1) between the beta8-alpha9 strand-helix decrease thermal stability. EstE1 (F276Y/L299Q) and rPPE WT, both with the beta8-alpha9 hydrogen bond, showed the same thermal stability as EstE1 WT and rPPE (Y281F/Q306L), which possess hydrophobic interactions instead. However, EstE1 (F276Y/L299Q) and rPPE WT exhibited higher enzymatic activity than EstE1 WT and rPPE (Y281F/Q306L), respectively. This suggests that alpha/beta-hydrolases favor the beta8-alpha9 hydrogen bond for catalytic activity in monomers or oligomers. Overall, these findings demonstrate how alpha/beta-hydrolases modulate hydrophobic interactions and hydrogen bonds to adapt to different environments. Both types of interactions contribute equally to thermal stability, but the hydrogen bond is preferred for catalytic activity. IMPORTANCE Esterases hydrolyze short to medium-chain monoesters and contain a catalytic His on a loop between the C-terminal beta8-strand and alpha9-helix. This study explores how hyperthermophilic esterase EstE1 and mesophilic esterase rPPE adapt to different temperatures by utilizing the beta8-alpha9 hydrogen bonds or hydrophobic interactions differently. EstE1 forms a hydrophobic dimer interface, while rPPE forms a monomer stabilized by a hydrogen bond. The study demonstrates that these enzymes stabilize beta8-alpha9 strand-helix differently but achieve similar thermal stability. While the beta8-alpha9 hydrogen bond or hydrophobic interactions contribute equally to thermal stability, the hydrogen bond provides higher activity due to increased catalytic His loop flexibility in both EstE1 and rPPE. These findings reveal how enzymes adapt to extreme environments while maintaining their functions and have implications for engineering enzymes with desired activities and stabilities.
ESTHER : Nguyen_2023_Appl.Environ.Microbiol__e0066223
PubMedSearch : Nguyen_2023_Appl.Environ.Microbiol__e0066223
PubMedID: 37289049
Gene_locus related to this paper: 9psed-l7pyq2 , 9arch-q5g935

Title : A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y - Nguyen_2020_Neuron_106_759
Author(s) : Nguyen TA , Wu K , Pandey S , Lehr AW , Li Y , Bemben MA , Badger JD, 2nd , Lauzon JL , Wang T , Zaghloul KA , Thurm A , Jain M , Lu W , Roche KW
Ref : Neuron , 106 :759 , 2020
Abstract : Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing approximately 97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.
ESTHER : Nguyen_2020_Neuron_106_759
PubMedSearch : Nguyen_2020_Neuron_106_759
PubMedID: 32243781
Gene_locus related to this paper: human-NLGN4X

Title : Neuroligins and Neurodevelopmental Disorders: X-Linked Genetics - Nguyen_2020_Front.Synaptic.Neurosci_12_33
Author(s) : Nguyen TA , Lehr AW , Roche KW
Ref : Front Synaptic Neurosci , 12 :33 , 2020
Abstract : Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results in social-communication impairments, as well as restricted and repetitive behaviors. Moreover, ASD is more prevalent in males, with a male to female ratio of 4 to 1. Although the underlying etiology of ASD is generally unknown, recent advances in genome sequencing have facilitated the identification of a host of associated genes. Among these, synaptic proteins such as cell adhesion molecules have been strongly linked with ASD. Interestingly, many large genome sequencing studies exclude sex chromosomes, which leads to a shift in focus toward autosomal genes as targets for ASD research. However, there are many genes on the X chromosome that encode synaptic proteins, including strong candidate genes. Here, we review findings regarding two members of the neuroligin (NLGN) family of postsynaptic adhesion molecules, NLGN3 and NLGN4. Neuroligins have multiple isoforms (NLGN1-4), which are both autosomal and sex-linked. The sex-linked genes, NLGN3 and NLGN4, are both on the X chromosome and were among the first few genes to be linked with ASD and intellectual disability (ID). In addition, there is a less studied human neuroligin on the Y chromosome, NLGN4Y, which forms an X-Y pair with NLGN4X. We will discuss recent findings of these neuroligin isoforms regarding function at the synapse in both rodent models and human-derived differentiated neurons, and highlight the exciting challenges moving forward to a better understanding of ASD/ID.
ESTHER : Nguyen_2020_Front.Synaptic.Neurosci_12_33
PubMedSearch : Nguyen_2020_Front.Synaptic.Neurosci_12_33
PubMedID: 32848696

Title : Potentially inappropriate prescribing before and after initiation of medicines for dementia: An Australian population-based study - Eshetie_2019_Geriatr.Gerontol.Int_19_654
Author(s) : Eshetie TC , Nguyen TA , Gillam MH , Kalisch Ellett LM
Ref : Geriatr Gerontol Int , 19 :654 , 2019
Abstract : AIM: To evaluate the prevalence of potentially inappropriate prescribing (PIP), as defined by the internationally validated Screening Tool of Older Person's Prescriptions (STOPP) criteria, in 12 months before and after initiation of medicines for dementia. METHODS: A retrospective cohort study was carried out involving people with their first claim for dispensing of medicines for dementia (cholinesterase inhibitor or memantine) between 1 January 2015 and 31 December 2015, aged >/=65 years at 1 January 2016 and alive at the end of 2016. The index date was defined as the date of first supply of medicines for dementia. PIP was identified using the Screening Tool of Older Person's Prescriptions criteria, and PIP prevalence was compared in the 12 months pre- and post-index date. The McNemar's test was used to test differences in the prevalence of PIP between the two time periods. RESULTS: The cohort included 1176 patients: 60% were women and the median age was 80 years. The overall PIP prevalence was 85% in the 12 months pre-initiation of medicines for dementia compared with 89% in the 12 months post-initiation (P < 0.0001). The median number of Screening Tool of Older Person's Prescriptions criteria was two (interquartile range 1-4) in the 12 months pre-initiation of medicines for dementia, increasing to three (range 2-4) in the 12 months post-initiation. CONCLUSIONS: PIP was common in people dispensed medicines for dementia, with a significant increase in prevalence post-initiation of medicines for dementia compared with pre-initiation. These results highlight the need for targeted interventions to minimize inappropriate use of medicines in people with dementia. Geriatr Gerontol Int 2019; 19: 654-659.
ESTHER : Eshetie_2019_Geriatr.Gerontol.Int_19_654
PubMedSearch : Eshetie_2019_Geriatr.Gerontol.Int_19_654
PubMedID: 31074090

Title : Potentially inappropriate prescribing in people with dementia: An Australian population-based study - Eshetie_2019_Int.J.Geriatr.Psychiatry_34_1498
Author(s) : Eshetie TC , Nguyen TA , Gillam MH , Kalisch Ellett LM
Ref : Int J Geriatr Psychiatry , 34 :1498 , 2019
Abstract : OBJECTIVE: To investigate the prevalence of potentially inappropriate prescribing (PIP) using the Screening Tool of Older Person's Prescriptions (STOPP) criteria in people with dementia compared with people without dementia. METHODS: A retrospective cohort study was conducted using the Pharmaceutical Benefits Scheme 10% sample of pharmacy claims. People with dementia were defined as those dispensed a medicine for dementia (cholinesterase inhibitors, memantine, or risperidone for behavioural and psychological symptoms of dementia) between 1 January 2005 and 31 December 2015, aged 65 years or older at 1 January 2016 and alive at the end of 2016. An age- and gender-matched comparison cohort of people not dispensed medicines for dementia was identified. PIP prevalence was determined between 1 January 2016 and 31 December 2016. RESULTS: In total, 8280 people dispensed medicines for dementia and 41 400 comparisons not dispensed medicines for dementia were included: 63% were female and the median age was 82 years. PIP prevalence was 79% among people with dementia compared with 70% among the comparison group (P < .0001). Use of anticholinergics, long-term use of high-dose proton pump inhibitors, and use of benzodiazepines were the most common instances of PIP in people with dementia. After adjustments for age, gender, comorbidity, and number of prescribers, people with dementia were more likely to be exposed to PIP than comparisons (adjusted OR 1.44, 95% CI, 1.35-1.53, P < .0001). CONCLUSIONS: PIP was more common in people dispensed medicines for dementia than comparisons. These results highlight the need for effective interventions to optimize prescribing in people with dementia.
ESTHER : Eshetie_2019_Int.J.Geriatr.Psychiatry_34_1498
PubMedSearch : Eshetie_2019_Int.J.Geriatr.Psychiatry_34_1498
PubMedID: 31173395

Title : Isoform-specific cleavage of neuroligin-3 reduces synapse strength - Bemben_2019_Mol.Psychiatry_24_145
Author(s) : Bemben MA , Nguyen TA , Li Y , Wang T , Nicoll RA , Roche KW
Ref : Mol Psychiatry , 24 :145 , 2019
Abstract : The assembly and maintenance of synapses are dynamic processes that require bidirectional contacts between the pre- and postsynaptic structures. A network of adhesion molecules mediate this physical interaction between neurons. How synapses are disassembled and if there are distinct mechanisms that govern the removal of specific adhesion molecules remain unclear. Here, we report isoform-specific proteolytic cleavage of neuroligin-3 in response to synaptic activity and protein kinase C signaling resulting in reduced synapse strength. Although neuroligin-1 and neuroligin-2 are not directly cleaved by this pathway, when heterodimerized with neuroligin-3, they too undergo proteolytic cleavage. Thus protein kinase C-dependent cleavage is mediated through neuroligin-3. Recent studies on glioma implicate the neuroligin-3 ectodomain as a mitogen. Here we demonstrate: (1) there are mechanisms governing specific adhesion molecule remodeling; (2) neuroligin-3 is a key regulator of neuroligin cleavage events; and (3) there are two cleavage pathways; basal and activity-dependent that produce the mitogenic form of neuroligin-3.
ESTHER : Bemben_2019_Mol.Psychiatry_24_145
PubMedSearch : Bemben_2019_Mol.Psychiatry_24_145
PubMedID: 30242227

Title : Medication Use for Comorbidities in People with Alzheimer's Disease: An Australian Population-Based Study - Eshetie_2019_Pharmacotherapy_39_1146
Author(s) : Eshetie TC , Nguyen TA , Gillam MH , Kalisch Ellett LM
Ref : Pharmacotherapy , 39 :1146 , 2019
Abstract : BACKGROUND: People with Alzheimer's disease (AD) often have multimorbidity and take multiple medicines. Yet few studies have examined medicine utilization for comorbidities comparing people with and without AD. OBJECTIVE: The aim was to investigate the patterns of medication use for comorbidities in people with and without AD. METHODS: An Australian population-based study was conducted using the Pharmaceutical Benefits Scheme 10% sample of pharmacy claims data. People with AD were defined as those dispensed medicines for dementia (cholinesterase inhibitors, memantine, or risperidone for behavioral and psychological symptoms of dementia) between January 1, 2005, and December 31, 2015, who were aged 65 years or older and alive at the end of 2016. An age- and gender-matched comparison cohort (5:1) of people without AD were identified. Medication use for comorbidities was identified using the validated comorbidity index, Rx-Risk-V. A chi(2) test was used to compare differences in the pattern of medicine use between the two groups. RESULTS: A total of 8280 people with AD and 41,400 comparisons without AD were included; 63.4% were female and the median age was 82 years. The median number of comorbidities was greater in people with AD {median [interquartile range (IQR)]: 5 [3-7]} than the comparison group (median [IQR]: 4 [3-6], p<0.0001). Medications for depression, pain (treated with opioid analgesics), anxiety, diabetes, hyperthyroidism, epilepsy, Parkinson's disease, and antipsychotics were used significantly more commonly in people with AD than in those without dementia. Medications for cardiac conditions, pain (treated with anti-inflammatory medications), chronic airways disease, gout, glaucoma, renal disease, benign prostatic hyperplasia, cancer, and steroid-responsive conditions were used significantly less commonly among people with AD than the comparison group. CONCLUSIONS: This study highlighted significant variations in medication use for comorbidities between people with and without AD. Future studies should evaluate the reasons for the disparity in medicine utilization for comorbidities in people with AD.
ESTHER : Eshetie_2019_Pharmacotherapy_39_1146
PubMedSearch : Eshetie_2019_Pharmacotherapy_39_1146
PubMedID: 31596509

Title : Use of Potentially Inappropriate Medications in People With Dementia in Vietnam and Its Associated Factors - Nguyen_2018_Am.J.Alzheimers.Dis.Other.Demen__1533317518768999
Author(s) : Nguyen TA , Pham T , Vu HTT , Nguyen TX , Vu TT , Nguyen BTT , Nguyen NQ , Nguyen BT , Nguyen TN , Phan SV , Nguyen AT , Pham TL , Dang HT , Kalisch-Ellett L , Gillam M , Pratt N , Qiang S , Wang H , Kanjanarach T , Hassali MAA , Babar ZU , Razak AA , Chinwong D , Roughead EE
Ref : Am J Alzheimers Dis Other Demen , :1533317518768999 , 2018
Abstract : This study examined the use of potentially inappropriate medicines that may affect cognition (PIMcog) in people with dementia and its associated factors. Medical records of all outpatients with dementia attending a tertiary hospital in Vietnam between January 1, 2015, and December 31, 2016, were examined. Medicine use was assessed against a list of PIMcog. Variables associated with having a PIMcog were assessed using a multiple logistic regression. Of the 128 patients, 41% used a PIMcog, 39.1% used cholinesterase inhibitors (CEIs) concomitantly with anticholinergics, and 18% used antipsychotics. The number of hospital visits (adjusted odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.02-1.16) and number of treating specialists (adjusted OR: 0.61; 95% CI: 0.45-0.83) were associated with PIMcog use. This study highlights a high-level use of medicines that can further impair cognition or reduce the effectiveness of CEIs in people with dementia. Efforts to improve quality use of medicines for this population are warranted.
ESTHER : Nguyen_2018_Am.J.Alzheimers.Dis.Other.Demen__1533317518768999
PubMedSearch : Nguyen_2018_Am.J.Alzheimers.Dis.Other.Demen__1533317518768999
PubMedID: 29642720

Title : alpha\/beta-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes - Zhao_2016_Cell.Rep_14_2872
Author(s) : Zhao S , Mugabo Y , Ballentine G , Attane C , Iglesias J , Poursharifi P , Zhang D , Nguyen TA , Erb H , Prentki R , Peyot ML , Joly E , Tobin S , Fulton S , Brown JM , Madiraju SR , Prentki M
Ref : Cell Rep , 14 :2872 , 2016
Abstract : Suppression of alpha/beta-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic beta cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARalpha and PPARgamma activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.
ESTHER : Zhao_2016_Cell.Rep_14_2872
PubMedSearch : Zhao_2016_Cell.Rep_14_2872
PubMedID: 26997277
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6