Psychometric evaluation of the Chinese version of alcohol relapse risk scale (C-ARRS) in patients with alcohol use disorder.

Alcohol use disorder (AUD) is recognized as a chronic relapsing disorder. Alcohol Relapse Risk Scale (ARRS), a multidimensionally self-rating scale, was developed initially by the Japanese to assess the risk of alcohol reuse. The study aimed to validate the reliability and factor structure of the Chinese version of the ARRS (C-ARRS) for patients with AUD. A total of 218 patients diagnosed with AUD according to DSM-5 were recruited for self-administering C-ARRS. We assessed the internal consistency of C-ARRS using Cronbach's α coefficients and examined the factor structure through confirmatory factor analysis (CFA). Additionally, we investigated the concurrent validity by correlating C-ARRS with the Visual Analog Scale of Alcohol Craving (VAS), Penn Alcohol Craving Score (PACS), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) scores. CFA demonstrated inadequate data fit for the original 32-item C-ARRS, prompting the development of a revised 27-item version consisting of 6 subscales with satisfactory model fit estimates. The 27-item C-ARRS exhibited favorable internal consistency, with Cronbach's α ranging from 0.611 to 0.798, along with adequate factor loadings. The 27-item C-ARRS scores displayed significant correlations with the scores of VAS, PACS, BDI and BAI (p < .001). Our results indicated favorable reliability and factor structure of the 27-item C-ARRS. The significant correlation between the 27-item C-ARRS and clinical measures (such as depression, anxiety, and craving) demonstrates satisfactory concurrent validity. These observations collectively support the feasibility of using 27-item C-ARRS to assess the risk of alcohol relapse in patients with AUD.

Changes of neurofilament light chain in patients with alcohol dependence following withdrawal and the genetic effect from ALDH2 Polymorphism.

Neurofilament light chain (NFL), as a measure of neuroaxonal injury, has recently gained attention in alcohol dependence (AD). Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme which metabolizes the alcohol breakdown product acetaldehyde. An ALDH2 single nucleotide polymorphism (rs671) is associated with less ALDH2 enzyme activity and increased neurotoxicity. We examined the blood NFL levels in 147 patients with AD and 114 healthy controls using enzyme-linked immunosorbent assay and genotyped rs671. We also followed NFL level, alcohol craving and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. We found the baseline NFL level was significantly higher in patients with AD than in controls (mean ± SD: 264.2 ± 261.8 vs. 72.1 ± 35.6 pg/mL, p < 0.001). The receiver operating characteristic curve revealed that NFL concentration could discriminate patients with AD from controls (area under the curve: 0.85; p < 0.001). The NFL levels were significantly reduced following 1 and 2 weeks of detoxification, with the extent of reduction correlated with the improvement of craving, depression, and anxiety (p < 0.001). Carriers with the rs671 GA genotype, which is associated with less ALDH2 activity, had higher NLF levels either at baseline or after detoxification compared with GG carriers. In conclusion, plasma NFL level was increased in patients with AD and reduced after early abstinence. Reduction in NFL level corroborated well with the improvement of clinical symptoms. The ALDH2 rs671 polymorphism may play a role in modulating the extent of neuroaxonal injury and its recovery.

Physiological and Physical Strategies to Minimize Damage at the Branch-Stem Junction of Trees: Using the Finite Element Method to Analyze Stress in Four Branch-Stem Features.

This study analyzed the mechanical and physiological strategies associated with four features in the branch-stem junction of a tree, namely the U-shaped branch attachment, the branch collar, the branch bark ridge, and the roughened lower stem. Models were established for each stage of tree growth by adding these four features sequentially to a base model, and the finite element method (FEM) was employed to create three-dimensional models of an Acer tree's branch-stem structure for static force analysis. According to the results, the development of the branch collar shifted the point of breakage to the outer part of the collar and, thus, constituted a physiological strategy that prevented decay in the stem. Additionally, the concentration of stress in the branch bark ridge limited the area of tear in the bark following breakage. Finally, the U-shaped branch attachment reduced stress and shifted the point of peak stress toward the branch, while the thickening of the lower stem reduced the overall stress. The development of these features, including the spatial positioning of the branch bark ridge and branch collar, resulted in two breakage points constituting a physical and a physiological strategy that limited damage to the tree and protected the xylem structure. This is the part that has been challenging to decipher in previous discussions of tree-related self-protection mechanisms.

Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

Comorbidity of ketamine dependence with major depressive disorder increases the vulnerability to neuroaxonal pathology.

We recently demonstrated that patients with ketamine dependence (KD) have increased serum levels of neurofilament light chain (NfL), a novel marker of active neuroaxonal pathology, with NfL levels being significantly higher in those KD patients comorbid with major depressive disorder (MDD). However, considering that NfL elevation has been associated with both ketamine-related brain pathology and MDD, we could not determine whether the observed elevation of NfL levels was driven by an interaction of KD with MDD or by MDD itself. Therefore, we compared serum NfL levels between 35 patients with MDD without ketamine use (MDD group), 23 with KD without MDD (KD without MDD group), 30 KD with MDD (KD with MDD group), and 86 healthy controls (HC group). Using a 2*2 (KD*MDD) generalized linear model controlling for age, sex, body mass index, and smoking status, we found that KD and KD*MDD interactions, but not MDD factor, significantly affected NfL levels. Posthoc tests showed that the KD with MDD group had significantly higher NfL levels than all other groups. The KD without MDD group also showed higher NfL levels than the MDD and, as shown before, HC groups. The levels in MDD group were not different from the HC group. These results suggest that the interaction of KD with MDD, but not MDD alone, results in increased vulnerability to neuroaxonal pathology.

Effects of message delivery on cross-cultural biosecurity compliance: Insights from experimental simulations.

Background: Effective biosecurity communication of transmission risks and associated protective behaviors can reduce the impacts of infectious diseases in US animal agriculture. Yet, more than 1/5 of animal production workers speak a language other than English at home, and more than 40 percent are less than fluent in English. Communicating with these workers often involves translating into their primary languages. However, communication strategies targeting different cultural groups are not well-understood. Aims: To identify cross-linguistic risk communication strategies to facilitate compliance, we hypothesized that uncertainty avoidance cultures associated with the languages might affect biosecurity compliance contingent upon two additional covariates: (1) the risk of acquiring an infection and (2) the delivery method of the infection risk. Methods: We designed an experimental game simulating a line of separation (LOS) biosecurity tactic in a swine production facility, where participants were tasked with completing tasks inside and outside of the facility. Data were collected using games in the two most spoken languages in the US: English (EN) and Spanish (SP). Participants made binary decisions about whether to use the LOS biosecurity tactic based on the risk information provided. Mixed-effect logistic models were used to test the effects of covariates on using the LOS tactic by different language groups. Results: We found that biosecurity compliance rates of participants who took the experiments in the language associated with high and low uncertainty cultures showed no significant differences. However, there are substantial differences in how risk information is perceived between the two language groups under different infection risks. Specifically, and counterintuitively, SP participants were more risk-averse in gain scenarios but more risk-taking in loss scenarios. These differences are most pronounced in numeric risk messaging, indicating that numbers may not be the best way to communicate risk information regarding biosecurity cross-culturally. Conclusions: When confronted with situational biosecurity decisions, risk perception and preferences vary by language group. Effective biosecurity communication needs to account for these differences and not assume that direct translation of risk messages will result in comparable compliance.

Comparing behavioral risk assessment strategies for quantifying biosecurity compliance to mitigate animal disease spread.

Understanding the impact of human behavior on the spread of disease is critical in mitigating outbreak severity. We designed an experimental game that emulated worker decision-making in a swine facility during an outbreak. In order to combat contamination, the simulation features a line-of-separation biosecurity protocol. Participants are provided disease severity information and can choose whether or not to comply with a shower protocol. Each simulated decision carried the potential for either an economic cost or an opportunity cost, both of which affected their potential real-world earnings. Participants must weigh the risk infection vs. an opportunity cost associated with compliance. Participants then completed a multiple price list (MPL) risk assessment survey. The survey uses a context-free, paired-lottery approach in which one of two options may be selected, with varying probabilities of a high and low risk payouts. We compared game response data to MPL risk assessment. Game risk was calculated using the normalized frequency of biosecurity compliance. Three predominant strategies were identified: risk averse participants who had the highest rate of compliance; risk tolerant participants who had the lowest compliance rate; and opportunists who adapted their strategy depending on disease risk. These findings were compared to the proportion of risk averse choices observed within the MPL and were classified into 3 categories: risk averse, risk tolerant and neutral. We found weak positive correlation between risk measured in our experimental game compared to the MPL. However, risk averse classified participants in the MPL tended to comply with the biosecurity protocol more often than those classified as risk tolerant. We also found that the behavioral risk clusters and categorization via the MPL were significantly, yet weakly associated. Overall, behavioral distributions were skewed toward more risk averse choices in both the MPL and game. However, the MPL risk assessment wasn't a strong predictor for observed game behavior. This may indicate that MPL risk aversion metrics might not be sufficient to capture these simulated, situational risk aversion behaviors. Experimental games have a large potential for expanding upon traditional survey instruments by immersing participants in a complex decision mechanism, and capturing dynamic and evolving behavioral signals.

Optic neuropathy caused by orbital Kimura disease: A rare case report.

RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disease characterized by painless subcutaneous nodules predominantly located in the head and neck regions. Orbital KD, which intrudes into the intraconal space and results in compressive optic neuropathy, is rare and has not been previously reported. PATIENT CONCERNS: A 68-year-old man presented with blurred vision and progressive proptosis in the left eye that had been present for 2 years. DIAGNOSIS: Magnetic resonance imaging of the brain revealed soft tissue lesions with contrast enhancement and restricted diffusion involving the bilateral eyelids, orbits, and intraconal region; those on the left side were more prominent than those on the right side. The lesion encased the left optic nerve. Laboratory test results revealed elevated serum immunoglobulin E level and peripheral eosinophilia. An orbital mass biopsy demonstrated hyperplastic lymphoid follicles with germinal centers in the subcutaneous area and abundant mononuclear and binuclear eosinophils infiltrating the interfollicular area. A pathological diagnosis of KD was made based on the blood test results. INTERVENTIONS: Orbital decompression and debulking surgery of the orbital tumor in the left eye were performed to treat the compressive optic neuropathy. OUTCOMES: After systemic oral steroid and immunosuppressive agent therapies, the patient's visual acuity in the left eye improved, and the KD activity was stable. CONCLUSIONS: We present a rare case of orbital KD-associated optic neuropathy, wherein early diagnosis and treatment preserved the patient's vision. This complication should be considered in patients with a history of compressive optic neuropathy during the differential diagnosis.

Is repeat wide excision plus radiotherapy of localized rectal melanoma another choice before abdominoperineal resection? A case report.

BACKGROUND: Rectal melanoma is an uncommon neoplasm that accounts for approximately 1 percent of rectal cancer cases. Abdominoperineal resection was regarded as the radical procedure for disease control. Nevertheless, it led to more postoperative complications than sphincter-sparing wide local excision (WLE) and reduced the patient's quality of life (QOL) owing to creation of colostomy. Therefore, in this study, WLE, radiotherapy (RT), and a second WLE were conducted on a patient who had been diagnosed with localized rectal melanoma. CASE SUMMARY: The patient was a 79-year-old woman who had been experiencing anal pain and bloody stool for 1 mo. Colonoscopy, magnetic resonance imaging, positron emission tomography-computed tomography, and histological analysis of tissue biopsy using the histological markers Melan-A (+), S-100 (+), and Ki-67 (+, 50%) lead to the diagnosis of localized rectal melanoma. The patient had initially undergone WLE to resolve problem of anal bleeding, followed by RT to treat the residual lesion with partial response. Subsequently, the residual lesion was removed with margin-free resection by the second WLE. The patient's postoperative course was smooth and uneventful. During the 2-year follow-up, no local recurrence was observed. Additionally, a good functional outcome and improved QOL were reported. CONCLUSION: Combining WLE, RT, and repeat WLE is proposed as a viable alternative for treating rectal melanoma accompanied by bleeding symptoms that cannot be completely resected at the beginning.

Association of the D-amino acid oxidase gene with methadone dose in heroin dependent patients under methadone maintenance treatment.

Methadone is a synthetic opioid used for the maintenance treatment (MMT) of heroin dependence. It primarily binds to the µ-opioid receptor (MOR; with its gene, namely OPRM1). Methadone is also an N-methyl-D-aspartate (NMDA) receptor antagonist. The role of NMDA receptor in the regulatory mechanisms of methadone dosage in heroin dependent patients is so far not clear. D-amino acid oxidase (DAO) is an important enzyme that indirectly activates the NMDA receptor through its effect on the D-serine level. To test the hypothesis that genetic polymorphisms in the DAO gene are associated with methadone treatment dose and responses, we selected four single nucleotide polymorphisms (SNPs) in DAO from the literature reports of the Taiwanese population. SNPs were genotyped in 344 MMT patients. In this study, we identified a functional SNP rs55944529 in the DAO gene that reveals a modest but significant association with the methadone dosage in the recessive model of analysis (P = 0.003) and plasma concentrations (P = 0.003) in MMT patients. However, it did not show association with plasma methadone concentration in multiple linear regression analysis. It is also associated with the methadone adverse reactions of dry mouth (P = 0.002), difficulty with urination (P = 0.0003) in the dominant model, and the withdrawal symptoms of yawning (P = 0.005) and gooseflesh skin (P = 0.004) in the recessive model. Our results suggest a role of the indirect regulatory mechanisms of the NMDA reporter, possibly via the DAO genetic variants, in the methadone dose and some adverse reactions in MMT patients.

Increase in plasma CCL11 (Eotaxin-1) in patients with alcohol dependence and changes during detoxification.

BACKGROUND: Alcohol is known to modulate the immune system. Neuroinflammatory cytokine dysregulation plays an essential role in the pathophysiology of alcohol dependence (AD). Preclinical studies have indicated that alcohol consumption upregulates the pro-inflammatory cytokine CC motif ligand 11 (CCL11, also known as eotaxin-1). We examined CCL11 levels in patients with AD and in mice administered alcohol. METHODS: The plasma CCL11 levels of 151 patients with AD and 116 healthy controls were measured. In addition, we followed the CCL11 levels, alcohol cravings and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. Furthermore, we examined CCL11 changes in mice administered alcohol for 5 days. RESULTS: CCL11 levels were higher in patients with AD than in controls and declined during detoxification. CCL11 levels were positively correlated with AD severity (p < 0.001). Furthermore, mice exposed to alcohol exhibited a higher CCL11 level. The receiver operating characteristic curve revealed that a CCL11 level of 72.5 pg/mL could significantly differentiate patients with AD from controls (area under the curve: 0.77; p < 0.001). Reductions in CCL11 levels during detoxification were correlated with reductions in alcohol craving, depression, and anxiety. CONCLUSIONS: Our data from humans and mice suggest that chronic alcohol consumption is associated with an increase in CCL11 levels. CCL11 levels are correlated with AD severity and may be a potential indicator of AD. The CCL11 reduction after alcohol discontinuation is associated with alleviation of clinical symptoms. Collectively, our findings suggest that CCL11 is involved in the neurobiological mechanisms underlying AD.

Splice-Site Variants in the Gene Encoding GABA-A Receptor Delta Subunit Are Associated with Amphetamine Use in Patients under Methadone Maintenance Treatment.

Chronic opioid use disorder patients often also use other substances such as amphetamines. The gene-based analysis method was applied in the genomic database obtained from our previous study with 343 methadone maintenance treatment (MMT) patients. We found that the gene encoding gamma-aminobutyric acid type A receptors (GABA-A receptor) delta subunit isoforms (GABRD) was associated with amphetamine use in heroin dependent patients under MMT in Taiwan. A total of 15% of the 343 MMT patients tested positive for amphetamine in the urine toxicology test. Two genetic variants in the GABRD, rs2889475 and rs2376805, were found to be associated with the positive urine amphetamine test. They are located in the exon 1 of the splice variant and altered amino acid compositions (T126I, C/T, for rs2889475, and R252Q, G/A, for rs2376805). The CC genotype carriers of rs2889475 showed a four times higher risk of amphetamine use than those with TT genotype. The GG genotype carriers of rs2376805 showed a three times higher risk of amphetamine use than the AA genotype carriers. To our knowledge, this is the first report that demonstrated an association of the delta splice variant isoform in the GABA-A receptor with an increased risk of amphetamine use in MMT patients. Our results suggest that rs2889475 and rs2376805 may be indicators for the functional role and risk of amphetamine use in MMT patients.

Dual Skip Connections Minimize the False Positive Rate of Lung Nodule Detection in CT images.

Pulmonary cancer is one of the most commonly diagnosed and fatal cancers and is often diagnosed by incidental findings on computed tomography. Automated pulmonary nodule detection is an essential part of computer-aided diagnosis, which is still facing great challenges and difficulties to quickly and accurately locate the exact nodules' positions. This paper proposes a dual skip connection upsampling strategy based on Dual Path network in a U-Net structure generating multiscale feature maps, which aims to minimize the ratio of false positives and maximize the sensitivity for lesion detection of nodules. The results show that our new upsampling strategy improves the performance by having 85.3% sensitivity at 4 FROC per image compared to 84.2% for the regular upsampling strategy or 81.2% for VGG16-based Faster-R-CNN.

Understanding APE1 cellular functions by the structural preference of exonuclease activities.

Mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1) has versatile enzymatic functions, including redox, endonuclease, and exonuclease activities. APE1 is thus broadly associated with pathways in DNA repair, cancer cell growth, and drug resistance. Unlike its AP site-specific endonuclease activity in Base excision repair (BER), the 3'-5' exonucleolytic cleavage of APE1 using the same active site exhibits complex substrate selection patterns, which are key to the biological functions. This work aims to integrate molecular structural information and biocatalytic properties to deduce the substrate recognition mechanism of APE1 as an exonuclease and make connection to its diverse functionalities in the cell. In particular, an induced space-filling model emerges in which a bridge-like structure is formed by Arg177 and Met270 (RM bridge) upon substrate binding, causing the active site to adopt a long and narrow product pocket for hosting the leaving group of an AP site or the 3'-end nucleotide. Rather than distinguishing bases as other exonucleases, the hydrophobicity and steric hindrance due to the APE1 product pocket provides selectivity for substrate structures, such as matched or mismatched blunt-ended dsDNA, recessed dsDNA, gapped dsDNA, and nicked dsDNA with 3'-end overhang shorter than 2 nucleotides. These dsDNAs are similar to the native substrates in BER proofreading, BER for trinucleotide repeats (TNR), Nucleotide incision repair (NIR), DNA single-strand breaks (SSB), SSB with damaged bases, and apoptosis. Integration of in vivo studies, in vitro biochemical assays, and structural analysis is thus essential for linking the APE1 exonuclease activity to the specific roles in cellular functions.

Increased Nectin-4 levels in chronic ketamine abusers and the relationship with lower urinary tract symptoms.

Persistent ketamine use causes susceptibility to addiction and bladder toxicity. We examined the association of lower urinary tract symptoms and levels of Nectin-4, a member of the cell adhesion molecules that is essential for maintaining the urothelium barrier in chronic ketamine abusers. We measured the plasma levels of Nectin-4 in 88 patients with ketamine dependence and 69 controls. Patients with ketamine dependence were assessed for ketamine use variables, psychological symptoms, and lower urinary tract symptoms. We found Nectin-4 levels were increased in ketamine-dependent patients compared to the controls (p < 0.0001). Patients with urinary tract symptoms exhibited lower Nectin-4 levels than those without (p = 0.021). Our results suggest an up-regulation of Nectin-4 following chronic and heavy ketamine use. Patients with ketamine dependence with a compromised upregulation of Nectin-4 are likely to have more severe urinary tract symptoms. The mechanisms underlying the involvement of Nectin-4 in ketamine addiction and bladder toxicity warrant future investigation.

Neurofilament light chain as novel blood biomarker of disturbed neuroaxonal integrity in patients with ketamine dependence.

OBJECTIVES: Chronic and heavy ketamine use has been associated with persistent neurocognitive impairment and structural brain abnormalities. Blood levels of neurofilament light chain (NFL) was recently proposed as a measure of axonal integrity in several neuropsychiatric disorders. We aimed to characterise the axonal neurotoxicity of chronic ketamine use and its relationship to relevant clinical outcomes. METHODS: We enrolled 65 treatment-seeking ketamine-dependent patients (55 males and 10 females) and 60 healthy controls (51 males and 9 females). Blood NFL levels measured by single molecule array (SiMoA) immunoassay. We compared NFL levels between groups and used regression analyses to identify clinical variables related to NFL levels. RESULTS: Ketamine-dependent patients had significantly higher NFL levels compared to controls (p < 0.001). A multivariate regression showed that age (p < 0.05) and lifetime history of major depressive disorder (MDD) (p < 0.01) predicted high NFL blood levels in patients. Subsequent group comparisons showed that specifically ketamine-dependent patients with a lifetime history of MDD had significantly increased NFL levels than those without (p < 0.05). CONCLUSIONS: These results suggest substantial neuroaxonal alterations following chronic and heavy ketamine use. The pronounced increase of NFL levels in the MDD subgroup warrants further investigation of a potential neuroaxonal vulnerability of depressed patients to ketamine.

APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling.

The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

CUX2, BRAP and ALDH2 are associated with metabolic traits in people with excessive alcohol consumption.

Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts. This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. We analysed the Taiwan Biobank data of 18,363 Taiwanese people, including 1945 with excessive alcohol use. We found that one or two copies of the G allele in rs671 (ALDH2) increased the risk of excessive alcohol consumption, while one or two copies of the C allele in rs3782886 (BRAP) reduced the risk of excessive alcohol consumption. To minimize the influence of extensive regional linkage disequilibrium, we used the ridge regression. The ridge coefficients of rs7398833, rs671 and rs3782886 were unchanged across different values of the shrinkage parameter. The three variants corresponded to posttranscriptional activity, including cut-like homeobox 2 (a protein coded by CUX2), Glu504Lys of acetaldehyde dehydrogenase 2 (a protein encoded by ALDH2) and Glu4Gly of BRCA1-associated protein (a protein encoded by BRAP). We found that Glu504Lys of ALDH2 and Glu4Gly of BRAP are involved in the negative regulation of excessive alcohol consumption. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver-brain endocrine axis connecting metabolic shifts with excessive alcohol consumption.

Genetic variants in NECTIN4 encoding an adhesion molecule are associated with continued opioid use.

Methadone is a synthetic opioid used as maintenance treatment for patients addicted to heroin. Skin irritation is one of the adverse events caused by opioid use. 344 methadone maintenance treatment (MMT) patients were recruited with records and measurements on methadone dose, plasma methadone concentrations, and treatment emergent symptom scales (TESS). 15 patients reported with skin irritation. Five SNPs located within the NECTIN4 genetic region were genotyped. The NECTIN4 gene within the adherens junction interaction pathway was associated with methadone dose in pathway-based genome wide association analyses (P = 0.0008). Three highly-linked SNPs, rs11265549, rs3820097, and rs4656978, were significantly associated with methadone dose (P = 0.0003), plasma concentrations of R,S-methadone (P = 0.0004) and TNF-α (P = 0.010) in all 344 MMT patients, and with self-report skin irritation symptom scores (P = 0.010) in the 15 MMT patients who reported with skin irritation. To identify the possible roles of plasma level of Nectin-4 in the responses to MMT and opioid use, additional age- and gender-matched 51 controls and 83 methadone-free abstinent former heroin users were recruited. Plasma level of Nectin-4 was the highest in MMT patients among the three groups. The results suggest involvement of genetic variants on NECTIN4 in methadone dose. Plasma Nectin-4 level is likely an indicator for continued use of opioids.