Experimentally validated inverse design of multi-property Fe-Co-Ni alloys.

This study presents a machine learning (ML) framework aimed at accelerating the discovery of multi-property optimized Fe-Ni-Co alloys, addressing the time-consuming, expensive, and inefficient nature of traditional methods of material discovery, development, and deployment. We compiled a detailed heterogeneous database of the magnetic, electrical, and mechanical properties of Fe-Co-Ni alloys, employing a novel ML-based imputation strategy to address gaps in property data. Leveraging this comprehensive database, we developed predictive ML models using tree-based and neural network approaches for optimizing multiple properties simultaneously. An inverse design strategy, utilizing multi-objective Bayesian optimization (MOBO), enabled the identification of promising alloy compositions. This approach was experimentally validated using high-throughput methodology, highlighting alloys such as Fe66.8Co28Ni5.2 and Fe61.9Co22.8Ni15.3, which demonstrated superior properties. The predicted properties data closely matched experimental data within 14% accuracy. Our approach can be extended to a broad range of materials systems to predict novel materials with an optimized set of properties.

Major depressive disorder and the risk of irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: The association between major depressive disorder (MDD) and irritable bowel syndrome (IBS) has been found in observational research; however, the causative relationship between MDD and IBS remains uncertain. Using the two-sample Mendelian randomization (MR) approach, we attempted to examine the causal effect of MDD on IBS. METHODS: Independent genetic variants for MDD identified by Howard et al. based on a genome-wide meta-analysis were selected for this study. Gene-Outcome associations for IBS were gathered from UK Biobank and FinnGen databases. The MR analysis included inverse variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and MR-PRESSO sensitivity analyses. RESULTS: FinnGen database subjected to inverse variance weighted (IVW) analysis revealed that MDD may be a risk factor for the development of IBS (OR = 1.356, 95% CI: 1.125-1.632, p = 0.0013). The same finding was reached in UK Biobank for IVW (OR = 1.011, 95% CI: 1.006-1.015, p = 3.18 × 10-7 ), MR-Egger progression (OR = 1.030, 95% CI: 1.008-1.051, p = 0.007), and weighted median (OR = 1.011, 95% CI: 1.005-1.016, p = 0.0001). CONCLUSION: Our findings supported a causal relationship between MDD and IBS, which may have implications for the clinical management of IBS in individuals with MDD.

Disrupted inter-brain synchronization in the prefrontal cortex between adolescents and young adults with gaming disorders during the real-world cooperating video games.

BACKGROUND: Gaming disorder (GD) and hazardous gaming (HG) have a high incidence among adolescents and young adults and have caused various negative consequences. Interpersonal interaction deficits are closely related to GD and HG, however, the underlying brain mechanisms are still unclear. METHODS: The current study recruited 46 healthy subjects and 32 subjects with GD/HG. Gaming time and frequency, gaming disorder risks, life events, strengths, and difficulties were measured with scales. Subjects were randomly paired into 12 HC-HC dyads, 15 GD/HG-HC dyads, and 7 GD/HG-GD/HG dyads and in pairs completed a real-world cooperating video game - "Tied Together" with functional near-infrared spectroscopy hyperscanning recording in the prefrontal cortex. The inter-brain synchronization in each region of the PFC between dyads was calculated by wavelet to transform coherence to measure brain-to-brain synchronization. RESULTS: We found subjects with GD/HG reported higher risks of gaming. The highest IBS in the left dorsolateral prefrontal cortex significantly decreased in the GD/HG-HC and GD/HG-GD/HG dyads compared with healthy controls. A decreasing highest IBS of the left dlPFC was related to a decreasing level of peer problems. LIMITATIONS: We declare limitations of age gaps of samples, undistinguishing GD from HG, use of sub-samples, and the broad concept of interpersonal interaction. CONCLUSIONS: The current study found a decreased highest IBS in the left dlPFC among adolescents and young adults with gaming diseases. It may provide new prevention and treatment insights into gaming disorders targeting disrupted interpersonal interaction.

Predicting Synthesizability using Machine Learning on Databases of Existing Inorganic Materials.

Defining the metric for synthesizability and predicting new compounds that can be experimentally realized in the realm of data-driven research is a pressing problem in contemporary materials science. The increasing computational power and advancements in machine learning (ML) algorithms provide a new avenue to solve the synthesizability challenge. In this work, using the Inorganic Crystal Structure Database (ICSD) and the Materials Project (MP) database, we represent crystal structures in Fourier-transformed crystal properties (FTCP) representation and use a deep learning model to predict synthesizability in the form of a synthesizability score (SC). Such an SC model, as a synthesizability filter for new materials, enables an efficient and accurate classification to identify promising material candidates. The SC prediction model achieved 82.6/80.6% (precision/recall) overall accuracy in predicting ternary crystal materials. We also trained the SC model by only considering compounds uploaded on the MP before 2015 as the training set and testing on multiple sets of materials uploaded after 2015. In the post-2019 test set, we obtain a high 88.60% true positive rate accuracy, coupled with 9.81% precision, indicating that newly added materials remain unexplored and have high synthesis potential. Further, we provide a list of 100 materials predicted to be synthesizable from this post-2019 dataset (highest SC) for future studies, and our SC model, as a validation filter, is beneficial for future material screening and discovery.

Decreased inter-brain synchronization in the right middle frontal cortex in alcohol use disorder during social interaction: An fNIRS hyperscanning study.

BACKGROUND: Alcohol use disorder (AUD) is a widespread mental disorder and has thrust a heavy burden on the health system all over the world. Social cognition and function are reported to be impaired in AUD, but its neural mechanism is rarely investigated. The current study attempts to fill this gap. METHODS: 28 subjects with AUD and 36 healthy controls (HC) were recruited in this study and were paired into 14 AUD dyads and 18 HC dyads. The drinking problems, depression, anxiety, and impulsivity of subjects were measured. Each dyad completed cooperation and competition tasks with simultaneous frontal functional near-infrared spectroscopy (fNIRS) hyperscanning recording. The inter-brain synchronization (IBS) in the frontal cortex was calculated for each dyad and compared between AUD and HC. The significantly altered IBS in AUD was correlated with clinical measures to explore possible influencing factors. RESULTS: The IBS in the right middle frontal cortex was significantly decreased in AUD under both cooperation (t = -2.257, P = 0.028) and competition (t = -2.488, P = 0.016) task. The IBS during the cooperation task in the right middle frontal cortex in AUD was negatively correlated with non-planning impulsivity (r = -0.673, P = 0.006). LIMITATIONS: This study used cross-sectional data, which limited the causal inference. The synchronization between other brain regions besides the frontal cortex should be further explored in patients with AUD. CONCLUSION: The current study could provide new insights into the neural mechanism of social dysfunction in AUD and facilitate clinical intervention in future practice.

The impact of irrigation modes on agricultural water-energy­carbon nexus.

Despite the tremendous contribution of irrigated agriculture in addressing global food security, there is still confusion for farmers and governments about the choice of irrigation mode owing to the drastic environmental impacts of irrigation, including water shortage, energy crisis, and global warming. Exploring the agricultural water-energy­carbon (WEC) nexus under different irrigation modes helps to accomplish the multi-objective of water & energy saving and carbon emission reduction. In this paper, a conceptual framework was nominated to evaluate the water & energy consumption and carbon emissions for winter wheat irrigation at township level and quantitatively discuss the complex interaction by the coupling coordination degree (CCD) of the WEC system under different irrigation modes in Henan Province, China. We discovered that irrigation modes profoundly affect water and energy consumption and carbon emissions in agriculture, as well as the spatial distribution of CCD from WEC system. Townships under irrigation mode with diversion and irrigation projects as the primary method (WDI) clustered together in the north and east with highest water consumption and carbon emissions, while townships under irrigation mode with rain-fed agriculture as the primary method (PI) accumulated in the west and south with lower water consumption and carbon emissions. Meanwhile, the CCD of the WEC nexus system was in basic coordination (0.40) and showed an unbalanced spatial distribution pattern with high in the southeast and low in the northwest. By comparing four irrigation modes, the coupling level of the WEC nexus system under irrigation mode with groundwater irrigation as the primary method (GI) was better and PI mode was the least ideal. This study helps to further understand agricultural WEC nexus under different irrigation modes and provide references for local governments in selecting appropriate irrigation modes to realize water-energy saving and carbon emission reduction in agricultural activities.

Hippocampal damage and white matter lesions contribute to cognitive impairment in MPTP-lesioned mice with chronic cerebral hypoperfusion.

OBJECTIVES: Strong evidence has proven that cerebral hypoperfusion is closely related to Parkinson's disease (PD) with cognitive impairment. The aim of this study was to investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive dysfunction, structural abnormalities of the hippocampus and white matter (WM), and levels of inflammatory cytokines in control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse models. METHODS: In the present study, bilateral common carotid artery stenosis (BCCAS) was performed using microcoils, and the cognitive function and WM lesions (WMLs) after BCCAS were compared between microcoil with 0.18 mm and 0.20 mm diameters. CCH and MPTP-lesioned mice were induced by intraperitoneal injection of MPTP and BCCAS. These mice were further divided into seven groups: a control group, sham-operated group, BCCAS group, PD with normal cognition (PDCN) group, PD with mild cognitive impairment (PDMCI) group, PDCN + BCCAS group, and PDMCI + BCCAS group. After 28 days of BCCAS, the mice were tested through pole-climbing experiments and by TUNEL, Nissl, and Bielschowsky silver staining. Immunohistochemistry was used to evaluate lesions in the dopaminergic (DAergic) nigrostriatal system and the number of activated microglia. Chip-based liquid chromatography was employed to measure the levels of inflammatory cytokines in the plasma. RESULTS: The results indicated that the histological results of the 0.18 mm microcoil were superior to that of the 0.20 mm microcoil. Based on these finding, BCCAS impaired the climbing ability of MPTP-lesioned PD mice. Moreover, immunohistochemistry for tyrosine hydroxylase (TH) revealed a significant reduction in the number of DAergic neurons in the substantia nigra of PD mice following BCCAS, particularly in the PDMCI + BCCAS group. In addition, Nissl, TUNEL and Bielschowsky silver staining confirmed decreased hippocampal neuron numbers, increased neuronal apoptosis and more significant WM fiber damage in the corpus callosum of the PDMCI + BCCAS group. Finally,immunohistochemistry for ionized calcium binding adaptor molecule-1 (Iba-1) and chip-based liquid chromatography revealed significantly increased microglial activation (P < 0.01) and significantly increased levels of interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ) (P < 0.05) in the PDMCI + BCCAS group compared with the corresponding levels in the PDCN + BCCAS group. CONCLUSIONS: Cerebral hypoperfusion can aggravate the cognitive impairment in MPTP-lesioned PD mice. This finding may be related to the hypoperfusion-mediated deterioration of neuroinflammation, aggravation of WM damage, and induction of hippocampal neuron apoptosis in PD mice.

Scoparone protects neuronal cells from oxygen glucose deprivation/reoxygenation injury.

Ischemic stroke is one of the leading causes of death and disability in the world. The cerebral ischemia/reperfusion (I/R) injury is considered as the major molecular mechanism in the pathogenesis of ischemic stroke. Scoparone, a major constituent of Artemisia capillaries, has been found to exhibit protective effects against I/R-induced myocardial injury. However, the role of scoparone in cerebral I/R injury has not been elucidated. In the current study, the hippocampal neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate I/R injury in vitro. The results showed that scoparone improved OGD/R-induced inhibitory effect on cell viability of hippocampal neurons. Scoparone displayed anti-oxidative activity as proved by the decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in OGD/R-induced hippocampal neurons. In addition, cell apoptosis was markedly decreased after scoparone treatment in OGD/R-induced hippocampal neurons. The expression of bax was significantly decreased, while bcl-2 expression was increased in the scoparone pretreated hippocampal neurons. Furthermore, the expressions of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were obviously induced by scoparone. Knockdown of Nrf2 by siRNA transfection dramatically attenuated the protective effects of scoparone on OGD/R-induced hippocampal neurons. Collectively, scoparone protected hippocampal neurons from OGD/R-induced injury via activating Nrf2/HO-1 signaling pathway, suggesting that scoparone might be a potential agent for the ischemic stroke therapy.

Tangeretin protects human brain microvascular endothelial cells against oxygen-glucose deprivation-induced injury.

Tangeretin, a citrus flavonoid extracted from the peel of citrus fruits, was reported to possess antiasthmatic, antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of tangeretin on human brain microvascular endothelial cells (HBMECs) has not been examined. This study was designed to investigate the protective effects of tangeretin on oxygen-glucose deprivation (OGD)-induced injury of HBMECs, and explore the underlying mechanisms. Our results showed that tangeretin improved HBMECs viability in response to OGD. In addition, tangeretin was able to increase the activity of superoxide dismutase and decrease the levels of reactive oxygen species and malondialdehyde (MDA), as well as ameliorate cell apoptosis in OGD-stimulated HBMECs. Mechanistic studies showed that tangeretin prevented the activation of JNK signaling pathway in OGD-stimulated HBMECs. Taken together, our current study demonstrated that tangeretin could ameliorate OGD-induced HBMECs injury through the JNK signaling pathway. Thus, tangeretin might be used as a therapeutic strategy for ischemia-reperfusion brain injury and related diseases.

Transcutaneous electrical acupoint stimulation for post-traumatic stress disorder: Assessor-blinded, randomized controlled study.

AIM: Transcutaneous electrical acupoint stimulation (TEAS) has the potential to alleviate post-traumatic stress disorder (PTSD). The purpose of this study was to determine whether adding TEAS to sertraline or cognitive behavioral therapy (CBT) could improve the anti-PTSD efficacy. METHODS: In this randomized controlled trial, 240 PTSD patients (60 in each group) were assigned to receive simulated TEAS combined with sertraline (group A) or with CBT (group B), active TEAS combined with CBT (group C), or active TEAS combined with CBT plus sertraline (group D) for 12 weeks. The outcomes were measured using the Clinician-Administered PTSD Scale, PTSD Check List-Civilian Version, and 17-item Hamilton Rating Scale for Depression. RESULTS: While PTSD symptoms reduced over time in all patients, groups C and D had markedly greater improvement in both PTSD and depressive measures than groups A and B in all post-baseline measurement points, with moderate to very large effect sizes of 0.484-2.244. Groups C and D also had a significantly higher rate than groups A and B on clinical response (85.0% and 95.0% vs 63.3% and 60.0%, P < 0.001) and on remission (15.0% and 25.0% vs 3.3% and 1.7%, P < 0.001). The incidence of adverse events was similar between groups A and D and between groups B and C. CONCLUSIONS: Additional TEAS augments the anti-PTSD and antidepressant efficacy of antidepressants or CBT, without increasing the incidence of adverse effects. TEAS could serve as an effective intervention for PTSD and comorbid depression. This trial was registered with www.chictr.org (no.: ChiCTR1800017255).

Nicotinamide phosphoribosyltransferase regulates cocaine reward through Sirtuin 1.

Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis in mammals, converts nicotinamide into nicotinamide mononucleotide (NMN). NMN is subsequently converted to NAD, a component that is critical for cell energy metabolism and survival. Sirtuin 1 (SIRT1), an NAD-dependent histone deacetylase, plays an important role in mediating memory and synaptic plasticity. Here, we found that NAMPT was significantly upregulated in the ventral tegmental area (VTA) of cocaine-conditioned mice. Intraperitoneal or intra-VTA injection of FK866, a specific inhibitor of NAMPT, significantly attenuated cocaine reward. However, such effects were clearly repressed by intra-VTA expression of NAMPT or supplementation with NMN. Using 1H-nuclear magnetic resonance metabolomic analysis, we found that the content of NAD and NMN were increased in the VTA of cocaine-conditioned mice; moreover, the expression of SIRT1 was also upregulated. Interestingly, the inhibitory effect of FK866 on cocaine reward was significantly weakened in Sirt1 midbrain conditional knockout mice. Our results suggest that NAMPT-mediated NAD biosynthesis may modify cocaine behavioral effects through SIRT1. Moreover, our findings reveal that the interplay between NAD biosynthesis and SIRT1 regulation may comprise a novel regulatory pathway that responds to chronic cocaine stimuli.

Toll-like receptor 3 modulates the behavioral effects of cocaine in mice.

BACKGROUND: The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. METHODS: The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3-/- mice. The protein levels of phospho-NF-κB p65, IKKß, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. RESULTS: We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3-/- mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKß, and p-IκBα. CONCLUSIONS: Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.

Brain Renin-Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity.

Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin-angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT1-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT1-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT1-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT1-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT1-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT1 with lentiviral virus expressing AT1 reversed the weakened locomotor activity of AT1-/- mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II-AT1-R in METH-induced hyperlocomotion.

Remodeling of brain lipidome in methamphetamine-sensitized mice.

Lipids are predominant components of the brain and key regulators for neural structure and function. The effect of methamphetamine (METH) on behavior, cognition as well as memory has been intensively investigated; however, the impact of METH on brain lipid profiles is largely unknown. Here, we used a global lipidomic approach to investigate brain lipidome of METH-sensitized mice. We found that repeated METH significantly modified the lipidome in the hippocampus, prefrontal cortex (PFC) and striatum. Interestingly, nucleus accumbens showed no obvious alteration in lipidomic profiling. Phospholipid and sphingolipid metabolisms were profoundly modified in the hippocampus of METH-sensitized mice, exhibiting increased phosphatidic acid and ether phosphatidylcholine but decreased lysophosphatidylethanolamine, lactosylceramide and triglycerides. The fatty acyl length of phospholipids and diacylglycerol longer than 40 carbon were clearly decreased in the hippocampus, and that 36 carbon was decreased in the PFC. These results indicate METH can profoundly affect the metabolism of phospholipids, sphingolipids and glycerolipids in the brain. Our findings reveal a link between remodeled brain lipidome and neurobehavior induced by METH.

Role of Nicotinamide N-Methyltransferase in Dorsal Striatum in Cocaine Place Preference.

Nicotinamide N-methyltransferase (NNMT) transfers the methyl from S-adenosyl-L-methionine (SAM) to nicotinamide (NA) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide (MeN). NNMT has been implicated in a variety of diseases; however, the role of NNMT in drug addiction is largely unknown. Here, we found that the expression of Nnmt was significantly upregulated in the dorsal striatum (DS) of cocaine-conditioned mice. Cocaine significantly decreased SAM/SAH ratio levels in the DS, which was accompanied with the decreased activities of Rac1 and RhoA. Lentivirus-mediated knockdown of Nnmt in the dorsomedial striatum (DMS) attenuated cocaine conditioned place preference (CPP) reward, but increased striatal SAM/SAH ratio levels as well as Rac1 and RhoA activities. In addition, pharmacological inhibition of NNMT through intra-DMS infusion of MeN attenuated cocaine CPP and the activities of Rac1 and RhoA, but increased SAM/SAH ratio. These results suggest that NNMT-dependent transmethylation is involved in the activation of Rac1 and RhoA, which utilize SAM as a methyl donor cofactor. Co-immunoprecipitation assay using a RhoGDIα antibody indirectly captured Rac1 or RhoA that were bound to RhoGDIα. The results showed that cocaine increased the association of RhoGDIα with Rac1 or RhoA, whereas such effect was inhibited by Nnmt knockdown. Collectively, our findings show that NNMT regulates cocaine CPP through SAM-mediated modification of Rac1 and RhoA.

Chronic cerebral hypoperfusion independently exacerbates cognitive impairment within the pathopoiesis of Parkinson's disease via microvascular pathologys.

To date, the role of microvascular pathology and chronic cerebral hypoperfusion (CHH) in the development of mild cognitive impairment in Parkinson's disease (PD-MCI) is unclear. Here, we investigated how the combined injury through interaction of CHH and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity act as an exacerbating element to damagae cognitive fuction in a mouse model. In the present study, C57BL/6 mice underwent MPTP injection. Subjects were classified into a PD with normal cognitive performance (PDCN) group or a PD-MCI group using the Morris Water Maze test. Further, CHH was induced by stenosis of the bilateral common carotid arteries (BCCAs). Consequently, the animals were divided into 7 groups: they are control, sham, BCCAs, PDCN, PD-MCI, PDCN+BCCAs and PD-MCI+BCCAs. The Morris Water Maze test, open field test, histological investigation and western blotting were performed to analyze cerebral microvascular impairment in each group. The results showed that CHH and MPTP injection caused spatial memory and behavioral impairment, accompanied by microvascular impairment and down-regulation of ZO-1 and Occludin at the protein level compared to the control group. The above injuries were synergistically exacerbated in the PDCN+BCCAs group and the PD-MCI+BCCAs group, which paralleled the elevated expression of p-MAPK and p-Akt. In short, our data demonstrate that CHH and MPTP caused cognitive and microvascular impairment separately. Moreover, CHH may exacerbate cognitive impairment in a mouse model of PD. The study provides a new opportunity for understanding the pathogenesis of PD-MCI.

Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson's disease.

OBJECTIVE: The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to be associated with increased risk of Parkinson's disease (PD) and have a specific impact on dopamine-mediated prefrontal executive function in an inverted-U curve manner. We explored the influence of this genetic polymorphism on prefrontal executive function in a well-established Chinese cohort of early PD patients with no current or past history of motor fluctuations or dyskinesias. METHODS: Cognitive functions were assessed in 250 patients with early PD using Wechsler Adult Intelligence Scale-Chinese Revision (WAIS-RC) and Wechsler Memory Scale-Chinese Revision (WMS-RC). These patients and 300 healthy controls were subsequently genotyped for the COMT gene Val158Met polymorphism. We employed analysis of covariance (ANCOVA) and a stratified analysis to determine the associations between the COMT Val158Met genotype and cognitive functions. RESULTS: The COMT Val158Met allele frequency and genotype distributions showed no statistically significant differences between PD patients and controls. However, patients with met/met genotype performed significantly worse on WAIS-RC similarities, a measure of executive function, compared to individuals with val/val genotype. Subsequent ANCOVA analysis revealed that COMT genotype interacted with sex and daily levodopa equivalent dose (LED) to influence executive function. Further stratified analysis showed that the lower-activity COMT met/met genotype has a detrimental effect on executive function among women. CONCLUSIONS: Our results demonstrate that COMT Val158Met polymorphism is probably not associated with increased risk of PD, but has an effect on prefrontal executive function interacting with gender and dopaminergic medication.

Transcutaneous electrical acupoint stimulation as an adjunct therapy for obsessive-compulsive disorder: A randomized controlled study.

BACKGROUND: Transcutaneous electrical acupoint stimulation (TEAS) is thought to have potential to treat obsessive-compulsive disorder (OCD). OBJECTIVE: The purpose of this study was to determine whether adding TEAS to cognitive behavioral therapy (CBT) and clomipramine would improve the efficacy of these conventional treatments in OCD. METHODS: In this randomized controlled trial, 360 OCD patients were assigned to receive TEAS combined with CBT plus clomipramine (Group A, n = 120), TEAS combined with CBT plus placebo (Group B, n = 120), and simulated (placebo) TEAS combined with CBT plus clomipramine (Group C, n = 120) for 12 weeks. The primary outcome was measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). RESULTS: OCD symptoms in all patients reduced over time, however Groups A and B had a significantly greater reduction in Y-BOCS total score and the subscale for obsession and compulsion between week 2 and week 12 compared to Group C. Groups A and B had similar scores on these measures. Both groups had significantly higher rates of clinical response than Group C (88.3% and 81.7% vs. 67.5%, respectively, p < 0.001); and higher rates of remission (30.0% and 22.5% vs. 9.2%, respectively, p < 0.001). Group B experienced fewer adverse events than the other two groups. CONCLUSIONS: TEAS enhances the efficacy of conventional OCD interventions and avoids the adverse effects associated with conventional pharmacological treatment. It can be considered as an effective adjunct intervention for OCD.

Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine.

Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginine N-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases levels of CaMKII and Cdk5 in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine. SIGNIFICANCE STATEMENT: This work demonstrated that repeated cocaine injections led to an increase of protein arginine N-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.

NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib.

Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs.