Association between 5-HT1A receptor C-1019G, 5-HTTLPR polymorphisms and panic disorder: a meta-analysis.

HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism - 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

Structural and biophysical analysis of a Haemophilus influenzae tripartite ATP-independent periplasmic (TRAP) transporter.

Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble-binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-electron microscopy (cryo-EM) structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 Å resolution (extending to 2.2 Å at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 Å resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate-binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (KD) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the 'elevator-with-an-operator' mechanism of TRAP transporters.

Microbial membrane transport proteins and their biotechnological applications.

Because of the hydrophobic nature of the membrane lipid bilayer, the majority of the hydrophilic solutes require special transportation mechanisms for passing through the cell membrane. Integral membrane transport proteins (MTPs), which belong to the Major Intrinsic Protein Family, facilitate the transport of these solutes across cell membranes. MTPs including aquaporins and carrier proteins are transmembrane proteins spanning across the cell membrane. The easy handling of microorganisms enabled the discovery of a remarkable number of transport proteins specific to different substances. It has been realized that these transporters have very important roles in the survival of microorganisms, their pathogenesis, and antimicrobial resistance. Astonishing features related to the solute specificity of these proteins have led to the acceleration of the research on the discovery of their properties and the development of innovative products in which these unique properties are used or imitated. Studies on microbial MTPs range from the discovery and characterization of a novel transporter protein to the mining and screening of them in a large transporter library for particular functions, from simulations and modeling of specific transporters to the preparation of biomimetic synthetic materials for different purposes such as biosensors or filtration membranes. This review presents recent discoveries on microbial membrane transport proteins and focuses especially on formate nitrite transport proteins and aquaporins, and advances in their biotechnological applications.

Internalization and trafficking of zinc transporters.

In huma, two transporter families, the zinc transporters (ZNT/solute carrier 30 family [SLC30A]) and the Zrt- and Irt-like proteins (ZIP/solute carrier 39 family [SLC39A]), play vital roles in maintaining zinc homeostasis. ZIPs could increase the concentration of cytosolic Zn2+ by importing zinc from the extracellular environment or organelles into the cytosol, while ZnTs work in the opposite direction as they mediate the export of zinc from the cytosol into organelles or out of the cells. Mammalian cells express 10 ZnT exporters and 14 ZIP importers, and zinc or other transition metal ions may modulate their gene expression. The localization and post-translational trafficking of zinc transporters within the cells are often controlled in response to varying zinc concentrations, which likely impact the regulation of cellular zinc homeostasis. This chapter briefly summarizes the progress made on the intracellular trafficking of ZIPs and outlines the protocols used to study the endocytosis and trafficking of a representative human zinc transporter, ZIP4.

An update on drug-drug interactions for care of the acutely ill in the era of COVID-19.

PURPOSE: To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19. SUMMARY: DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed. CONCLUSION: Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes.

Dopamine receptor and dopamine transporter in obesity: A meta-analysis.

The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords "dopamine receptor," "dopamine transporter," "obesity," and "neuroimaging." Body mass index (BMI) and the corresponding binding potential (BPND ) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m2 or higher, DR availability from 11 C-Racloprie was negatively associated with BMI. However, DR availability from 11 C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from 11 C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.

The role of botulinum toxin type A related axon transport in neuropathic pain induced by chronic constriction injury.

Background: The mechanism of peripheral axon transport in neuropathic pain is still unclear. Chemokine ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) as well as GABA transporter 1 (GAT-1) play an important role in the development of pain. The aim of this study was to explore the axonal transport of CXCL13/CXCR5 and GAT-1 with the aid of the analgesic effect of botulinum toxin type A (BTX-A) in rats. Methods: Chronic constriction injury (CCI) rat models were established. BTX-A was administered to rats through subcutaneous injection in the hind paw. The pain behaviors in CCI rats were measured by paw withdrawal threshold and paw withdrawal latencies. The levels of CXCL13/CXCR5 and GAT-1 were measured by western blots. Results: The subcutaneous injection of BTX-A relieved the mechanical allodynia and heat hyperalgesia induced by CCI surgery and reversed the overexpression of CXCL13/CXCR5 and GAT-1 in the spinal cord, dorsal root ganglia (DRG), sciatic nerve, and plantar skin in CCI rats. After 10 mmol/L colchicine blocked the axon transport of sciatic nerve, the inhibitory effect of BTX-A disappeared, and the levels of CXCL13/CXCR5 and GAT-1 in the spinal cord and DRG were reduced in CCI rats. Conclusions: BTX-A regulated the levels of CXCL13/CXCR5 and GAT-1 in the spine and DRG through axonal transport. Chemokines (such as CXCL13) may be transported from the injury site to the spine or DRG through axonal transport. Axon molecular transport may be a target to enhance pain management in neuropathic pain.

The emergent role of mitochondrial surveillance in cellular health.

Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.

Characterization of the nigroestriatal system in a sample of patients with amyotrophic lateral sclerosis / Caracterização do sistema nigroestriatal em uma amostra de pacientes com esclerose lateral amiotrófica

Abstract Background The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and PD are still not fully understood, and the coexistence of these two diseases suggests that they could share mechanisms in common. Objective Here we present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography SPECT/TRODAT and compared with non-ALS controls. Methods Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of PD with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases. Results A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the PD group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05. Conclusions Our study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS. Further research to better understand the role of these changes in the pathophysiological process of ALS needs to be performed.

Resumo Antecedentes A coexistência da esclerose lateral amiotrófica (ELA) com formas clínicas da doença de Parkinson (DP), embora incomum, é encontrada em um grau maior do que seria esperado ao acaso. Os mecanismos patológicos da ELA e da DP ainda não são totalmente compreendidos e a coexistência dessas duas doenças sugere que elas podem compartilhar mecanismos em comum. Objetivo Apresentamos uma amostra de pacientes com ELA clinicamente definida ou provável que foram avaliados com tomografia computadorizada por emissão de fóton único (SPECT)/TRODAT e comparados com controles sem ELA. Métodos Pacientes com ELA clinicamente definida ou provável foram avaliados com a escala funcional de esclerose lateral amiotrófica (ALSFRS) para definir a gravidade e foram coletados os seus dados demográficos. Os resultados do TRODAT de pacientes com ELA foram comparados com aqueles de pacientes com diagnóstico de DP com menos de 10 anos de duração e com pacientes com diagnóstico de outros distúrbios do movimento não associados a doenças neurodegenerativas. Resultados Um total de 75% dos pacientes com ELA apresentou resultados de TRODAT abaixo dos níveis considerados normais; 25% no grupo controle sem doença neurodegenerativa e 100% no grupo DP. Uma diferença estatisticamente significativa foi encontrada entre os pacientes com ELA e o grupo controle sem doença neurodegenerativa nos valores de TRODAT p< 0,05. Conclusões Nosso estudo está de acordo com as evidências neuropatológicas e funcionais que demonstram a existência de disfunção nigroestriatal em pacientes com ELA. Mais pesquisas para entender melhor o papel dessas mudanças no processo fisiopatológico da ELA precisam ser realizadas.

De novo design of membrane transport proteins.

Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across biomembranes. Accumulated structural and functional knowledge allows for the de novo design of transport proteins with new structures that do not exist in nature. Analysis based on these novel proteins provides new insights into the principles that govern protein assembly, conformational change, and substrate recognition. Here, we review the advances in the de novo design of transporters and channels over recent years and highlight the challenges and opportunities in this field.

Limited power of dopamine transporter mRNA mapping for predicting dopamine transporter availability.

Dopamine transporters (DAT) are transmembrane proteins that translocate dopamine from the extracellular space into presynaptic neurons. We aimed to investigate the predictive power of DAT mRNA for DAT protein expression, measured using positron emission tomography (PET). We performed 18 F-FP-CIT PET scans in 35 healthy individuals. Binding potentials (BPND ) from the ventral striatum, caudate nucleus, putamen, and middle frontal, orbitofrontal, cingulate, parietal, and temporal cortices were measured. DAT gene expression data were obtained from the freely available Allen Human Brain Atlas derived from six healthy donors. The auto-correlation of PET-derived BPND s for DAT was intermediate (mean ρ2  = .66) with ρ2 ranging from .0811 to 1. However, the auto-correlation of mRNA expression was weak across the probes with a mean ρ2 of .09-.23. Cross-correlations between PET-derived BPND s and mRNA expression were weak with a mean ρ2 ranging from 0 to .22 across the probes. In conclusion, we observed weak associations between DAT mRNA expression and DAT availability in human brains. Therefore, DAT mRNA mapping may have only limited predictive power for DAT availability in humans. However, the difference in distribution of DAT mRNA and DAT protein may influence this limitation.

Serotonin transporter is negatively associated with body mass index after glucose loading in humans.

Serotonin transporter (SERT) is a presynaptically localized membrane protein that regulates the serotonin transmission via its reuptake of released serotonin. We hypothesized that glucose loading may change SERT availability from brainstem in humans. An intravenous bolus injection of 18F-FP-CIT was administered after the infusion of glucose or placebo (normal saline), and the emission data were acquired over 90 mins in 33 healthy nonobese subjects. For a volume-of-interest-based analysis, an atlas involving midbrain, and pons was applied. SERT availability, binding potential (BPND), were measured via the simplified reference tissue method with a reference of cerebellum. For a voxel-based analysis, statistical parametric mapping 12 was used with parametric BPND images. BPNDs from midbrain (p=0.8937), and pons (p=0.1115) were not different between glucose and placebo loading. Both of BPNDs from midbrain after glucose, and placebo loading were negatively correlated with body mass index (BMI). BMI showed a trend of negative correlation with glucose-loaded BPND from pons, whereas, placebo-loaded BPNDs from pons did not show any significant association with BMI. In conclusion, SERT availability was negatively correlated with BMI after glucose loading in humans. SERT might have a role in eating behavior through the action of insulin. Further studies are needed to elucidate the underlying mechanism of this phenomenon.

SLC6A3 gene polymorphisms are associated with striatal dopamine transporter changes after glucose loading.

We investigated the association between SLC6A3 gene polymorphisms and changes in dopamine transporter (DAT) availability after glucose loading in humans. An intravenous injection of 18 F-FP-CIT was administered after infusion of glucose or placebo, and the emission data were acquired over 90 min in 38 healthy male participants. DAT availability expressed in terms of binding potential (BPND ) was recorded. The 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region and two single nucleotide polymorphisms (SNPs), rs2652511 and rs2937639, in the SLC6A3 gene were genotyped. Among the 38 participants, those with a VNTR other than 10R/10R (n = 7) were excluded. The alleles of the two SNPs (rs2652511 and rs2937639) appeared to be inherited together in two fixed combinations (C-G or T-A) in 29 of 31 individuals. The BPND in the ventral striatum (VST), caudate nucleus, and putamen was not significantly different after glucose or placebo loading according to genotype. However, BPND s from the caudate nucleus and putamen of all participants with rs2652511 CT/rs2937639 AG (n = 6) were higher after glucose loading. In conclusion, the SLC6A3 gene polymorphism is associated with the changes in DAT availability after glucose loading. DAT availability after glucose or placebo loading in the VST, caudate nucleus, and putamen did not differ according to the SLC6A3 genotype.

Hedonic Rating of Sucrose Is Sub-Regionally Associated with Striatal Dopamine Transporter in Humans.

BACKGROUND: Eating behavior is determined by both homeostatic and hedonic values. OBJECTIVE: We investigated the association of hedonic value with striatal dopamine transporter (DAT) availability sub-regionally. METHOD: An intravenous bolus injection of 18F-FP-CIT was administered after the infusion of glucose or placebo, and the emission data were acquired over 90 min. DAT availability and binding potential (BPND) were measured via the simplified reference tissue method. Subjects were assessed with sensory taste test of sucrose solutions. The "most liked" sucrose concentration (%) was determined as the hedonic rating for sucrose. RESULTS: Twenty healthy males participated in this study. After glucose loading, BPNDs of putamen significantly increased, and those of caudate nucleus showed the increasing trend, while those of ventral striatum were not significantly different. After glucose loading, the "most liked" sucrose concentration (%) was negatively associated with BPNDs of caudate nucleus and showed the trend of positive association with those from ventral striatum. Slopes of regression lines were significantly different according to the sub-regions of striatum. CONCLUSION: We have highlighted that striatal DAT increased after glucose loading in dorsal striatum, not in ventral striatum. These changes of striatal DAT were sub-regionally associated with the hedonic rating of sucrose from each subject.

Effects of cisplatin and acacetin on total antioxidant status, apoptosis and expression of OCTN3 in mouse testis.

Cisplatin is a chemotherapeutic medication that also exhibits toxic effects on normal cells. Acacetin (ACA) is an herbal compound that exhibits anticancer properties with few side effects. We investigated the use and side effects of ACA and cisplatin on the male reproductive system. Mature male mice were divided into six groups: control group treated with DMSO, cisplatin group treated with 1 mg/kg cisplatin and three ACA groups treated with 10, 25 or 50 mg/kg ACA. All treatments were applied for three days. A final experimental group was treated with 50 mg/kg ACA for 10 days. At the end of the experiment, animals were sacrificed and reactive oxygen species (ROS), total antioxidant capacity (TAC), OCTN3 gene expression and apoptosis were measured in testis. TAC and OCTN3 gene expression were decreased, while ROS and apoptosis were increased in cisplatin group compared to other groups. All ACA groups exhibited decreased apoptosis and ROS levels, and increased TAC and OCTN3 gene expression compared to the cisplatin treated mice. ACA caused fewer adverse effects in testicular tissue than cisplatin. ACA appears to improve the oxidant-antioxidant system, accelerates cell regeneration and inhibits apoptosis.

Genetic and evolutionary characterization of the Major Facilitator Superfamily transporters of the antibacterial, Pantoea Natural Product 3.

Pantoea Natural Product 3 (PNP-3) is an antibiotic produced by Pantoea agglomerans that is effective against a broad range of multi-drug resistant bacteria. PNP-3 is encoded by a unique, eight-gene biosynthetic gene cluster composed of predicted enzymes (pnp3b, pnp3e-h), a regulator (pnp3d), and two Major Facilitator Superfamily transporters (pnp3a and pnp3c). To better characterize the role of the transporters, we generated pnp3a and pnp3c mutants and evaluated PNP-3 production. Disruption of pnp3a in Pantoea results in impaired growth and loss of antibiosis, suggesting a role in PNP-3 export and resistance. In contrast, pnp3c mutants display only reduced antibiotic production/export, suggesting a minor role for Pnp3c. Expression of pnp3a in susceptible Erwinia amylovora led to increased PNP-3 tolerance, while co-expression of pnp3a and pnp3e-h resulted in the production and export of PNP-3. Comparative genomic analyses identified pnp3a in 12 other Pantoea strains, eight of which carry a complete or nearly complete PNP-3 biosynthetic cluster. The four other Pantoea strains that carry pnp3a lack most of the PNP-3 cluster; however, they are PNP-3 tolerant. These results suggest Pnp3a plays an essential role in PNP-3 export and resistance in Pantoea.

In vitro drug-drug interactions of decitabine and tetrahydrouridine involving drug transporters and drug metabolising enzymes.

1. NDec is a novel, oral, fixed-dose formulation of decitabine and tetrahydrouridine that is currently being developed for the treatment of patients with sickle cell disease. Here, we examine the potential for both components of NDec to interact with key drug metabolising enzymes (tetrahydrouridine only) and drug transporters (decitabine and tetrahydrouridine).2. This study assessed the inhibition and induction of cytochrome P450 (CYP) enzymes by tetrahydrouridine, as well as the involvement of specific drug metabolising enzymes in tetrahydrouridine metabolism. Inhibition of efflux and uptake transporters by both decitabine and tetrahydrouridine was also studied.3. Tetrahydrouridine did not inhibit or induce relevant CYP enzymes at concentrations ranging from 0.1 to 100 µM. Metabolism of tetrahydrouridine did not occur in the presence of the human drug metabolising enzymes tested. Tetrahydrouridine showed weak inhibition towards the MATE2-K transporter (∼30% inhibition at 5 and 50 µM), which was not deemed clinically relevant. Tetrahydrouridine did not inhibit any of the remaining uptake or efflux transporters. Decitabine (0.5 and 5 µM) did not inhibit any of the evaluated uptake or efflux drug transporters.4. Data presented confirm that tetrahydrouridine and decitabine are unlikely to be involved in metabolism- or transporter-based drug-drug interactions.

Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments.

BACKGROUND: In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it. METHODS: We perfused labelled gadobenate dimeglumine (Bopta, 200 µM, 7% liver extraction ratio) and mebrofenin (Meb, 64 µM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used. RESULTS: Hepatocyte concentrations were 2,043 ± 333 µM (Meb) versus 360 ± 69 µM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers. CONCLUSION: Hepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.

Striatal DAT availability does not change after supraphysiological glucose loading dose in humans.

Brain dopamine neurotransmission is regulated by the dopamine transporter (DAT), which drives reuptake of extracellular dopamine into the presynaptic neurons. We hypothesized that the glucose loading dose would affect the striatal DAT availability. An i.v. bolus injection of 18F-FP-CIT was administered after infusion of low-dose glucose (300 mg/kg), high-dose glucose (600 mg/kg) or placebo (normal saline). The emission data were acquired over 90 min in 23 healthy male subjects. Substantial increases of binding potential (BPNDs) from ventral striatum (VST), caudate nucleus, and putamen were observed after low-dose glucose loading (+26.0, +87.0, and +37.8%) and after high-dose glucose loading (+10.4, +51.9, and +22.0%). BPNDs of the caudate nucleus and putamen showed significant differences (P = 0.0472 and 0.0221) after placebo, low-dose glucose, and high-dose glucose loading. BPNDs in the caudate nucleus and putamen after placebo, low-dose glucose, and high-dose glucose loading were positively intercorrelated with each other. In conclusion, striatal DAT changes after physiological glucose loading, but not after supraphysiological glucose loading in humans. DAT availabilities after placebo, low-dose glucose, high-dose glucose loading were correlated to each other in the caudate nucleus and putamen, but not in the VST. Therefore, sub-regional variability in DAT regulatory mechanisms mediated by insulin may exist in humans.

Genetic markers of the stress generation model: A systematic review.

AIM: Robust evidence suggests that depression, and risk for depression, are associated with the generation of stressful life events. This tendency to generate stress may be genetically determined. This systematic review aimed to identify specific molecular genetic markers associated with the generation of interpersonal stressful life events, at least in part dependent on individuals' behavior. METHOD: We followed the PRISMA guidelines in searching six electronic databases (PubMed, MEDLINE, PsycINFO, CINAHL, Cochrane, and EMBASE) from inception to January 2021, and we reviewed the reference lists of eligible articles for additional records. We restricted eligibility to empirical studies involving at least one genetic marker and including proximal life events. We evaluated the risk of bias using the Newcastle Ottawa Scale for observational studies. The outcome permitted a distinction between life events dependent on the individual's agency versus independent events. RESULTS: Seven studies, including 3585 participants, met eligibility criteria. Three were longitudinal, and four were cross-sectional; six included adolescents and young adults, and one focused on middle adulthood. Four examined the serotonin-transporter-linked promoter region (5-HTTLPR), two examined the rs53576 single nucleotide polymorphism of the oxytocin receptor gene (OXTR), and one examined a multilocus genetic profile score including four hypothalamic-pituitary-adrenal (HPA) axis genes. There were no significant direct correlations between genotype and life events in any study. Instead, their relation was significantly moderated by symptoms, exposure to early adversity, or attachment. Consistent with the stress generation hypothesis, this moderation relation was significant in predicting exposure to dependent life events but was not significant in predicting independent life event exposure. CONCLUSIONS: There is evidence that genetic variation in the serotonin, HPA axis, and oxytocin systems moderates the effects of psychosocial vulnerability markers on the generation of proximal, dependent life events. Future research should examine additional genetic markers in systems known to confer risk for stress generation. PROSPERO: CRD42019136886.