\n\nResults During a mean follow-up of 1164 months, 79 patients self-treated 213 arrhythmic episodes; treatment was successful in 201 episodes (94%). Major adverse events occurred in five patients (6%) and in four www.selleckchem.com/products/qnz-evp4593.html (5%) of these during the first oral treatment (one syncope, two presyncope,

one sinus arrest). No patient reported symptoms attributable to bradyarrhythmia or hypotension during the self-treatment of arrhythmic recurrences when the first oral treatment was not accompanied by any major adverse effects. The study was prematurely terminated because of the high incidence of major adverse effects during the first out-of-hospital treatment.\n\nConclusion The patient’s tolerance of intravenous administration of flecainide or propafenone does not seem to predict adverse effects during out-of-hospital self-administration of these drugs.”
“BACKGROUND: Constitutively activated nuclear factor kappa B (NF kappa B) contributes to the development of cancer by regulating the expression of genes involved in cell survival,

metastasis, and angiogenesis. The authors have demonstrated that MEKK3 plays a critical role in cytokine-mediated NF kappa B activation, and that stable expression of MEKK3 in cultured CBL0137 concentration cells leads to increased NF kappa B activity. METHODS: MEKK3 expression in ovarian cancer cells or tumors was assessed by Western blotting and real-time polymerase chain reaction. NF kappa B activities were analyzed by electrophoretic mobility shift assay and luciferase reporter assays. Western blot analysis for the survival factors were also performed and correlated with MEKK3 and NF kappa B activities. Cell survival assays were used

to determine the sensitivity of ovarian cancer cells to various chemotherapeutic agents. RESULTS: The authors found that 63% of the ovarian cancers had higher MEKK3 expression than the normal ovarian epithelial cells. Ovarian cancers with high MEKK3 showed correspondingly high I kappa B kinase and NF kappa B activity. Moreover, MEKK3 coimmunoprecipitated with Akt and cooperated with Akt to synergistically activate NF kappa B. Consistent with increased MEKK3 and NF kappa B activity in ovarian cancers, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis levels were increased, which correlated with increased resistance to chemotherapeutic Stem Cell Compound Library screening agents. Knockdown of MEKK3 with small interfering RNA significantly increased cancer cell sensitivity to paclitaxel. CONCLUSIONS: MEKK3 may be aberrantly expressed in ovarian cancers and plays an important role in tumors with constitutively activated NF kappa B. Cancer 2009;115:3897-908. (C) 2009 American Cancer Society.”
“Like many other bacterial lipases Pseudomonas aeruginosa lipase has a very strong structure-function relationship. Herein, the effect of structural compactness of lipase has been investigated on its activity. P.

g., fictive eupnea and sighs)? (3) How is preBotC activity affected by surrounding structures? Using newborn rat slices with systematically varied dimensions in physiological [K+] (3 mM), we found that a 175 mu m thickness is sufficient for generating inspiratory-related rhythms. In 700-mu m-thick slices with unilaterally exposed preBotC, a kernel <100 mu m thick, centered 0.5 mm caudal to the facial nucleus, is necessary for rhythm Cyclopamine research buy generation. Slices containing this kernel plus caudal structures produced eupneic bursts of

regular amplitude, whereas this kernel plus rostral tissue generated sighs, intermingled with eupneic bursts of variable amplitude (“eupnea-sighpattern”). After spontaneous arrest of rhythm, substance-P or neurokinin-1 GSK2879552 purchase (NK1) receptor agonist induced the eupnea-sigh burst pattern in >= 250-mu m-thick slices, whereas thyrotropin-releasing hormone or phosphodiesterase-4 blockers evoked the eupnea burst pattern. Endogenous rhythm was depressed by NK1 receptor antagonism. Multineuronal Ca2+ imaging revealed that preBotC neurons reconfigure between eupnea and eupnea-sigh burst patterns. We hypothesize a (gradient-like) spatio-chemical organization of regions adjacent to the preBotC, such

that a small preBotC inspiratory-related oscillator generates eupnea under the dominant influence of caudal structures or thyrotropin-releasing hormone-like transmitters but eupnea-sigh activity when the influence of rostral structures or substance-P-like transmitters predominates.”
“The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-ylpentan-1-yl]

thymidine, designated N5-2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma Prexasertib supplier model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(-) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of B-10-enriched N5-20H were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(+) L929 tumors had a 15x reduction in tumor volume compared with TK1(-) controls. Based on these favorable results, BINICT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5-20H by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BIPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 +/- 7.2 days, 35.0 +/- 3.3 days, and 52.9 +/- 8.9 days, respectively, for animals that received N5-20H, BIPA, or both.

Further adjustment for personal socioeconomic differences eliminates the IRRs associated with various disorders only to a limited extend. Recurrent depression and borderline personality disorder increase suicide risk the strongest while dementia increases the risk the least for both males and females. The influence of various disorders generally weakens with increasing age; however, there are important exceptions. Schizophrenia affects people aged <= 35 years the strongest in terms click here of both IRR and PAR. Recurrent depression increases suicide risk particularly strong in all age groups and the associated PAR increases steadily

with age. Borderline personality disorder has a strong effect in young people, especially those <= 35 years. Alcohol use disorder accounts the

highest PAR of suicides in males of 36-60 years old. For the elderly above 60 years old, reaction to stress and adjustment disorder increases Sonidegib the risk for suicide the most in both sexes. These findings suggest that approaches to psychiatric suicide prevention should be varied according to diagnosis and sex and age of subjects. (C) 2011 Elsevier Ltd. All rights reserved.”
“A coarse grained computer model is presented in the context of dynamic mechanical analysis of filled elastomer networks. The model relates both storage and loss modulus as functions of shear frequency and strain amplitude to filler content and structure as well as to parameters describing NSC-732208 matrix-filler and filler-filler interaction on the nano-scale. We show how such a coarse grained model may be used to guide the developer of filled elastomer applications in the understanding of the interplay between molecular interface design and macroscopic performance with respect to the Payne effect. (C) 2012 Elsevier Ltd. All rights reserved.”
“Background: Pro- and antiinflammatory genes are expressed in epicardial adipose tissue (EAT). Our objectives were to characterize genes in EAT that may contribute specifically to coronary atherogenesis and to measure circulating

adipokines matched to their messenger RNAs (mRNAs) in EAT. We hypothesized that severe coronary atherosclerosis (CAD) would preferentially affect gene expression in EAT as compared to substernal fat or subcutaneous thoracic adipose tissue (SAT), as well as circulating levels of adipokines.\n\nMethods: Fat mRNA was quantified using reverse transcription polymerase chain reaction (RT-PCR), and circulating adipokines were measured by enzyme-linked immunosorbent assays (ELISAs) in patients with severe stable CAD and controls without severe CAD undergoing open heart surgery.\n\nResults: A total of 39 of 70 mRNAs in EAT were significantly increased in CAD. Only 4 and 3 of these mRNAs were increased in substernal fat and SAT, respectively.

Decreased levels of testosterone in the peripheral blood and diminished volume size of testes are found in patients suffering from alcoholic liver cirrhosis. Erectile dysfunction in patients with liver cirrhosis needs further evaluation.”
“Thromboxane A(2) (TXA(2)) is known to stimulate colonic cancer cell proliferation, although the mechanism has not been clarified. In this study, we compared the expression levels of Kv7.1 K+ channels between human colorectal cancer tissue and the accompanying non-tumor mucosa. Kv7.1 proteins were found to be consistently up-regulated in the cancer tissues from different patients.

Kv7.1 was also expressed in human colonic cancer cell lines. Treatment of colonic cancer cells with 9,11-epithio-11,12-methano-thromboxane A(2) buy IPI-145 (STA(2)), a stable analogue of TXA(2), significantly increased whole-cell K+ currents sensitive to chromanol 293B, an inhibitor of Kv7.1 channels, in parallel with an increased expression of Kv7.1 proteins. In contrast, TXB2, an inactive metabolite of TXA(2), had no effects on expression level and function of Kv7.1. A TXA(2) receptor antagonist (SQ29548) and an inhibitor of cAMP-dependent protein kinase (Rp-8-Br-MB-cAMPS) inhibited STA(2)-induced selleckchem increases in both Kv7.1 expression and chromanol 293B-sensitive

K+ currents. Interestingly, STA(2)-stimulated proliferation of colonic cancer cells was inhibited by chromanol 293B. These results suggest that Kv7.1 channels are involved in the TXA(2)-induced cancer cell proliferation and that they are up-regulated by the TXA(2) receptor-mediated cAMP pathway.”
“Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of Alzheimer’s disease (AD), especially when additional cognitive domains are affected (Petersen et al., 2009). Thus, single-domain amnestic MCI (sdaMCI) and multiple-domain-amnestic MCI (mdaMCI) biomarkers are important for enabling early interventions to help slow down progression of the disease. Recording event-related potentials

(ERPs) is a non-invasive and inexpensive measure of brain activity associated with cognitive processes, and it is of interest from a clinical point of view. The ERP technique may also be useful for obtaining early sdaMCI and mdaMCI biomarkers because ERPs are sensitive to impairment in processes that are not manifested at behavioral see more or clinical levels. In the present study, EEG activity was recorded in 25 healthy participants and 30 amnestic MCI patients (17 sdaMCI and 13 mdaMCI) while they performed a Simon task. The ERPs associated with visuospatial (N2 posterior-contralateral – N2pc -) and motor (lateralized readiness potential – LRP -) processes were examined. The N2pc amplitude was smaller in participants with mdaMCI than in healthy participants, which indicated a decline in the correlates of allocation of attentional resources to the target stimulus. In addition, N2pc amplitude proved to be a moderately good biomarker of mdaMCI subtype (0.77 sensitivity, 0.76 specificity).

There are few data on the adherence in real life for pharmacological treatments of allergic rhinitis (e.g. nasal steroids or antihistamines),

whereas more data are available for specific immunotherapy. In this latter case, in real life, adherence seems to be far from optimal, for both sublingual and subcutaneous immunotherapy, although the recent studies agree on the fact that some interventions (i.e. patients education, strict follow-up, regular contacts) could effectively improve the adherence. In this article, the literature concerning the adherence to pharmacological Autophagy Compound high throughput screening treatments and immunotherapy in allergic rhinitis was searched and reviewed.”
“Nuclear factor-kappa B (NF-kappa B) and Akt are two major cell-survival pathways that are often constitutively activated in cancer cells. It has been established that these two pathways contribute substantially toward the chemoresistance of cancer cells. Our previous study has demonstrated that NF-kappa B and Akt cooperatively blunt cytotoxicity induced by cisplatin or etopside in different types of cancer cells in vitro, indicating that LY2835219 nmr the concurrent blocking of these pathways may effectively improve the anticancer efficacy of anticancer therapeutics. In this study, we further investigated the effect of concurrent blockade of NF-kappa B and Akt on the anticancer activity of cisplatin in vivo in

a xenograft tumor model. The NF-kappa B and Akt pathways in the A549 lung cancer cells were blocked individually or concurrently by the stable transfection of plasmids expressing short hairpin RNAs that target Akt1 and I kappa B kinase

beta. The resultant cells with concurrent NF-kappa B and Akt blockade were significantly more sensitive to cisplatin-induced cell death in vitro. Consistently, tumors Compound Library cost derived from cells with the concurrent blockade of NF-kappa B and Akt were much more sensitive to cisplatin compared with those derived from cells with individual blockage of NF-kappa B or Akt in a nude mouse xenograft tumor model. Apoptosis was significantly enhanced in the double pathway-suppressed and cisplatin-treated tumors. These results show for the first time that the concurrent blockage of the NF-kappa B and Akt pathways cooperatively potentiates the antitumor activity of cisplatin in vivo, indicating that this strategy may be potentially useful for clinical anticancer therapy. Anti-Cancer Drugs 23:1039-1046 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“Invasive infections due to filamentous fungi, such as Aspergillus spp., Zygomycetes, Scedosporium and Fusarium spp., cause significant morbidity and mortality in immunocompromised patients with hematological malignancies, recipients of hematopoietic stem cell transplants and those with chronic granulomatous disease.

Compared to cells washed in non-immunogenic human serum albumin (HSA), MSCs washed with ABP elicited stronger blood responses after exposure PND-1186 to blood from healthy O donors in vitro, containing high titers of ABO antibodies. Clinical evaluation of hematopoietic stem cell transplant (HSCT) recipients found only very low titers of anti-A/B agglutination in these strongly immunocompromised patients at the time of MSC treatment. Patient analysis revealed a trend for lower clinical response

in blood group O recipients treated with ABP-exposed MSC products, but not with HSA-exposed products. We conclude, that clinical grade MSCs are ABO-neutral, but the ABP used for washing and infusion of MSCs can contaminate the cells with immunogenic ABO substance and should therefore be substituted by non-immunogenic HSA, particularly when cells are given to immunocompentent individuals.”
“Deprenyl has been discovered by Knoll and co-workers. The R-enantiomer of deprenyl (selegiline) is a selective and irreversible inhibitor of the B-isoform of monoamine oxidase

(MAO-B) enzyme. Due to its dopamine potentiating and possible neuroprotective properties it has an established role in the treatment of parkinsonian patients. By inhibiting MAO-B enzyme, R-deprenyl decreases the formation of hydrogen peroxide, alleviating Napabucasin cell line the oxidative stress also reduced by increased expression of antioxidant enzymes (superoxide dismutases and catalase) reported during chronic treatment. It was shown to prevent the detrimental effects of neurotoxins like MPTP and DSP-4. R-Deprenyl elicits neuroprotective and neuronal rescue activities in concentrations too low to inhibit MAO-B. It is extensively metabolized and some of the metabolites possess pharmacological activities, thus their contribution to neuroprotective properties was also suggested. The recently identified deprenyl-N-oxide is extensively studied in our laboratory. Effects other than neuroprotection, like influencing cell adhesion and proliferation cannot be neglected.”
“Factor IX-binding protein (AHP

this website IX-bp), a Ca(2+)- and Zn(2+)-binding protein from the venom of Agkistrodon Halys Pallas was reported to bind specifically with factor IX in a Zn(2+)-dependent manner. Here we have purified AHP IX-bp by a simple two-step of chromatography procedure and found that AHP IX-bp also binds factor Xa (FXa) with high binding-affinity in a Mg(2+)-dependent manner. Although Mg(2+) ions have a significantly low binding-affinity for apo-AHP IX-bp as determined by isothermal titration calorimetry, they can induce the binding of apo-AHP IX-bp with FXa even in the absence of Ca(2+) as determined by native PAGE and surface plasmon resonance. Mg(2+) ions are required to maintain in vivo function of FX Gla domain for its recognition of AHP IX-bp. Both Ca(2+) and Zn(2+) ions fail to induce the binding between apo-AHP IX-bp and FXa.

Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. Methods: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable

dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), beta-amyloid 1-42 (A beta 42) and the light subunit of neurofilament protein (NFL) were determined. Results: Patients with converting MCI and stable dementia had lower CSF A beta 42 concentrations and higher T-tau concentrations Dihydrotestosterone concentration and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. Conclusion: As expected, biomarker deviations Dorsomorphin predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the

underlying cause in this patient group. Copyright (C) 2011 S. Karger AG, Basel”
“Objective: To compare perforation characteristics of standard 22 G (0.7 mm) to 29 G needle (0.34 mm) for amniocentesis.\n\nMethods: Seventeen human chorio-amnion membranes were perforated immediately after cesarean section using 22 G needle for spinal anesthesia and 29 G “pencil-point” needles for amniocentesis under in-vitro conditions. Area of perforation was determined using a microscope and volume of fluid leakage was measured over a period of 5 min.\n\nResults: Membrane perforation with the 22 G needle resulted in a mean damaged area of 225,147.4 mu m(2), a hole with a mean area of 50,154 mu m(2) and amniotic fluid volume passage of 17.5 mL/5 min, whereas the 29 G needle

generated a mean damaged area of 114,812.4 mu m(2), a hole with an average area Momelotinib of 1382.5 mu m(2) and volume passage of 0.28 mL/5 min. These differences were significant.\n\nConclusion: The hole formed by membrane perforation with 29 G “pencil-point” needle for amniocentesis is 36 times smaller, and the amniotic fluid loss is 61 times less than that measured with the 22 G standard needle for spinal anesthesia. Significant reduction of complications following amniocentesis is expected with the 29 G needle.”
“Microorganisms were first described by van Leeuwenhoek in the 17th century. Later, Pasteur and Koch related them to diseases. Since then, the scientific community has striven to extend awareness of the many functions of microorganisms. Science museums provide an excellent setting in which to disseminate such knowledge, but the presentation of living microorganisms is a challenge.

“
“Reactive oxygen MI-503 supplier species and their detrimental effects on the brain after transient ischemia/reperfusion (I/R) have been implicated in the pathogenesis of ischemic reperfusion

injury. Thioredoxin-1 (Trx-1) is an endogenous antioxidant protein that has neuroprotective effects. We hypothesized that Trx-1 plays a crucial role in regulating cerebral I/R injury. To be able to test this, 190 Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) with Trx-1 siRNA (small interference RNA) injected 24 h prior to ischemia. At 24 h after tMCAO, we measured neurological deficits, infarct volume, and brain water content, and found that neurological dysfunction, brain infarct size, and brain edema were worse in the Trx-1 siRNA group than in the control group. Oxidative stress was evaluated by measuring superoxide dismutase activity and malondialdehyde level. The levels of Trx-1 and its cofactor, peroxiredoxin (Prdx), were significantly decreased after Trx-1 down-regulated. However, there is no significant difference in the Prdx mRNA level after administration of Trx-1 siRNA. In contrast, Prdx-SO3 protein levels were significantly increased in the Trx-1 siRNA group. We also investigated the

specific role of nuclear factor erythroid 2-related factor 2 (Nrf2) in Trx-1 induction by knocking down Nrf2. Nrf2 siRNA injection decreased Trx-1 Galunisertib mw mRNA and protein expression. Our results suggest that the exacerbation of brain damage was associated with enhanced cerebral peroxidation in brain tissues. Moreover, A-1210477 these results revealed that Trx-1, which is more likely regulated by Nrf2, exerts a neuroprotective role probably through maintaining the reduction activity of Prdx1-4. (C) 2014 Published by Elsevier Ltd. on behalf of IBRO.”
“The central importance of chorismate enzymes in bacteria, fungi, parasites, and plants combined with their absence in mammals makes them attractive

targets for antimicrobials and herbicides. Two of these enzymes, anthranilate synthase (AS) and aminodeoxychorismate synthase (ADCS), are structurally and mechanistically similar. The first catalytic step, amination at C2, is common between them, but AS additionally catalyzes pyruvate elimination, aromatizing the aminated intermediate to anthranilate. Despite prior attempts, the conversion of a pyruvate elimination-deficient enzyme into an elimination-proficient one has not been reported. Janus, a bioinformatics method for predicting mutations required to functionally interconvert homologous enzymes, was employed to predict mutations to convert ADCS into AS. A genetic selection on a library of Janus-predicted mutations was performed. Complementation of an AS-deficient strain of Escherichia coli grown on minimal medium led to several ADCS mutants that allow growth in 6 days compared to 2 days for wild-type AS.

Liver function tests were found normal. Thus, the children working in garbage dumping site are in severe health risk.”
“Phenology and crop stand are the two important determinants that fix crop growth cycle as well as directly or indirectly affect the crop productivity. In this connection, we carried out a field trial at Horticulture Research Farm of the University of Agriculture,

Peshawar during 2010 in order to sort out how N and P influence the phenology of okra using various okra varieties. The experiment was laid out in Randomized complete block design (RCBD) with split plot arrangement. The parameters studied were survival MDV3100 clinical trial percentage (%), days to flowering, plant height (cm), pod length (cm), and sound seeds pod(-1) of the okra plants at various levels of nitrogen (N) and phosphorus (P) fertilizers. The different

levels of N and P had a significant effect on days to flowering, plant height (cm), and pod length (cm). However, among varieties, maximum days to flowering (39.57) were recorded in Sabz Pari and minimum (36.33) in Arka Anamika; maximum plant height (104.47 cm) in Sabz Pari and minimum (86.86 cm) in Green Star. Among the fertilizer levels, maximum days to flowering (41.11) were recorded in plots of N and P fertilizers applied at rate of 150 and 120 kg ha(-1), respectively, while minimum days to flowering (33.11) were there in control plots. Similarly, the tallest plants of height 106.51 cm were observed in N and P treated plots at 150 and 90 kg ha(-1), respectively, whereas plant height was least (72.17 cm) in control selleck inhibitor plots. Pod length was highest i.e., 17.97 cm recorded in N and P combined treated plots at 100 and 120 kg ha(-1) as compared to the lowest pod length (15.35 cm) in control plots. In light of the results it could be concluded that okra is phonologically vulnerable to different levels of N and P applications in Peshawar region.”
“Resting EEG asymmetry evident early in life is thought to

bias affective behaviors and contribute to the development of psychopathology. However, it remains unclear at what stage of information processing this bias occurs. Asymmetry selleck kinase inhibitor may serve as an afferent filter, modulating emotional reactivity to incoming stimuli; or as an efferent filter, modulating behavioral response tendencies under emotional conditions. This study examines 209 kindergarten children (M=6.03 years old) to test predictions put forth by the two models. Resting asymmetry was examined in conjunction with electrodermal and cardiac measures of physiological reactivity to four emotion-inducing film clips (fear, sad, happy, anger) and teacher ratings of psychopathology. Results confirm an association between increased right side cortical activation and internalizing symptom severity as well as left activation and externalizing symptom severity.

01) with increasing yeast supplementation. Live yeast addition did not modify the total tract digestibility of nutrients, or the growth performance. Mortality rate between 42 and 56d of age was lower at the highest yeast level (C10: 4 dead on 40; P<0.05) compared to C0 and C1 groups (average 13/40),. The structure of the caecal bacterial community was not modified after 11d of yeast presence in the caecum, while the bacterial diversity tended to be higher (5.0 vs 5.4,

P=0.10, for C0 vs [C1+C10]). The redox FG-4592 purchase potential of the caecal content increased with yeast addition (-227 vs -251 my, P<0.05 for CO vs [C1+C10]), whereas the fermentation pattern and the caecal pH remain unaffected (meanly 5.88). (C) 2012 Elsevier B.V. All rights reserved.”
“Background: Rare genetic variation is an important class of autism spectrum disorder (ASD) risk factors and can implicate biological networks for investigation. Altered serotonin (5-HT) signaling has been implicated in ASD, and we and others have discovered multiple, rare, ASD-associated variants in the 5-HT transporter (SERT) gene leading to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci

encoding SERT regulators harbor variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and other signaling pathways leading to enhanced SERT surface expression and catalytic activity.\n\nMethods:

To test CYC202 our hypothesis, we asked whether rare variants selleck compound in the A3AR gene (ADORA3) were increased in ASD cases vs. controls. Discovery sequencing in a case-control sample and subsequent analysis of comparison exome sequence data were conducted. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity.\n\nResults: Sequencing discovery showed an increase of rare coding variants in cases vs. controls (P=0.013). While comparison exome sequence data did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90-A3AR revealed elevated basal cGMP levels compared with the wildtype receptor. Additionally, a specific A3AR agonist increased cGMP levels across the full time course studied in Val90-A3AR cells, compared to wildtype receptor. In Val90-A3AR/SERT co-transfections, agonist stimulation elevated SERT activity over the wildtype receptor with delayed 5-HT uptake activity recovery. In contrast, Ile171-A3AR was unable to support agonist stimulation of SERT.