It has been reported that inhibition of RAD52 either by specific shRNA or a small peptide aptamer induced synthetic lethality in tumor cell lines carrying BRCA1 and BRCA2 inactivating mutations. ...Molecular docking was used to screen two chemical libraries: 1) 1,217 FDA approved drugs, and 2) 139,735 drug-like compounds to identify candidates for interacting with DNA binding domain of human RAD52. Thirty six lead candidate compounds were identified that were predicted to interfere with RAD52 -DNA binding. Further biological testing confirmed that 9 of 36 candidate compounds were able to inhibit the binding of RAD52 to single-stranded DNA in vitro. Based on molecular binding combined with functional assays, we propose a model in which the active compounds bind to a critical "hotspot" in RAD52 DNA binding domain 1. In addition, one of the 9 active compounds, adenosine 5'-monophosphate (A5MP), and also its mimic 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 5' phosphate (ZMP) inhibited RAD52 activity in vivo and exerted synthetic lethality against BRCA1 and BRCA2-mutated carcinomas. These data suggest that active, inhibitory RAD52 binding compounds could be further refined for efficacy and safety to develop drugs inducing synthetic lethality in tumors displaying deficiencies in BRCA1/2-mediated homologous recombination.
Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly ...developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.
•KOR is expressed in peptidergic primary afferents in mouse and human•KOR is expressed in LTMRs that form circumferential and lanceolate endings•KOR signaling inhibits nociceptor sensitization and neurogenic inflammation•Peripherally selective KOR agonists inhibit nociception
Snyder et al. identify primary afferents that express the kappa opioid receptor in mouse and human and show that kappa opioid receptor signaling inhibits these cells in physiological and behavioral experiments.
Aim
To investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin versus dipeptidyl peptidase‐4 (DPP‐4) inhibitor treatment across the broad ...spectrum of cardiovascular risk.
Methods
In a population‐based cohort study we identified 39 072 pairs of 1:1 propensity score‐matched adult patients with T2D initiating empagliflozin or DPP‐4 inhibitors, using data from 2 US commercial insurance databases and Medicare between August 2014 and September 2017. The primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower‐limb amputations (LLAs), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for more than 140 baseline covariates.
Results
Study participants had a mean age of 60 years and only 28% had established cardiovascular disease. Compared to DPP‐4 inhibitors, empagliflozin was associated with similar risk of MI/stroke (HR 0.99 95% CI 0.81‐1.21), and lower risk of HHF (HR 0.48 95% CI 0.35‐0.67 and 0.63 95% CI 0.54‐0.74, based on a primary and any heart failure discharge diagnosis, respectively). The HR was 0.52 (95% CI 0.38‐0.72) for all‐cause mortality (ACM) and 0.83 (95% CI 0.70‐0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA (HR 1.71 95% CI 1.08‐2.71) and a decreased risk of AKI (HR 0.60 95% CI 0.43‐0.85).
Conclusions
In clinical practice, the initiation of empagliflozin versus a DPP‐4 inhibitor was associated with a lower risk of HHF, ACM and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information.
Animal studies suggest that phthalates and bisphenol A (BPA), endocrine-disrupting chemicals found in many consumer products, may impact the timing of puberty.
We aimed to determine the association ...of prenatal exposure to high-molecular-weight phthalates and BPA with pubertal timing in boys and girls participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study.
We quantified urinary concentrations of eight phthalate metabolites and BPA at two time points during pregnancy among participating mothers (Formula: see text) and conducted clinical Tanner staging of puberty on their children every 9 months between 9 and 13 y of age. We conducted accelerated failure time models and examined the role of child overweight/obese status in this association.
The sum of urinary metabolites of di(2-ethylhexyl) phthalate Formula: see text, monobenzyl phthalate (MBzP), and BPA were associated with later onset of at least one of the three outcomes assessed in girls (thelarche, pubarche, or menarche) and with earlier onset of at least one of the two outcomes assessed in boys (gondarche and pubarche). We found that monocarboxynonyl phthalate, monocarboxyoctyl phthalate, mono(3-carboxypropyl) phthalate, and BPA were associated with later pubarche and menarche mostly among normal-weight girls but not overweight/obese girls. MBzP was associated with later thelarche in all girls, and Formula: see text was associated with later thelarche and menarche in all girls. BPA and all phthalate biomarkers were associated with earlier gonadarche and pubarche in all boys as well as in overweight/obese boys when stratified by weight. Among normal-weight boys, associations with BPA were also inverse, whereas associations with phthalate metabolites were close to the null or positive.
Several high-molecular-weight phthalates and BPA were associated with later puberty in girls and earlier puberty in boys included in the CHAMACOS cohort study. Childhood overweight/obesity may modify these associations. https://doi.org/10.1289/EHP3424.
The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. ...The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.
genome-wide association study of alcohol dependence Bierut, Laura J; Agrawal, Arpana; Bucholz, Kathleen K ...
Proceedings of the National Academy of Sciences - PNAS,
03/2010, Letnik:
107, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol ...dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10⁻⁵, but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
The use of online mass spectrometry for detecting volatile organic compounds (VOCs) has proven to be a powerful technique, allowing for real-time analysis of many chemical and biochemical processes. ...Unfortunately, online mass spectrometry has had limited application due to high instrument costs and limited availability. Here, we detail the design, construction, and performance characteristics of a custom ion–molecule reactor retrofitted to a commonly used single quadrupole mass spectrometer to operate as an online chemical ionization mass spectrometer (CIMS). This low-cost modified CIMS is capable of limits of detection below 10 parts per trillion for select VOCs including dimethyl sulfide, dimethylamine, and trimethylamine.
Borenium ions, originally synthesized as fundamentally important laboratory curiosities, have attracted significant attention due to their applications in catalysis and frustrated Lewis pair ...chemistry. However, investigations of the materials properties of these types of compounds are exceptionally rare. Herein, we report the synthesis, molecular structures, and optical properties of a new class of air-stable borenium ions, stabilized by the strongly donating carbodicarbene (CDC) ligand (2, 3, 6). Notably, CDC-borafluorenium ions exhibit thermoluminescence in solution, a result of a twisted intramolecular charge transfer process. The temperature responsiveness, which is observable by the naked eye, is assessed over a 20 to −60 °C range. Significantly, compound 2 emits white light at lower temperatures. In the solid state, these borocations exhibit increased quantum yields due to aggregation-induced emission. CDC-borafluorenium ions with two different counteranions (Br–, BPh4 –) were investigated to evaluate the effect of anion size on the solution and solid-state optical properties. In addition, CDCs containing both symmetrical and unsymmetrical N-heterocycles (bis(1-isopropyl-3-methylbenzimidazol-2-ylidene)methane and bis(1,3-dimethyl-1,3-dihydro-2H-benzodimidazol-2-ylidene)methane) were tested to understand the implications of free rotation about the CDC ligand carbon–carbon bonds. The experimental work is complemented by a comprehensive theoretical analysis of the excited-state dynamics.
A series of BN-incorporated borafluorenate heterocycles, bis(borafluorene-phosphinimine)s (11–15), have been formed via intramolecular Staudinger-type reactions. The reactions were promoted by ...light or heat using monodentate phosphine-stabilized 9-azido-9-borafluorenes (R3P-BF-N3; 6–10) and involve the release of dinitrogen (N2), migration of phosphine from boron to nitrogen, and oxidation of the phosphorus center (PIII to PV). Density functional theory (DFT) calculations provide mechanistic insight into the formation of these compounds. Compounds 11–15 are blue emissive in the solution and solid states with absolute quantum yields (ΦF) ranging from 12 to 68%.
N-glycolylneuraminic acid (Neu5Gc) is a non-human red-meat-derived sialic acid immunogenic to humans. Neu5Gc can be metabolically incorporated into glycan chains on human endothelial and epithelial ...surfaces. This represents the first example of a "xeno-autoantigen", against which circulating human "xeno-autoantibodies" can react. The resulting inflammation ("xenosialitis") has been demonstrated in human-like Neu5Gc-deficient mice and contributed to carcinoma progression via antibody-mediated inflammation. Anti-Neu5Gc antibodies have potential as biomarkers for diseases associated with red meat consumption such as carcinomas, atherosclerosis, and type 2 diabetes.
ELISA assays measured antibodies against Neu5Gc or Neu5Gc-glycans in plasma or serum samples from the Nurses' Health Studies, the Health Professionals Follow-up Study, and the European Prospective Investigation into Cancer and Nutrition, including inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over 1-3 years in archived samples. We also assessed associations between antibody levels and coronary artery disease risk (CAD) or red meat intake. A glycan microarray was used to detected antibodies against multiple Neu5Gc-glycan epitopes. A nested case-control study design assessed the association between total anti-Neu5Gc antibodies detected in the glycan array assay and the risk of colorectal cancer (CRC).
ELISA assays showed a wide range of anti-Neu5Gc responses and good inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over time, but these antibody levels did not correlate with CAD risk or red meat intake. Antibodies against Neu5Gc alone or against individual Neu5Gc-bearing epitopes were also not associated with colorectal cancer (CRC) risk. However, a sialoglycan microarray study demonstrated positive association with CRC risk when the total antibody responses against all Neu5Gc-glycans were combined. Individuals in the top quartile of total anti-Neu5Gc IgG antibody concentrations had nearly three times the risk compared to those in the bottom quartile (Multivariate Odds Ratio comparing top to bottom quartile: 2.98, 95% CI: 0.80, 11.1; P for trend = 0.02).
Further work harnessing the utility of these anti-Neu5Gc antibodies as biomarkers in red meat-associated diseases must consider diversity in individual antibody profiles against different Neu5Gc-bearing glycans. Traditional ELISA assays for antibodies directed against Neu5Gc alone, or against specific Neu5Gc-glycans may not be adequate to define risk associations. Our finding of a positive association of total anti-Neu5Gc antibodies with CRC risk also warrants confirmation in larger prospective studies.
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