Neuroadaptations in the Cellular and Postsynaptic Group 1 Metabotropic Glutamate Receptor mGluR5 and Homer Proteins Following Extinction of Cocaine Self-administration

This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, orwere placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic densitywere examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations aswell as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function

Bridging Cancer Biology with the Clinic: Relative Expression of a <i>GRHL2</i>-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis

Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.</p

Utilization of Dantrolene in Stiff-Person Syndrome: A Case Report

Setting: University hospital-based acute rehabilitation. Patient: 75-year-old woman with Stiff-Person Syndrome (SPS) with a recent fall and Colles fracture. Case Description: Four months prior to admission, the patient was diagnosed with SPS, negative for anti-GAD antibodies. Diagnosis was based on a 3-year history of progressive rigidity leading to frequent falls and fractures. Anxiety and fear of falling limited her mobility, and she sustained a sacral pressure ulcer during acute hospitalization. On admission, history was remarkable for unsteady gait and muscle cramps exacerbated when startled or excited. Examination was remarkable for rigidity in her axial and limb muscles. She presented at the maximal assist level for transfers and toileting and moderate assist level for grooming and ambulation using a platform walker (right arm in cast). She was unable to tolerate titration of diazepam due to sedation, or baclofen due to hypotension. Results: During acute rehabilitation, rigidity was treated with titration of dantrolene (from 25 to 50 mg four times daily) in addition to maximal tolerated doses of diazepam (1 mg qAM/2 mg qPM) and baclofen (20mg TID). The addition of dantrolene reduced rigidity and improved range of motion, both subjectively per patient and objectively by exam. Functional gains stalled with dose decrease and resumed with dose increase. She had pronounced gains in grooming to the supervision level, modest gains in transfers and toileting to the moderate assist level, but remained at the moderate assist level for ambulation. Progress was limited due to a change to non-weight bearing status of her right arm. Anxiety and depression were improved with buspirone, paroxetine, and psychological counseling. Discussion: SPS results in significant activity of daily life and ambulatory dysfunction as exemplified by her pressure ulcer and multiple falls. Although GABA agonists are the preferred treatment for SPS, the adverse effects of high doses can increase the risk of falls. Dantrolene reduced muscle rigidity and improved function without sedative or hypotensive effects. Conclusion: Dantrolene is a useful additional treatment for SPS rigidity

Substituted dipyridophenazine complexes of Cr(III): synthesis, enantiomeric resolution and binding interactions with calf thymus DNA

[Cr(phen)2(X2dppz)]3+ {X = H, Me, or F} have been synthesised, characterised, and chromatographically resolved into their constituent Δ and Λ enantiomers. The DNA-binding interactions of each of the racemic complexes were investigated, with the results of linear dichroism, thermal denaturation, and emission quenching studies indicative of intercalative binding to CT-DNA with a significant electrostatic contribution. UV/Vis absorption titrations suggest strong DNA binding by each of the racemic complexes, with the methylated analogue [Cr(phen)2(Me 2dppz)]3+ exhibiting the largest equilibrium binding constant. Emission quenching and UV-Vis titrations of the enantiomers of [Cr(phen)2(dppz)]3+ imply similar binding affinities for the Δ and Λ isomers, although significant differences between the circular dichroism spectra of the enantiomers in the presence of DNA connote differences in binding orientation and/or conformation between the two

The Impact of Body Mass Index on Functional Rehabilitation Outcomes of Working-age Inpatients with Stroke

BACKGROUND: Stroke is the most relevant cause of acquired persistent disability in adulthood. The relationship between patient’s weight during rehabilitation and stroke functional outcome is controversial, previous research reported positive, negative and no effects, with scarce studies specifically addressing working-age patients.AIM: To evaluate the association between Body Mass Index (BMI) and the functional progress of adult (\u3c65 \u3eyears) patients with stroke admitted to a rehabilitation hospital.DESIGN: Retrospective observational cohort study.SETTING: Inpatient rehabilitation center.POPULATION: 178 stroke patients (ischemic or hemorrhagic).METHODS: Point-biserial and Spearman’s correlations, multivariate linear regressions and analysis of covariance were used to describe differences in functional outcomes after adjusting for age, sex, severity, dysphagia, depression and BMI category. Functional Independence Measure (FIM), FIM gain, efficiency and effectiveness were assessed.RESULTS: Participants were separated in 3 BMI categories: normal weight (47%), overweight (33%) and obese (20%). There were no significant differences between BMI categories in any functional outcome (total FIM (TFIM), cognitive (CFIM), motor (MFIM)) at discharge, admission, gain, efficiency or effectiveness. In regression models BMI (as continuous variable) was not significant predictor of TFIM at discharge after adjusting for age, sex, severity, dysphagia, depression and ataxia (R2=0.4813), significant predictors were TFIM at admission (β = 0.528) and NIHSS (β=-0.208). MFIM efficiency did not significantly differ by BMI subgroups, neither did CFIM efficiency. Length of stay (LOS) and TFIM effectiveness were associated for normal (r=0.33) and overweight (r=0.43), but not for obese. LOS and TFIM efficiency were strongly negatively associated only for obese (r=-0.50).CONCLUSIONS: FIM outcomes were not associated to BMI, nevertheless each BMI category when individually considered (normal weight, overweight or obese) was characterized by different associations involving FIM outcomes and clinical factors. CLINICAL REHABILITATION IMPACT: In sub-acute post-stroke working-age patients undergoing rehabilitation, BMI was not associated to FIM outcomes (no obesity paradox was reported in this sample). Distinctive significant associations emerged within each BMI category, (supporting their characterization) such as length of stay and TFIM effectiveness were associated for normal weight and overweight, but not for obese. Length of stay and TFIM efficiency were strongly negatively associated only for obese

JWST/NIRCam coronagraph: mask design and fabrication

The NIRCam instrument on the James Webb Space Telescope will provide coronagraphic imaging from λ =1-5 μm of high contrast sources such as extrasolar planets and circumstellar disks. A Lyot coronagraph with a variety of circular and wedge-shaped occulting masks and matching Lyot pupil stops will be implemented. The occulters approximate grayscale transmission profiles using halftone binary patterns comprising wavelength-sized metal dots on anti-reflection coated sapphire substrates. The mask patterns are being created in the Micro Devices Laboratory at the Jet Propulsion Laboratory using electron beam lithography. Samples of these occulters have been successfully evaluated in a coronagraphic testbed. In a separate process, the complex apertures that form the Lyot stops will be deposited onto optical wedges. The NIRCam coronagraph flight components are expected to be completed this year

18F-fluorodeoxyglucose positron emission tomography as a window into human dengue pathophysiology.

In mouse models of dengue virus (DENV) infection, 18F-FDG PET is able to sensitively detect tissue-specific sites of inflammation and disease activity, as well as track therapeutic response to anti- DENV agents. However, the use of 18F-FDG PET to study the pathogenesis of inflammation and disease activity in DENV infection in humans, has not been clinically validated. Here we report the 18F-FDG PET imaging results of two patients during the febrile phase of acute DENV infection, paired with serial serum viral load, NS1 and proinflammatory cytokine measurements. Our findings demonstrate that 18F-FDG PET is able to sensitively detect and quantify organ-specific inflammation in the lymph nodes and spleen, in classic acute dengue fever. This raises the potential for 18F-FDG PET to be used as a research tool that may provide further insights into disease pathogenesis

Computational Prediction of Intronic microRNA Targets using Host Gene Expression Reveals Novel Regulatory Mechanisms

Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes