Topological organization of whole-brain white matter in HIV infection

Infection with human immunodeficiency virus (HIV) is associated with neuroimaging alterations. However, little is known about the topological organization of whole-brain networks and the corresponding association with cognition. As such, we examined structural whole-brain white matter connectivity patterns and cognitive performance in 29 HIV+ young adults (mean age = 25.9) with limited or no HIV treatment history. HIV+ participants and demographically similar HIV− controls (n = 16) residing in South Africa underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural network models were constructed using diffusion MRI-based multifiber tractography and T(1)-weighted MRI-based regional gray matter segmentation. Global network measures included whole-brain structural integration, connection strength, and structural segregation. Cognition was measured using a neuropsychological global deficit score (GDS) as well as individual cognitive domains. Results revealed that HIV+ participants exhibited significant disruptions to whole-brain networks, characterized by weaker structural integration (characteristic path length and efficiency), connection strength, and structural segregation (clustering coefficient) than HIV− controls (p < 0.05). GDSs and performance on learning/recall tasks were negatively correlated with the clustering coefficient (p < 0.05) in HIV+ participants. Results from this study indicate disruption to brain network integrity in treatment-limited HIV+ young adults with corresponding abnormalities in cognitive performance

Negative cooperativity across 1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 1-adrenoceptor binding conformation

At the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 of the β1-adrenoceptor as key for this low-affinity conformation. Others suggested that TM4 has a role in β1-adrenoceptor oligomerization. Here, assessment of the dissociation rate of a fluorescent analog of CGP 12177 [bordifluoropyrromethane-tetramethylrhodamine-(±)CGP 12177 (BODIPY-TMR-CGP)] at the human β1-adrenoceptor expressed in Chinese hamster ovary cells revealed negative cooperative interactions between 2 distinct β1-adrenoceptor conformations. The dissociation rate of 3 nM BODIPY-TMR-CGP was 0.09 ± 0.01 min−1 in the absence of competitor ligands, and this was enhanced 2.2- and 2.1-fold in the presence of 1 µM CGP 12177 and 1 µM propranolol, respectively. These effects on the BODIPY-TMR-CGP dissociation rate were markedly enhanced in β1-adrenoceptor homodimers constrained by bimolecular fluorescence complementation (9.8- and 9.9-fold for 1 µM CGP 12177 and 1 µM propranolol, respectively) and abolished in β1-adrenoceptors containing TM4 mutations vital for the second conformation pharmacology. This study suggests that negative cooperativity across a β1-adrenoceptor homodimer may be responsible for generating the low-affinity pharmacology of the secondary β1-adrenoceptor conformatio

Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-alpha in conscious dogs

We used a load-insensitive index of systolic left ventricular (LV) function and an analysis of diastolic pressure-dimension relationships to test the hypothesis that recombinant human (rh) tumor necrosis factor-alpha (TNF alpha) impairs LV function in dogs. Animals were studied 7-10 d after aseptic implantation of instrumentation to monitor cardiac output, external anterior-posterior LV diameter, and LV and pleural pressures. Data were analyzed from seven dogs that received active rhTNF alpha (100 micrograms/kg over 60 min) and from five dogs that received heat-inactivated rhTNF alpha. At 24 h after infusion of active rhTNF alpha, the slope of the LV end-diastolic dimension-stroke work relationship decreased significantly, indicating a decrement in LV systolic contractility. Simultaneously, LV unstressed dimension increased significantly, suggesting diastolic myocardial creep. The end-diastolic relationship between LV transmural pressure and normalized LV dimension (strain) was markedly displaced to the left, suggesting increased diastolic elastic stiffness. Despite these changes in LV performance, cardiac index was maintained by tachycardia. The abnormalities in LV function were resolved by 72 h. We conclude that rhTNF alpha reversibly impairs LV systolic and diastolic function in unanesthetized dogs. Because dysfunction occurs greater than 6 h after the infusion of rhTNF alpha and persists for 24-48 h, the mechanism underlying this phenomenon may involve secondary mediators or a change in myocardial gene expression

SUMO-Targeted Ubiquitin Ligases (STUbLs) Reduce the Toxicity and Abnormal Transcriptional Activity Associated With a Mutant, Aggregation-Prone Fragment of Huntingtin

Cell viability and gene expression profiles are altered in cellular models of neurodegenerative disorders such as Huntington\u27s Disease (HD). Using the yeast model system, we show that the SUMO-targeted ubiquitin ligase (STUbL) Slx5 reduces the toxicity and abnormal transcriptional activity associated with a mutant, aggregation-prone fragment of huntingtin (Htt), the causative agent of HD. We demonstrate that expression of an aggregation-prone Htt construct with 103 glutamine residues (103Q), but not the non-expanded form (25Q), results in severe growth defects in slx5Delta and slx8Delta cells. Since Slx5 is a nuclear protein and because Htt expression affects gene transcription, we assessed the effect of STUbLs on the transcriptional properties of aggregation-prone Htt. Expression of Htt 25Q and 55Q fused to the Gal4 activation domain (AD) resulted in reporter gene auto-activation. Remarkably, the auto-activation of Htt constructs was abolished by expression of Slx5 fused to the Gal4 DNA-binding domain (BD-Slx5). In support of these observations, RNF4, the human ortholog of Slx5, curbs the aberrant transcriptional activity of aggregation-prone Htt in yeast and a variety of cultured human cell lines. Functionally, we find that an extra copy of SLX5 specifically reduces Htt aggregates in the cytosol as well as chromatin-associated Htt aggregates in the nucleus. Finally, using RNA sequencing, we identified and confirmed specific targets of Htt\u27s transcriptional activity that are modulated by Slx5. In summary, this study of STUbLs uncovers a conserved pathway that counteracts the accumulation of aggregating, transcriptionally active Htt (and possibly other poly-glutamine expanded proteins) on chromatin in both yeast and in mammalian cells

Observation- and model-based estimates of particulate dry nitrogen deposition to the oceans

Anthropogenic nitrogen (N) emissions to the atmosphere have increased significantly the deposition of nitrate (NO− 3 ) and ammonium (NH+ 4 ) to the surface waters of the open ocean, with potential impacts on marine productivity and the global carbon cycle. Global-scale understanding of the impacts of N deposition to the oceans is reliant on our ability to produce and validate models of nitrogen emission, atmospheric chemistry, transport and deposition. In this work, ∼ 2900 observations of aerosol NO− 3 and NH+ 4 concentrations, acquired from sampling aboard ships in the period 1995–2012, are used to assess the performance of modelled N concentration and deposition fields over the remote ocean. Three ocean regions (the eastern tropical North Atlantic, the northern Indian Ocean and northwest Pacific) were selected, in which the density and distribution of observational data were considered sufficient to provide effective comparison to model products. All of these study regions are affected by transport and deposition of mineral dust, which alters the deposition of N, due to uptake of nitrogen oxides (NOx ) on mineral surfaces. Assessment of the impacts of atmospheric N deposition on the ocean requires atmospheric chemical transport models to report deposition fluxes; however, these fluxes cannot be measured over the ocean. Modelling studies such as the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP), which only report deposition flux, are therefore very difficult to validate for dry deposition. Here, the available observational data were averaged over a 5◦×5 ◦ grid and compared to ACCMIP dry deposition fluxes (ModDep) of oxidised N (NOy ) and reduced N (NHx ) and to the following parameters from the Tracer Model 4 of the Environmental Chemical Processes Laboratory (TM4): ModDep for NOy , NHx and particulate NO− 3 and NH+ 4 , and surface-level particulate NO− 3 and NH+ 4 concentrations. As a model ensemble, ACCMIP can be expected to be more robust than TM4, while TM4 gives access to speciated parameters (NO− 3 and NH+ 4 ) that are more relevant to the observed parameters and which are not available in ACCMIP. Dry deposition fluxes (CalDep) were calculated from the observed concentrations using estimates of dry deposition velocities. Model–observation ratios (RA,n), weighted by gridcell area and number of observations, were used to assess the performance of the models. Comparison in the three study regions suggests that TM4 overestimates NO− 3 concentrations (RA,n = 1.4–2.9) and underestimates NH+ 4 concentrations (RA,n = 0.5–0.7), with spatial distributions in the tropical Atlantic and northern Indian Ocean not being reproduced by the model. In the case of NH+ 4 in the Indian Ocean, this discrepancy was probably due to seasonal biases in the sampling. Similar patterns were observed in the various comparisons of CalDep to ModDep (RA,n = 0.6–2.6 for NO− 3 , 0.6–3.1 for NH+ 4 ). Values of RA,n for NHx CalDep– ModDep comparisons were approximately double the corresponding values for NH+ 4 CalDep–ModDep comparisons due to the significant fraction of gas-phase NH3 deposition incorporated in the TM4 and ACCMIP NHx model products. All of the comparisons suffered due to the scarcity of observational data and the large uncertainty in dry deposition velocities used to derive deposition fluxes from concentrations. These uncertainties have been a major limitation on estimates of the flux of material to the oceans for several decades. Recommendations are made for improvements in N deposition estimation through changes in observations, modelling and model–observation comparison procedures. Validation of modelled dry deposition requires effective comparisons to observable aerosol-phase species’ concentrations, and this cannot be achieved if model products only report dry deposition flux over the ocean

The Grizzly, April 29, 2004

As the School Years Ends, The Search for Jobs Begins • Life-Changing Volunteer Work Found At the Clinic • Fad Diets: Do They Work? • Opinions: Chronic Back Pain: Ouch!; Lacking Luster (Again) at La Fontana; Is Donald Trump the Ideal Boss?; Eating Your Veggies Now More Appetizing than Mom Tried to Make it • Staff Spotlight: Jamal Elliot • Ursinus Students Put Learning Into Practice at Model U.N. • Goldwater Scholar Kari Baker • Softball Team Rolls Past Muhlenberg • Leadership: A Key Ingredient in the Success of the Men\u27s Baseball Team • Final Exam Schedulehttps://digitalcommons.ursinus.edu/grizzlynews/1561/thumbnail.jp

Enhanced biofilm and extracellular matrix production by chronic carriage versus acute isolates of Salmonella Typhi.

Salmonella Typhi is the primary causative agent of typhoid fever; an acute systemic infection that leads to chronic carriage in 3-5% of individuals. Chronic carriers are asymptomatic, difficult to treat and serve as reservoirs for typhoid outbreaks. Understanding the factors that contribute to chronic carriage is key to development of novel therapies to effectively resolve typhoid fever. Herein, although we observed no distinct clustering of chronic carriage isolates via phylogenetic analysis, we demonstrated that chronic isolates were phenotypically distinct from acute infection isolates. Chronic carriage isolates formed significantly thicker biofilms with greater biomass that correlated with significantly higher relative levels of extracellular DNA (eDNA) and DNABII proteins than biofilms formed by acute infection isolates. Importantly, extracellular DNABII proteins include integration host factor (IHF) and histone-like protein (HU) that are critical to the structural integrity of bacterial biofilms. In this study, we demonstrated that the biofilm formed by a chronic carriage isolate in vitro, was susceptible to disruption by a specific antibody against DNABII proteins, a successful first step in the development of a therapeutic to resolve chronic carriage

A cross sectional study examining social desirability bias in caregiver reporting of children's oral health behaviors

Abstract: Background: Our previous research (Pediatrics 2010:126) found a strong association between caregiver oral health literacy (OHL) and children’s oral health status; however, we found a weak association with oral health behaviors (OHBs). We hypothesize that this may be due to social desirability bias (SDB). Our objectives were to compare caregivers’ responses to traditional OHB items and newer SDB-modulating items, and to examine the association of caregiver literacy with OHBs. Methods: We performed a cross-sectional study of 102 caregiver-child dyads, collecting data for OHBs using both traditional and new SDB-modulating items. We measured OHL using REALD-30, a validated word recognition test. We relied upon percent agreement and Cohen’s kappa (k) to quantify the concordance in caregivers’ responses and multivariate log-binomial regression to estimate the impact of OHL on OHBs. Results: Caregivers’ mean REALD-30 score was 20.7 (SD = 6.0), range 1-30. We found an association between OHL and 4 of 8 OHBs examined. A subset of behavior questions compared traditional versus SDB-modulating items: history of bottle-feeding: agreement = 95%, k = 0.83 (95% CL:0.68,0.99); daily tooth brushing: agreement = 78%, k = 0.25 (95% CL:0.04,0.46); fluoridated toothpaste use: agreement = 88%, k = 0.67 (95% CL:0.49,0.85). After controlling for caregivers’ race, marital status and study site, higher literacy scores remained associated with a decreased prevalence of parental report of “decided not brush the child’s teeth because it would be frustrating”. Conclusions: Agreement between responses was high for 2 of 3 behavior items. Item 3 (tooth brushing frequency) revealed discordance, likely due to SDB. Use of the SDB-modulating items appears to yield a better estimate of OHB

European Clinical Neuropsychology : Role in Healthcare and Access to Neuropsychological Services

This study analyzed aspects of the work of clinical neuropsychologists across Europe. There are no published comparisons between European countries regarding the nature of clinical neuropsychologists' work. Forty-one national psychological and neuropsychological societies were approached, of which 31 (76%) responded. Data from seven countries with less than 10 neuropsychologists were excluded. A license is required to practice clinical neuropsychology in 50% of the countries. Clinical neuropsychologists work independently in 62.5%. Diagnostic/assessment work is the most frequently reported activity (54%). Most neuropsychologists work in public hospitals, followed by health centers. Adult neuropsychology was the most frequent area of activity. Services in public institutions are covered by public entities (45.8%), or by a combination of patient funds and public entities (29.2%) and only 4.2% by the patient; whereas services in private institutions are covered by the patient (26.1%) and the combination of patient, public entities (21.7%) or patient and private entities (17.4%). The data suggest that the number of neuropsychologists working across European countries is considerably low in comparison to other medical professionals. The results of the survey identified similar aspects of neuropsychologists' work, despite variations in terms of reimbursement and mechanisms, reflecting economic and healthcare differences. Estimates on the number of clinical neuropsychologists suggest insufficient access to neuropsychological services.Peer reviewe