Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1

Mapping as a knowledge translation tool for Ontario Early Years Centres: views from data analysts and managers

<p>Abstract</p> <p>Background</p> <p>Local Ontario Early Years Centres (OEYCs) collect timely and relevant local data, but knowledge translation is needed for the data to be useful. Maps represent an ideal tool to interpret local data. While geographic information system (GIS) technology is available, it is less clear what users require from this technology for evidence-informed program planning. We highlight initial challenges and opportunities encountered in implementing a mapping innovation (software and managerial decision-support) as a knowledge translation strategy.</p> <p>Methods</p> <p>Using focus groups, individual interviews and interactive software development events, we taped and transcribed verbatim our interactions with nine OEYCs in Ontario, Canada. Research participants were composed of data analysts and their managers. Deductive analysis of the data was based on the Ottawa Model of Research Use, focusing on the innovation (the mapping tool and maps), the potential adopters, and the environment.</p> <p>Results</p> <p>Challenges associated with the innovation included preconceived perceptions of a steep learning curve with GIS software. Challenges related to the potential adopters included conflicting ideas about tool integration into the organization and difficulty with map interpretation. Lack of funds, lack of availability of accurate data, and unrealistic reporting requirements represent environmental challenges.</p> <p>Conclusion</p> <p>Despite the clear need for mapping software and maps, there remain several challenges to their effective implementation. Some can be modified, while other challenges might require attention at the systemic level. Future research is needed to identify barriers and facilitators related to using mapping software and maps for decision-making by other users, and to subsequently develop mapping best practices guidelines to assist community-based agencies in circumventing some challenges, and support information equity across a region.</p

Quantitative Analysis and Comparison Study of [18F]AlF-NOTA-PRGD2, [18F]FPPRGD2 and [68Ga]Ga-NOTA-PRGD2 Using a Reference Tissue Model

With favorable pharmacokinetics and binding affinity for αvβ3 integrin, 18F-labeled dimeric cyclic RGD peptide ([18F]FPPRGD2) has been intensively used as a PET imaging probe for lesion detection and therapy response monitoring. A recently introduced kit formulation method, which uses an 18F-fluoride-aluminum complex labeled RGD tracer ([18F]AlF-NOTA-PRGD2), provides a strategy for simplifying the labeling procedure to facilitate clinical translation. Meanwhile, an easy-to-prepare 68Ga-labeled NOTA-PRGD2 has also been reported to have promising properties for imaging integrin αvβ3. The purpose of this study is to quantitatively compare the pharmacokinetic parameters of [18F]FPPRGD2, [18F]AlF-NOTA-PRGD2, and [68Ga]Ga-NOTA-PRGD2. U87MG tumor-bearing mice underwent 60-min dynamic PET scans following the injection of three tracers. Kinetic parameters were calculated using Logan graphical analysis with reference tissue. Parametric maps were generated using voxel-level modeling. All three compounds showed high binding potential (BpND = k3/k4) in tumor voxels. [18F]AlF-NOTA-PRGD2 showed comparable BpND value (3.75±0.65) with those of [18F]FPPRGD2 (3.39±0.84) and [68Ga]Ga-NOTA-PRGD2 (3.09±0.21) (p>0.05). Little difference was found in volume of distribution (VT) among these three RGD tracers in tumor, liver and muscle. Parametric maps showed similar kinetic parameters for all three tracers. We also demonstrated that the impact of non-specific binding could be eliminated in the kinetic analysis. Consequently, kinetic parameter estimation showed more comparable results among groups than static image analysis. In conclusion, [18F]AlF-NOTA-PRGD2 and [68Ga]Ga-NOTA-PRGD2 have comparable pharmacokinetics and quantitative parameters compared to those of [18F]FPPRGD2. Despite the apparent difference in tumor uptake (%ID/g determined from static images) and clearance pattern, the actual specific binding component extrapolated from kinetic modeling appears to be comparable for all three dimeric RGD tracers

The SDSS-V Black Hole Mapper Reverberation Mapping Project: Unusual Broad-Line Variability in a Luminous Quasar

We present a high-cadence multi-epoch analysis of dramatic variability of three broad emission lines (MgII, H$\beta$, and H$\alpha$) in the spectra of the luminous quasar ($\lambda L_{\lambda}$(5100\r{A}) = $4.7 \times 10^{44}$ erg s$^{-1}$) SDSS J141041.25+531849.0 at $z = 0.359$ with 127 spectroscopic epochs over 9 years of monitoring (2013-2022). We observe anti-correlations between the broad emission-line widths and flux in all three emission lines, indicating that all three broad emission lines "breathe" in response to stochastic continuum variations. We also observe dramatic radial velocity shifts in all three broad emission lines, ranging from $\Delta{v}$ $\sim$400 km s$^{-1}$ to $\sim$800 km s$^{-1}$, that vary over the course of the monitoring period. Our preferred explanation for the broad-line variability is complex kinematics in the broad-line region gas. We suggest a model for the broad-line variability that includes a combination of gas inflow with a radial gradient, an azimuthal asymmetry (e.g., a hot spot), superimposed on the stochastic flux-driven changes to the optimal emission region ("line breathing"). Similar instances of line-profile variability due to complex gas kinematics around quasars are likely to represent an important source of false positives in radial velocity searches for binary black holes, which typically lack the kind of high-cadence data we analyze here. The long-duration, wide-field, and many-epoch spectroscopic monitoring of SDSS-V BHM-RM provides an excellent opportunity for identifying and characterizing broad emission-line variability, and the inferred nature of the inner gas environment, of luminous quasars

Differential Attraction of Malaria Mosquitoes to Volatile Blends Produced by Human Skin Bacteria

The malaria mosquito Anopheles gambiae sensu stricto is mainly guided by human odour components to find its blood host. Skin bacteria play an important role in the production of human body odour and when grown in vitro, skin bacteria produce volatiles that are attractive to A. gambiae. The role of single skin bacterial species in the production of volatiles that mediate the host-seeking behaviour of mosquitoes has remained largely unknown and is the subject of the present study. Headspace samples were taken to identify volatiles that mediate this behaviour. These volatiles could be used as mosquito attractants or repellents. Five commonly occurring species of skin bacteria were tested in an olfactometer for the production of volatiles that attract A. gambiae. Odour blends produced by some bacterial species were more attractive than blends produced by other species. In contrast to odours from the other bacterial species tested, odours produced by Pseudomonas aeruginosa were not attractive to A. gambiae. Headspace analysis of bacterial volatiles in combination with behavioural assays led to the identification of six compounds that elicited a behavioural effect in A. gambiae. Our results provide, to our knowledge, the first evidence for a role of selected bacterial species, common on the human skin, in determining the attractiveness of humans to malaria mosquitoes. This information will be used in the further development of a blend of semiochemicals for the manipulation of mosquito behaviour

If you build it, they still may not come: outcomes and process of implementing a community-based integrated knowledge translation mapping innovation

<p>Abstract</p> <p>Background</p> <p>Maps and mapping tools through geographic information systems (GIS) are highly valuable for turning data into useful information that can help inform decision-making and knowledge translation (KT) activities. However, there are several challenges involved in incorporating GIS applications into the decision-making process. We highlight the challenges and opportunities encountered in implementing a mapping innovation as a KT strategy within the non-profit (public) health sector, reflecting on the processes and outcomes related to our KT innovations.</p> <p>Methods</p> <p>A case study design, whereby the case is defined as the data analyst and manager dyad (a two-person team) in selected Ontario Early Year Centres (OEYCs), was used. Working with these paired individuals, we provided a series of interventions followed by one-on-one visits to ensure that our interventions were individually tailored to personal and local decision-making needs. Data analysis was conducted through a variety of qualitative assessments, including field notes, interview data, and maps created by participants. Data collection and data analysis have been guided by the Ottawa Model of Research Use (OMRU) conceptual framework.</p> <p>Results</p> <p>Despite our efforts to remove all barriers associated with our KT innovation (maps), our results demonstrate that both individual level and systemic barriers pose significant challenges for participants. While we cannot claim a causal association between our project and increased mapping by participants, participants did report a moderate increase in the use of maps in their organization. Specifically, maps were being used in decision-making forums as a way to allocate resources, confirm tacit knowledge about community needs, make financially-sensitive decisions more transparent, evaluate programs, and work with community partners.</p> <p>Conclusions</p> <p>This project highlights the role that maps can play and the importance of communicating the importance of maps as a decision support tool. Further, it represents an integrated knowledge project in the community setting, calling to question the applicability of traditional KT approaches when community values, minimal resources, and partners play a large role in decision making. The study also takes a unique perspective--where research producers and users work as dyad-pairs in the same organization--that has been under-explored to date in KT studies.</p

Predictors of 1-year compliance with adaptive servoventilation in patients with heart failure and sleep disordered breathing: preliminary data from the ADVENT-HF trial

Despite its effectiveness in suppressing sleep disordered breathing (SDB), positive airway pressure therapy (PAP) is not always well tolerated by patients and long-term adherence can be problematic. Recently, two multicentre, randomised clinical trials (RCTs) tested the effects of PAP for patients with cardiovascular disease and co-existing SDB on morbidity and mortality with negative outcomes [1, 2]. Relatively poor adherence to PAP therapy (mean 3.7 and 3.3 h·day-1, respectively) in these two trials might have contributed to their poor results. Indeed, higher PAP use per day is associated with better clinical outcomes than lower use [3]

Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel

BACKGROUND: Variance of peak bone mass has a substantial genetic component, as has been shown with twin studies examining quantitative measures such as bone mineral density (BMD) and quantitative ultrasound (QUS). Evidence implicating single nucleotide polymorphisms (SNPs) of the transforming growth factor beta-1 (TGFB1) gene is steadily accumulating. However, a comprehensive look at multiple SNPs at this locus for their association with indices of peak bone mass has not been reported. METHODS: A cohort of 653 healthy Caucasian females 18 to 35 years old was genotyped for seven TGFB1 SNPs. Polymorphisms were detected by restriction endonuclease digestion of amplified DNA segments. RESULTS: The frequencies of the least common allele at G-800A, C-509T, codon 10 (L10P), codon 25 (R25P), codon 263 (T263I), C861-20T, and 713-8 delC loci were 0.07, 0.33, 0.41, 0.08, 0.04, 0.25 and 0.01, respectively. A significant association was seen between QUS Stiffness Index (QUS-SI) and the SNP at codon 10 and the linked promoter SNP, C-509T. This association remained significant after multiple regression was used to incorporate important clinical covariates – age, BMI, level of activity, family history, and caffeine intake – into the model. CONCLUSION: The association of QUS-SI with -509T is consistent with a gene-dose effect, while only individuals homozygous for the codon 10P allele showed a significant increase. In this cohort of young healthy Caucasian females, the T allele at position -509 is associated with greater bone mass as measured by calcaneal ultrasound