The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease

Case report of homozygous E200D mutation of PRNP in apparently sporadic Creutzfeldt-Jakob disease

Background: Inherited prion diseases are rare autosomal dominant disorders associated with diverse clinical presentations. All are associated with mutation of the gene that encodes prion protein (PRNP). Homozygous mutations with atypical clinical phenotypes have been described but are extremely rare. Case presentation: A Chinese patient presented with a rapidly progressive cognitive and motor disorder in the clinical spectrum of sCJD. Investigations strongly suggested a diagnosis of CJD. He was found to carry a homozygous mutation at PRNP codon 200 (E200D), but there was no known family history of the disorder. The estimated allele frequency of E200D in East Asian populations is incompatible with it being a highly penetrant mutation in the heterozygous state. Conclusion: In our view the homozygous PRNP E200D genotype is likely to be causal of CJD in this patient. Homotypic PrP interactions are well known to favour the development of prion disease. The case is compatible with recessively inherited prion disease

Constraints on Hidden Photon Models from Electron g-2 and Hydrogen Spectroscopy

The hidden photon model is one of the simplest models which can explain the anomaly of the muon anomalous magnetic moment (g-2). The experimental constraints are studied in detail, which come from the electron g-2 and the hydrogen transition frequencies. The input parameters are set carefully in order to take dark photon contributions into account and to prevent the analysis from being self-inconsistent. It is shown that the new analysis provides a constraint severer by more than one order of magnitude than the previous result.Comment: 18 pages, 2 figures, 1 table. v2: minor correction

The Infant Feeding Genogram: a tool for exploring family infant feeding history and identifying support needs

Background: Family culture and beliefs are passed through the generations within families and influence what constitutes appropriate infant care. This includes infant feeding decisions where a family history and support network congruent with women’s infant feeding intentions has been shown to be important to women’s breastfeeding experience. This is reflected in breastfeeding rates where women who were not breastfed themselves are less likely to initiate and continue with breastfeeding. Given the importance of family infant feeding history in the initiation and duration of breastfeeding, and the limited ability of some families to provide support; it is unclear why infant feeding family history and support networks are not explored during pregnancy. Methods: The Infant Feeding Genogram was adapted from a simple pictorial device that is widely used in psychotherapy and genetic counselling. This tool was developed as part of a study investigating the experience of women when they were the first to breastfeed in their family. Fourteen Scottish participants completed their Infant Feeding Genogram as part of a semi-structured interview. The tool was adapted alongside their narratives to give a visual representation of each participant’s family infant feeding history. Results: The utility of the genogram is illustrated through two contrasting case examples with very different family feeding histories. The genogram showed family structures, patterns of infant feeding over time, and supportive or conflicting relationships. In the research setting it assisted women to explore their infant feeding history, identify challenges and sources of support and build rapport with the interviewer. Conclusions: The infant feeding genogram is proposed as a time efficient tool that could assist health professionals and other breastfeeding workers to support women and their families and by stimulating discussion around breastfeeding, Bby identifying strengths or possible deficits in social support for each individual, the tool could inform tailored support and care interventions. The effectiveness and acceptability of the Infant Feeding Genogram requires testing in the clinical environment. However, its successful application in other clinical contexts, combined with the interest in genealogy in popular culture, mean this is likely to be an acceptable, family friendly way to develop more effective breastfeeding conversations

Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4

Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3′-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms

Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation

We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD

Statistical Analysis of Paradigmatic Class Richness Supports Greater Paleoindian Projectile-Point Diversity in the Southeast

Ronald Mason\u27s hypothesis from the 1960s that the southeastern United States possesses greater Paleoindian projectile-point diversity than other regions is regularly cited, and often assumed to be true, but in fact has never been quantitatively tested. Even if valid, however, the evolutionary meaning of this diversity is contested. Point diversity is often linked to Clovis origins, but point diversity could also arise from group fissioning and drift, admixture, adaptation, or multiple founding events, among other possibilities. Before archaeologists can even begin to discuss these scenarios, it is paramount to ensure that what we think we know is representative of reality. To this end, we tested Mason\u27s hypothesis for the first time, using a sample of 1,056 Paleoindian points from eastern North America ami employing paradigmatic classification and rigorous statistical tools used in the quantification of ecological biodiversity. Our first set of analyses, which compared the Southeast to the Northeast, showed that the Southeast did indeed possess significantly greater point-class richness. Although this result was consistent with Mason\u27s hypothesis, our second set of analyses, which compared the Upper Southeast to the Lower Southeast and the Northeast showed that in terms of point-class richness the Upper Southeast \u3e Lower Southeast \u3e Northeast. Given current chronometric evidence, we suggest that this latter result is consistent with the suggestion that the area of the Ohio, Cumberland, and Tennessee River valleys, as well as the mid-Atlantic coastal plain, were possible initial and secondary staging areas for colonizing Paleoindian foragers moving from western to eastern North America

Formative research to develop a school-based, community-linked physical activity role model programme for girls: CHoosing Active Role Models to INspire Girls (CHARMING)

Background: Physical inactivity is a persistent challenge among girls. School-based physical activity (PA) interventions have shown mixed effects on girl's activity levels, with multi-component approaches involving both school and community links appearing more effective for sustainable change. The purpose of the current research was to gather views from preadolescent girls, parents, teachers and stakeholders in order to co-produce a multi-component school-based, community linked PA intervention programme. Methods: Focus groups were conducted in two primary schools with 34 girls aged 9-11 years and 11 parents (10 female, 1 male). In-depth interviews were conducted with four female teachers (including two head teachers). Focus groups and interviews focused on programme design (structure, content and delivery) and potential factors affecting intervention uptake and continued PA participation. A series of stakeholder engagement events occurred throughout the study period. All data were transcribed verbatim and thematically analysed in NVivo 11. Results: Girls reported that fun taster sessions delivered by role models would encourage them to participate in a school-based role model programme, with tailored taster sessions each week to enhance continued PA participation. Parents and teachers identified a number of barriers to uptake and continued PA participation, and active involvement of stakeholders facilitated the development of intervention strategies. Strategies included; single-sex after-school sessions, use of female role models, low-cost activity options and mapping community provision. Analyses revealed the importance of tailoring the programme to align with local needs, demands and provision. Conclusions: Data show numerous barriers to intervention uptake and continued PA participation when designing a school-based, community-linked intervention. Adopting a co-production approach, this formative work highlights a number of potential strategies for overcoming these barriers. Findings from the research directed the development and implementation of the CHARMING role model intervention and informed the creation of an intervention logic model

Visible Light Photo-oxidation of Model Pollutants Using CaCu3Ti4O12: An Experimental and Theoretical Study of Optical Properties, Electronic Structure, and Selectivity

[Image: see text] Charge transfer between metal ions occupying distinct crystallographic sublattices in an ordered material is a strategy to confer visible light absorption on complex oxides to generate potentially catalytically active electron and hole charge carriers. CaCu(3)Ti(4)O(12) has distinct octahedral Ti(4+) and square planar Cu(2+) sites and is thus a candidate material for this approach. The sol−gel synthesis of high surface area CaCu(3)Ti(4)O(12) and investigation of its optical absorption and photocatalytic reactivity with model pollutants are reported. Two gaps of 2.21 and 1.39 eV are observed in the visible region. These absorptions are explained by LSDA+U electronic structure calculations, including electron correlation on the Cu sites, as arising from transitions from a Cu-hybridized O 2p-derived valence band to localized empty states on Cu (attributed to the isolation of CuO(4) units within the structure of CaCu(3)Ti(4)O(12)) and to a Ti-based conduction band. The resulting charge carriers produce selective visible light photodegradation of 4-chlorophenol (monitored by mass spectrometry) by Pt-loaded CaCu(3)Ti(4)O(12) which is attributed to the chemical nature of the photogenerated charge carriers and has a quantum yield comparable with commercial visible light photocatalysts

Promises and pitfalls of digital knowledge exchange resulting from the COVID-19 pandemic

In this article, we integrate our authorship experiences with insights from nine interviews of knowledge exchange practitioners at the Canadian Forest Service about challenges and opportunities of digital knowledge exchange (KE) brought on by the COVID-19 pandemic. We aim to inform how best to maintain effective KE practices and processes in a digital-first world. Interpersonal trust and relationships are pivotal to effective knowledge exchange; thus, removing these dimensions risks losing aspects of social learning, informal and meaningful discussions, and personal connections that affect how we interpret and respond to subtle affective and social cues. For KE practitioners, lack of in-person interactions risks internal KE coordination and relevance of KE work, and diminished ability to predict and respond to user needs. However, the accelerated digital adoption has increased reach and accessibility for diverse people to exchange knowledge, and enables more frequent and rapid response to issues and events by virtually gathering diverse people almost instantly. The acceleration in digital innovation and culture has thus resulted in new tools and diversified approaches for the KE toolbox to inform decisions and practices. The long-term sustainability and effectiveness of digital KE depend on two interconnected factors: addressing the persistence of the digital divide and people’s abilities to make and maintain meaningful social connections in the absence of regular face-to-face contact. We thus offer three considerations to guide KE efforts and initiative in a digital-first world: (1) consider both digital divide and equity; (2) revisit user needs and preferences for KE to address the diversity of users, and (3) leverage the diversification of KE approaches and innovations