Classical homocystinuria: A common inborn error of metabolism? An epidemiological study based on genetic databases

Background: Biallelic pathogenic variants in CBS gene cause the most common form of homocystinuria, the classical homocystinuria (HCU). The worldwide prevalence of HCU is estimated to be 0.82:100,000 [95% CI, 0.39–1.73:100,000] according to clinical records and 1.09:100,000 [95% CI, 0.34–3.55:100,000] by neonatal screening. In this study, we aimed to estimate the minimal worldwide incidence of HCU. Methods: The 25 most common pathogenic alleles of HCU were identified through a literature review. The incidence of HCU was estimated based on the frequency of these common pathogenic alleles in a large genomic database (gnomAD). Results: The minimum worldwide incidence of HCU was estimated to be ~0.38:100,000, and the incidence was higher in Europeans non-Finnish (~0.72:100,000) and Latin Americans (~0.45:100,000) and lower in Africans (~0.20:100,000) and Asians (~0.02:100,000). Conclusion: Our data are in accordance with the only published metanalysis on this topic. To our surprise, the observed incidence of HCU in Europeans was much lower than those described in articles exploring small populations from northern Europe but was similar to the incidence described on the basis of neonatal screening programs. In our opinion, this large dataset analyzed and its population coverage gave us greater precision in the estimation of incidence

The role of the voluntary, community and social enterprise sector in Early Help: Critical reflections from embedded social care research

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data that support the findings of this study are available on request from the corresponding author, Thomas El-Hoss. The data are not publicly available due to their containing sensitive information that could compromise the privacy of research participants.The independent review of children's social care (2022) has proposed a radical reset of England's children's services, shifting a remote, assessment heavy system towards one that works alongside communities to help prevent statutory interventions. However, notions around the harnessing of community resources to deliver Early Help are often underpinned by assumptions regarding the voluntary, community and social enterprise (VCSE) sector and the ease with which such organizations can be integrated into preventative strategies. This paper reports findings from embedded research within a unitary authority in Southwest England during remodelling of its Early Help service to work more collaboratively with local VCSE organizations. The study generated data from ethnographic observations, semi-structured interviews and focus groups with 95 participants, including local parents, service providers, VCSE organizations and Council leaders. The findings illustrate that families value the compassionate, responsive and flexible support available within many VCSE settings. However, differences in practice cultures, regulatory pressures on statutory providers, the need to (re)build trust in communities and sensitivities around power-sharing and resourcing meant negotiating VCSE sector integration was fraught with complexities. Few studies have gained such privileged access to a Local Authority's remodelling of Early Help services, and this paper has significant insights for the debates surrounding the independent review of children's social care (2022) and its recommendation to bring services ‘closer to communities’.Torbay Medical Research Fun

Child protection and family support: Experiences in a seaside resort

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: The data that has been used is confidential.Effective Early Help services are key to halting rising rates of children in care in the UK. Yet despite family support and child welfare interventions being unequally distributed across the country, the role of ‘place’ has received limited attention in the children’s social care arena. This paper examines the connections between coastal challenges, Early Help and child welfare interventions, drawing on embedded research undertaken within a Local Authority on England’s coast with elevated levels of children in care. We focus on families’ experiences raising children in a seaside resort area as well as professionals’ perspectives on the place-based challenges faced delivering effective and accessible Early Help support. The study generated data from ethnographic observations, semi-structured interviews, and focus groups with local parents/carers (n = 57), service managers and frontline professionals (n = 14), and the Voluntary, Community, and Social Enterprise (VCSE) sector (n = 22). The findings highlight how the socio-economic challenges associated with many seaside resort areas, including housing pressures, a seasonal and low-wage economy, and the transience of the population, present difficulties for parents/carers in raising and supporting their children. For professionals delivering Early Help, high levels of housing instability, elevated inward migration, resource constraints and challenges around recruitment and retention presented challenges to delivering services. This paper recommends increased emphasis in regulation and resourcing around family support that considers the spatial and geographic dynamics that influence the incidence, structuring, and experiences of child and family welfare.Torbay Medical Support FundWellcome Centre for Cultures and Environments of HealthNational Institute for Health and Care Research (NIHR

Coherent low-energy charge transport in a diffusive S-N-S junction

We have studied the current voltage characteristics of diffusive mesoscopic Nb-Cu-Nb Josephson junctions with highly-transparent Nb-Cu interfaces. We consider the low-voltage and high-temperature regime eV<\epsilon_{c}<k_{B}T where epsilon_{c} is the Thouless energy. The observed excess current as well as the observed sub-harmonic Shapiro steps under microwave irradiation suggest the occurrence of low-energy coherent Multiple Andreev Reflection (MAR).Comment: 4 pages, 4 figures, final versio

Subgap anomaly and above-energy-gap structure in chains of diffusive SNS junctions

We present the results of low-temperature transport measurements on chains of superconductor--normal-constriction--superconductor (SNS) junctions fabricated on the basis of superconducting PtSi film. A comparative study of the properties of the chains, consisting of 3 and 20 SNS junctions in series, and single SNS junctions reveals essential distinctions in the behavior of the current-voltage characteristics of the systems: (i) the gradual decrease of the effective suppression voltage for the excess conductivity observed at zero bias as the quantity of the SNS junctions increases, (ii) a rich fine structure on the dependences dV/dI-V at dc bias voltages higher than the superconducting gap and corresponding to some multiples of 2\Delta/e. A model to explain this above-energy-gap structure based on energy relaxation of electron via Cooper-pair-breaking in superconducting island connecting normal metal electrods is proposed.Comment: RevTex, 5 pages, 4 figure

Reference standardization and triglyceride interference of a new homogeneous HDL-cholesterol assay compared with a former chemical precipitation assay

A homogeneous HDL-c assay (HDL-H), which uses polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin, was assessed for precision, accuracy, and cholesterol and triglyceride interference. In addition, its analytical performance was compared with that of a phosphotungstic acid (PTA)/MgCl2 precipitation method (HDL-P). Within-run CVs were < or = 1.87%; total CVs were < or = 3.08%. Accuracy was evaluated in fresh normotriglyceridemic sera using the Designated Comparison Method (HDL-H = 1.037 Designated Comparison Method + 4 mg/L; n = 63) and in moderately hypertriglyceridemic sera by using the Reference Method (HDL-H = 1.068 Reference Method - 17 mg/L; n = 41). Mean biases were 4.5% and 2.2%, respectively. In hypertriglyceridemic sera (n = 85), HDL-H concentrations were increasingly positively biased with increasing triglyceride concentrations. The method comparison between HDL-H and HDL-P yielded the following equation: HDL-H = 1.037 HDL-P + 15 mg/L; n = 478. We conclude that HDL-H amply meets the 1998 NCEP recommendations for total error; its precision is superior compared with that of HDL-P, and its average bias remains below +/-5% as long as triglyceride concentrations are < or = 10 g/L and in case of moderate hypercholesterolemia

MicroRNAs Located in the Hox Gene Clusters Are Implicated in Huntington's Disease Pathogenesis

Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington's disease (HD). MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9) of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p) up-regulated in HD at genome-wide significance (FDR q-value<0.05). Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C). Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as biomarkers for human diseases and given their relationship to disease expression, these miRNAs are biomarker candidates in HD

Current noise in long diffusive SNS junctions in the incoherent MAR regime

Spectral density of current fluctuations at zero frequency is calculated for a long diffusive SNS junction with low-resistive interfaces. At low temperature, T << Delta, the subgap shot noise approaches linear voltage dependence, S=(2/ 3R)(eV + 2Delta), which is the sum of the shot noise of the normal conductor and voltage independent excess noise. This result can also be interpreted as the 1/3-suppressed Poisson noise for the effective charge q = e(1+2Delta/eV) transferred by incoherent multiple Andreev reflections (MAR). At higher temperatures, anomalies of the current noise develop at the gap subharmonics, eV = 2Delta/n. The crossover to the hot electron regime from the MAR regime is analyzed in the limit of small applied voltages.Comment: improved version, to be published in Phys. Rev.

MicroRNAs located in the Hox gene clusters are implicated in huntington\u27s disease pathogenesis

Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington\u27s disease (HD). MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9) of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p) up-regulated in HD at genome-wide significance (FDR q-value \u3c 0.05). Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C). Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as biomarkers for human diseases and given their relationship to disease expression, these miRNAs are biomarker candidates in HD

Alternative splicing regulates stochastic NLRP3 activity

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3. exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus reveals unexpected regulatory roles of AS through differential utilization of LRRs modules in vertebrate innate immunity