Classical and controlled auditory mismatch responses to multiple physical deviances in anaesthetised and conscious mice

Human mismatch negativity (MMN) is modelled in rodents and other non-human species to examine its underlying neurological mechanisms, primarily described in terms of deviance-detection and adaptation. Using the mouse model, we aim to elucidate subtle dependencies between the mismatch response (MMR) and different physical properties of sound. Epidural field potentials were recorded from urethane anaesthetised and conscious mice during oddball and many-standards control paradigms with stimuli varying in duration, frequency, intensity, and inter-stimulus interval. Resulting auditory evoked potentials, classical MMR (oddball – standard), and controlled MMR (oddball – control) waveforms were analysed. Stimulus duration correlated with stimulus-off response peak latency, whereas frequency, intensity, and inter-stimulus interval correlated with stimulus-on N1 and P1 (conscious only) peak amplitudes. These relationships were instrumental in shaping classical MMR morphology in both anaesthetised and conscious animals, suggesting these waveforms reflect modification of normal auditory processing by different physical properties of sound. Controlled MMR waveforms appeared to exhibit habituation to auditory stimulation over time, which was equally observed in response to oddball and standard stimuli. These findings are inconsistent with the mechanisms thought to underlie human MMN, which currently do not address differences due to specific physical features of sound. Thus, no evidence was found to objectively support the deviance-detection or adaptation hypotheses of MMN in relation to anaesthetised or conscious mice. These findings highlight the potential risk of mischaracterising difference waveform components that are principally influenced by physical sensitivities and habituation of the auditory system

B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes

Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment

Number-Theoretic Nature of Communication in Quantum Spin Systems

The last decade has witnessed substantial interest in protocols for transferring information on networks of quantum mechanical objects. A variety of control methods and network topologies have been proposed, on the basis that transfer with perfect fidelity --- i.e. deterministic and without information loss --- is impossible through unmodulated spin chains with more than a few particles. Solving the original problem formulated by Bose [Phys. Rev. Lett. 91, 207901 (2003)], we determine the exact number of qubits in unmodulated chains (with XY Hamiltonian) that permit the transfer with fidelity arbitrarily close to 1, a phenomenon called pretty good state transfer. We prove that this happens if and only if the number of nodes is n=p-1, 2p-1, where p is a prime, or n=2^{m}-1. The result highlights the potential of quantum spin system dynamics for reinterpreting questions about the arithmetic structure of integers, and, in this case, primality.Comment: 6 pages, 1 EPS figur

The Combechem MQTT LEGO microscope: a grid enabled scientific apparatus demonstrator

Grid computing impacts directly on the experimental scientific laboratory in the areas of monitoring and remote control of experiments, and the storage, processing and dissemination of the resulting data. We highlight some of the issues in extending the use of an MQ Telemetry Transport (MQTT) broker from facilitating the remote monitoring of an experiment and its environment to the remote control of an apparatus. To demonstrate these techniques, an Intel-Play QX3 microscope has been "grid-enabled" using a combination of software to control the microscope imaging, and sample handling hardware built from LEGO Mindstorms. The whole system is controlled remotely by passing messages using an IBM WebSphere Message Broker. <br/

PGC-1 alpha induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma

INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes’ expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma

Child oral health and preventive dental service access among children with intellectual disabilities, autism and other educational additional support needs: a population-based record linkage cohort study

Objective: Inequalities in child oral health are a global challenge and the intersection of socioeconomic factors with educational additional support needs (ASN), including children with intellectual disabilities or autism, have thus far received limited attention in relatively small clinical studies. We aimed to address this evidence gap by investigating oral health and access to preventive dental services among children with ASN compared to the general child population. Methods: Cohort study linking data from six Scotland-wide health and education databases compared: dental caries experience and tooth extraction via general anaesthetic; receipt of school-based dental inspection; access to primary care and hospital dental services; and access to the Childsmile national oral health improvement programme between children with a range of ASN (intellectual disabilities, autism, social and other) and their peers for the school years 2016/17–2018/19 (n = 166 781). Results: Children with any ASN had higher rates of caries experience than those with no ASN, however, after adjustment for socioeconomic deprivation, sex, year, and school type only those with a social or other ASN remained at increased risk. Rates of tooth extraction under general anaesthesia in hospital were higher among children with intellectual disabilities (aRR = 1.67;95% CI = [1.16–2.37]). School-based dental inspection access improved for children with intellectual disability and/or autism from 2016/17 onwards, although higher rates of child refusal on the day were observed in these groups (no ASN refusal: 5.4%; intellectual disability: 35.8%; autism: 40.3%). Children with any ASN were less likely to attend primary dental-care regularly, and in those who attended, children with intellectual disability or autism were less likely than their peers to receive prevention (fluoride varnish, oral-hygiene instruction, or dietary advice). Childsmile nursery-supervised toothbrushing programme access among children with any ASN was similar to children with no ASN and children with intellectual disability (aRR = 1.27;95% CI = [1.12–1.45]) or autism (aRR = 1.32;95% CI = [1.19–1.45]) were more likely to receive support from Childsmile dental health support worker. Conclusions: We have identified inequalities in oral health and dental care for children with different ASN in Scotland with both a greater burden of disease among some groups and higher complexity of care; compounded by reduced and variable access to preventive dental services. Further efforts are needed to develop and improve preventive care pathways for children with ASN and integrate oral health to wider healthcare systems for these children to mitigate against oral health inequalities

Evaluation of a national complex oral health improvement programme: a population data linkage cohort study in Scotland

Objectives Child dental caries is a global public health challenge with high prevalence and wide inequalities. A complex public health programme (Childsmile) was established. We aimed to evaluate the reach of the programme and its impact on child oral health. Setting Education, health and community settings, Scotland-wide. Interventions Childsmile (national oral health improvement programme) interventions: nursery-based fluoride varnish applications (FVAs) and supervised daily toothbrushing, community-based Dental Health Support Worker (DHSW) contacts and primary care dental practice visits—delivered to the population via a proportionate universal approach. Participants: 50 379 children (mean age=5.5 years, SD=0.3) attending local authority schools (2014/2015). Design: Population-based individual child-level data on four Childsmile interventions linked to dental inspection survey data to form a longitudinal cohort. Logistic regression assessed intervention reach and the independent impact of each intervention on caries experience, adjusting for age, sex and area-based Scottish Index of Multiple Deprivation (SIMD). Outcome measures: Reach of the programme is defined as the percentage of children receiving each intervention at least once by SIMD fifth. Obvious dental caries experience (presence/absence) is defined as the presence of decay (into dentine), missing (extracted) due to decay or filled deciduous teeth. Results: 15 032 (29.8%) children had caries experience. The universal interventions had high population reach: nursery toothbrushing (89.1%), dental practice visits (70.5%). The targeted interventions strongly favoured children from the most deprived areas: DHSW contacts (SIMD 1: 29.5% vs SIMD 5: 7.7%), nursery FVAs (SIMD 1: 75.2% vs SIMD 5: 23.2%). Odds of caries experience were markedly lower among children participating in nursery toothbrushing (&gt;3 years, adjusted OR (aOR)=0.60; 95% CI 0.55 to 0.66) and attending dental practice (≥6 visits, aOR=0.55; 95% CI 0.50 to 0.61). The findings were less clear for DHSW contacts. Nursery FVAs were not independently associated with caries experience. Conclusions: The universal interventions, nursery toothbrushing and regular dental practice visits were independently and most strongly associated with reduced odds of caries experience in the cohort, with nursery toothbrushing having the greatest impact among children in areas of high deprivation

A national registry study of patient and renal survival in adult nephrotic syndrome

Introduction: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). Methods: We conducted a national registry–based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014–2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. Results: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%–4.6%) versus 0.9% (0.8%–1.0%) in patients aged &lt;60 years and 24.9% (18.4%–30.8%) versus 9.4% (8.3%–10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%–27.2%) versus 1.1% (0.9%–1.2%) in &lt;60-year-olds and 49.4% (36.6%–59.7%) versus 8.1% (6.6%–9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%–11.7%) in primary and 35.1% (24.3%–44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. Conclusions: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS

Neurofibromin Deficient Myeloid Cells are Critical Mediators of Aneurysm Formation In Vivo

Background Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Method and Results Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. Conclusion These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target