Exploiting big data survival information to unify risk-stratification related, adaptive immune receptor parameters for multiple myeloma.

With the improvement of treatment options, multiple myeloma related life expectancy has been prolonged, but the disease remains largely incurable. Immunotherapy is a growing field that shows promise in advancements for treatment, and recent work has demonstrated an opportunity to use immune receptor, complementarity determining region-3 (CDR3)-candidate antigen chemical complementarity scores to identify survival distinctions among subgroups of patients. Here, we have applied the complementarity scoring algorithm to identify multiple myeloma related, CDR3-cancer testis antigen (CTA) relationships associated with survival distinctions. Furthermore, we have overlapped these immune receptor features with a previous study that showed a dramatic survival distinction based on T-cell receptor, V- and J-gene segment usage, HLA allele combinations, whereby 100% of the patients in certain combination groups had no mortality related to multiple myeloma, during the study period. This overlap evaluation was consistent with the idea that there are likely considerable constraints on productive TRB-antigen-HLA combinations but more flexibility, and unpredictability, for the TRA-antigen-HLA combinations. Also, the approaches in this reported indicated the potential importance of the CTA, IGSF11, as a multiple myeloma antigen, an antigen previously, independently considered as a vaccine candidate in other settings.

Histological and immunohistochemical features suggesting aetiological differences in lymph node and (muco)cutaneous feline tuberculosis lesions.

OBJECTIVES: To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting. MATERIALS AND METHODS: Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl-Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid-fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining. RESULTS: Twenty-two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis-associated lesions more often featured large multi-layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti-associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers. CLINICAL SIGNIFICANCE: Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid-fast bacilli. This implies that a high bacterial index does not infer infection with non-zoonotic non-tuberculous mycobacteria.

Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.

XRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5'-3' direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.

A functional linear modeling approach to sleep-wake cycles in dogs.

The study of companion (pet) dogs is an area of great translational potential, as they share a risk for many conditions that afflict humans. Among these are conditions that affect sleep, including chronic pain and cognitive dysfunction. Significant advancements have occurred in the ability to study sleep in dogs, including development of non-invasive polysomnography; however, basic understanding of dog sleep patterns remains poorly characterized. The purpose of this study was to establish baseline sleep-wake cycle and activity patterns using actigraphy and functional linear modeling (FLM), for healthy, adult companion dogs. Forty-two dogs were enrolled and wore activity monitors for 14 days. FLM demonstrated a bimodal pattern of activity with significant effects of sex, body mass, and age; the effect of age was particularly evident during the times of peak activity. This study demonstrated that FLM can be used to describe normal sleep-wake cycles of healthy adult dogs and the effects of physiologic traits on these patterns of activity. This foundation makes it possible to characterize deviations from normal patterns, including those associated with chronic pain and cognitive dysfunction syndrome. This can improve detection of these conditions in dogs, benefitting them and their potential as models for human disease.

Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.

Dis3L2 is a highly conserved 3'-5' exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms' tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.

Impact of a Child's Celiac Disease Diagnosis and Management on the Family.

BACKGROUND: Little attention has been paid to family-wide repercussions of a child's celiac disease diagnosis and concomitant gluten-free diet management. AIMS: We quantitatively and qualitatively describe positive and negative family-wide effects of a child's celiac disease diagnosis and disease management. METHODS: We interviewed 16 families with at least one child currently following a gluten-free diet, with a biopsy-confirmed celiac disease diagnosis ≥ 1 year prior. Mothers and fathers independently rated child's dietary adherence, concern about child's health status, burden in caring for child's dietary needs, and level of change in various aspects of life post- diagnosis. Children rated their own celiac-specific quality of life through a validated scale. Seventy-one in-depth semi-structured interviews were conducted with 16 children with celiac disease, 31 parents, and 24 siblings. RESULTS: Mothers and fathers rated the effects of their child's celiac disease differently, with mothers reporting more lifestyle changes and heavier burden. Negative and positive themes emerged from the interviews. Mothers felt the burden of managing a gluten-free diet. Fathers felt guilty for carrying a celiac disease-associated gene and both fathers and siblings regretted limited food choices at restaurants and home. The need to be a more creative cook was seen as a positive effect by mothers. Fathers appreciated new family traditions. Siblings felt they had developed empathy for others. A framework is proposed to illustrate these family-wide interactions. CONCLUSIONS: A child's celiac disease diagnosis and disease management affects the entire family. Our results will inform family-centered interventions that maximize quality of life for families.

Development of a national conceptual framework and measuring tool for Organisational Social Responsibility and Accountability for Health (OSRAH).

Organisations can have a significant impact (positive or negative) on society through their actions and decisions. Given this reality, it is important that they are held responsible and accountable for the consequences of their actions. This concept is often referred to as 'social responsibility'. However, 'social responsibility', as currently conceived in the literature, neglects a specific focus on health as a social goal. Additionally, there are no practical tools to capture this concept in a holistic way to facilitate implementation and monitoring of organisational improvement. This paper reports on the process of developing a more holistic conceptual framework and tool for assessing organisational social responsibility and accountability for health (OSRAH). We conducted a review of the published and grey literature and engaged in expert consultation and focus group discussions. The initial OSRAH framework and the self-assessment tool were finalised for implementation and used by 95 organisations at a national event in Iran in February 2017. The results of the assessment data collected at the event showed organisations scored lowest in the domain of community health and highest in the domain of employee health. The OSRAH framework and assessment tool represents a new understanding of health and its determinants in organisations outside the health sector. It integrates health within the existing Corporate Social Responsibility (CSR) culture of organisations. The process of creating the tool and implementing it at the national festival of OSRAH in Iran created momentum for intersectoral action. This experience can inspire researchers and practitioners in other countries, especially in developing countries, to develop their own local definition and practical assessment framework for responsibility and accountability.

Phenology of Emerald Ash Borer (Coleoptera: Buprestidae) and Its Introduced Larval Parasitoids in the Northeastern United States.

Biological control offers a long-term and sustainable option for controlling the destructive forest pest emerald ash borer (EAB), Agrilus planipennis Fairmaire, in North America. Three larval parasitoids, Spathius agrili Yang (Hymenoptera: Braconidae), Tetrastichus planipennisi Yang (Eulophidae), and Spathius galinae Belokobylskij & Strazanac, have been introduced to North America from the native range of EAB (northeastern Asia). While T. planipennisi appears to be persisting where it has been introduced in northern United States, S. agrili failed to establish in northeastern states. The more recently identified parasitoid S. galinae was recovered from the Russian Far East and climate matching suggests it should be suited for release in colder climates. We collected data on the phenology of EAB and its introduced larval parasitoids from colonies established in an insectary, growth chambers, and field-caged trees in Syracuse, New York to determine whether asynchrony between parasitoids and EAB or climate could impact establishment and persistence. Phenological data indicated EAB has one and 2-yr life cycles in New York, with parasitoid-susceptible EAB larvae available spring to fall for parasitism. Insectary and growth chamber studies indicated S. galinae and T. planipennisi were synchronous with EAB phenology, and field studies suggested both species could overwinter in northeastern climates. Spathius agrili was asynchronous with EAB phenology and climate, emerging when fewer parasitoid-susceptible EAB larvae were available and temperatures were not optimal for survival. Our results suggest S. galinae and T. planipennisi are suited for biological control of EAB at the northern limits of its range in North America.

Increasing signal amplitude in electrical impedance tomography of neural activity using a parallel resistor inductor capacitor (RLC) circuit.

OBJECTIVE: To increase the impedance signal amplitude produced during neural activity using a novel approach of implementing a parallel resistor inductor capacitor (RLC) circuit across the current source used in electrical impedance tomography (EIT) of peripheral nerve. APPROACH: The frequency response of the impedance signal was characterized in the range 4-18 kHz, then a frequency range with significant capacitive charge transfer was selected for experiment with the RLC circuit. Design of the RLC circuit was aided by in vitro impedance measurements on nerve and nerve cuff in the range 5 Hz to 50 kHz. MAIN RESULTS: The frequency response of the impedance signal across 4-18 kHz showed maximum amplitude at 6-8 kHz, and steady decline in amplitude between 8 and 18 kHz with -6 dB reduction at 14 kHz. The frequency range 17 ± 1 kHz was selected for the RLC experiment. The RLC experiment was performed on four subjects using an RLC circuit designed to produce a resonant frequency of 17 kHz with a bandwidth of 3.6 kHz, and containing a 22 mH inductive element and a 3.45 nF capacitive element with +0.8/- 3.45 nF manual tuning range. With the RLC circuit connected, relative increases in the impedance signal (±3σ noise) of 44% (±15%), 33% (±30%), 37% (±8.6%), and 16% (±19%) were produced. SIGNIFICANCE: The increase in impedance signal amplitude at high frequencies, generated by the novel implementation of a parallel RLC circuit across the drive current, improves spatial resolution by increasing the number of parallel drive currents which can be implemented in a frequency division multiplexed (FDM) EIT system, and aids the long term goal of a real-time FDM EIT system by reducing the need for ensemble averaging.

Extracting impedance changes from a frequency multiplexed signal during neural activity in sciatic nerve of rat: preliminary study in vitro.

OBJECTIVE: To establish suitable frequency spacing and demodulation steps to use when extracting impedance changes from frequency division multiplexed (FDM) carrier signals in peripheral nerve. APPROACH: Experiments were performed in vitro on cadavers immediately following euthanasia. Neural activity was evoked via stimulation of nerves in the hind paw, while carrier signals were injected, and recordings obtained, with a dual ring nerve cuff implanted on the sciatic nerve. Frequency analysis of recorded compound action potentials (CAPs) and extracted impedance changes, with the latter obtained using established demodulation methods, were used to determine suitable frequency spacing of carrier signals, and bandpass filter (BPF) bandwidth and order, for a frequency multiplexed signal. MAIN RESULTS: CAPs and impedance changes were dominant in the frequency band 200 to 500 Hz and 100 to 200 Hz, respectively. A Tukey window was introduced to remove ringing from Gibbs phenomena. A ±750 Hz BPF bandwidth was selected to encompass 99.99% of the frequency power of the impedance change. Modelling predicted a minimum BPF order of 16 for 2 kHz spacing, and 10 for 4 kHz spacing, were required to avoid ringing from the neighbouring carrier signal, while FDM experiments verified BPF orders of 12 and 8, respectively, were required. With a notch filter centred on the neighbouring signal, a BPF order of at least 6 or 4 was required for 2 and 4 kHz, respectively. SIGNIFICANCE: The results establish drive frequency spacing and demodulation settings for use in FDM electrical impedance tomography (EIT) experiments, as well as a method for their selection, and, for the first time, demonstrates the viability of FDM-EIT of neural activity on peripheral nerve, which will be a central aspect of future real-time neural-EIT systems and EIT-based neural prosthetics interfaces.

Cytokine and Chemokine Concentrations as Biomarkers of Feline Mycobacteriosis.

Mycobacteriosis is an emerging zoonotic disease of domestic cats and timely, accurate diagnosis is currently challenging. To identify differential cytokine/chemokine concentrations in serum/plasma of cats, which could be diagnostic biomarkers of infection we analysed plasma/serum from 116 mycobacteria-infected cats, 16 healthy controls and six cats hospitalised for unrelated reasons was analysed using the Milliplex MAP Feline Cytokine Magnetic Bead multiplex assay. Three cytokines; sFAS, IL-13 and IL-4 were reduced while seven; GM-CSF, IL-2, PDGF-BB, IL-8, KC, RANTES and TNF-α were elevated in mycobacteria-infected cats compared to healthy controls. However, IL-8 and KC concentrations were not significantly different from cats hospitalised for other reasons. Elevations in TNF-α and PDGF-BB may have potential to identify M. bovis and M. microti infected cats specifically while GM-CSF, IL-2 and FLT3L were increased in MTBC infected cats. This study demonstrates potential use of feline tuberculosis as a spontaneously occurring model of this significant human disease. Cytokine profiling has clear diagnostic potential for mycobacteriosis of cats and could be used discriminate tuberculous from non-tuberculous disease to rapidly inform on zoonotic risk. Future work should focus on the in-field utility of these findings to establish diagnostic sensitivity and specificity of these markers.

Curricula and methods for physician compassion training: protocol for a systematic review.

INTRODUCTION: Compassionate patient care has been associated with improved clinical outcomes for patients. However, current evidence suggests that healthcare is experiencing a compassion crisis, with physicians frequently overlooking opportunities to treat patients with compassion. Although there is evidence that compassionate care can be enhanced through training interventions, it is currently unclear what specific skills and behaviours ought to be taught and how best to transfer this information to the learner. The objectives of this systematic review are to collate the world's literature on compassion training to determine (1) the specific skills and behaviours that should be taught (curriculum), and (2) the methods of training that are most effective at improving compassionate patient care. METHODS AND ANALYSIS: We will perform a qualitative systematic review of studies aimed at improving compassionate patient care among physicians and physicians in training. We will comprehensively search CENTRAL, MEDLINE, EMBASE and CINAHL. Additional recommended techniques for systematic reviews of complex evidence will be performed including pursuing selected 'references of references', electronic citation tracking and consulting experts in the field. Two investigators will independently review all search results. After identification and inclusion of papers, we will use a standardised form for data extraction. We will use tables to describe the study populations, interventions tested (including specific skill/behaviours taught and training methods used), outcome measures and effects of interventions on outcome measures compared with control groups. Where appropriate, meta-analysis will be used for quantitative analysis of the data. ETHICS AND DISSEMINATION: The proposed systematic review does not require ethical approval since no individual patient-level data will be collected. Results of this study will contribute to the understanding of compassion training and help inform the development of compassion training curricula. PROSPERO REGISTRATION NUMBER: CRD42018095040.

Early Interventions for the Prevention of Posttraumatic Stress Symptoms in Survivors of Critical Illness: A Qualitative Systematic Review.

OBJECTIVES: Posttraumatic stress disorder among survivors of critical illness is of public health importance, as it is common and reduces patient quality of life. The objective of this systematic review was to collate the world's literature on interventions aimed at preventing posttraumatic stress disorder among survivors of critical illness. DATA SOURCES: We performed a search of CENTRAL, MEDLINE, EMBASE, CINAHL, and clinical trials registry platforms, with no restriction to language using a comprehensive strategy. STUDY SELECTION: Study inclusion criteria were as follows: 1) adult human subjects, 2) patients treated in an ICU setting, 3) intervention arm aimed at reducing posttraumatic stress disorder symptoms, 4) use of a control arm, and 5) an outcome measure assessing development of acute stress or posttraumatic stress disorder symptoms. DATA EXTRACTION: We performed a qualitative analysis to collate and summarize effects of identified interventions according to the recommended methodology from the Cochrane Handbook. DATA SYNTHESIS: Seventeen studies met all inclusion and no exclusion criteria. There was heterogeneity in interventions and outcome measures used. All studies had some concern for risk of bias as per the Cochrane tool for assessing risk of bias. In eight of 12 studies (67%) testing early interventions (i.e., initiated in the ICU course) and one of five studies (20%) testing delayed interventions following ICU discharge, posttraumatic stress disorder symptoms were decreased among the intervention group compared with controls. CONCLUSIONS: Despite a paucity of high-quality clinical investigations, the preponderance of evidence to date suggests that 1) posttraumatic stress disorder among survivors of critical illness may be preventable and 2) early interventions may be the most effective.

A model of electrical impedance tomography implemented in nerve-cuff for neural-prosthetics control.

OBJECTIVE: In neural interfaces for peripheral nerve a trade-off exists between the level of invasiveness and the selectivity of neural recordings. In this study, we implement electrical impedance tomography (EIT) in a nerve cuff with the aim to investigate the achievable level of selectivity. APPROACH: Established modelling approaches in neural-EIT are expanded on to be used, for the first time, on myelinated fibres which are abundant in mammalian peripheral nerves and transmit motor commands. The model is then used to evaluate the viability of using EIT with a nerve cuff to record neural activity in peripheral nerves. MAIN RESULTS: Fibre impedance models indicate activity in unmyelinated fibres can be screened out from activity in myelinated fibres using operating frequencies above 100 Hz. At 1 kHz the transverse impedance magnitude, which is perpendicular to the fibre length axis, of inactive intra-fascicle tissue and the fraction change during neural activity are estimated to be 1142 Ω cm and -8.8 × 10-4, respectively. At 1 kHz and 10 mm spacing between the impedance measurement electrode pair, the longitudinal impedance magnitude, which is parallel to the fibre length axis, and the fraction change during neural activity are estimated to be 328 Ω cm and -0.30, respectively. We show that a novel EIT drive and measurement electrode pattern which utilises longitudinal current and longitudinal differential boundary voltage measurements could distinguish activity in different fascicles, as well as simultaneous activity in multiple fascicles, of a three-fascicle mammalian nerve using simulated data. SIGNIFICANCE: The results of this study provide an estimate of the transient change in impedance of intra-fascicle tissue during neural activity in mammalian nerve, and present a viable EIT electrode pattern, both of which are critical steps towards implementing EIT in a nerve cuff for a recording neural interface.

Drive and measurement electrode patterns for electrode impedance tomography (EIT) imaging of neural activity in peripheral nerve.

Objective; To establish the performance of several drive and measurement patterns in EIT imaging of neural activity in peripheral nerve, which involves large impedance changes in the nerve's anisotropic length axis.Approach; Twelve drive and measurement electrode patterns are compared using a finite element (FE) four-cylindrical shell model of a peripheral nerve and a 32 channel dual-ring nerve cuff. The central layer of the FE model contains impedance changes representative of neural activity of -0.30 in length axis and -8.8 × 10-4in the radial axis. Six of the electrode patterns generate longitudinal drive current, which runs parallel to the anisotropic axis, while the remaining six patterns generate transverse drive current, which runs perpendicular to the anisotropic axis.Main results; Of the twelve patterns evaluated, transverse current patterns produce higher resolution than longitudinal current patterns but are also more susceptible to noise and errors, and exhibit poorer sensitivity to impedance changes in central sample locations. Three of the six longitudinal current patterns considered can reconstruct fascicle level impedance changes with up to 0.2 mV noise and error, which corresponds to between -5.5 and +0.18 dB of the normalised signal standard deviation. Reducing the spacing between the two electrode rings in all longitudinal current patterns reduced the signal to error ratio across all depth locations of the sample.Significance; Electrode patterns which target the large impedance change in the anisotropic length axis can provide improved robustness against noise and errors, which is a critical step towards real time EIT imaging of neural activity in peripheral nerve.

Is there a decline in bovine spongiform encephalopathy cases born after reinforced feed bans? A modelling study in EU member states.

Occasional cases of classical bovine spongiform encephalopathy (BSE) still continue to occur within the European Union (EU) for animals born after reinforced feed bans (BARBs), which should in theory have eliminated all risk of infection. The study aimed to determine (i) whether a common rate of decline of BSE infection was evident across EU member states, i.e. to determine whether control measures have been equally effective in all member states, (ii) whether there was any evidence of spontaneous occurrence of BSE in the data and (iii) the expected date for the last BSE case in UK. It was found that there was no significant difference in the rate of decline of BSE prevalence between member states, with a common rate of decline of 33·9% per annum (95% CI 30·9-37%) in successive annual birth cohorts. Trend analysis indicated an ultimate decline to 0 prevalence, suggesting that spontaneous occurrence does not explain the majority of cases. Projecting forward the trends from the back-calculation model indicated that there was approximately a 50% probability of further cases in the UK, and should the current rate of decline continue, there remains the possibility of further occasional cases up until 2026.

Case-control study on the use of pituitary-derived hormones from sheep as a potential risk factor for the occurrence of atypical scrapie in Great Britain.

A case-control study was conducted in 2013 to investigate the use of pituitary-derived hormones from sheep as a potential risk factor for the presence of atypical scrapie in Great Britain sheep holdings. One hundred and sixty-five holdings were identified as cases. Two equal sets of controls were selected: no case of scrapie and cases of classical scrapie. A total of 495 holdings were selected for the questionnaire survey, 201 responses were received and 190 (38.3 per cent) were suitable for analysis. The variables 'use-of-heat-synchronisation/superovulation' and 'flock size' were significantly associated with the occurrence of atypical scrapie. Farms with atypical cases were less likely (OR 0.25, 95 per cent CI 0.07 to 0.89) to implement heat synchronisation/superovulation in the flock than the control group. Atypical cases were 3.3 times (95 per cent CI 1.38 to 8.13) more likely to occur in large holdings (>879 sheep) than in small flocks (<164 sheep). If the 'use-of-heat-synchronisation/superovulation' is a proxy for the use of pituitary-derived hormones, the significant negative association between having a case of atypical scrapie and the use of these practices rules out the initial hypothesis that using these drugs is a risk factor for the occurrence of atypical scrapie. Flock size was a significant risk factor for atypical scrapie, consistent with a previous generic case-control study.

A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity.

CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human CaV3.3 α1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents. Recently, two de novo missense variations, T797M and R1346H, of hCaV3.3 were identified in individuals with schizophrenia. Here we show that R1346H, but not T797M, is associated with lower hCaV3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCaV3.3 when expressed in human cell lines compared to wild-type. Consistent with our biochemical analyses, whole-cell hCaV3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCaV3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCaV3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons. Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.

Fast machine-learning online optimization of ultra-cold-atom experiments.

We apply an online optimization process based on machine learning to the production of Bose-Einstein condensates (BEC). BEC is typically created with an exponential evaporation ramp that is optimal for ergodic dynamics with two-body s-wave interactions and no other loss rates, but likely sub-optimal for real experiments. Through repeated machine-controlled scientific experimentation and observations our 'learner' discovers an optimal evaporation ramp for BEC production. In contrast to previous work, our learner uses a Gaussian process to develop a statistical model of the relationship between the parameters it controls and the quality of the BEC produced. We demonstrate that the Gaussian process machine learner is able to discover a ramp that produces high quality BECs in 10 times fewer iterations than a previously used online optimization technique. Furthermore, we show the internal model developed can be used to determine which parameters are essential in BEC creation and which are unimportant, providing insight into the optimization process of the system.