YY1 control of mitochondrial-related genes does not account for regulation of immunoglobulin class switch recombination in mice.

Immunoglobulin class switch recombination (CSR) occurs in activated B cells with increased mitochondrial mass and membrane potential. Transcription factor Yin Yang 1 (YY1) is critical for CSR and for formation of the DNA loops involved in this process. We therefore sought to determine if YY1 knockout impacts mitochondrial gene expression and mitochondrial function in murine splenic B cells, providing a potential mechanism for regulating CSR. We identified numerous genes in splenic B cells differentially regulated when cells are induced to undergo CSR. YY1 conditional knockout caused differential expression of 1129 genes, with 59 being mitochondrial-related genes. ChIP-seq analyses showed YY1 was directly bound to nearly half of these mitochondrial-related genes. Surprisingly, at the time when YY1 knockout dramatically reduces DNA loop formation and CSR, mitochondrial mass and membrane potential were not significantly impacted, nor was there a significant change in mitochondrial oxygen consumption, extracellular acidification rate, or mitochondrial complex I or IV activities. Our results indicate that YY1 regulates numerous mitochondrial-related genes in splenic B cells, but this does not account for the impact of YY1 on CSR or long-distance DNA loop formation.

Transcription factor YY1 can control AID-mediated mutagenesis in mice.

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1f/f ) or that express normal AID levels (yy1f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sµ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.

Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.

Spiking Neural Classifier with Lumped Dendritic Nonlinearity and Binary Synapses: A Current Mode VLSI Implementation and Analysis.

We present a neuromorphic current mode implementation of a spiking neural classifier with lumped square law dendritic nonlinearity. It has been shown previously in software simulations that such a system with binary synapses can be trained with structural plasticity algorithms to achieve comparable classification accuracy with fewer synaptic resources than conventional algorithms. We show that even in real analog systems with manufacturing imperfections (CV of 23.5% and 14.4% for dendritic branch gains and leaks respectively), this network is able to produce comparable results with fewer synaptic resources. The chip fabricated in [Formula: see text]m complementary metal oxide semiconductor has eight dendrites per cell and uses two opposing cells per class to cancel common-mode inputs. The chip can operate down to a [Formula: see text] V and dissipates 19 nW of static power per neuronal cell and [Formula: see text] 125 pJ/spike. For two-class classification problems of high-dimensional rate encoded binary patterns, the hardware achieves comparable performance as software implementation of the same with only about a 0.5% reduction in accuracy. On two UCI data sets, the IC integrated circuit has classification accuracy comparable to standard machine learners like support vector machines and extreme learning machines while using two to five times binary synapses. We also show that the system can operate on mean rate encoded spike patterns, as well as short bursts of spikes. To the best of our knowledge, this is the first attempt in hardware to perform classification exploiting dendritic properties and binary synapses.

YY1 controls Igκ repertoire and B-cell development, and localizes with condensin on the Igκ locus.

Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.

Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015.

Importance: Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective: To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design: A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures: Mean SBP level, cause-specific deaths, and health burden related to SBP (≥110-115 mm Hg and also ≥140 mm Hg) by age, sex, country, and year. Results: Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). For loss of DALYs associated with systolic blood pressure of 140 mm Hg or higher, the loss increased from 95.9 million (95% uncertainty interval [UI], 87.0-104.9 million) to 143.0 million (95% UI, 130.2-157.0 million) [corrected], and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0-8.7 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance: In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (≥110-115 and ≥140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher.

An Online Structural Plasticity Rule for Generating Better Reservoirs.

In this letter, we propose a novel neuro-inspired low-resolution online unsupervised learning rule to train the reservoir or liquid of liquid state machines. The liquid is a sparsely interconnected huge recurrent network of spiking neurons. The proposed learning rule is inspired from structural plasticity and trains the liquid through formating and eliminating synaptic connections. Hence, the learning involves rewiring of the reservoir connections similar to structural plasticity observed in biological neural networks. The network connections can be stored as a connection matrix and updated in memory by using address event representation (AER) protocols, which are generally employed in neuromorphic systems. On investigating the pairwise separation property, we find that trained liquids provide 1.36 0.18 times more interclass separation while retaining similar intraclass separation as compared to random liquids. Moreover, analysis of the linear separation property reveals that trained liquids are 2.05 0.27 times better than random liquids. Furthermore, we show that our liquids are able to retain the generalization ability and generality of random liquids. A memory analysis shows that trained liquids have 83.67 5.79 ms longer fading memory than random liquids, which have shown 92.8 5.03 ms fading memory for a particular type of spike train inputs. We also throw some light on the dynamics of the evolution of recurrent connections within the liquid. Moreover, compared to separation-driven synaptic modification', a recently proposed algorithm for iteratively refining reservoirs, our learning rule provides 9.30%, 15.21%, and 12.52% more liquid separations and 2.8%, 9.1%, and 7.9% better classification accuracies for 4, 8, and 12 class pattern recognition tasks, respectively.

YY1 DNA binding and interaction with YAF2 is essential for Polycomb recruitment.

Polycomb Group (PcG) proteins are crucial for epigenetic inheritance of cell identity and are functionally conserved from Drosophila to humans. PcG proteins regulate expression of homeotic genes and are essential for axial body patterning during development. Earlier we showed that transcription factor YY1 functions as a PcG protein. YY1 also physically interacts with YAF2, a homolog of RYBP. Here we characterize the mechanism and physiologic relevance of this interaction. We found phenotypic and biochemical correction of dRYBP mutant flies by mouse YAF2 demonstrating functional conservation across species. Further biochemical analysis revealed that YAF2 bridges interaction between YY1 and the PRC1 complex. ChIP assays in HeLa cells showed that YAF2 is responsible for PcG recruitment to DNA, which is mediated by YY1 DNA binding. Knock-down of YY1 abrogated PcG recruitment, which was not compensated by exogenous YAF2 demonstrating that YY1 DNA binding is a priori necessary for Polycomb assembly on chromatin. Finally, we found that although YAF2 and RYBP regulate a similar number of Polycomb target genes, there are very few genes that are regulated by both implying functional distinction between the two proteins. We present a model of YAF2-dependent and independent PcG DNA recruitment by YY1.

Hardware-amenable structural learning for spike-based pattern classification using a simple model of active dendrites.

This letter presents a spike-based model that employs neurons with functionally distinct dendritic compartments for classifying high-dimensional binary patterns. The synaptic inputs arriving on each dendritic subunit are nonlinearly processed before being linearly integrated at the soma, giving the neuron the capacity to perform a large number of input-output mappings. The model uses sparse synaptic connectivity, where each synapse takes a binary value. The optimal connection pattern of a neuron is learned by using a simple hardware-friendly, margin-enhancing learning algorithm inspired by the mechanism of structural plasticity in biological neurons. The learning algorithm groups correlated synaptic inputs on the same dendritic branch. Since the learning results in modified connection patterns, it can be incorporated into current event-based neuromorphic systems with little overhead. This work also presents a branch-specific spike-based version of this structural plasticity rule. The proposed model is evaluated on benchmark binary classification problems, and its performance is compared against that achieved using support vector machine and extreme learning machine techniques. Our proposed method attains comparable performance while using 10% to 50% less in computational resource than the other reported techniques.

Chronic Paraspinal Pain due to Multiple Aortic Aneurysms.

Aneurysms of the aorta are not uncommon, both of the thoracic aorta or the abdominal aorta and may be associated with congenital aortic valve diseases, cystic medial necrosis, Marfan's Syndrome or Ehlers-Danlos syndrome, or atherosclerosis. We report a case of a 46 year old smoker who had developed multiple aneurysms of the aorta in both the thoracic and abdominal parts and was incidentally diagnosed on work-up of a chronic back pain associated with venous prominence on left side of chest and left arm.

The transcription factor Atonal homolog 8 regulates Gata4 and Friend of Gata-2 during vertebrate development.

GATA and Friend of GATA (FOG) form a transcriptional complex that plays a key role in cardiovascular development in both fish and mammals. In the present study we demonstrate that the basic helix-loop-helix transcription factor Atonal homolog 8 (Atoh8) is required for development of the heart in fish but not in mice. Genetic studies reveal that Atoh8 interacts specifically with Gata4 and Fog1 during development of the heart and swim bladder in the fish. Biochemical studies reveal that ATOH8, GATA4, and FOG2 associate in a single complex in vitro. In contrast to fish, ATOH8-deficient mice exhibit normal cardiac development and loss of ATOH8 does not alter cardiac development in Gata4(+/-) mice. This species difference in the role of ATOH8 is explained in part by LacZ and GFP reporter alleles that reveal restriction of Atoh8 expression to atrial but not ventricular myocardium in the mouse. Our findings identify ATOH8 as a novel regulator of GATA-FOG function that is required for cardiac development in the fish but not the mouse. Whether ATOH8 modulates GATA-FOG function at other sites or in more subtle ways in mammals is not yet known.

Correlates of functional outcome among stroke survivors in a developing country--a prospective community-based study from India.

Stroke survivors (SS) are rising with higher incidence of stroke in developing countries. In addition to physical impairment, other factors such as cognition, social interaction, and depression determine the functional outcome after stroke. Considering the paucity of data from developing countries, we planned to determine the change in various functional parameters among SS. This community-based prospective study was carried out in Kolkata, India among 283 SS between 2006 and 2010. Functional outcome was assessed at baseline and at 3 annual follow-up visits using validated tools. A stepwise regression analysis was performed with demographic and stroke-related covariates against various measures of functional outcome. Result showed that mean Barthel Index score at baseline was 76.4 ± 30.8. Bengali version of mental status examination and Geriatric Depression Scale scores trended down over time with a negative regression coefficient of -.2061 (standard error [SE], .0937) and -.4488 (SE, .2145). Other outcomes did not change. Female gender, depression, and cognitive dysfunction had an unfavorable impact, whereas education correlated positively. In conclusions female gender and neuropsychiatric disturbances showed poor functional outcome compared with education, which correlates with better outcome. This information will be helpful for patients in developing countries for planning stroke rehabilitation.

A case of ADEM following Chikungunya fever.

Chikungunya most often is a self-limiting febrile illness with polyarthritis and the virus is not known to be neurotropic. We are reporting a case of chikugunya fever presenting as acute demyelinating encephalomyelitis(ADEM) which is very rare.

Ion-Mediated Recombination Dynamics in Perovskite-Based Memory Light-Emitting Diodes for Neuromorphic Control Systems.

Neuromorphic devices can help perform memory-heavy tasks more efficiently due to the co-localization of memory and computing. In biological systems, fast dynamics are necessary for rapid communication, while slow dynamics aid in the amplification of signals over noise and regulatory processes such as adaptation- such dual dynamics are key for neuromorphic control systems. Halide perovskites exhibit much more complex phenomena than conventional semiconductors due to their coupled ionic, electronic, and optical properties which result in modulatable drift, diffusion of ions, carriers, and radiative recombination dynamics. This is exploited to engineer a dual-emitter tandem device with the requisite dual slow-fast dynamics. Here, a perovskite-organic tandem light-emitting diode (LED) capable of modulating its emission spectrum and intensity owing to the ion-mediated recombination zone modulation between the green-emitting quasi-2D perovskite layer and the red-emitting organic layer is introduced. Frequency-dependent response and high dynamic range memory of emission intensity and spectra in a LED are demonstrated. Utilizing the emissive read-out, image contrast enhancement as a neuromorphic pre-processing step to improve pattern recognition capabilities is illustrated. As proof of concept using the device's slow-fast dynamics, an inhibition of the return mechanism is physically emulated.

High-performance one-dimensional halide perovskite crossbar memristors and synapses for neuromorphic computing.

Despite impressive demonstrations of memristive behavior with halide perovskites, no clear pathway for material and device design exists for their applications in neuromorphic computing. Present approaches are limited to single element structures, fall behind in terms of switching reliability and scalability, and fail to map out the analog programming window of such devices. Here, we systematically design and evaluate robust pyridinium-templated one-dimensional halide perovskites as crossbar memristive materials for artificial neural networks. We compare two halide perovskite 1D inorganic lattices, namely (propyl)pyridinium and (benzyl)pyridinium lead iodide. The absence of conjugated, electron-rich substituents in PrPyr+ prevents edge-to-face type π-stacking, leading to enhanced electronic isolation of the 1D iodoplumbate chains in (PrPyr)[PbI3], and hence, superior resistive switching performance compared to (BnzPyr)[PbI3]. We report outstanding resistive switching behaviours in (PrPyr)[PbI3] on the largest flexible crossbar implementation (16 × 16) to date - on/off ratio (>105), long term retention (105 s) and high endurance (2000 cycles). Finally, we put forth a universal approach to comprehensively map the analog programming window of halide perovskite memristive devices - a critical prerequisite for weighted synaptic connections in artificial neural networks. This consequently facilitates the demonstration of accurate handwritten digit recognition from the MNIST database based on spike-timing-dependent plasticity of halide perovskite memristive synapses.

Depression among stroke survivors: a community-based, prospective study from Kolkata, India.

OBJECTIVE: Post-stroke depression (PSD) is a disabling entity among stroke survivors (SS). Longitudinal studies on PSD, essential to determine its prognosis, are lacking from developing countries. This prospective study was undertaken to assess the prevalence, natural history, and correlates of depression among SS in an Indian community. METHODS: From a community based stroke registry, SS were assessed annually for cognition, disability, and depression using Bengali validated scales. PSD was diagnosed if score on geriatric depression scale was greater than or equal to 21. Complex sample strategy was considered when calculating prevalence of post stroke depression. An age- and sex-matched case-control study was undertaken to determine the odds of depression in SS. RESULTS: Prevalence of PSD was 36.98% (95% confidence interval [CI]: 31.89%-42.06%) among 241 patients assessed at baseline. About 17% developed depression annually and a similar proportion had spontaneous improvement. Peak rate of PSD was beyond 3 months and continued up to 18 months after stroke. Compared to the non-depressed group, PSD subjects were significantly older, had higher age at first stroke, less education, lower socioeconomic status, and greater cognitive impairment and disability. Education had a protective role. Mortality in PSD was nearly twice that in non-depressed patients, though not significant statistically (hazard ratio: 1.84; 95% CI: 0.90-3.77). Compared with controls, odds ratio of PSD was 19.95 (95% CI: 10.09-39.47). CONCLUSIONS: Approximately one-third of SS develop PSD, similar to developed countries. Prevalence remains stable annually. Delayed peak of PSD suggested later realization of underlying disability. Predictors of PSD have been described and higher literacy was protective in this study.

Trajectories of Successful Aging Among Older Adults in Aotearoa New Zealand.

Successful aging was defined as having no multimorbidity, high functional capacity, active life engagement, and good health-related quality of life. This study analyzed data from 1433 older adults who were followed up for 12 years across seven waves from the New Zealand Health, Work and Retirement study by examining the trajectories of successful aging. Latent growth curve modeling was used to assess the growth factors of successful aging trajectories of older adults. The mean successful aging score was 3.53 (range: 0-6) in 2006 and linearly declined by 0.064 units every year. Those with higher successful aging scores at baseline had a slower decline. Successful aging scores were lower among females, Maori, and those aged 65 years and above at baseline. The findings from this study suggest that gender and ethnic inequalities play significant roles in successful aging among older adults in New Zealand.

A Hybrid Neuromorphic Object Tracking and Classification Framework for Real-Time Systems.

Deep learning inference that needs to largely take place on the "edge" is a highly computational and memory intensive workload, making it intractable for low-power, embedded platforms such as mobile nodes and remote security applications. To address this challenge, this article proposes a real-time, hybrid neuromorphic framework for object tracking and classification using event-based cameras that possess desirable properties such as low-power consumption (5-14 mW) and high dynamic range (120 dB). Nonetheless, unlike traditional approaches of using event-by-event processing, this work uses a mixed frame and event approach to get energy savings with high performance. Using a frame-based region proposal method based on the density of foreground events, a hardware-friendly object tracking scheme is implemented using the apparent object velocity while tackling occlusion scenarios. The frame-based object track input is converted back to spikes for TrueNorth (TN) classification via the energy-efficient deep network (EEDN) pipeline. Using originally collected datasets, we train the TN model on the hardware track outputs, instead of using ground truth object locations as commonly done, and demonstrate the ability of our system to handle practical surveillance scenarios. As an alternative tracker paradigm, we also propose a continuous-time tracker with C ++ implementation where each event is processed individually, which better exploits the low latency and asynchronous nature of neuromorphic vision sensors. Subsequently, we extensively compare the proposed methodologies to state-of-the-art event-based and frame-based methods for object tracking and classification, and demonstrate the use case of our neuromorphic approach for real-time and embedded applications without sacrificing performance. Finally, we also showcase the efficacy of the proposed neuromorphic system to a standard RGB camera setup when simultaneously evaluated over several hours of traffic recordings.

Telehealth as a Component of One Health: a Position Paper.

INTRODUCTION: One Health (OH) refers to the integration of human, animal, and ecosystem health within one framework in the context of zoonoses, antimicrobial resistance and stewardship, and food security. Telehealth refers to distance delivery of healthcare. A systems approach is central to both One Health and telehealth, and telehealth can be a core component of One Health. Here we explain how telehealth might be integrated into One Health. METHODS: We have considered antimicrobial resistance (AMR) as a use case where both One Health and telehealth can be used for coordination among the farming sector, the veterinary services, and human health providers to mitigate the risk of AMR. We conducted a narrative review of the literature to develop a position on the inter-relationships between telehealth and One Health. We have summarised how telehealth can be incorporated within One Health. RESULTS: Clinicians have used telehealth to address antimicrobial resistance, zoonoses, food borne infection, improvement of food security and antimicrobial stewardship. We identified little existing evidence in support of the usage of telehealth within a One Health paradigm, although in isolation, both are useful for the same purpose, i.e., mitigation of the significant public health risks posed by zoonoses, food borne infections, and antimicrobial resistance. CONCLUSIONS: It is possible to integrate telehealth within a One Health framework to develop effective inter-sectoral communication essential for the mitigation and addressing of zoonoses, food security, food borne infection containment and antimicrobial stewardship. More research is needed to substantiate and investigate this model of healthcare.