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Prior experiments in explants of human lymphoid tissue have demonstrated that human immunodeficiency virus type 1 (HIV-1) productively infects diverse cellular targets including T cells and tissue macrophages. We sought to determine the specific contribution of macrophages and T cells to the overall viral burden within lymphoid tissue. To block infection of macrophages selectively while preserving infection of T cells, we used viruses deficient for viral protein R (Vpr) that exhibit profound replication defects in nondividing cells in vitro. We inoculated tonsil histocultures with matched pairs of congenic viruses that differed only by the presence of a wild-type or truncated vpr gene. Although these viruses exhibited no reduction in the infection or depletion of T cells, the ability of the Vpr-deficient R5 virus to infect tissue macrophages was severely impaired compared with matched wild-type R5 virus. Interestingly, the Vpr-deficient R5 virus also exhibited a 50% reduction in overall virus replication compared with its wild-type counterpart despite the fact that macrophages represent a small fraction of the potential targets of HIV-1 infection in these tissues. Collectively, these data highlight the importance of tissue macrophages in local viral burden and further implicate roles for CC chemokine receptor 5, macrophages, and Vpr in the life cycle and pathogenesis of HIV-1.

Prior studies have described the complex interplay that exists between glioma cells and neurons; however, the electrophysiological properties endogenous to glioma cells remain obscure. To address this, we employed Patch-sequencing (Patch-seq) on human glioma specimens and found that one-third of patched cells in IDH mutant (IDH mut ) tumors demonstrate properties of both neurons and glia. To define these hybrid cells (HCs), which fire single, short action potentials, and discern if they are of tumoral origin, we developed the single cell rule association mining (SCRAM) computational tool to annotate each cell individually. SCRAM revealed that HCs possess select features of GABAergic neurons and oligodendrocyte precursor cells, and include both tumor and non-tumor cells. These studies characterize the combined electrophysiological and molecular properties of human glioma cells and describe a cell type in human glioma with unique electrophysiological and transcriptomic properties that may also exist in the non-tumor brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Sexual health education among individuals with autism spectrum disorder (ASD) is unique and may not be adequately addressed both at home and at school. Parents have an important role in delivering sexual health education to their children. This is a pilot study to evaluate parental awareness and effectiveness of parent sexual health training for children with ASD., Materials and Methods: Parents of 30 children with ASD with ages ranging from 8 to 12 years attending Child Development Clinic, Hospital Pulau Pinang (CDC HPP) were recruited. Parents attended two-hour virtual parent sexual health training and educational materials were provided to be utilised at home. Follow-up via phone consultation were done at three and six months to ensure training was carried out. Both structured interview and Vineland adaptive behaviour scales (VABS-3) were done at recruitment and at eight months via phone consultation. Wilcoxon-signed rank test was used to analyse differences between pre- and postintervention outcome measures., Results: Statistically significant increase in number of sexual health topics taught by parents and appropriate socio-sexual behaviours of children were found. Intellectual function of children with ASD influenced the study outcomes., Conclusion: Parent sexual health training can be done to empower parents to educate children with ASD and promote appropriate socio-sexual behaviours.

AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the physicochemical characteristics and volatile flavor of fried tilapia skins under three frying methods. Conventional deep-fat frying usually increases the oil content of the fried fish skin and leads to lipid oxidation, which reduces the product quality. Alternative frying methods, such as air frying for 6 and 12 min under 180 °C (AF6, and AF12) and vacuum frying at 0.085 MPa for 8 and 24 min under 120 °C (VF8, and VF24) were compared to conventional frying for 2 and 8 min under 180 °C (CF2, and CF8) for tilapia skin. Physical properties of fried skin, such as the moisture content, water activity, L* values and breaking force decreased under all frying methods, while the lipid oxidation and a*, b* values increased with the increase in frying time. In general, VF offered higher hardness of product compared to AF which had a lower breaking force. Especially AF12 and CF8 had the lowest breaking force, which indicated higher crispness. For the oil quality inside the product, AF and VF reduced conjugated dienes formation and retarded oxidation compared to CF. The results of the flavor compositions of fish skin measured using gas chromatography mass spectrometry (GC/MS) with solid phase microextraction (SPME) showed that CF obtained higher unpleasant oily odor (nonanal, 2,4-decadienal, etc.), while AF presented greater grilling flavor (pyrazine derivatives). Because fish skin fried by AF only relied on hot air, Maillard reaction derived compounds, such as methylpyrazine, 2,5-dimethylpyrazine, and benzaldehyde were the leading flavors. This made the aroma profiles of AF very different from VF and CF. Among all the approaches, AF and VF developed lower oil content, mild fat oxidation and better flavor attributes, which proves their practical applications for frying tilapia fish skin.

Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related odors. Optogenetic activation of BF-to-LHb circuitry drives robust, reflexive-like aversion. Furthermore, activation of this circuitry suppresses the drive to eat in a fasted state. Together, these data reveal a role of basal forebrain glutamatergic neurons in modulating LHb-associated aversion and feeding behaviors by sensing environmental cues., (© 2022. The Author(s).)

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors currently being used to investigate circuit architecture and function. Finally, it discusses methods for acute or chronic manipulation of neural activity, including genetically-targeted cellular ablation, optogenetics, chemogenetics, and over-expression of ion channels. With this ever-evolving genetic toolbox, scientists are continuing to probe neural circuits with increasing resolution, elucidating the structure and function of the incredibly complex mammalian brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Swanson, Chin, Romero, Srivastava, Ortiz-Guzman, Hunt and Arenkiel.)

Acute myeloid leukemia (AML) is caused by recurrent mutations in members of the gene regulatory and signaling machinery that control hematopoietic progenitor cell growth and differentiation. Here, we show that the transcription factor WT1 forms a major node in the rewired mutation-specific gene regulatory networks of multiple AML subtypes. WT1 is frequently either mutated or upregulated in AML, and its expression is predictive for relapse. The WT1 protein exists as multiple isoforms. For two main AML subtypes, we demonstrate that these isoforms exhibit differential patterns of binding and support contrasting biological activities, including enhanced proliferation. We also show that WT1 responds to oncogenic signaling and is part of a signaling-responsive transcription factor hub that controls AML growth. WT1 therefore plays a central and widespread role in AML biology., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness. One of the best-studied AML-subtypes is the t(8;21) AML which carries a translocation fusing the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO gene. The resulting oncoprotein, RUNX1/ETO has been studied for decades, both at the biochemical but also at the systems biology level. It functions as a dominant-negative version of RUNX1 and interferes with multiple cellular processes associated with myeloid differentiation, growth regulation and genome stability. In this review, we summarize our current knowledge of how this protein reprograms normal into malignant cells and how our current knowledge could be harnessed to treat the disease., Competing Interests: The authors declare no conflict of interest.

Acute myeloid leukemia development occurs in a stepwise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e., RUNX1, DNMT3A, TET2), while the secondary mutations often involve genes encoding members of signaling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. Expression of N822K-c-KIT strongly increases the self-renewal capacity of RUNX1-ETO-expressing cells. Global analysis of gene expression changes and alterations in the epigenome revealed that N822K-c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also revealed that double mutant cells still differ from their patient-derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumorigenesis., Competing Interests: Conflict of interest disclosure The authors declare no competing financial interests., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy caused by recurrent mutations in haematopoietic stem and progenitor cells that affect both the epigenetic regulatory machinery and signalling molecules. The t(8;21) or RUNX1-RUNX1T1 translocation generates the RUNX1-ETO chimeric transcription factor which primes haematopoietic stem cells for further oncogenic mutational events that in their sum cause overt disease. Significant progress has been made in generating both in vitro and in vivo model systems to recapitulate t(8;21) AML which are crucial for the understanding of the biology of the disease and the development of effective treatment. This review provides a comprehensive overview of the in vivo and in vitro model systems that were developed to gain insights into the molecular mechanisms of RUNX1-ETO oncogenic activity and their contribution to the advancement of knowledge in the t(8;21) AML field. Such models include transgenic mice, patient-derived xenografts, RUNX1-ETO transduced human progenitor cells, cell lines and human embryonic stem cell model systems, making the t(8;21) as one of the well-characterized sub-type of AML at the molecular level., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Coronavirus disease 2019 (COVID-19) is a major healthcare disaster in the modern times. Healthcare services must adapt to effectively juggle between pandemic management and maintenance of business-as-usual services so that both COVID-19 and non-COVID-19 patients receive appropriate clinical care. We share our experience of significant cardiac rhythm abnormalities seen in COVID-19 patients in Singapore, how the viral pandemic has affected the cardiac electrophysiology and pacing service in a large acute care general hospital and the steps taken to alleviate the negative impact.

Alzheimer's disease is characterized by the progressive deterioration of cognitive abilities particularly working memory while mild cognitive impairment (MCI) represents its prodrome. It is generally believed that neural compensation is intact in MCI but absent in Alzheimer's disease. This study investigated the effects of increasing task load as a means to induce neural compensation through a novel visual working memory (VSWM) task using functional near-infrared spectroscopy (fNIRS). The bilateral prefrontal cortex (PFC) was explored due to its relevance in VSWM and neural compensation. A total of 31 healthy controls (HC), 12 patients with MCI and 18 patients with mild Alzheimer's disease (mAD) were recruited. Although all groups showed sensitivity in terms of behavioral performance (i.e. score) towards increasing task load (level 1 to 3), only in MCI load effect on cortical response (as measured by fNIRS) was significant. At lower task load, bilateral PFC activation did not differ between MCI and HC. Neural compensation in the form of hyperactivation was only noticeable in MCI with a moderate task load. Lack of hyperactivation in mAD, coupled with significantly poorer task performance across task loads, suggested the inability to compensate due to a greater degree of neurodegeneration. Our findings provided an insight into the interaction of cognitive load theory and neural compensatory mechanisms. The experiment results demonstrated the feasibility of inducing neural compensation with the proposed VSWM task at the right amount of cognitive load. This may provide a promising avenue to develop an effective cognitive training and rehabilitation for dementia population.

Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery., Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness., Results: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening., Conclusion: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery, resulting in abnormal growth and a block in differentiation. One type of recurrent mutations affects RUNX1 , which is subject to mutations and translocations, the latter giving rise to fusion proteins with aberrant transcriptional activities. We recently compared the mechanism by which the products of the t(8;21) and the t(3;21) translocation RUNX1-ETO and RUNX1-EVI1 reprogram the epigenome. We demonstrated that a main component of the block in differentiation in both types of AML is direct repression of the gene encoding the myeloid regulator C/EBPα by both fusion proteins. Here, we examined at the global level whether C/EBPα is able to reverse aberrant chromatin programming in t(8;21) and t(3;21) AML. C/EBPα overexpression does not change oncoprotein expression or globally displace these proteins from their binding sites. Instead, it upregulates a core set of common target genes important for myeloid differentiation and represses genes regulating leukemia maintenance. This study, therefore, identifies common CEBPA -regulated pathways as targets for therapeutic intervention., (© 2018 by The American Society of Hematology.)

Listeria spp. are ubiquitous in nature and can be found in various environmental niches such as soil, sewage, river water, plants, and foods, but the most frequently isolated species are Listeria monocytogenes and Listeria innocua. In this study, the presence of Listeria spp. in raw chicken meat and chicken-related products sold in local markets in Klang Valley, Malaysia was investigated. A total of 44 Listeria strains (42 L. innocua and 2 L. welshimeri) were isolated from 106 samples. Antibiotic susceptibility tests of the L. innocua strains revealed a high prevalence of resistance to clindamycin (92.9%), ceftriaxone (76.2%), ampicillin (73.8%), tetracycline (69%), and penicillin G (66.7%). Overall, 31 L. innocua and 1 L. welshimeri strain were multidrug resistant, i.e., nonsusceptible to at least one antimicrobial agent in three or more antibiotic classes. The majority of the L. innocua strains were placed into five AscI pulsogroups, and overall 26 distinct AscI pulsotypes were identified. The detection of multidrug-resistant Listeria strains from different food sources and locations warrants attention because these strains could serve as reservoirs for antimicrobial resistance genes and may facilitate the spread and emergence of other drug-resistant strains.

Understanding and blocking the self-renewal pathway of preleukemia stem cells could prevent acute myeloid leukemia (AML) relapse. In this study, we show that increased FOXO1 represents a critical mechanism driving aberrant self-renewal in preleukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). Although generally considered as a tumor suppressor, FOXO1 is consistently upregulated in t(8;21) AML. Expression of FOXO1 in human CD34 + cells promotes a preleukemic state with enhanced self-renewal and dysregulated differentiation. The DNA binding domain of FOXO1 is essential for these functions. FOXO1 activates a stem cell molecular signature that is also present in AE preleukemia cells and preserved in t(8;21) patient samples. Genome-wide binding studies show that AE and FOXO1 share the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is required for their activation. In agreement with this observation, genetic and pharmacological ablation of FOXO1 inhibited the long-term proliferation and clonogenicity of AE cells and t(8;21) AML cell lines. Targeting of FOXO1 therefore provides a potential therapeutic strategy for elimination of stem cells at both preleukemic and leukemic stages., (© 2017 by The American Society of Hematology.)

Background: Cognitive performance is relatively well preserved during early cognitive impairment owing to compensatory mechanisms. Methods: We explored functional near-infrared spectroscopy (fNIRS) alongside a semantic verbal fluency task (SVFT) to investigate any compensation exhibited by the prefrontal cortex (PFC) in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). In addition, a group of healthy controls (HC) was studied. A total of 61 volunteers (31 HC, 12 patients with MCI and 18 patients with mild AD) took part in the present study. Results: Although not statistically significant, MCI exhibited a greater mean activation of both the right and left PFC, followed by HC and mild AD. Analysis showed that in the left PFC, the time taken for HC to achieve the activation level was shorter than MCI and mild AD ( p = 0.0047 and 0.0498, respectively); in the right PFC, mild AD took a longer time to achieve the activation level than HC and MCI ( p = 0.0469 and 0.0335, respectively); in the right PFC, HC, and MCI demonstrated a steeper slope compared to mild AD ( p = 0.0432 and 0. 0107, respectively). The results were, however, not significant when corrected by the Bonferroni-Holm method. There was also found to be a moderately positive correlation ( R = 0.5886) between the oxygenation levels in the left PFC and a clinical measure [Mini-Mental State Examination (MMSE) score] in MCI subjects uniquely. Discussion: The hyperactivation in MCI coupled with a better SVFT performance may suggest neural compensation, although it is not known to what degree hyperactivation manifests as a potential indicator of compensatory mechanisms. However, hypoactivation plus a poorer SVFT performance in mild AD might indicate an inability to compensate due to the degree of structural impairment. Conclusion: Consistent with the scaffolding theory of aging and cognition, the task-elicited hyperactivation in MCI might reflect the presence of compensatory mechanisms and hypoactivation in mild AD could reflect an inability to compensate. Future studies will investigate the fNIRS parameters with a larger sample size, and their validity as prognostic biomarkers of neurodegeneration.

Objectives: Salmonella spp. represent one of the main diarrhoeal pathogens that are transmitted via the food supply chain. Here we report the draft genome sequence of a multidrug-resistant Salmonella enterica serovar Brancaster (PS01) that was isolated from poultry meat in Malaysia., Methods: Genomic DNA was extracted from Salmonella strain PS01 and was sequenced using an Illumina HiSeq 2000 platform. The generated reads were de novo assembled using CLC Genomics Workbench. The draft genome was annotated and the presence of antimicrobial resistance genes was identified., Results: The 5 036 442bp genome contains various antimicrobial resistance genes conferring resistance to aminoglycosides, fluoroquinolones, fosfomycin, macrolides, phenicols, sulphonamides, tetracyclines and trimethoprim. The β-lactamase gene bla TEM-176 encoding TEM-176 was also found in this strain., Conclusions: The genome sequence will aid in the understanding of drug resistance mechanisms in foodborne Salmonella Brancaster and highlights the need to ensure the judicious use of antibiotics in animal husbandry as well as the importance of implementing proper food handling and preparation practices., (Copyright © 2017. Published by Elsevier Ltd.)

Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.

Reliable, multi-channel neural recording is critical to the neuroscience research and clinical treatment. However, most hardware development of fully integrated, multi-channel wireless neural recorders to-date, is still in the proof-of-concept stage. To be ready for practical use, the trade-offs between performance, power consumption, device size, robustness, and compatibility need to be carefully taken into account. This paper presents an optimized wireless compressed sensing neural signal recording system. The system takes advantages of both custom integrated circuits and universal compatible wireless solutions. The proposed system includes an implantable wireless system-on-chip (SoC) and an external wireless relay. The SoC integrates 16-channel low-noise neural amplifiers, programmable filters and gain stages, a SAR ADC, a real-time compressed sensing module, and a near field wireless power and data transmission link. The external relay integrates a 32 bit low-power microcontroller with Bluetooth 4.0 wireless module, a programming interface, and an inductive charging unit. The SoC achieves high signal recording quality with minimized power consumption, while reducing the risk of infection from through-skin connectors. The external relay maximizes the compatibility and programmability. The proposed compressed sensing module is highly configurable, featuring a SNDR of 9.78 dB with a compression ratio of 8×. The SoC has been fabricated in a 180 nm standard CMOS technology, occupying 2.1 mm × 0.6 mm silicon area. A pre-implantable system has been assembled to demonstrate the proposed paradigm. The developed system has been successfully used for long-term wireless neural recording in freely behaving rhesus monkey.

RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders.

Objective: This paper describes a low power closed-loop compressive sensing (CS) based neural recording system. This system provides an efficient method to reduce data transmission bandwidth for implantable neural recording devices. By doing so, this technique reduces a majority of system power consumption which is dissipated at data readout interface. The design of the system is scalable and is a viable option for large scale integration of electrodes or recording sites onto a single device., Approach: The entire system consists of an application-specific integrated circuit (ASIC) with 4 recording readout channels with CS circuits, a real time off-chip CS recovery block and a recovery quality evaluation block that provides a closed feedback to adaptively adjust compression rate. Since CS performance is strongly signal dependent, the ASIC has been tested in vivo and with standard public neural databases., Main Results: Implemented using efficient digital circuit, this system is able to achieve >10 times data compression on the entire neural spike band (500-6KHz) while consuming only 0.83uW (0.53 V voltage supply) additional digital power per electrode. When only the spikes are desired, the system is able to further compress the detected spikes by around 16 times. Unlike other similar systems, the characteristic spikes and inter-spike data can both be recovered which guarantes a >95% spike classification success rate. The compression circuit occupied 0.11mm(2)/electrode in a 180nm CMOS process. The complete signal processing circuit consumes <16uW/electrode., Significance: Power and area efficiency demonstrated by the system make it an ideal candidate for integration into large recording arrays containing thousands of electrode. Closed-loop recording and reconstruction performance evaluation further improves the robustness of the compression method, thus making the system more practical for long term recording.

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end., (© 2015 American Academy of Neurology.)

Here, we present the draft genome sequence of Aeromonas caviae strain L12, which shows quorum-sensing activity. The availability of this genome sequence is important to the research of the quorum-sensing regulatory system in this isolate., (Copyright © 2015 Chan et al.)

Background: In the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data., Objective: To use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon β-1a (IFNβ-1a IM) 30 μg/mL once weekly to oral fingolimod 0.5 or 1.25mg once daily vs. remaining on IFNβ-1a IM., Methods: Post hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time., Results: Log-linear regression model results showed that fingolimod 0.5 and 1.25mg prolonged time to relapse, with an estimated median time to first relapse of 5.07 years (P=0.0026 vs. IFNβ-1a IM) and 4.11 years (P=0.0113), respectively, versus 2.26 years with IFNβ-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNβ-1a IM was 2.09 (95% CI, 1.45-3.04) for switching to fingolimod 0.5mg and 1.84 (95% CI, 1.30-2.65) for switching to fingolimod 1.25mg., Conclusion: During the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNβ-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data., (Copyright © 2015. Published by Elsevier Inc.)

Widely utilized in the field of Neuroscience, implantable neural recording devices could capture neuron activities with an acquisition rate on the order of megabytes per second. In order to efficiently transmit neural signals through wireless channels, these devices require compression methods that reduce power consumption. Although recent Compressed Sensing (CS) approaches have successfully demonstrated their power, their full potential is yet to be explored. Built upon our previous on-chip CS implementation, we propose an energy efficient multi-mode CS framework that focuses on improving the off-chip components, including (i) a two-stage sensing strategy, (ii) a sparsifying dictionary directly using data, (iii) enhanced compression performance from Full Signal CS mode and Spike Restoration mode to Spike CS + Restoration mode and; (iv) extension of our framework to the Tetrode CS recovery using joint sparsity. This new framework achieves energy efficiency, implementation simplicity and system flexibility simultaneously. Extensive experiments are performed on simulation and real datasets. For our Spike CS + Restoration mode, we achieve a compression ratio of 6% with a reconstruction SNDR > 10 dB and a classification accuracy > 95% for synthetic datasets. For real datasets, we get a 10% compression ratio with  ∼  10 dB for Spike CS + Restoration mode.

Objective: To report on the diagnosis and management of Müllerian adenosarcoma of the uterine cervix at a gynecologic oncology unit in Singapore., Methods: Nine cases (1992-2008) were identified from the unit registry. All hospital records were retrospectively analyzed., Results: Mean age at diagnosis was 45±12 years (range, 17-61 years). Presenting symptoms were abnormal vaginal bleeding (5 [55.6%] patients), introital mass (3 [33.3%] patients), and foul-smelling vaginal discharge (1 [11.1%] patient). Two (22.2%) patients were asymptomatic, with cervical polyps discovered incidentally on routine gynecologic check-up. All women had benign-looking cervical polyps and underwent polypectomy. Histology showed increased stromal cellularity with periglandular cuffs in all patients, and heterologous differentiation in 1(11.1%) patient. All 9 women had FIGO stage 1B disease. Seven (77.8%) patients underwent radical hysterectomy with bilateral adnexectomy and pelvic lymphadenectomy. One (11.1%) woman underwent cervical wedge resection and 1 (11.1%) refused definitive surgery. There was no recurrence in the 6 patients for whom complete follow-up data were available., Conclusion: Clinical diagnosis of Müllerian adenosarcoma of the uterine cervix may be challenging owing to the benign gross appearance of the cervical polyps. Surgery provides a good chance of cure with no recurrence., (Copyright © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

We report a newborn baby girl with acute dengue due to vertical transmission. A 31 year old factory worker of 38+ week gestation, gravida 5 para 3+1, developed acute dengue fever two days prior to delivery. She delivered a normal term baby girl by spontaneous vaginal delivery and recovered uneventfully without peripartum haemorrhage despite the presence of thrombocytopenia. The baby girl developed low grade fever on day four of post-natal life and except for the transient thrombocytopenia, also recovered uneventfully following three days of mild illness. The clinical diagnosis of acute dengue virus infection was confirmed by laboratory tests.

Purpose: Analyze determinates of employment changes from before to 2 years after surgery in refractory focal epilepsy patients., Methods: Preoperative employment was prospectively assessed in 375 adults with refractory epilepsy. Two-year postsurgical employment status was obtained for 299; factors potentially associated with employment status change among subgroups unemployed and employed at baseline were analyzed., Results: Presurgical employment status was full-time (n = 148, 39.5%), part-time (n = 26, 6.9%), disabled and unemployed (n = 100, 26.7%), unemployed (n = 44, 11.7%), and other (n = 57, 15.2%). Those with and without 2-year follow-up did not differ on baseline characteristics (all p > 0.10). Two years after surgery, 42.8% were employed full-time and 12.4%, part-time. Among those unemployed before surgery, better seizure outcome was associated with gaining employment at 2 years (p = 0.03)., Conclusions: Net employment gains were modest 2 years after surgery and higher with better seizure outcomes, reinforcing the need for optimizing surgical candidate selection, long-term follow-up studies, and postsurgical vocational rehabilitation.

Objective: The objective of the study was to compare the effectiveness of bedside test kits for pIGFBP-1 and fetal fibronectin test in predicting preterm delivery., Materials and Methods: Patients presenting with symptoms of preterm labour between 24 and 34 weeks of gestation were recruited. Both pIGFBP-1 and fetal fibronectin bedside tests were performed. Managing obstetricians and patients were blinded to the pIGFBP-1 and fetal fibronectin results. Tocolysis and steroid therapy were administered to all the recruited patients. Outcome data were collected after delivery., Results: One hundred and eight patients were recruited into the study. Fourteen patients had to be excluded from the final analysis due to incomplete data and failure to meet inclusion criteria. Ninety-four patients had complete data for analysis. Among those with negative pIGFBP-1 and fetal fibronectin results, the median [+/-standard deviation (SD)] gestational age at delivery was 37.4 weeks (+/-2.8 weeks) and 37.4 weeks (+/-2.1 weeks), respectively. Among those with positive pIGFBP-1 and fetal fibronectin results, the median (+/-SD) gestational age at delivery was 32.9 weeks (+/-4.0 weeks) and 34.2 weeks (+/-4.2 weeks), respectively (P <0.001 for both pIGFBP-1 and fetal fibronectin). A positive result with either test was associated with a significantly reduced admission-to-delivery interval. The median admission-to-delivery interval was 2.8 weeks shorter in the group with positive pIGFBP-1 results compared to those with a negative pIGFBP-1 result (2.3 weeks compared with 5.1 weeks) (P <0.001). This is 1.8 weeks shorter in the group with positive fibronectin results, compared to those with a negative result (3.3 weeks compared with 5.1 weeks) (P=0.002). Both pIGFBP-1 and fetal fibronectin tests have high negative predictive value (NPV) in predicting risk of delivery within 48 hours, 7, or 14 days (1.00; 0.92; 0.92 and 0.97; 0.89; 0.89, respectively)., Conclusions: Both pIGFBP-1 and fetal fibronectin tests are effective adjuvant bedside test kits for the prediction of preterm delivery in patients presenting with signs or symptoms of preterm labour. pIGFBP-1 has the higher NPV of 1.00 in predicting risk of delivery within 48 hours.

Aims: In Malaysia, about 4.5% of the Malay and Chinese populations are heterozygous carriers of beta-thalassaemia. The initial identification of rare beta-globin gene mutations by genomic sequencing will allow the development of simpler and cost-effective PCR-based techniques to complement the existing amplification refractory mutation system (ARMS) and gap-PCR used for the identification of beta-thalassaemia mutations., Methods: DNA from 173 beta-thalassaemia carriers and five beta-thalassaemia major patients from the Malay, Chinese and Indian ethnic groups were first analysed by ARMS and gap-PCR. Ninety-five per cent (174/183) of the 183 beta-globin genes studied were characterised using these two techiques. The remaining nine uncharacterised beta-globin genes (4.9%) were analysed using genomic sequencing of a 904 bp amplified PCR product consisting of the promoter region, exon 1, intervening sequence (IVS) 1, exon 2 and the 5' IVS2 regions of the beta-globin gene., Results: The rare beta-globin mutations detected in the Chinese patients were CD27/28 (+C) and CD43 (GAG-TAG), and -88 (C-T) in an Indian patient. Beta-globin mutations at CD16 (-C), IVS1-1 (G-A), IVS2-1 (G-A), -86 (C-G) and Haemoglobin South Florida (CD1, GTG-ATG) were confirmed in the Malay patients., Conclusions: The seven rare beta-globin mutations and a rare haemoglobin variant confirmed in this study have been described in other populations but have not been previously described in Malaysian beta-thalassemia patients.

Focal physical signs may occur with generalized seizures. The authors retrospectively reviewed video-EEG studies of 20 patients with apparent primary generalized epilepsy to assess the frequency of head version during generalized tonic-clonic seizures. Five patients (25%) demonstrated forced head version, including two with turning to the right and left on consecutive seizures. Forced head turning can occur in generalized epilepsy and may not necessarily indicate focal seizure origin.