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Abstract The Maintenance of Wakefulness Test (MWT) is a widely accepted objective test used to evaluate daytime somnolence and is commonly used in clinical studies evaluating novel therapeutics for excessive daytime sleepiness. In the latter, sleep onset latency (SOL) is typically the sole MWT endpoint. Here, we explored microsleeps, sleep probability measures derived from automated sleep scoring, and quantitative electroencephalography (qEEG) features as additional MWT biomarkers of daytime sleepiness, using data from a phase 1B trial of the selective orexin receptor 2 agonist danavorexton (TAK-925) in people with narcolepsy type 1 (NT1) or type 2 (NT2). Danavorexton treatment reduced the rate and duration of microsleeps during the MWT in NT1 (days 1 and 7; p ≤ .005) and microsleep rate in NT2 (days 1 and 7; p < .0001). The use of an EEG-sleep-staging − derived measure to determine the probability of wakefulness for each minute revealed a novel metric to track changes in daytime sleepiness, which were consistent with the θ/α ratio, a known biomarker of drowsiness. The slopes of line-fits to both the log-transformed sleepiness score or log-transformed θ/α ratio correlated well to (inverse) MWT SOL for NT1 (R = 0.93 and R = 0.83, respectively) and NT2 (R = 0.97 and R = 0.84, respectively), suggesting that individuals with narcolepsy have increased sleepiness immediately after lights-off. These analyses demonstrate that novel EEG-based biomarkers can augment SOL as predictors of sleepiness and its response to treatment and provide a novel framework for the analysis of wake EEG in hypersomnia disorders. Graphical Abstract Graphical Abstract

To store, analyse and process the large volume of data generated by IoT traditional cloud computing, is used everywhere. However, the traditional cloud data centres have their limitations to handle high latency issues in time-critical applications of IoT and cloud. Their applications are computer gaming, e-healthcare, telemedicine and robot surgery. The high latency in IoTs and cloud includes high computational, communication latency (service) and network latencies. The vital requirement of IoT is to have minimum network, service and computation latencies for real-time applications. Network latency causes a delay in transmitting a message or communication from one location to another. Services that require data in real-time are almost impossible to access the data via the cloud. Traditional cloud computing approaches are unable to fulfil the quality-of-service (QoS) requirements in IoT devices. Researches related to latency reduction techniques are still in infancy. Some new approaches to minimize the latency for transmitting time-sensitive data in real-time are discussed in this paper for cloud and IoT devices. This research will help the researchers and industries to identify the techniques and technologies to minimize the latencies in IoT and cloud. The paper also discusses the research trends and the technical differences between the various technologies and techniques. With the increasing interest in the literature on latency minimization and its requirements for time-sensitive applications; it is important to systematically review and synthesize the approaches, tools, challenges and techniques to minimize latencies in IoT and cloud. This paper aims at systematically reviewing the state of the art of latency minimization to classify approaches, and techniques. The paper uses a PRISMA technique for a systematic review. The paper further identifies challenges and gaps in this regard for future research. We have identified 23 approaches and 32 technologies associated with latencies in the cloud and IoT. A total of 112 papers on latency reduction have been examined under this study. The existing research gaps and works for latency reduction in IoTs are discussed in detail. There are several challenges and gaps, which requires future research work for improving the latency minimization techniques and technologies. Finally, we present some open issues which will determine the future research direction.

Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The ‘shock and kill’ approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4+ T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs. non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of ‘shock and kill’, and suggest the need to explore other strategies to control the latent HIV reservoir.

Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.

Scientific knowledge evolves in small steps, with occasional backsteps to correct inaccuracies, all occurring within a competitive environment. This perspective for the first time looks at the history of latency-related RNA (LR-RNA) that was later renamed latency-associated transcript (LAT). At the 1986 International Herpesvirus Workshop (IHW) meeting in Leeds, England, Daniel L Rock and Anthony B Nesburn first reported the discovery of human herpes virus 1 (HSV-1) latency-related (LR) RNA that is antisense to ICP0. Less than a month after the IHW meeting, a paper was submitted to Science magazine and 8 months later appeared in print thanking “D. Rock for suggesting RNA complementary to the ICP0 message may be present in latently infected cells”. This perspective is not a review of the LAT literature but intends to clarify the timeline of LAT discovery and subsequent breakthroughs such as reactivation, apoptosis, CD8+ T cell exhaustion, and LAT expression in different cell types detected during latency. While many review articles have been written about LAT since 1987, the most comprehensive and balanced review about LAT was written by Dr. David Bloom’s group. In this overview, I will discuss our original collaboration with Dr. Dan Rock and subsequent work that our group performed, which is still ongoing. Finally, I will discuss the controversies associated with LAT from its inception to current times.

In this phase 2 randomized, placebo-controlled trial involving 112 participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks.

Optical imaging is commonly used for both scientific and technological applications across industry and academia. In image sensing, a measurement, such as of an object’s position or contour, is performed by computational analysis of a digitized image. An emerging image-sensing paradigm relies on optical systems that—instead of performing imaging—act as encoders that optically compress images into low-dimensional spaces by extracting salient features; however, the performance of these encoders is typically limited by their linearity. Here we report a nonlinear, multilayer optical neural network (ONN) encoder for image sensing based on a commercial image intensifier as an optical-to-optical nonlinear activation function. This nonlinear ONN outperforms similarly sized linear optical encoders across several representative tasks, including machine-vision benchmarks, flow-cytometry image classification and identification of objects in a three-dimensionally printed real scene. For machine-vision tasks, especially those featuring incoherent broadband illumination, our concept allows for a considerable reduction in the requirement of camera resolution and electronic post-processing complexity. In general, image pre-processing with ONNs should enable image-sensing applications that operate accurately with fewer pixels, fewer photons, higher throughput and lower latency.A nonlinear optical neural network image sensor based on an image intensifier enables efficient all-optical image encoding for a variety of machine-vision tasks.

HIV‐1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV‐1 infection, but its role in the development and maintenance of HIV‐1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV‐1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD + /NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV‐1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV‐1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV‐1 latency that can be exploited to target latently infected cells with eradication strategies. SYNOPSIS The upregulation of glycolysis in activated cells favors HIV‐1 infection and initial viral replication. This study discovers that, to transit into a latent form, which can shield the virus from immunity and antiretroviral drugs, HIV‐1 needs to downregulate glycolysis. Restoration of glycolytic activity is required for HIV‐1 reactivation from latency. Latently infected cells rely on pentose phosphate metabolism and its downstream effectors, i.e., the antioxidant glutathione and thioredoxin pathways, for their survival. Preferential targeting of latently infected cells with drugs inhibiting thioredoxin and glutathione pathways leads to both HIV‐1 reactivation from latency and death of infected cells. Graphical Abstract The upregulation of glycolysis in activated cells favors HIV‐1 infection and initial viral replication. This study discovers that, to transit into a latent form, which can shield the virus from immunity and antiretroviral drugs, HIV‐1 needs to downregulate glycolysis.