Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the
antiviral activity of remdesivir in a cobicistat-like manner. When administered
to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19.
The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.
Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained.
...Six-hundred-and-seventy-one patients (299 males; 55 ± 22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3 min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3 min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively.
Higher resting CT-proET-1 predicted BP fall at 3 min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18-2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28-2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3 min (1.33, 1.03-1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38-2.51; p = 0.00005) and epinephrine (1.47, 1.12-1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3 min (0.37, 0.24-0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29-0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15-2.21; p = 0.005), and norepinephrine (1.87, 1.38-2.53; p = 0.005).
Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.
RoboCup simulated soccer presents many challenges to reinforcement learning methods, including a large state space, hidden and uncertain state, multiple independent agents learning simultaneously, ...and long and variable delays in the effects of actions. We describe our application of episodic SMDP Sarsa(λ) with linear tile-coding function approximation and variable λ to learning higher-level decisions in a keepaway subtask of RoboCup soccer. In keepaway, one team, “the keepers,” tries to keep control of the ball for as long as possible despite the efforts of “the takers.” The keepers learn individually when to hold the ball and when to pass to a teammate. Our agents learned policies that significantly outperform a range of benchmark policies. We demonstrate the generality of our approach by applying it to a number of task variations including different field sizes and different numbers of players on each team.
We studied whether comorbid conditions affect strength and duration of immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccination in a US-based, ...adult population.
Sera (before and after BNT162b2 vaccination) were tested serially up to 12 months after 2 doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Postbooster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects, respectively.
After completion of primary vaccine series, neutralizing antibody half maximal inhibitory concentration (IC50) values were high at 1 month (14-fold increase from prevaccination), declined at 6 months (3.3-fold increase), and increased at 1 month postbooster (41.5-fold increase). Three months postbooster, IC50 decreased in coronavirus disease (COVID)-naïve individuals (18-fold increase) and increased in prior COVID 2019 (COVID-19+) individuals (132-fold increase). Age >65 years (β = -0.94, P = .001) and malignancy (β = -0.88, P = .002) reduced strength of response at 1 month. Both neutralization strength and durability at 6 months, respectively, were negatively affected by end-stage renal disease (β = -1.10, P = .004; β = -0.66, P = .014), diabetes mellitus (β = -0.57, P = .032; β = -0.44, P = .028), and systemic steroid use (β = -0.066, P = .032; β = -0.55, P = .037). Postbooster IC50 was robust against WA-1 and B.1.617.2. Postbooster neutralization increased with prior COVID-19 (β = 2.9, P < .0001), and malignancy reduced neutralization response (β = -0.68, P = .03), regardless of infection status.
Multiple clinical factors affect the strength and duration of neutralization response after primary series vaccination, but not the postbooster dose strength. Malignancy was associated with lower booster-dose response regardless of prior COVID infection, suggesting a need for clinically guided vaccine regimens.
RNA viruses are sensed by RIG-I-like receptors (RLRs), which signal through a mitochondria-associated adaptor molecule, MAVS, resulting in systemic antiviral immune responses. Although RLR signaling ...is essential for limiting RNA virus replication, it must be stringently controlled to prevent damage from inflammation. We demonstrate here that among all tested UBX-domain-containing protein family members, UBXN1 exhibits the strongest inhibitory effect on RNA-virus-induced type I interferon response. UBXN1 potently inhibits RLR- and MAVS-induced, but not TLR3-, TLR4-, or DNA-virus-induced innate immune responses. Depletion of UBXN1 enhances virus-induced innate immune responses, including those resulting from RNA viruses such as vesicular stomatitis, Sendai, West Nile, and dengue virus infection, repressing viral replication. Following viral infection, UBXN1 is induced, binds to MAVS, interferes with intracellular MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. These findings underscore a critical role of UBXN1 in the modulation of a major antiviral signaling pathway.
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► UBXN1 inhibits RNA-virus-induced immune response ► Depletion of UBXN1 enhances immune response to RNA virus infection ► UBXN1 is induced and recruited to MAVS after viral infection ► UBXN1 specifically disrupts the MAVS-TRAF3/6 signalosome
Humans are equipped with pattern-recognition receptors such as RIG-I-like receptors (RLRs) for recognizing invading viruses and initiating systemic antiviral immune responses. Although RLR signaling is essential for limiting infection, it must be stringently controlled to prevent damage from inflammation. Sutton and colleagues demonstrate that UBXN1 serves as a brake to prevent excessive RLR signaling, probably at late stages of viral infection. Its action may help avoid cell death and tissue destruction due to hyperimmune responses without compromising necessary antiviral immunity.
Abstract Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current ...studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000 mg/kg, i.p.) or ethyl pyruvate (EP; 40 mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24 h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24 h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6 h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24 h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1 day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40 mg/kg of EP being as effective as 1000 mg/kg of SP, and multiple treatments within 6 h of injury did not improve upon outcomes seen following a single treatment.
Background Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive heart rate increase on standing and orthostatic intolerance. Previous data indicate autoimmune involvement. ...We studied serum activity against G protein-coupled receptors in relation to symptoms in patients with POTS and controls using a commercial cell-based assay. Methods and Results Forty-eight patients with POTS (aged 28.6±10.5 years; 44 women) and 25 healthy individuals (aged 30.7±8.6 years; 21 women) were included. The 10-item Orthostatic Hypotension Questionnaire (OHQ) was completed by 33 patients with POTS and all controls. Human embryonic kidney 293 cells overexpressing one G protein-coupled receptor: adrenergic α
receptor, adrenergic β
receptor, cholinergic muscarinic type 2 receptor, and opioid receptor-like 1 were treated with sera from all patients. Receptor response was analyzed using a β-arrestin-linked transcription factor driving transgenic β-lactamase transcription by fluorescence resonance energy transfer method. Receiver operating characteristic curves were constructed. G protein-coupled receptor activation was related to OHQ indices in linear regression models. Sera from patients with POTS activated all 4 receptors to a higher degree compared with controls (
<0.01 for all). The area under the curve was 0.88 (0.80-0.97,
<0.001) combining all 4 receptors. Adrenergic α
receptor activation associated with OHQ composite score (β=0.77 OHQ points per SD of activity,
=0.009) and with reduced tolerability for prolonged standing (
=0.037) and walking for short (
=0.042) or long (
=0.001) periods. All 4 receptors were associated with vision problems (
<0.05 for all). Conclusions Our results indicate the presence of circulating proteins activating adrenergic, muscarinic, and nociceptin receptors in patients with POTS. Serum-mediated activation of these receptors has high predictive value for POTS. Activation of adrenergic α
receptor is associated with orthostatic symptoms severity in patients with POTS.
CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 ...expression in HIV
viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4
T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4
T cells were relatively resistant, specifically to R5-tropic HIV infection. Furthermore, single JAK2, STAT3, STAT5A, and STAT5B knockout and different combinations of JAK/STAT knockout significantly reduced CCR2/CCR5 expression of both RNA and protein levels, indicating that CCR5/CCR2 expression was positively regulated by JAK-STAT pathway in CD4
T cells. Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout affected CCR2/CCR5 gene expression, suggesting that SGK1 is involved in CCR2/CCR5 regulation. If cell surface CCR5 levels can be specifically and markedly down-regulated without adverse effects, that may have a major impact on the HIV cure agenda.
Learning, planning, and representing knowledge at multiple levels of temporal abstraction are key, longstanding challenges for AI. In this paper we consider how these challenges can be addressed ...within the mathematical framework of reinforcement learning and Markov decision processes (MDPs). We extend the usual notion of action in this framework to include options—closed-loop policies for taking action over a period of time. Examples of options include picking up an object, going to lunch, and traveling to a distant city, as well as primitive actions such as muscle twitches and joint torques. Overall, we show that options enable temporally abstract knowledge and action to be included in the reinforcement learning framework in a natural and general way. In particular, we show that options may be used interchangeably with primitive actions in planning methods such as dynamic programming and in learning methods such as Q-learning. Formally, a set of options defined over an MDP constitutes a semi-Markov decision process (SMDP), and the theory of SMDPs provides the foundation for the theory of options. However, the most interesting issues concern the interplay between the underlying MDP and the SMDP and are thus beyond SMDP theory. We present results for three such cases: (1) we show that the results of planning with options can be used during execution to interrupt options and thereby perform even better than planned, (2) we introduce new intra-option methods that are able to learn about an option from fragments of its execution, and (3) we propose a notion of subgoal that can be used to improve the options themselves. All of these results have precursors in the existing literature; the contribution of this paper is to establish them in a simpler and more general setting with fewer changes to the existing reinforcement learning framework. In particular, we show that these results can be obtained without committing to (or ruling out) any particular approach to state abstraction, hierarchy, function approximation, or the macro-utility problem.
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