HIV gene expression from intact proviruses positioned in bacterial artificial chromosomes at integration sites previously identified in latently infected T cells

AbstractHIV integration predominantly occurs in introns of transcriptionally active genes. To study the impact of the integration site on HIV gene expression, a complete HIV-1 provirus (with GFP as a fusion with Nef) was inserted into bacterial artificial chromosomes (BACs) at three sites previously identified in latent T cells of patients: topoisomerase II (Top2A), DNA methyltransferase 1 (DNMT1), or basic leucine transcription factor 2 (BACH2). Transfection of BAC-HIV into 293T cells resulted in a fourfold difference in production of infectious HIV-1. Cell lines were established that contained BAC–Top2A, BAC–DNMT1, or BAC–BACH2, but only BAC–DNMT1 spontaneously produced virus, albeit at a low level. Stimulation with TNF-α resulted in virus production from four of five BAC–Top2A and all BAC–DNMT1 cell lines, but not from the BAC–BACH2 lines. The results of these studies highlight differences between integration sites identified in latent T cells to support virus production and reactivation from latency

Lesions of the ventral hippocampus attenuate the acquisition but not expression of sign‐tracking behavior in rats

Individual variation in the attribution of motivational salience to reward‐related cues is believed to underlie addiction vulnerability. Pavlovian conditioned approach measures individual variation in motivational salience by identifying rats that are attracted to and motivated by reward cues (sign‐trackers) or motivationally fixed on the reward itself (goal‐trackers). Previously, it has been demonstrated that sign‐trackers are more vulnerable to addiction‐like behavior. Moreover, sign‐trackers release more dopamine in the nucleus accumbens than goal‐trackers in response to reward‐related cues, and sign‐ but not goal‐tracking behavior is dopamine‐dependent. In the present study, we investigated whether the ventral hippocampus, a potent driver of dopaminergic activity in the nucleus accumbens, modulates the acquisition and expression of Pavlovian conditioned approach behavior. In Experiment 1, lesions of the ventral, but not dorsal or total hippocampus, decreased sign‐tracking behavior. In Experiment 2, lesions of the ventral hippocampus did not affect the expression of sign‐ or goal‐tracking behaviors nor conditioned reinforcement. In addition, temporary inactivation of the ventral subiculum, the main output pathway of the ventral hippocampus, did not affect the expression of sign‐ or goal‐tracking behaviors. High‐pressure liquid chromatography of nucleus accumbens tissue punches revealed that ventral hippocampal lesions decreased levels of homovanillic acid and the homovanillic acid/dopamine ratio (a marker of dopamine release and metabolism) in only sign‐trackers, and decreased accumbal norepinephrine levels in both sign‐ and goal‐trackers. These results suggest that the ventral hippocampus is important for the acquisition but not expression of sign‐tracking behavior, possibly as a result of altered dopamine and norepinephrine in the nucleus accumbens. © 2016 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134415/1/hipo22619.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134415/2/hipo22619_am.pd

Critical care triage during the COVID-19 pandemic in South Africa: A constitutional imperative!

Triage and rationing of scarce intensive care unit (ICU) resources are an unavoidable necessity. In routine circumstances, ICU triage is premised on the best interests of an individual patient; however, when increased demand exceeds capacity, as during an infectious disease outbreak, healthcare providers need to make difficult decisions to benefit the broader community while still respecting individual interests. We are currently living through an unprecedented period, with South Africa (SA) facing the challenges of the global COVID-19 pandemic. The Critical Care Society of Southern Africa (CCSSA) expedited the development of a triage guidance document to inform the appropriate and fair use of scarce ICU resources during this pandemic. Triage decision-making is based on the clinical odds of a positive ICU outcome, balanced against the risk of mortality and longer-term morbidity affecting quality of life. Factors such as age and comorbid conditions are considered for their potential impact on clinical outcome, but are never the sole criteria for denying ICU-level care. Arbitrary, unfair discrimination is never condoned. The CCSSA COVID-19 triage guideline is aligned with SA law and international ethical standards, and upholds respect for all persons. The Bill of Rights, however, does not mandate the level of care enshrined in the constitutional right to healthcare. ICU admission is not always appropriate, available or feasible for every person suffering critical illness or injury; however, everyone has the right to receive appropriate healthcare at another level. If ICU resources are used for people who do not stand to benefit, this effectively denies others access to potentially life-saving healthcare. Appropriate triaging can therefore be considered a constitutional imperative

Memory and comprehension for health information among older adults: distinguishing the effects of domain-general and domain-specific knowledge

While there is evidence that knowledge influences understanding of health information, less is known about the processing mechanisms underlying this effect and its impact on memory. We used the moving window paradigm to examine how older adults varying in domain-general crystallised ability (verbal ability) and health knowledge allocate attention to understand health and domain-general texts. Participants (n = 107, age: 60-88 years) read and recalled single sentences about hypertension and about non-health topics. Mixed-effects modelling of word-by-word reading times suggested that domain-general crystallised ability increased conceptual integration regardless of text domain, while health knowledge selectively increased resource allocation to conceptual integration at clause boundaries in health texts. These patterns of attentional allocation were related to subsequent recall performance. Although older adults with lower levels of crystallised ability were less likely to engage in integrative processing, when they did, this strategy had a compensatory effect in improving recall. These findings suggest that semantic integration during reading is an important comprehension process that supports the construction of the memory representation and is engendered by knowledge. Implications of the findings for theories of text processing and memory as well as for designing patient education materials are discussed

Rats that sign-track are resistant to Pavlovian but not instrumental extinction

Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward

Laws relating runs, long runs, and steps in gambler's ruin, with persistence in two strata

Define a certain gambler's ruin process \mathbf{X}_{j}, \mbox{ \ }j\ge 0, such that the increments $\varepsilon_{j}:=\mathbf{X}_{j}-\mathbf{X}_{j-1}$ take values $\pm1$ and satisfy $P(\varepsilon_{j+1}=1|\varepsilon_{j}=1, |\mathbf{X}_{j}|=k)=P(\varepsilon_{j+1}=-1|\varepsilon_{j}=-1,|\mathbf{X}_{j}|=k)=a_k$, all $j\ge 1$, where $a_k=a$ if $0\le k\le f-1$, and $a_k=b$ if $f\le k<N$. Here $0<a, b <1$ denote persistence parameters and $f ,N\in \mathbb{N}$ with $f<N$. The process starts at $\mathbf{X}_0=m\in (-N,N)$ and terminates when $|\mathbf{X}_j|=N$. Denote by ${\cal R}'_N$, ${\cal U}'_N$, and ${\cal L}'_N$, respectively, the numbers of runs, long runs, and steps in the meander portion of the gambler's ruin process. Define $X_N:=\left ({\cal L}'_N-\frac{1-a-b}{(1-a)(1-b)}{\cal R}'_N-\frac{1}{(1-a)(1-b)}{\cal U}'_N\right )/N$ and let $f\sim\eta N$ for some $0<\eta <1$. We show $\lim_{N\to\infty} E\{e^{itX_N}\}=\hat{\varphi}(t)$ exists in an explicit form. We obtain a companion theorem for the last visit portion of the gambler's ruin.Comment: Presented at 8th International Conference on Lattice Path Combinatorics, Cal Poly Pomona, Aug., 2015. The 2nd version has been streamlined, with references added, including reference to a companion document with details of calculations via Mathematica. The 3rd version has 2 new figures and improved presentatio

Functional changes in prefrontal cortex following frequency-specific training

Altres ajuts: European ANR (COEN4007-18, COEN-0003-01); PHRC grants from the French Ministry of Health and research funding; France Parkinson and ARSLA charity.Numerous studies indicate a significant role of pre-frontal circuits (PFC) connectivity involving attentional and reward neural networks within attention deficit hyperactivity disorder (ADHD) pathophysiology. To date, the neural mechanisms underlying the utility of non-invasive frequency-specific training systems in ADHD remediation remain underexplored. To address this issue, we created a portable electroencephalography (EEG)-based wireless system consisting of a novel headset, electrodes, and neuro program, named frequency specific cognitive training (FSCT). In a double-blind, randomized, controlled study we investigated the training effects in N = 46 school-age children ages 6-18 years with ADHD. 23 children in experimental group who underwent FCST training showed an increase in scholastic performance and meliorated their performance on neuropsychological tests associated with executive functions and memory. Their results were compared to 23 age-matched participants who underwent training with placebo (pFSCT). Electroencephalogram (EEG) data collected from participants trained with FSCT showed a significant increase in 14-18 Hz EEG frequencies in PFC brain regions, activities that indicated brain activation in frontal brain regions, the caudate nucleus, and putamen. These results demonstrate that FSCT targets specific prefrontal and striatal areas in children with ADHD, suggesting a beneficial modality for non-invasive modulation of brain areas implicated in attention and executive functions