Boundary cells in the representation of episodes in the human hippocampus

The representation of episodes is a fundamental requirement for forming episodic memories, but the specific electrophysiological mechanisms supporting episode construction in the human hippocampus remain unknown. Experiments in rodent models indicate that a population of neurons sensitive to edges of an environment, termed border or boundary neurons in spatial navigation, fulfills a role analogous to episode demarcation. We hypothesized that such boundary neurons could be identified in the human mesial temporal lobe, with firing rates sensitive specifically to the beginning and end of mnemonically-relevant episodes in the free recall task. Using a generalized linear model to control for factors such as encoding success and item onset times along with other variables, we found 44 Boundary neurons out of a total 736 single neurons recorded across 27 subjects. We distinguish boundary neurons from a separate population of ramping neurons, which are time-sensitive neurons whose activity provides complementary but distinct information during episodic representation. We also describe evidence that the firing of boundary neurons within the preferred windows (at the beginning and end of episodes) is organized by hippocampal theta oscillations, using spike-field coherence metrics.

Distinct threat and valence signals in rat nucleus accumbens core

Appropriate responding to threat and reward is essential to survival. The nucleus accumbens core (NAcc) is known to support and organize reward behavior. More recently our laboratory has shown the NAcc is necessary to discriminate cues for threat and safety. To directly reveal NAcc threat responding, we recorded single-unit activity from 7 female rats undergoing Pavlovian fear discrimination. Rats fully discriminated cues for danger, uncertainty, and safety. Demonstrating direct threat responding, most NAcc neurons showed greatest firing changes to danger and uncertainty. Heterogeneity in cue and reward firing led to the detection of multiple, functional populations. One NAcc population specifically decreased firing to threat (danger and uncertainty). A separate population bi-directionally signaled valence through firing decreases to negative valence events (danger and uncertainty) and opposing firing increases to positive valence events (reward and safety onset). The findings point to the NAcc as a neural source of threat information and a more general valence hub.

Fate mapping analysis reveals a novel murine dermal migratory Langerhans-like cell population

Dendritic cells residing in the skin represent a large family of antigen-presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single-cell RNA-sequencing, we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the lymph nodes (LNs). These LClike cells are long-lived and radio-resistant but, unlike LCs, they are gradually replenished by bone marrow-derived precursors under steady state. LClike cells together with cDC1s are the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which are barely detectable, if at all. Cutaneous tolerance to haptens depends on LClike cells, whereas LCs suppress effector CD8+ T-cell functions and inflammation locally in the skin during contact hypersensitivity. These findings bring new insights into the dynamism of cutaneous dendritic cells and their function opening novel avenues in the development of treatments to cure inflammatory skin disorders.

Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population

Dendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the LNs. These LClike cells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClike cells together with cDC1s were the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.

Widespread cis-regulation of RNA-editing in a large mammal

Post-transcriptional RNA editing may regulate transcript expression and diversity in cells, with potential impacts on various aspects of physiology and environmental adaptation. A small number of recent genome-wide studies in Drosophila, mouse, and human have shown that RNA editing can be genetically modulated, highlighting loci that quantitatively impact editing of transcripts. The potential gene expression and physiological consequences of these RNA editing quantitative trait loci (edQTL), however, are almost entirely unknown. Here, we present analyses of RNA editing in a large domestic mammal (Bos taurus), where we use whole genome and high depth RNA sequencing to discover, characterise, and conduct genetic mapping studies of novel transcript edits. Using a discovery population of nine deeply-sequenced cows, we identify 2,001 edit sites in the mammary transcriptome, the majority of which are adenosine to inosine edits (97.4%). Most sites are predicted to reside in double-stranded secondary structures (85.7%), and quantification of the rates of editing in an additional 355 cows reveals editing is negatively correlated with gene expression in the majority of cases. Genetic analyses of RNA editing and gene expression highlights 67 cis-regulated edQTL, of which seven appear to co-segregate with expression QTL effects. Trait association analyses in a separate population of 9,988 lactating cows also shows nine of the cis-edQTL coincide with at least one co-segregating lactation QTL. Together, these results enhance our understanding of RNA editing dynamics in mammals, and suggest mechanistic links by which loci may impact phenotype through RNA-editing mediated processes.

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

ABSTRACTTrimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistantStaphylococcus aureus(CA-MRSA) andPneumocystis jiroveciiinfections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/Fincreased with age. In addition, TMP and SMX CL/Fwere inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Paroxysmal Atrial Fibrillation in the Course of Acute Pulmonary Embolism: Clinical Significance and Impact on Prognosis

The relationship and clinical implications of atrial fibrillation (AF) in acute pulmonary embolism (PE) are poorly investigated. We aimed to analyze clinical characteristics and prognosis in PE patients with paroxysmal AF episode. Methods. From the 391 patients with PE 31 subjects with paroxysmal AF were selected. This group was compared with patients with PE and sinus rhythm (SR) and 32 patients with PE and permanent AF. Results. Paroxysmal AF patients were the oldest. Concomitant DVT varies between groups: paroxysmal AF 32.3%, SR 49.5%, and permanent AF 28.1% (p=0.02). The stroke history frequency was 4.6% SR, 12.9% paroxysmal AF, and 21.9% permanent AF (p<0.001). Paroxysmal AF comparing to permanent AF and SR individuals had higher estimated SPAP (56 versus 48 versus 47 mmHg, p=0.01) and shorter ACT (58 versus 65 versus 70 ms, p=0.04). Patients with AF were more often classified into high-risk group according to revised Geneva score and sPESI than SR patients. In-hospital mortality was lower in SR (5%) and paroxysmal AF (6.5%) compared to permanent AF group (25%) (p<0.001). Conclusions. Patients with PE-associated paroxysmal AF constitute a separate population. More severe impairment of the parameters reflecting RV afterload may indicate relation between PE severity and paroxysmal AF episode. Paroxysmal AF has no impact on short-term mortality.

Perspectives in pediatric clinical trials: a review

<p class="abstract">Children are different from adults in many aspects of pharmacotherapy, including capacity to absorb, distribute, metabolize and excrete drugs and have their own taste preferences. International Conference on Harmonisation (ICH) guidelines classify pediatric age groups into five groups namely preterm, term new born infants, infants and toddlers, children and adolescents. United States conducts maximum number of pediatric drug trials as compared to developing countries. Most of the prescribed drugs are either unlicensed or have an off label use. That is these have not been evaluated for their safety and efficacy in children. As children are separate population entity and not mini-adults, these clinical trials with adults cannot be simply generalized or extrapolated to pediatric population. Thus it is mandatory to conduct clinical trials involving pediatric population in order to get full benefits to the children. To study this gap between adults and children for their wellbeing, disease prevention, diagnosis and treatment, high quality clinical trials are required<span lang="EN-US">.</span></p>

Staying well connected – Lithistid sponges on seamounts

Three species of lithistid sponges, Neoaulaxinia zingiberadix, Isabella mirabilis and Neoschrammeniella fulvodesmus were collected from deep seamounts off New Caledonia to address questions about their population structure, gene flow and the relative contribution of sexual and asexual reproductive strategies to their populations. The sponges were tested by sequencing the ITS (internal transcribed spacer) and CO1 regions of their genomes. These rare and presumably ancient sponges have a distribution restricted to seamounts in the south-western Pacific. Deep seamounts represent geographically separated islands. Although the sponges could be expected to have sexual reproduction restricted to near neighbours due to low sexual dispersal opportunities via larvae, this study found surprisingly high levels of gene flow between the seamounts. Amongst the specimens of N. zingiberadix taken from two seamounts there was no population structure; CO1 resulted in identical genotypes. For the population structure within N. fulvodesmus, as revealed by ITS, most of the variation was within each individual from the six seamounts on which it occurred and CO1 revealed no difference between individuals or seamounts. The third species I. mirabilis showed four genotypes based on CO1, which were distributed across all the seamounts. Indirect measures of different species showed a range of reproductive strategies from asexual to sexual, but with much higher connection between seamounts than previously thought. Individual seamounts did not show a separate population structure as one might expect from ‘islands’. The conclusion must be that these sponges have mechanisms to attain greater dispersal than previously thought.