Sex Differences in the Physiological Response to Ethanol of Rat Basolateral Amygdala Neurons Following Single-Prolonged Stress

Females are more likely to develop post-traumatic stress disorder (PTSD) than males. Also, symptoms of PTSD frequently precede alcohol abuse in females. Stressful, threat-related stimuli are evaluated by the amygdala, which is critical for establishing the emotional salience of environmental stimuli. Ethanol and stress have been shown to modify amygdala excitability, but effects of acute ethanol on neurons of the basolateral amygdala (BLA) in both males and females exposed to stress is unknown. The purpose of this study is to determine stress-induced changes in membrane properties of BLA neurons and to determine how ethanol modulates these changes in male and female rats. Whole-cell recordings were obtained from BLA neurons of both male and female rats exposed to single-prolonged stress (SPS). Neuronal excitability, quantified as the number of action potentials, was determined in current clamp mode by applying a series of depolarizing current steps. Hyperpolarization-activated current (Ih) was elicited in voltage clamp. Excitability and Ih amplitude were determined before and during the superfusion of ethanol (EtOH; 30 mM) in BLA neurons from SPS-treated male and female rats. SPS alone did not alter the firing properties of BLA neurons from either males or females. However, following SPS, BLA neurons from males and females respond differently to ethanol. Superfusion of EtOH (30 mM) inhibited spike firing in BLA neurons from rats exposed to SPS, and EtOH-induced inhibition was greater in females than in males exposed to stress. Also, EtOH (30 mM) selectively decreased Ih amplitude in BLA neurons from SPS-treated male rats from 171 ± 46 pA in (pre-EtOH) control to 53 ± 51 pA in the presence of EtOH (30 mM). EtOH did not reduce Ih in BLA neurons from SPS-treated females. Together, these suggest important sex differences in the physiological responses to EtOH in stress disorders such as PTSD, that have high comorbidity with alcohol use disorders

Trends in the utilization of medicines sold in the private sector post-registration in South Africa and the implications for similar countries

Background: Regulatory authorities register medicines for patients to access them within a reasonable period of time. There is a paucity of available data regarding the extent to which registered medicines reach the public after market authorisation is granted by the South African Health Products Regulatory Authority (SAHPRA). This is important since time spent by SAHPRA assessing medicines that are subsequently not launched onto the South African market means time wasted, which could be spent on assessing new medicines that address an unmet need in the country. Consequently, we initially analysed the time taken for registered medicines to reach patients and the relationship between medicines registered at SAHPRA and those subsequently dispensed in private pharmacies. The extent of registration of multiple sourced versus new patented medicines was also explored. Methods: A retrospective, descriptive and quantitative investigation was conducted for medicines registered between 2014 and 2019. Registered and dispensed medicines were compared to establish accessibility post registration. Data sources included SAHPRA and IQVIA datasets. Microsoft Excel and SAS were used for data storage, analysis, and computation of descriptive statistical analysis. Results: Of (N=2175) registered medicines, only 358 (16.5%; 95% CI 15.0% - 18.1%) were dispensed to patients, and out of 1735 medicines registered between 2015 and2019, only 57 (3.3%; 95% CI 2.5% - 4.2%) were dispensed during the study period. Medicines acting on the central nervous system were registered and dispensed the most at 21.0% and 18.0%, respectively, whereas antineoplastic and immunomodulation agents were registered and dispensed only 11% and 5%, respectively. A concern was that only 13.0% of registered medicines were originators, with most either as generics, including branded generics, or pseudo-generics. Conclusion: Regulatory measures should be implemented to ensure increased medicine access post-registration for new originators, especially for priority disease areas that benefit patients. Mental health diseases and improved access to oncology medicines require special attention and further investigation in South Africa

Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle

Our previous experiments demonstrated that systemic depletion of serotonin (5-hydroxytryptamine, 5-HT), similar to levels reported in patients with emotional disorders, enhanced glutamateric activity in the lateral nucleus of the amygdala (LA) and potentiated fear behaviors. However, the effects of isolated depletion of 5-HT in the LA, and the molecular mechanisms underlying enhanced glutamatergic activity are unknown. In the present study, we tested the hypothesis that depletion of 5-HT in the LA induces increased fear behavior, and concomitantly enhances glutamate receptor (GluR) expression. Bilateral infusions of 5,7-dihydroxytryptamine (4 μg per side) into the LA produced a regional reduction of serotonergic fibers, resulting in decreased 5-HT concentrations. The induction of low 5-HT in the LA elevated fear-potentiated startle, with a parallel increase in GluR1 mRNA and GluR1 protein expression. These findings suggest that low 5-HT concentrations in the LA may facilitate fear behavior through enhanced GluR-mediated mechanisms. Moreover, our data support a relationship between 5-HT and glutamate in psychopathologies

Tracing a Disk Wind in NGC 3516

X-ray spectra of AGN often contain signatures indicative of absorption in multiple layers of gas whose ionization-state and covering fraction may vary with time. It has been unclear to date how much of the observed X-ray spectral and timing behavior in AGN can be attributed to variations in absorption, versus variations in the strengths of emission or reflection components. Diagnostics of the inner regions of AGN cannot be reliably performed until the origin of observed effects is understood. We investigate the role of the X-ray absorbers in the Seyfert 1 galaxy NGC 3516. Time-averaged and flux-selected spectroscopy is used to examine the behavior of NGC 3516 observed in Chandra HETG and XMM data from Oct 2006. New H-like and He-like emission and absorption features discovered in the Fe K regime reveal a previously unknown zone of circumnuclear gas in NGC 3516 with log xi ~ 4.3 and column density 1E23 cm^-2. A lower-ionization layer with log xi ~2 and of similar column density is confirmed from previous observations, this layer has a covering fraction around 50%, and changes in covering provide a simple explanation of a deep dip in the light curve that we interpret as an eclipse of the continuum due to passage of a cloud across the sight line within half a day. These inner zones of absorbing gas are detected to have outflow velocities in the range 1000-2000 km/s, this, and constraints on radial location are consistent with an origin as part of a disk wind in NGC 3516.Comment: 10 pages, 8 figures, accepted by A&A Feb 26 2008 Version 2: Figs 1 & 2 were corrected for a problem with ACIS section of the data. Little impact on text of the pape

Evolutionary Relationships of Wild Hominids Recapitulated by Gut Microbial Communities

Although bacteria are continually acquired over the lifetime of an individual, the phylogenetic relationships of great ape species is mirrored in the compositions of their gut microbial communities

Conserved presence of G-quadruplex forming sequences in the Long Terminal Repeat Promoter of Lentiviruses

G-quadruplexes (G4s) are secondary structures of nucleic acids that epigenetically regulate cellular processes. In the human immunodeficiency lentivirus 1 (HIV-1), dynamic G4s are located in the unique viral LTR promoter. Folding of HIV-1 LTR G4s inhibits viral transcription; stabilization by G4 ligands intensifies this effect. Cellular proteins modulate viral transcription by inducing/unfolding LTR G4s. We here expanded our investigation on the presence of LTR G4s to all lentiviruses. G4s in the 5'-LTR U3 region were completely conserved in primate lentiviruses. A G4 was also present in a cattle-infecting lentivirus. All other non-primate lentiviruses displayed hints of less stable G4s. In primate lentiviruses, the possibility to fold into G4s was highly conserved among strains. LTR G4 sequences were very similar among phylogenetically related primate viruses, while they increasingly differed in viruses that diverged early from a common ancestor. A strong correlation between primate lentivirus LTR G4s and Sp1/NF\u3baB binding sites was found. All LTR G4s folded: their complexity was assessed by polymerase stop assay. Our data support a role of the lentiviruses 5'-LTR G4 region as control centre of viral transcription, where folding/unfolding of G4s and multiple recruitment of factors based on both sequence and structure may take place

Cue properties change timing strategies in group movement synchronisation

To maintain synchrony in group activities, each individual within the group must continuously correct their movements to remain in time with the temporal cues available. Cues might originate from one or more members of the group. Current research suggests that when synchronising movements, individuals optimise their performance in terms of minimising variability of timing errors (asynchronies) between external cues and their own movements. However, the cost of this is an increase in the timing variability of their own movements. Here we investigate whether an individual’s timing strategy changes according to the task, in a group scenario. To investigate this, we employed a novel paradigm that positioned six individuals to form two chains with common origin and termination on the circumference of a circle. We found that participants with access to timing cues from only one other member used a strategy to minimise their asynchrony variance. In contrast, the participant at the common termination of the two chains, who was required to integrate timing cues from two members, used a strategy that minimised movement variability. We conclude that humans are able to flexibly switch timekeeping strategies to maintain task demands and thus optimise the temporal performance of their movements

Context dependent learning in the serial RT task

This study investigated the development of contextual dependencies for sequential perceptual-motor learning on static features in the learning environment. In three experiments we assessed the effect of manipulating task irrelevant static context features in a serial reaction-time task. Experiment 1 demonstrated impaired performance after simultaneously changing display color, placeholder shape, and placeholder location. Experiment 2 showed that this effect was mainly caused by changing placeholder shape. Finally, Experiment 3 indicated that changing context affected both the application of sequence knowledge and the selection of individual responses. It is proposed either that incidental stimulus features are integrated with a global sequence representation, or that the changed context causes participants to strategically inhibit sequence skills