Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice

Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (-/-) and heterozygous (+/-) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/- mice, 5-HTT-/- mice showed impaired recall of extinction. In addition, 5-HTT-/- and +/- experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/- and +/- losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT-/- naive and in 5-HTT-/- and +/- loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network.     

Event-related Potential Study of the Effects of Emotional Facial Expressions on Task Performance in Euthymic Bipolar Patients

There appears to be a significant disconnect between symptomatic and functional recovery in bipolar disorder (BD). Some evidence points to interepisode cognitive dysfunction. We tested the hypothesis that some of this dysfunction was related to emotional reactivity in euthymic bipolar subjects may effect cognitive processing. A modification of emotional gender categorization oddball task was used. The target was gender (probability 25%) of faces with negative, positive, and neutral emotional expression. The experiment had 720 trials (3 blocks × 240 trials each). Each stimulus was presented for 150 ms, and the EEG/ERP responses were recorded for 1,000 ms. The inter-trial interval was varied in 1,100–1,500 ms range to avoid expectancy effects. Task took about 35 min to complete. There were 9 BD and 9 control subjects matched for age and gender. Reaction time (RT) was globally slower in BD subjects. The centro-parietal amplitudes at N170 and N200, and P200 and P300 were generally smaller in the BD group compared to controls. Latency was shorter to neutral and negative targets in BD. Frontal P200 amplitude was higher to emotional negative facial non-targets in BD subjects. The frontal N200 in response to positive facial emotion was less negative in BD subjects. The frontal P300 of BD subjects was lower to emotionally neutral targets. ERP responses to facial emotion in BD subjects varied significantly from normal controls. These variations are consistent with the common depressive symptomology seen in long term studies of bipolar subjects.     

A comparison of chemical pretreatment methods for improving saccharification of cotton stalks

The effectiveness of sulfuric acid (H(2)SO(4)), sodium hydroxide (NaOH), hydrogen peroxide (H(2)O(2)), and ozone pretreatments for conversion of cotton stalks to ethanol was investigated. Ground cotton stalks at a solid loading of 10% (w/v) were pretreated with H(2)SO(4), NaOH, and H(2)O(2) at concentrations of 0.5%, 1%, and 2% (w/v). Treatment temperatures of 90 degrees C and 121 degrees C at 15 psi were investigated for residence times of 30, 60, and 90 min. Ozone pretreatment was performed at 4 degrees C with constant sparging of stalks in water. Solids from H(2)SO(4), NaOH, and H(2)O(2) pretreatments (at 2%, 60 min, 121 degrees C/15 psi) showed significant lignin degradation and/or high sugar availability and hence were hydrolyzed by Celluclast 1.5L and Novozym 188 at 50 degrees C. Sulfuric acid pretreatment resulted in the highest xylan reduction (95.23% for 2% acid, 90 min, 121 degrees C/15 psi) but the lowest cellulose to glucose conversion during hydrolysis (23.85%). Sodium hydroxide pretreatment resulted in the highest level of delignification (65.63% for 2% NaOH, 90 min, 121 degrees C/15 psi) and cellulose conversion (60.8%). Hydrogen peroxide pretreatment resulted in significantly lower (p相似文献   

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis

Background:Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear.Methods:We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results:We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir–ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir–ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty).Interpretation:Molnupiravir and nirmatrelvir–ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir–ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Most trials addressing the treatment of patients with COVID-19 have targeted patients admitted to hospital with severe or critical disease.¹ However, more recently, several treatments, including antiviral drugs, antidepressants, monoclonal antibodies and inhaled corticosteroids, have been studied for patients with nonsevere COVID-19.² Preliminary evidence from ongoing or recently completed trials suggests that 2 novel antiviral drugs — molnupiravir and nirmatrelvir–ritonavir (Paxlovid) — may be effective at reducing risk of hospital admission.^3–5 To date, evidence on antiviral drugs for nonsevere COVID-19 has not been systematically synthesized or appraised. Furthermore, although efficacy data from trials of molnupiravir, nirmatrelvir–ritonavir and remdesivir are promising, no head-to-head trials have compared these drugs.A network meta-analysis allows for comparison of treatments that have not been compared in randomized controlled trials (RCTs), using pooled estimates from direct and indirect evidence. They can provide guidance to clinicians and evidence users in determining which treatments are superior. This is particularly important as health care systems attempt to prioritize access to effective COVID-19 treatments in the early stages of the disease.We sought to compare the effectiveness of antiviral drugs for patients with nonsevere COVID-19.     

Updating age-specific contact structures to match evolving demography in a dynamic mathematical model of tuberculosis vaccination

We investigated the effects of updating age-specific social contact matrices to match evolving demography on vaccine impact estimates. We used a dynamic transmission model of tuberculosis in India as a case study. We modelled four incremental methods to update contact matrices over time, where each method incorporated its predecessor: fixed contact matrix (M0), preserved contact reciprocity (M1), preserved contact assortativity (M2), and preserved average contacts per individual (M3). We updated the contact matrices of a deterministic compartmental model of tuberculosis transmission, calibrated to epidemiologic data between 2000 and 2019 derived from India. We additionally calibrated the M0, M2, and M3 models to the 2050 TB incidence rate projected by the calibrated M1 model. We stratified age into three groups, children (<15y), adults (≥15y, <65y), and the elderly (≥65y), using World Population Prospects demographic data, between which we applied POLYMOD-derived social contact matrices. We simulated an M72-AS01_E-like tuberculosis vaccine delivered from 2027 and estimated the per cent TB incidence rate reduction (IRR) in 2050 under each update method. We found that vaccine impact estimates in all age groups remained relatively stable between the M0–M3 models, irrespective of vaccine-targeting by age group. The maximum difference in impact, observed following adult-targeted vaccination, was 7% in the elderly, in whom we observed IRRs of 19% (uncertainty range 13–32), 20% (UR 13–31), 22% (UR 14–37), and 26% (UR 18–38) following M0, M1, M2 and M3 updates, respectively. We found that model-based TB vaccine impact estimates were relatively insensitive to demography-matched contact matrix updates in an India-like demographic and epidemiologic scenario. Current model-based TB vaccine impact estimates may be reasonably robust to the lack of contact matrix updates, but further research is needed to confirm and generalise this finding.     

MAGI-1 Modulates AMPA Receptor Synaptic Localization and Behavioral Plasticity in Response to Prior Experience

It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience.     

The Internal Organization of Mycobacterial Partition Assembly: Does the DNA Wrap a Protein Core?

Before cell division in many bacteria, the ParBs spread on a large segment of DNA encompassing the origin-proximal parS site(s) to form the partition assembly that participates in chromosome segregation. Little is known about the structural organization of chromosomal partition assembly. We report solution X-ray and neutron scattering data characterizing the size parameters and internal organization of a nucleoprotein assembly formed by the mycobacterial chromosomal ParB and a 120-meric DNA containing a parS-encompassing region from the mycobacterial genome. The cross-sectional radii of gyration and linear mass density describing the rod-like ParB-DNA assembly were determined from solution scattering. A “DNA outside, protein inside” mode of partition assembly organization consistent with the neutron scattering hydrogen/deuterium contrast variation data is discussed. In this organization, the high scattering DNA is positioned towards the outer region of the partition assembly. The new results presented here provide a basis for understanding how ParBs organize the parS-proximal chromosome, thus setting the stage for further interactions with the DNA condensins, the origin tethering factors and the ParA.     

Disruption of Intrinsic Motions as a Mechanism for Enzyme Inhibition

Clostridium difficile (C. diff) is one of the most common and most severe hospital-acquired infections; its consequences range from lengthened hospital stay to outright lethality. C. diff causes cellular damage through the action of two large toxins TcdA and TcdB. Recently, there has been increased effort toward developing antitoxin therapies, rather than antibacterial treatments, in hopes of mitigating the acquisition of drug resistance. To date, no analysis of the recognition mechanism of TcdA or TcdB has been attempted. Here, we use small molecule flexible docking followed by unbiased molecular dynamics to obtain a more detailed perspective on how inhibitory peptides, exemplified by two species HQSPWHH and EGWHAHT function. Using principal component analysis and generalized masked Delaunay analysis, an examination of the conformational space of TcdB in its apo form as well as forms bound to the peptides and UDP-Glucose was performed. Although both species inhibit by binding in the active site, they do so in two very different ways. The simulations show that the conformational space occupied by TcdB bound to the two peptides are quite different and provide valuable insight for the future design of toxin inhibitors and other enzymes that interact with their substrates through conformational capture mechanisms and thus work by the disruption of the protein’s intrinsic motions.