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Post-encoding coordinated reactivation of memory traces distributed throughout interconnected brain regions is thought to be critical for consolidation of memories. However, little is known about the role of neural circuit pathways during postlearning periods for consolidation of memories. To investigate this question, we optogenetically silenced the inputs from both auditory cortex and thalamus in the lateral amygdala (LA) for 15 min immediately following auditory fear conditioning (FC) and examined its effect on fear memory formation in mice of both sexes. Optogenetic inhibition of both inputs disrupted long-term fear memory formation tested 24 h after FC. This effect was specific such that the same inhibition did not affect short-term memory and context-dependent memory. Moreover, long-term memory was intact if the inputs were inhibited at much later time points after FC (3 h or 1 d after FC), indicating that optical inhibition for 15 min itself does not produce any nonspecific deleterious effect on fear memory retrieval. Selective inhibition of thalamic input was sufficient to impair consolidation of auditory fear memory. In contrast, selective inhibition of cortical input disrupted remote fear memory without affecting recent memory. These results reveal a dissociated role of thalamic and cortical input to the LA during early post-learning periods for consolidation of long-term fear memory. [ABSTRACT FROM AUTHOR]

Background The tobacco industry has aggressively introduced new and diverse products in the market, including electronic cigarettes (e-cigarettes) and heat-not-burn (HNB) tobacco products, to which adolescents are readily susceptible. Conventional cigarettes have a well-established relationship with adolescent risky behaviors such as alcohol and drug use; however, no studies exist on the association between alcohol consumption and use of e-cigarettes or HNB tobacco products among Korean adolescents. This study evaluated alcohol-related behaviors and drug use in relation to whether a Korean nationally representative adolescent sample had ever used e-cigarettes and HNB tobacco products. Methods Data from the 2018 Korean Youth Risk Behavior Web-based Survey were analyzed. The final study sample comprised 60,040 adolescents. Chi-square and logistic regression were used to examine whether the ever having used e-cigarettes and HNB tobacco products was associated with alcohol-related behaviors and drug use. P-values for trends were calculated to examine the dose-response relationship for each variable. Results Respondents with higher drinking frequency, drinking quantity, alcohol intoxication, alcohol availability, and drug use were more likely to report having used e-cigarettes and HNB tobacco products, thus implying a significant relationship between substance use and novel tobacco product (P < .001). Conclusions Our findings suggest that at-risk adolescents who are engaged in other forms of risk-taking behaviors are prone to attract the experimentation with e-cigarettes or HNB tobacco products. Thus, smoking cessation programs related to substance use should be implemented, and there is an urgent need to monitor and regulate these products effectively. [ABSTRACT FROM AUTHOR]

Background: Ibuprofen, a well-known analgesic, is commonly used as a component of a multimodal analgesic approach for postoperative pain. This systematic review and meta-analysis aimed to investigate whether a single-dose preoperative intravenous ibuprofen can reduce postoperative pain and opioid consumption. Methods: PubMed/MEDLINE, Embase, Cochrane Library (CENTRAL), and Web of Science databases were searched to identify relevant studies published up to May 2020. Randomized controlled trials comparing preoperative single-dose intravenous ibuprofen effect with the control group on postoperative pain and opioid consumption after surgery under general anesthesia were included. Results: Six studies involving 366 participants were included. Single-dose administration of intravenous ibuprofen preoperatively significantly reduced postoperative pain score on a scale of 0-10 at 1 h (MD: -1.64, 95% CI [-2.56, -0.72], P < 0.001, I² = 95%), at 4-6 h (MD: -1.17, 95% CI [-2.09, -0.26], P < 0.001, I² = 94%), and 24 h (MD: -0.58, 95% CI [-0.99, -0.18], P < 0.001, I² = 90%). Cumulative opioid consumption, presented as fentanyl equivalents, was also reduced significantly in the ibuprofen group compared to placebo group until postoperative 4-6 h (MD: -56.35 µg, 95% CI [-101.10, -11.60], P < 0.001, I² = 91%) and 24 h (MD: -131.39 µg, 95% CI [-224.56, -38.21], P < 0.001, I² = 95%). Conclusions: Preoperative single-dose intravenous ibuprofen can reduce postoperative pain and opioid consumption until 24 h postoperatively. Considering the high heterogeneity and small number of studies included, care should be taken when generalizing these findings. [ABSTRACT FROM AUTHOR]

The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly. [ABSTRACT FROM AUTHOR]

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology. [ABSTRACT FROM AUTHOR]