Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the Dorsolateral Prefrontal Cortex.

Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking.

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson's-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

Identifying Dyslexia: Link between Maze Learning and Dyslexia Susceptibility Gene, DCDC2, in Young Children.

Dyslexia is a common learning disability that affects processing of written language despite adequate intelligence and educational background. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which influence future success in all aspects of their life. Dyslexia has a 60% heritability rate, and genetic studies have identified multiple dyslexia susceptibility genes (DSGs). DSGs, such as DCDC2, are consistently associated with the risk and severity of reading disability (RD). Altered neural connectivity within temporoparietal regions of the brain is associated with specific variants of DSGs in individuals with RD. Genetically altering DSG expression in mice results in visual and auditory processing deficits as well as neurophysiological and neuroanatomical disruptions. Previously, we demonstrated that learning deficits associated with RD can be translated across species using virtual environments. In this 2-year longitudinal study, we demonstrate that performance on a virtual Hebb-Williams maze in pre-readers is able to predict future reading impairment, and the genetic risk strengthens, but is not dependent on, this relationship. Due to the lack of oral reporting and use of letters, this easy-to-use tool may be particularly valuable in a remote working environment as well as working with vulnerable populations such as English language learners.

Efficacy and Safety of Basal Analog Regimens in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: This study compared basal analog (BA: glargine U100/mL and detemir) and premix (PM: human, lispro and aspart biphasic) insulin regimens in terms of their efficacy and safety in type 2 diabetes mellitus patients. METHODS: Searches of MEDLINE, Embase, and CENTRAL identified primary randomized controlled trials (RCTs) ≥ 12 weeks in duration that compared BA or PM insulin regimens in adults with T2DM, with ≥ 30 patients per arm. A systematic literature review and a pairwise meta-analysis were performed using a random effects model adjusted for between-study variability. Analyses were conducted based on frequency of bolus insulin and PM injections, PM ratio and type, BA type, race, follow-up period, and baseline glycosylated hemoglobin (HbA1c). RESULTS: Twenty-two primary RCTs with 9691 patients were included. The BA and PM regimens yielded similar changes in HbA1c and postprandial glucose levels, with a statistically significant reduction in fasting glucose [mean difference (MD) - 0.61 mmol/L (95% confidence interval (CI) - 0.90, - 0.32), I2 = 89.6%]. The BA regimens showed significantly reduced rates of total hypoglycemia [odds ratio (OR) 0.77 (95% CI 0.64, 0.92), I2 = 65.3%] and changes in body weight [MD - 0.48 kg (95% CI - 0.86, - 0.11), I2 = 75.7%] compared to PM regimens. Stratification by PM type and dosing ratio demonstrated statistically significant reductions in HbA1c favoring BA compared to human [MD - 0.39% (95% CI - 0.60, - 0.18), I2 = 61.8%] or 50/50-ratio [MD - 0.22% (95% CI - 0.40, - 0.04), I2 = 0.0%] PM regimens. Other subgroup analyses found no difference in HbA1c change between the BA and PM regimens. CONCLUSION: When compared to PM regimens, BA regimens yielded similar efficacies and better safety profiles in patients with type 2 diabetes mellitus. FUNDING: Sanofi (Shanghai, China).

Arthropod predation in a dendrobatid poison frog: does frog life stage matter?

Frogs in the family Dendrobatidae are well known for their conspicuous colors and variable alkaloid-based chemical defenses. The aposematic coloration in dendrobatid frogs appears to deter predators with color vision, but relatively little is known about how these frogs are protected and their defenses are perceived by non-color vision dominated predators. The neotropical bullet ant Paraponera clavata and the red-legged banana spider Cupiennius coccineus are predators that avoid adults of the dendrobatid Oophaga pumilio, but readily consume non-toxic frogs. Juvenile O. pumilio possess the same warning coloration as adult O. pumilio, but may be more palatable given that they have lower quantities of defensive chemicals. This may provide juvenile O. pumilio protection from color-sighted predators, while leaving them susceptible to predators that use chemoreception. To test this hypothesis, we presented juveniles and adults of both O. pumilio and the non-chemically defended frog Craugastor bransfordii to bullet ants and banana spiders. Both bullet ants and banana spiders preyed upon C. bransfordii significantly more than on O. pumilio. Adult and juvenile C. bransfordii experienced similar predation rates by both predators. The life stage of O. pumilio significantly predicted predation by bullet ants, with juveniles being consumed significantly more often than adults. However, the life stage of O. pumilio did not predict predation by banana spiders, as no adults or juveniles were consumed. Our study provides evidence that bullet ants can detect differences in chemical defenses between juvenile and adult O. pumilio, resulting in differential predation on the more palatable juvenile frogs. The avoidance of both adults and juveniles by C. coccineus suggests the alkaloids in O. pumilio act as an effective chemical deterrent to banana spiders, regardless of quantity. Overall, our results suggest that differences in alkaloid defenses among life stages in O. pumilio correspond to differences in relative palatability to at least one arthropod predator.

Mitochondrial and plastid genome analysis of the heteromorphic red alga Mastocarpus papillatus (C. Agardh) Kützing (Phyllophoraceae, Rhodophyta) reveals two characteristic florideophyte organellar genomes.

Analysis of the marine red algal species Mastocarpus papillatus (C. Agardh) Kützing using paired-end 36 bp Illumina sequences resulted in the assembly of its complete mitochondrial and plastid genomes. The mitogenome is 25,906 bp in length and contains 50 genes, and the plastid genome is 184,382 bp with 234 genes. The mitochondrial and plastid genomes show high gene synteny with published Florideophyceae.