Conditionally Deleterious Mutation Load Accumulates in Genomic Islands of Local Adaptation but Can Be Purged with Sufficient Genotypic Redundancy.

AbstractLocal adaptation frequently evolves in patches or environments that are connected via migration. In these cases, genomic regions that are linked to a locally adapted locus experience reduced effective migration rates. Via individual-based simulations of a two-patch system, we show that this reduced effective migration results in the accumulation of conditionally deleterious mutations, but not universally deleterious mutations, adjacent to adaptive loci. When there is redundancy in the genetic basis of local adaptation (i.e., genotypic redundancy), turnover of locally adapted polymorphisms allows conditionally deleterious mutation load to be purged. The amount of mutational load that accumulates adjacent to locally adapted loci is dependent on redundancy, recombination rate, migration rate, population size, strength of selection, and the phenotypic effect size of adaptive alleles. Our results highlight the need to be cautious when interpreting patterns of local adaptation at the level of phenotype or fitness, as the genetic basis of local adaptation can be transient, and evolution may confer a degree of maladaptation to nonlocal environments.

Lateralized grey matter volume changes in adolescents versus adults with major depression: SDM-PSI meta-analysis.

The current study is the first meta-analysis to examine grey matter volume (GMV) changes in adolescents and across the lifespan in major depressive disorder (MDD). Seed-based d mapping-with permutation of subject images (SDM-PSI) has advantages over previous coordinate-based meta-analytical methods (CBMA), such as reducing bias (via the MetaNSUE algorithm) and including non-statistically significant unreported effects. SDM-PSI was used to analyze 105 whole-brain GMV voxel-based morphometry (VBM) studies comparing 6,530 individuals with MDD versus 6,821 age-matched healthy controls (HC). A laterality effect was observed in which adults with MDD showed lower GMV than adult HC in left fronto-temporo-parietal structures (superior temporal gyrus, insula, Rolandic operculum, and inferior frontal gyrus). However, these abnormalities were not statistically significant for adolescent MDD versus adolescent HC. Instead, adolescent MDD showed lower GMV than adult MDD in right temporo-parietal structures (angular gyrus and middle temporal gyrus). These regional differences may be used as potential biomarkers to predict and monitor treatment outcomes as well as to choose the most effective treatments in adolescents versus adults. Finally, due to the paucity of youth, older adult, and longitudinal studies, future studies should attempt to replicate these GMV findings and examine whether they correlate with treatment response and illness severity.

Neuropsychological Performance in Alzheimer's Disease versus Late-Life Depression: A Systematic Review and Meta-Analysis.

OBJECTIVE: Despite decades of research, neuropsychological tests (NPTs) that clearly differentiate between Alzheimer's disease (AD) and late-life depression (LLD) have yet to be agreed upon. Given this gap in knowledge and the rapid deployment of disease-modifying drugs for the two disorders, accurate clinical diagnosis using evidence-based assessment is essential. This study aims to systematically examine the literature to identify NPTs that would be able to differentiate AD and LLD. METHOD: Databases and bibliographies were searched to identify articles for analysis. Two major inclusion criteria were that the studies compared neuropsychological functioning of AD versus LLD using normed NPTs and provided data for effect size calculation. Risk of bias was minimized by having independent coders for all steps in the review. RESULTS: Forty-one studies met inclusion criteria (N = 2,797) and provided effect sizes for tests that were classified as belonging to 15 domains of functioning. The two groups were well differentiated by tasks of delayed contextual verbal memory as compared to immediate or non-contextual memory, recognition cueing, confrontation naming, visuospatial construction, and conceptualization. Specific NPTs that appear to be useful for differential diagnosis include the Rey Auditory Verbal Learning Test-Delayed Recognition; Boston Naming Test; the Dementia Rating Scale's memory, conceptualization, and construction subscales; and the CERAD Constructional Praxis. CONCLUSIONS: The NPTs highlighted in this systematic review could be used as a relatively simple and cost-effective method to differentiate between patients with cognitive dysfunction due to AD versus LLD.

Functional neuroanatomy of craving in heroin use disorder: voxel-based meta-analysis of functional magnetic resonance imaging (fMRI) drug cue reactivity studies.

Background: The neuroanatomy of craving, typically investigated using the functional magnetic resonance imaging (fMRI) drug cue reactivity (FDCR) paradigm, has been shown to involve the mesocorticolimbic, nigrostriatal, and corticocerebellar systems in several substances. However, the neuroanatomy of craving in heroin use disorder is still unclear.Objective: The current meta-analysis examines previous research on the neuroanatomy of craving in abstinent individuals with opioid use disorder (OUD).Method: Seven databases were searched for studies comparing abstinent OUD versus healthy controls on drug > neutral contrast interaction at the whole-brain level. Voxel-based meta-analysis was performed using seed-based d mapping with permuted subject images (SDM-PSI). Thresholds were set at a family-wise error rate of less than 5% with the default pre-processing parameters of SDM-PSI.Results: A total of 10 studies were included (296 OUD and 187 controls). Four hyperactivated clusters were identified with Hedges' g of peaks that ranged from 0.51 to 0.82. These peaks and their associated clusters correspond to the three systems identified in the previous literature: a) mesocorticolimbic, b) nigrostriatal, and c) corticocerebellar. There were also newly revealed hyperactivation regions including the bilateral cingulate, precuneus, fusiform gyrus, pons, lingual gyrus, and inferior occipital gyrus. The meta-analysis did not reveal areas of hypoactivation.Conclusion: Recommendations based on the functional neuroanatomical findings of this meta-analysis include pharmacological interventions such as buprenorphine/naloxone and cognitive-behavioral treatments such as cue-exposure combined with HRV biofeedback. In addition, research should utilize FDCR as pre- and post-measurement to determine the effectiveness and mechanism of action of such interventions.

Giant siliconoma mimicking locally advanced breast cancer: A case report and review of literature.

INTRODUCTION: Silicone prosthetics are widely used for breast augmentation and reconstruction. These devices may extrude free silicone into surrounding tissue, stimulating a granulomatous foreign body reaction. The resulting mass can mimic breast cancer. PRESENTATION OF CASE: 71 year old female with a history of a ruptured silicone implant presents with an enlarging left breast mass. Exam demonstrated and ulcerated, fungating mass with active infection. CT scan demonstrated a 23 × 15 cm mass involving the breast and chest wall with axillary lymphadenopathy. Preoperative biopsies were inconclusive and the patient underwent a modified radical mastectomy. Pathology demonstrated a siliconoma. DISCUSSION: While benign, silicone granulomas of the breast can present similarly to malignancy and are an important differential in the diagnosis of a breast or axillary mass for appropriate patients. MRI is the study of choice and core needle biopsies cannot always establish the diagnosis preoperatively. PET scans can be falsely positive and the diagnosis requires an extensive workup to rule out cancer. CONCLUSION: Siliconomas develop as a result of implant rupture and present with many of the signs and symptoms of breast cancer. The majority of patients should undergo surgery for symptom relief or to rule out cancer.