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Abstract A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

Abstract Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals.

Demonstration that SMAD2/3 regulate regeneration and differentiation of the endometrium in a manner important for suppression of endometrial carcinogenesis.

Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their “RNA fingerprints”, which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.

Background: To date, studies have not explored whether a dual diagnosis of aphasia plus apraxia of speech (AOS) versus aphasia alone (APH) affects the response to language-based naming treatments. Aims: To compare the effects of semantic feature analysis (SFA) treatment for individuals with APH versus aphasia plus AOS, and to test if the presence of AOS impacted the effects of treatment. Methods and Procedures: A non-randomized experimental group study was conducted to explore the treatment, generalization and maintenance effects between the AOS and APH groups. Participants included nine individuals with aphasia and 11 with concomitant aphasia and AOS. Dependent measures included lexical accuracy, number of sound-level distortions, and lexical stress and syllable segmentation errors. Outcomes and Results: Both groups showed significantly improved naming accuracy of trained items for up to 2 months post-treatment. Improvement on naming accuracy of untrained items post-treatment, both semantically related and unrelated to trained items, was lower in magnitude. That this may have been due to effects of repeated probing (which included target repetition) or regression to the mean cannot be excluded. There was a tendency for the AOS group to respond slightly better to treatment than the APH group overall, which was not correlated with aphasia severity. Also, measures of phonetic accuracy and fluency improved for both groups, with no main effect of group. Treatment effects did not generalize to formal measures of (untrained) picture naming or expression of correct information units in discourse in a story retelling task. Conclusions and Implications: Findings indicate that individuals with aphasia plus AOS can gain equivalent benefits in word retrieval and production from the language-based SFA treatment as individuals with aphasia alone. This may be, in part, due to the tendency for SFA to incorporate principles of practice that are known to support motor learning in AOS, such as high intensity, random stimulus presentation and variable practice. Findings provide further support for high-intensity practice and use of self-generated features to facilitate maintenance of effects.

Impaired phonological processing is a leading symptom of multifactorial language and learning disorders suggesting a common biological basis. Here we evaluated studies of dyslexia, dyscalculia, specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA) seeking for shared risk genes in Broca’s and Wernicke’s regions, being key for phonological processing within the complex language network. The identified “phonology-related genes” from literature were functionally characterized using Atlas-based expression mapping (JuGEx) and gene set enrichment. Out of 643 publications from the last decade until now, we extracted 21 candidate genes of which 13 overlapped with dyslexia and SLI, six with dyslexia and dyscalculia, and two with dyslexia, dyscalculia, and SLI. No overlap was observed between the childhood disorders and the late-onset lvPPA often showing symptoms of learning disorders earlier in life. Multiple genes were enriched in Gene Ontology terms of the topics learning (CNTNAP2, CYFIP1, DCDC2, DNAAF4, FOXP2) and neuronal development (CCDC136, CNTNAP2, CYFIP1, DCDC2, KIAA0319, RBFOX2, ROBO1). Twelve genes showed above-average expression across both regions indicating moderate-to-high gene activity in the investigated cortical part of the language network. Of these, three genes were differentially expressed suggesting potential regional specializations: ATP2C2 was upregulated in Broca’s region, while DNAAF4 and FOXP2 were upregulated in Wernicke’s region. ATP2C2 encodes a magnesium-dependent calcium transporter which fits with reports about disturbed calcium and magnesium levels for dyslexia and other communication disorders. DNAAF4 (formerly known as DYX1C1) is involved in neuronal migration supporting the hypothesis of disturbed migration in dyslexia. FOXP2 is a transcription factor that regulates a number of genes involved in development of speech and language. Overall, our interdisciplinary and multi-tiered approach provided evidence that genetic and transcriptional variation of ATP2C2, DNAAF4, and FOXP2 may play a role in physiological and pathological aspects of phonological processing.

Abstract Background Proximal humeral fractures can be treated non-operatively or operatively with open reduction and internal fixation (ORIF) and arthroplasty. Our objective was to assess practice patterns for operative and non-operative treatment of proximal humeral fractures. We also report on complications, readmissions, in-hospital mortality, and need for surgery after initial treatment of proximal humeral fractures in California, Florida, and New York. Methods The State Inpatient Databases and State Emergency Department Databases from the Healthcare Cost and Utilization Project, sponsored by the Agency for Healthcare Research and Quality, were used for the states of California (2005–2011), Florida (2005–2014), and New York (2008–2014). Data on patients with proximal humeral fractures was extracted. Patients underwent non-operative or operative (ORIF or arthroplasty) treatment at baseline and were followed for at least 4 years from the index presentation. If the patient needed subsequent surgery, time to event was calculated in days, and Kaplan-Meier survival curves were plotted. Results At the index visit, 90.3% of patients with proximal humeral fractures had non-operative treatment, 6.7% had ORIF, and 3.0% had arthroplasty. 7.6% of patients initially treated non-operatively, 6.6% initially treated with ORIF, and 7.2% initially treated with arthroplasty needed surgery during follow-up. Device complications were the primary reason for readmission in 5.3% of ORIF patients and 6.7% of arthroplasty patients (p

The uterus plays an essential role in the reproductive health of women and controls critical processes such as embryo implantation, placental development, parturition, and menstruation. Progesterone receptor (PR) regulates key aspects of the reproductive function of several mammalian species by directing the transcriptional program in response to progesterone (P4). P4/PR signaling controls endometrial receptivity and decidualization during early pregnancy and is critical for the establishment and outcome of a successful pregnancy. PR is also essential throughout gestation and during labor, and it exerts critical roles in the myometrium, mainly by the specialized function of its two isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), which display distinct and separate roles as regulators of transcription. This review summarizes recent studies related to the roles of PR function in the decidua and myometrial tissues. We discuss how PR acquired key features in placental mammals that resulted in a highly specialized and dynamic role in the decidua. We also summarize recent literature that evaluates the myometrial PR-A/PR-B ratio at parturition and discuss the efficacy of current treatment options for preterm birth.

Trail-making tests are widely used as part of neuropsychological assessments, although the prevalence of processing speed deficits in schizophrenia spectrum disorders may limit their utility when administered to this population. In response, our study sought to explore D-KEFS TMT performance among a forensic-oriented schizophrenia spectrum sample, with the goal of generating normative data to enhance the utility of the TMT with this population. Archival data was collected from a sample of patients admitted to a forensic maximum-security psychiatric facility. Analyses revealed a large percentage of individuals achieved an "impaired" result across D-KEFS TMT trials, ranging from 20% to more than 60%. The most noteworthy finding was for Number-Letter Switching, in which approximately 48% of participants performed at the floor level. Following reclassification of performance, 36% of our sample were identified as "below average," while greater than 60% of individuals were captured as average to above average. The current analyses revealed a problematic skew in TMT performance among schizophrenia spectrum patients, in turn complicating interpretation of cognitive status as well as the ability to compare performance between patients and over time. The present adjustments account for this skew and yield more variability in standardized scoring. [ABSTRACT FROM AUTHOR]

Performance validity tests (PVTs) are an integral part of neuropsychological assessments. Yet no studies have examined how Spanish-speaking forensic inpatients perform on PVTs, making it difficult to interpret these tests in this population. The present study examined archival data collected from monolingual Spanish-speaking forensic inpatients (n = 55; Mage = 49.6 years, SD = 12.0; 84.9% male; 93.5% diagnosed with a Psychotic Spectrum Disorder) to determine how this population performs on several PVTs. Most participants' scores on the Dot Counting Test (DCT; 82.2%; n = 45), Repeatable Battery for Assessment of Neuropsychological Status-Effort Index (RBANS EI; 84.4%; n = 33), and Test of Memory Malingering (TOMM; 79.1%; n = 43) were indicative of valid performance. Few participants, however, had Rey-15 Item Test (FIT) scores in the valid range (24.5% to 48.0%; Recall n = 50 and Combined n = 49, respectively); although FIT Recall specificity was improved when cutoff scores were lowered. Total years of education, but not other educational factors, were significantly associated with performance on PVTs (r =.33–.40, p =.01–.03). Study results suggest the DCT, TOMM, and RBANS EI may be more appropriate PVTs for Spanish-speaking forensic inpatients compared to the FIT. [ABSTRACT FROM AUTHOR]

Exposure to adversity has been shown to amplify individuals' sensitivity to stress, increasing the risk of developing mental health problems in adulthood. Romantic relationships can serve as a broad resource in mitigating the negative impacts of adversity and stress on mental health; however, less is known about how everyday moments of closeness with one's romantic partner impact experiences of daily stress for people exposed to adversity. The present study uses ecological momentary assessment to examine moment-to-moment relationship closeness as a protective buffer against the effects of stress and adversity history (AH) on mood. Using a mobile app, 109 emerging adult couples (M age = 23.1) reported hourly feelings of stress, relationship closeness, and mood (i.e., happy, sad, nervous, angry) for one day. Results showed AH and relationship closeness each moderated the association between stress and negative mood. Specifically, greater AH was associated with increased same-hour links between stress and heightened nervousness and anger. Greater relationship closeness was associated with decreased drops in happiness and decreased rises in sadness and anger when stressed. A 3-way interaction between stress, AH, and relationship closeness indicated higher relationship closeness was a buffer against the impact of stress on happiness and anger. Specifically, high relationship closeness mitigated drops in happiness when stressed, especially for those with high AH; relationship closeness also mitigated rises in anger, but this effect was heightened for those with low AH. Exploratory gender moderation analyses showed complex links between stress, AH, closeness, and mood, with evidence indicating enhanced emotional intensity in women when stressed and enhanced protective benefits of relationship closeness in men, although this pattern was inconsistent. The discussion focuses on how experiences of AH can carry forward to shape emotional responses in adults and how relationship closeness may serve as a protective factor against the sensitizing effects of AH. [ABSTRACT FROM AUTHOR]

Piwi proteins and piRNAs protect eukaryotic germlines against the spread of transposons. During development in the ciliate Paramecium, two Piwi-dependent sRNA classes are involved in the elimination of transposons and transposon-derived DNA: scan RNAs (scnRNAs), associated with Ptiwi01 and Ptiwi09, and iesRNAs, whose binding partners we now identify as Ptiwi10 and Ptiwi11. scnRNAs derive from the maternal genome and initiate DNA elimination during development, whereas iesRNAs continue DNA targeting until the removal process is complete. Here, we show that scnRNAs and iesRNAs are processed by distinct Dicer-like proteins and bind Piwi proteins in a mutually exclusive manner, suggesting separate biogenesis pathways. We also demonstrate that the PTIWI10 gene is transcribed from the developing nucleus and that its transcription depends on prior DNA excision, suggesting a mechanism of gene expression control triggered by the removal of short DNA segments interrupting the gene.