Polygenic risk prediction: why and when out-of-sample prediction R2 can exceed SNP-based heritability.

In polygenic score (PGS) analysis, the coefficient of determination (R2) is a key statistic to evaluate efficacy. R2 is the proportion of phenotypic variance explained by the PGS, calculated in a cohort that is independent of the genome-wide association study (GWAS) that provided estimates of allelic effect sizes. The SNP-based heritability (hSNP2, the proportion of total phenotypic variances attributable to all common SNPs) is the theoretical upper limit of the out-of-sample prediction R2. However, in real data analyses R2 has been reported to exceed hSNP2, which occurs in parallel with the observation that hSNP2 estimates tend to decline as the number of cohorts being meta-analyzed increases. Here, we quantify why and when these observations are expected. Using theory and simulation, we show that if heterogeneities in cohort-specific hSNP2 exist, or if genetic correlations between cohorts are less than one, hSNP2 estimates can decrease as the number of cohorts being meta-analyzed increases. We derive conditions when the out-of-sample prediction R2 will be greater than hSNP2 and show the validity of our derivations with real data from a binary trait (major depression) and a continuous trait (educational attainment). Our research calls for a better approach to integrating information from multiple cohorts to address issues of between-cohort heterogeneity.

Redefining microglia states: Lessons and limits of human and mouse models to study microglia states in neurodegenerative diseases.

Microglia are resident macrophages of the brain parenchyma and play an essential role in various aspects of brain development, plasticity, and homeostasis. With recent advances in single-cell RNA-sequencing, heterogeneous microglia transcriptional states have been identified in both animal models of neurodegenerative disorders and patients. However, the functional roles of these microglia states remain unclear; specifically, the question of whether individual states or combinations of states are protective or detrimental (or both) in the context of disease progression. To attempt to answer this, the field has largely relied on studies employing mouse models, human in vitro and chimeric models, and human post-mortem tissue, all of which have their caveats, but used in combination can enable new biological insight and validation of candidate disease pathways and mechanisms. In this review, we summarize our current understanding of disease-associated microglia states and phenotypes in neurodegenerative disorders, discuss important considerations when comparing mouse and human microglia states and functions, and identify areas of microglia biology where species differences might limit our understanding of microglia state.

Patterns of Verbal and Nonverbal Communication During Sex.

Sexual communication functions as an important relational process expediating satisfying sexual experiences (Sprecher & Hendrick, 2004). Much of the existing literature on sexual communication concerning sexual pleasure biases verbal communication (Babin, 2012). This study adds to the existing research regarding patterns of communication surrounding sex and during sex through qualitative analysis. Further, this inquiry focused on participants' full histories, rather than their tendencies within any current relationship. We analyzed 78 qualitative interview transcripts from participants between the ages of 18 and 69. Participants reported a reluctance to communicate anything but pleasure, discomfort, or dislike during sex to avoid discouraging their partners. Though participants reported a perception that communicating pleasure served as encouragement and affirmation to their partners, most preferred to communicate pleasure nonverbally. Some participants reported a tendency to communicate pain or dislike verbally. Some preferred communication about sexual topics only before or after sexual activities. Participants shared that a high level of comfort with their partner increased sexual communication. How sexual partners communicate sex not only affects pleasure but can only affect intimacy between partners and health. This adds to the scant literature on nonverbal communication during sex and some people's preference for that style (Blunt-Vinti et al., 2019).

Factors that affect handball execution in Australian Football.

A handball is one of two technical skills used to dispose of the ball in Australian Football. Previous research has only considered handball effectiveness in the analysis of team performance and there is a need to understand whether there are other more important characteristics of handball execution that explain effectiveness (i.e., performance). 1342 handballs from Australian Football League matches were analysed. Ten characteristic variables were created that represent the context and execution of each handball included in the analysis. A mixed effects generalised linear model was used to evaluate the effect of the (ten) characteristics on handball outcome. Three out of ten characteristics were associated with handball outcome, and these related to the posture of the handballer and the type of defensive pressure applied to the handballer and the receiver of the handball. These findings explain both how to increase handball effectiveness and how to reduce the handball effectiveness of an opposition team. Given the important role of handballing in passing sequences and maintaining ball possession, the practical application of these findings could enhance overall team performance.

Piscichuvirus-Associated Severe Meningoencephalomyelitis in Aquatic Turtles, United States, 2009-2021.

Viruses from a new species of piscichuvirus were strongly associated with severe lymphocytic meningoencephalomyelitis in several free-ranging aquatic turtles from 3 coastal US states during 2009-2021. Sequencing identified 2 variants (freshwater turtle neural virus 1 [FTuNV1] and sea turtle neural virus 1 [STuNV1]) of the new piscichuvirus species in 3 turtles of 3 species. In situ hybridization localized viral mRNA to the inflamed region of the central nervous system in all 3 sequenced isolates and in 2 of 3 additional nonsequenced isolates. All 3 sequenced isolates phylogenetically clustered with other vertebrate chuvirids within the genus Piscichuvirus. FTuNV1 and STuNV1 shared ≈92% pairwise amino acid identity of the large protein, which narrowly places them within the same novel species. The in situ association of the piscichuviruses in 5 of 6 turtles (representing 3 genera) with lymphocytic meningoencephalomyelitis suggests that piscichuviruses are a likely cause of lymphocytic meningoencephalomyelitis in freshwater and marine turtles.

The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration.

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer's disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer's disease.

Caring, Chemistry, and Orgasms: Components of Great Sexual Experiences.

Sexual satisfaction is important to individual well-being and relationship satisfaction, making it a research topic relevant for sex clinicians and relationship therapists. The current study adds to sexuality literature by asking participants questions about the factors involved in "great sex." We conducted 78 interviews via email or phone with participants ranging in age from 18 to 69. The sample included a diverse range of sexual orientations and identities, and various relationship statuses. Three primary themes emerged regarding great sex: orgasm, an emotional component, and chemistry/connection. Though some participants equated an emotional aspect as love; most participants made clear the difference between love and emotional elements in sex. Many participants shared their belief that a man only invests in his female partner's orgasm when he also invests in her emotionally. Thus, some women explained that the emotional component helped them be present enough to orgasm. Others explained the emotional component as trust and affection. Participants also elaborated to define chemistry, which they regarded as out of one's control and impossible to manufacture. A smaller number of participants stated unequivocally the lack of necessity of an emotional aspect to great sex; they stated instead that physical connection trumped an emotional component.

Pathways and Patterns of Entrance into BDSM.

Prior limited research on entrance into BDSM divided paths of entry into external or internal factors (Yosta & Hunter, 2012), while research on age at entry into BDSM has not considered variation by BDSM role identity, gender, sexual orientation, and other demographic differences. In this mixed-methods exploratory study, we contribute to this literature by collecting and analyzing qualitative interviews with 96 self-described practitioners of BDSM to more fully describe distinct pathways into BDSM, adding nuance to prior descriptions of entry. We also collected and analyzed surveys with 2,017 self-described practitioners of BDSM to examine patterns of age at entry into BDSM practices and fantasies, and selection into older or younger age at practice and age at fantasy by BDSM role identity, gender, sexual orientation, and other demographic characteristics. Interview respondents told "constructionist sexual stories" describing introductions to BDSM via popular culture including pornography and other media, the Internet, or a sexual partner that awaked an inherent interest, along with "essentialist sexual stories" which described self-discovery solely attributed to an inherent personality characteristic. Survey data revealed that age at fantasy and onset of behavior varied by social-environmental factors. Pathways and patterns into BDSM behavior and fantasies therefore reflect a combination of idiosyncratic interests, exposure to ideas via the media or partners, and stratified social norms and opportunities related to sexual behavior.

Heterosexual College Students Who Hookup with Same-Sex Partners.

Individuals who identify as heterosexual but engage in same-sex sexual behavior fascinate both researchers and the media. We analyzed the Online College Social Life Survey dataset of over 24,000 undergraduate students to examine students whose last hookup was with a same-sex partner (N = 383 men and 312 women). The characteristics of a significant minority of these students (12% of men and 25% of women) who labelled their sexual orientation "heterosexual" differed from those who self-identified as "homosexual," "bisexual," or "uncertain." Differences among those who identified as heterosexual included more conservative attitudes, less prior homosexual and more prior heterosexual sexual experience, features of the hookups, and sentiments about the encounter after the fact. Latent class analysis revealed six distinctive "types" of heterosexually identified students whose last hookup was with a same-sex partner. Three types, comprising 60% of students, could be classified as mostly private sexual experimentation among those with little prior same-sex experience, including some who did not enjoy the encounter; the other two types in this group enjoyed the encounter, but differed on drunkenness and desire for a future relationship with their partner. Roughly, 12% could be classified as conforming to a "performative bisexuality" script of women publicly engaging in same-sex hookups at college parties, and the remaining 28% had strong religious practices and/or beliefs that may preclude a non-heterosexual identity, including 7% who exhibited "internalized heterosexism." Results indicate several distinctive motivations for a heterosexual identity among those who hooked up with same-sex partners; previous research focusing on selective "types" excludes many exhibiting this discordance.

FEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins.

Although engulfment is a hallmark of microglia function, fully validated platforms that facilitate high-throughput quantification of this process are lacking. Here, we present FEAST (Flow cytometric Engulfment Assay for Specific Target proteins), which enables interrogation of in vivo engulfment of synaptic material by brain resident macrophages at single-cell resolution. We optimize FEAST for two different analyses: quantification of fluorescent material inside live cells and of engulfed endogenous proteins within fixed cells. To overcome false-positive engulfment signals, we introduce an approach suitable for interrogating engulfment in microglia from perfusion-fixed tissue. As a proof-of-concept for the specificity and versatility of FEAST, we examine the engulfment of synaptic proteins after optic nerve crush and of myelin in two mouse models of demyelination (treatment with cuprizone and injections of lysolecithin). We find that microglia, but not brain-border associated macrophages, engulf in these contexts. Our work underscores how FEAST can be utilized to gain critical insight into functional neuro-immune interactions that shape development, homeostasis, and disease.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain.

A key aspect of nearly all single-cell sequencing experiments is dissociation of intact tissues into single-cell suspensions. While many protocols have been optimized for optimal cell yield, they have often overlooked the effects that dissociation can have on ex vivo gene expression. Here, we demonstrate that use of enzymatic dissociation on brain tissue induces an aberrant ex vivo gene expression signature, most prominently in microglia, which is prevalent in published literature and can substantially confound downstream analyses. To address this issue, we present a rigorously validated protocol that preserves both in vivo transcriptional profiles and cell-type diversity and yield across tissue types and species. We also identify a similar signature in postmortem human brain single-nucleus RNA-sequencing datasets, and show that this signature is induced in freshly isolated human tissue by exposure to elevated temperatures ex vivo. Together, our results provide a methodological solution for preventing artifactual gene expression changes during fresh tissue digestion and a reference for future deeper analysis of the potential confounding states present in postmortem human samples.

Plasma ghrelin and growth hormone regulation in response to metabolic state in hybrid striped bass: effects of feeding, ghrelin and insulin-like growth factor-I on in vivo and in vitro GH secretion.

The regulation of growth hormone (GH) secretion by ghrelin during variable metabolic states is poorly understood. We examined plasma GH and ghrelin in hybrid striped bass (HSB) undergoing seasonally-based feeding and temperature manipulations. Fasting for 21 days (d) at 24 degrees C resulted in catabolism and up-regulation of plasma GH and ghrelin relative to fed controls. Continued fasting during cold-banking (14 degrees C, 90 d) resulted in a further 43-fold increase in ghrelin while GH remained elevated. A subsequent 19 day refeeding period at 24 degrees C elicited hyperphagic and compensatory growth responses, accompanied by declines in ghrelin and GH. We then tested the role of ghrelin in stimulating GH release in vivo and in vitro. Intraperitoneal injections of ghrelin resulted in dose-dependent increases in plasma GH after 6 hours (h). Ghrelin also increased GH release from HSB pituitaries during 6h incubations. Lastly, we assessed how metabolic state, ghrelin and insulin-like growth factor-I (IGF-I) affect in vitro pituitary GH release. Spontaneous GH release was 5.2-fold higher from pituitaries of fasted compared with fed animals. Ghrelin was equally effective in stimulating GH release from pituitaries of fed and starved animals, while it was ineffective in enhancing GH release from pituitaries of starved (21 d) then refed (4d) HSB. Incubation with IGF-I inhibited GH release regardless of metabolic state. These studies are the first to show that seasonally-based periods of feed deprivation and low temperature yield sustained increases in GH secretion that are likely mediated, at least partially, through elevated ghrelin, reduced IGF-I negative feedback and fasting-induced spontaneous GH release.

Glucose regulates ghrelin, neuropeptide Y, and the GH/IGF-I axis in the tilapia, Oreochromis mossambicus.

In general, a fish's ability to clear glucose is sluggish in relation to mammals, which has lead to the idea that fish are glucose intolerant. It has been reported that circulating glucose levels do fluctuate in response to environmental challenges. Recent reports suggest that glucose may function as a metabolic signal regulating 'glucosensors' in the brain in fish, as has been reported in mammals. The current study was designed to investigate the effect of glucose on ghrelin and neuropeptide Y (NPY) signaling in the brain, and on the growth hormone/insulin-like growth factor-I (GH/IGF-I) in the tilapia, Oreochromis mossambicus. Glucose treatment significantly increased plasma and stomach mRNA levels of ghrelin. In the brain, mRNA levels of the ghrelin receptor (GRLN-R) were significantly reduced, whereas NPY mRNA levels were significantly elevated; suggesting that NPY containing neurons may be a "glucosensor" as reported in mammals. Glucose treatment resulted in changes in the GH/IGF-I axis. Liver mRNA levels of both GH receptors (GHR1 and GHR2) were significantly elevated, whereas liver IGF-I mRNA were unaltered by glucose treatment. No change in plasma or pituitary mRNA levels of GH was observed. Glucose significantly reduced plasma IGF-I levels. These data show that glucose regulates endocrine factors involved in appetite, growth, and possibly energy homeostasis, and suggests that glucose may be acting as a signal of metabolic status in fish.

GREEN TREE FROG ( HYLA CINEREA) AND GROUND SQUIRREL ( XEROSPERMOPHILUS SPILOSOMA) MORTALITY ATTRIBUTED TO INLAND BREVETOXIN TRANSPORT AT PADRE ISLAND NATIONAL SEASHORE, TEXAS, USA, 2015.

: On 16 September 2015, a red tide ( Karenia brevis) bloom impacted coastal areas of Padre Island National Seashore Park, Texas, US. Two days later and about 0.9 km inland, 30-40 adult green tree frogs ( Hyla cinerea) were found dead after displaying tremors, weakness, labored breathing, and other signs of neurologic impairment. A rainstorm accompanied by high winds, rough surf, and high tides, which could have aerosolized brevetoxin, occurred on the morning of the mortality event. Frog carcasses were in good body condition but contained significant brevetoxin in tissues. Tissue brevetoxin was also found in two dead or dying spotted ground squirrels ( Xerospermophilus spilosoma) and a coyote ( Canis latrans) found in the area. Rainwater collected from the location of the mortality event contained brevetoxin. Green tree frog and ground squirrel mortality has not been previously attributed to brevetoxin exposure and such mortality suggested that inland toxin transport, possibly through aerosols, rainfall, or insects, may have important implications for coastal species.