Specialized structure of neural population codes in parietal cortex outputs.

Do cortical neurons that send axonal projections to the same target area form specialized population codes for transmitting information? We used calcium imaging in mouse posterior parietal cortex (PPC), retrograde labeling, and statistical multivariate models to address this question during a delayed match-to-sample task. We found that PPC broadcasts sensory, choice, and locomotion signals widely, but sensory information is enriched in the output to anterior cingulate cortex. Neurons projecting to the same area have elevated pairwise activity correlations. These correlations are structured as information-limiting and information-enhancing interaction networks that collectively enhance information levels. This network structure is unique to sub-populations projecting to the same target and strikingly absent in surrounding neural populations with unidentified projections. Furthermore, this structure is only present when mice make correct, but not incorrect, behavioral choices. Therefore, cortical neurons comprising an output pathway form uniquely structured population codes that enhance information transmission to guide accurate behavior.

What makes a histone variant a variant: Changing H2A to become H2A.Z.

Chromatin structure and underlying DNA accessibility is modulated by the incorporation of histone variants. H2A.Z, a variant of the H2A core histone family, plays a distinct and essential role in a diverse set of biological functions including gene regulation and maintenance of heterochromatin-euchromatin boundaries. Although it is currently unclear how the replacement of H2A with H2A.Z can regulate gene expression, the variance in their amino acid sequence likely contributes to their functional differences. To tease apart regions of H2A.Z that confer its unique identity, a set of plasmids expressing H2A-H2A.Z hybrids from the native H2A.Z promoter were examined for their ability to recapitulate H2A.Z function. First, we found that the H2A.Z M6 region was necessary and sufficient for interaction with the SWR1-C chromatin remodeler. Remarkably, the combination of only 9 amino acid changes, the H2A.Z M6 region, K79 and L81 (two amino acids in the α2-helix), were sufficient to fully rescue growth phenotypes of the htz1Δ mutant. Furthermore, combining three unique H2A.Z regions (K79 and L81, M6, C-terminal tail) was sufficient for expression of H2A.Z-dependent heterochromatin-proximal genes and GAL1 derepression. Surprisingly, hybrid constructs that restored the transcription of H2A.Z-dependent genes, did not fully recapitulate patterns of H2A.Z-specific enrichment at the tested loci. This suggested that H2A.Z function in transcription regulation may be at least partially independent of its specific localization in chromatin. Together, this work has identified three regions that can confer specific H2A.Z-identity to replicative H2A, furthering our understanding of what makes a histone variant a variant.

The effect of sexual dysfunction on health-related quality of life in men following traumatic pelvic fractures.

BACKGROUND: Pelvic trauma disproportionately affects a younger population and has the potential to cause long-term sexual dysfunction. We hypothesized that the presence of sexual dysfunction after traumatic pelvic fracture negatively impacts health-related quality of life (HrQOL) in men. METHODS: A total of 228 patients with traumatic pelvic fractures treated at a level 1 trauma center between 2012 and 2017 completed a survey that evaluated postinjury HrQOL and sexual function. Inverse probability weighting was used to adjust for survey nonresponse. Pelvic fracture characteristics were classified based on the Orthopedic Trauma Association classification system. Sexual function was evaluated using the International Index of Erectile Function, and HrQOL was evaluated using the EuroQol 5 Dimensions Questionnaire (EQ-5D). Quality-adjusted life years were determined based on calculated EQ-5D utility indices. Multiple regression models were created to evaluate the association between sexual health and HrQOL. RESULTS: After inverse probability weighting and adjustment for potential confounders, a decrease in International Index of Erectile Function was associated with a decline in overall HrQOL as measured by the EQ-5D visual analog scale (ß = 0.28, p = 0.02). No association was identified between Orthopedic Trauma Association pelvic fracture configuration and risk of postinjury erectile dysfunction (ED) (p = 0.99). Furthermore, 53.3% of men reported persistent ED at a median of 42.6 months (interquartile range, 28.0-63.3 months) following injury. The presence of ED was independently associated with a decrease in HrQOL (ß = 10.92, p < 0.001). This difference equates to a loss of 1.6 quality-adjusted life years per 10 years for men with ED following pelvic fracture relative to those without. CONCLUSION: Sexual dysfunction is an independent risk factor for decreased HrQOL in pelvic trauma survivors. Further work is needed to create appropriate patient-centered survivorship care pathways that incorporate sexual health evaluation. LEVEL OF EVIDENCE: Prognostic, level IV.

Recent Advances in the Management of High-Risk Localized Prostate Cancer: Local Therapy, Systemic Therapy, and Biomarkers to Guide Treatment Decisions.

High-risk prostate cancer accounts for approximately 15% of all prostate cancer diagnoses. Patients with high-risk disease have an increased risk of developing biochemical recurrence, metastases, and death from prostate cancer. As the optimal management of high-risk disease in patients with prostate cancer continues to evolve, the contemporary treatment paradigm is moving toward a multidisciplinary integrated approach of systemic and local therapy for patients with high-risk disease. The strategies for definitive, adjuvant, and salvage local treatment, including radical prostatectomy or radiation therapy, serve as the backbone of therapy for patients with localized disease. Systemic therapy decisions regarding use in combination with surgery, choice of therapy (hormone therapy, chemotherapy), and treatment duration continue to be refined. As more effective hormonal agents populate the treatment landscape for advanced prostate cancer, including abiraterone and next-generation antiandrogens, an opportunity is provided to explore these treatments in patients with localized disease in the hope of improving the long-term outcome for patients. Integration of innovative blood and tissue-based biomarkers to guide therapy selection for patients with high-risk disease is an area of active research. Contemporary studies are using such biomarkers to stratify patients and select therapies. In this review, we summarize contemporary evidence for local treatment strategies, systemic therapy options, and biomarkers in development for the management of high-risk prostate cancer in patients.

Technical Considerations and Clinical Outcomes in the Endovascular Management of Celiac Arterial Aneurysms.

This retrospective case series details a single-center experience of 8 patients (mean age, 54.4 years) with celiac artery aneurysms (CAAs) who underwent 1 parent vessel-sparing, 5 partial parent vessel-sparing, and 2 non-parent vessel-sparing procedures. Technical success was achieved in 6 of 8 (75%) patients. Both technical failures arose from type II endoleaks, which spontaneously resolved, resulting in clinical success of all cases. In-stent restenosis requiring reintervention complicated 3 of 5 (60%) partial parent vessel-sparing techniques, with 2 of 3 developing complete thrombosis. Two Society of Interventional Radiology grade C complications were recorded, none of which resulted in permanent sequelae. The endovascular management of CAAs is safe and amenable to various techniques.

Estrogens and prostate cancer.

BACKGROUND: Hormonal influences such as androgens and estrogens are known contributors in the development and progression of prostate cancer (CaP). While much of the research to the hormonal nature of CaP has focused on androgens, estrogens also have critical roles in CaP development, physiology as well as a potential therapeutic intervention. METHODS: In this review, we provide a critical literature review of the current basic science and clinical evidence for the interaction between estrogens and CaP. RESULTS: Estrogenic influences in CaP include synthetic, endogenous, fungi and plant-derived compounds, and represent a family of sex hormones, which cross hydrophobic cell membranes and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus triggering changes in gene expression in various organ systems. CONCLUSIONS: Estrogens represent a under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.

Subthalamic nucleus deep brain stimulation affects distractor interference in auditory working memory.

Computational and theoretical accounts hypothesize the basal ganglia play a supramodal "gating" role in the maintenance of working memory representations, especially in preservation from distractor interference. There are currently two major limitations to this account. The first is that supporting experiments have focused exclusively on the visuospatial domain, leaving questions as to whether such "gating" is domain-specific. The second is that current evidence relies on correlational measures, as it is extremely difficult to causally and reversibly manipulate subcortical structures in humans. To address these shortcomings, we examined non-spatial, auditory working memory performance during reversible modulation of the basal ganglia, an approach afforded by deep brain stimulation of the subthalamic nucleus. We found that subthalamic nucleus stimulation impaired auditory working memory performance, specifically in the group tested in the presence of distractors, even though the distractors were predictable and completely irrelevant to the encoding of the task stimuli. This study provides key causal evidence that the basal ganglia act as a supramodal filter in working memory processes, further adding to our growing understanding of their role in cognition.

Role of Nanotechnology in Erectile Dysfunction Treatment.

INTRODUCTION: The biological importance of nanotechnology-based delivery vehicles for in vivo tissue regeneration is gaining acceptance by the medical community; however, its relevance and incorporation into the treatment of sexual dysfunction are evolving and have not been well evaluated. AIM: To provide scientific evidence examining the use of state-of-the-art nanotechnology-based delivery methodology in the treatment of erectile dysfunction (ED) in animal models and in patients. METHODS: This review assessed the current basic science literature examining the role of nanotechnology-based delivery vehicles in the development of potential ED therapies. RESULTS: There are four primary areas where nanotechnology has been applied for ED treatment: (i) topical delivery of drugs for on-demand erectile function, (ii) injectable gels into the penis to prevent morphologic changes after prostatectomy, (iii) hydrogels to promote cavernous nerve regeneration or neuroprotection, and (iv) encapsulation of drugs to increase erectile function (primarily of phosphodiesterase type 5 inhibitors). CONCLUSION: Basic science studies provide evidence for a significant and evolving role for nanotechnology in the development of therapies for ED and suggest that properly administered nano-based therapies might be advantageous for treating male sexual dysfunction.

Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied by an altered bile acid (BA) homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data. METHODS: This was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH) and healthy controls (HC). Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) and intestinal BA signalling, as well as IM composition were assessed. RESULTS: 53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA), chenodeoxycholic acid (CDCA) and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons). The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004), but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively). C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA) (r = 0.526, p = 0.003) and inversely with unconjugated CA (r = -0.669, p<0.0001) and unconjugated CDCA (r = - 0.630, p<0.0001). FGF19 levels were not different between the groups (p = 0.114). CONCLUSIONS: In adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury.

Eaf5/7/3 form a functionally independent NuA4 submodule linked to RNA polymerase II-coupled nucleosome recycling.

The NuA4 histone acetyltransferase complex is required for gene regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and this Eaf5/7/3 trimer is anchored to NuA4 through Eaf5. This trimeric subcomplex represents a functional module, and a large portion exists in a native form outside the NuA4 complex. Gene-specific and genome-wide location analyses indicate that Eaf5/7/3 correlates with transcription activity and is enriched over the coding region. In agreement with a role in transcription elongation, the Eaf5/7/3 trimer interacts with phosphorylated RNA polymerase II and helps its progression. Loss of Eaf5/7/3 partially suppresses intragenic cryptic transcription arising in set2 mutants, supporting a role in nucleosome destabilization. On the other hand, loss of the trimer leads to an increase of replication-independent histone exchange over the coding region of transcribed genes. Taken together, these results lead to a model where Eaf5/7/3 associates with elongating polymerase to promote the disruption of nucleosomes in its path, but also their refolding in its wake.

The dorsomedial striatum encodes net expected return, critical for energizing performance vigor.

Decision making requires an actor to not only steer behavior toward specific goals but also determine the optimal vigor of performance. Current research and models have largely focused on the former problem of how actions are directed while overlooking the latter problem of how they are energized. Here we designed a self-paced decision-making paradigm, which showed that rats' performance vigor globally fluctuates with the net value of their options, suggesting that they maintain long-term estimates of the value of their current state. Lesions of the dorsomedial striatum (DMS) and, to a lesser degree, in the ventral striatum impaired such state-dependent modulation of vigor, rendering vigor to depend more exclusively on the outcomes of immediately preceding trials. The lesions, however, spared choice biases. Neuronal recordings showed that the DMS is enriched in net value-coding neurons. In sum, the DMS encodes one's net expected return, which drives the general motivation to perform.

Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region.

GABAergic interneurons synchronize network activities and monitor information flow. Post-mortem studies have reported decreased densities of cortical interneurons in schizophrenia (SZ) and bipolar disorder (BPD). The entorhinal cortex (EC) and the adjacent subicular regions are a hub for integration of hippocampal and cortical information, a process that is disrupted in SZ. Here we contrast and compare the density of interneuron populations in the caudal EC and subicular regions in BPD type I (BPD-I), SZ, and normal control (NC) subjects. Post-mortem human parahippocampal specimens of 13 BPD-I, 11 SZ and 17 NC subjects were used to examine the numerical density of parvalbumin-, somatostatin- or calbindin-positive interneurons. We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. Calbindin-positive interneuron densities were normal in all brain areas examined. The profile of decreased density was strikingly similar in BPD-I and SZ. Our results demonstrate a specific reduction of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region in BPD-I and SZ, likely disrupting synchronization and integration of cortico-hippocampal circuits.

Key functional regions in the histone variant H2A.Z C-terminal docking domain.

The incorporation of histone variants into nucleosomes represents one way of altering the chromatin structure to accommodate diverse functions. Histone variant H2A.Z has specific roles in gene regulation, heterochromatin boundary formation, and genomic integrity. The precise features required for H2A.Z to function and specify an identity different from canonical H2A remain to be fully explored. Analysis of the C-terminal docking domain of H2A.Z in Saccharomyces cerevisiae using epistatic miniarray profile (E-MAP) uncovered nuanced requirements of the H2A.Z C-terminal region for cell growth when additional genes were compromised. Moreover, the H2A.Z(1-114) truncation, lacking the last 20 amino acids of the protein, did not support regular H2A.Z functions, such as resistance to genotoxic stress, restriction of heterochromatin in its native context, GAL1 gene activation, and chromatin anchoring. The corresponding region of H2A could fully rescue the strong defects caused by loss of this functionally essential region in the C terminus of H2A.Z. Despite the dramatic reduction in function, the H2A.Z(1-114) truncation still bound the H2A.Z deposition complex SWR1-C, the histone chaperone Chz1, and histone H2B. These data are consistent with a model in which retaining the variant in chromatin after its deposition by SWR1-C is a crucial determinant of its function.

EMBO Conference Series on the Assembly and Function of Neuronal Circuits.

The 2011 EMBO Conference Series on the Assembly and Function of Neuronal Circuits was held from 25 to 30 September 2011 at Monte Verità in Ascona, Switzerland. Approximately 100 participants explored current challenges and approaches to studying neural circuit function and organization.

Reading chromatin: insights from yeast into YEATS domain structure and function.

Chromatin-modifying complexes typically contain signature domains that either have catalytic activity or recognize and bind to specific histone modifications such as acetylation, methylation, and phosphorylation. Despite tremendous progress in this area, much remains to be learned in particular about the mechanistic functions of less well characterized signature domains. One such module is the evolutionary conserved YEATS domain, found in a variety of chromatin-modifying and transcription complexes from yeast to human. Three yeast proteins contain a YEATS domain, including Yaf9, a subunit of both the histone variant H2A.Z deposition complex SWR1-C and the histone acetyltransferase complex NuA4. The three-dimensional structure of the YEATS domain from Yaf9 was solved recently, revealing the existence of three distinct structural regions. One region is characterized by a shallow groove that might constitute a potential acetyl-lysine binding pocket, raising questions about potential protein interaction partners of the Yaf9 YEATS domain.

Roles for H2A.Z and its acetylation in GAL1 transcription and gene induction, but not GAL1-transcriptional memory.

H2A.Z is a histone H2A variant conserved from yeast to humans, and is found at 63% of promoters in Saccharomyces cerevisiae. This pattern of localization suggests that H2A.Z is somehow important for gene expression or regulation. H2A.Z can be acetylated at up to four lysine residues on its amino-terminal tail, and acetylated-H2A.Z is enriched in chromatin containing promoters of active genes. We investigated whether H2A.Z's role in GAL1 gene regulation and gene expression depends on H2A.Z acetylation. Our findings suggested that H2A.Z functioned both in gene regulation and in gene expression and that only its role in gene regulation depended upon its acetylation. Our findings provided an alternate explanation for results that were previously interpreted as evidence that H2A.Z plays a role in GAL1 transcriptional memory. Additionally, our findings provided new insights into the phenotypes of htz1Delta mutants: in the absence of H2A.Z, the SWR1 complex, which deposits H2A.Z into chromatin, was deleterious to the cell, and many of the phenotypes of cells lacking H2A.Z were due to the SWR1 complex's activity rather than to the absence of H2A.Z per se. These results highlight the need to reevaluate all studies on the phenotypes of cells lacking H2A.Z.

Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation.

Chromatin can be modified by posttranslational modifications of histones, ATP-dependent remodeling, and incorporation of histone variants. The Saccharomyces cerevisiae protein Yaf9 is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodeling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin. Yaf9 contains a YEATS domain, found in proteins associated with multiple chromatin-modifying enzymes and transcription complexes across eukaryotes. Here, we established the conservation of YEATS domain function from yeast to human, and determined the structure of this region from Yaf9 by x-ray crystallography to 2.3 A resolution. The Yaf9 YEATS domain consisted of a beta-sandwich characteristic of the Ig fold and contained three distinct conserved structural features. The structure of the Yaf9 YEATS domain was highly similar to that of the histone chaperone Asf1, a similarity that extended to an ability of Yaf9 to bind histones H3 and H4 in vitro. Using structure-function analysis, we found that the YEATS domain was required for Yaf9 function, histone variant H2A.Z chromatin deposition at specific promoters, and H2A.Z acetylation.

Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain.

BACKGROUND: Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36. RESULTS: Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP) under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine) and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH), and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36. CONCLUSION: Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.

YEATS domain proteins: a diverse family with many links to chromatin modification and transcription.

Chromatin modifications play crucial roles in various biological processes. An increasing number of conserved protein domains, often found in multisubunit protein complexes, are involved in establishing and recognizing different chromatin modifications. The YEATS domain is one of these domains, and its role in chromatin modifications and transcription is just beginning to be appreciated. The YEATS domain family of proteins, conserved from yeast to human, contains over 100 members in more than 70 eukaryotic species. Yaf9, Taf14, and Sas5 are the only YEATS domain proteins in Saccharomyces cerevisiae. Human YEATS domain family members, such as GAS41, ENL, and AF9, have a strong link to cancer. GAS41 is amplified in glioblastomas and astrocytomas; ENL and AF9 are among the most frequent translocation partners of the mixed lineage leukemia (MLL) gene. This review will focus on the best characterized YEATS proteins, discuss their diverse roles, and reflect potential functions of the YEATS domain.