The white matter of the brain consists of fiber tracts that connect different regions of the brain. Among these tracts, the intrahemispheric cortico-cortical connections are called association fibers. The U-fibers are short association fibers that connect adjacent gyri. These fibers were thought to work as part of the cortico-cortical networks to execute associative brain functions. However, their anatomy and functions have not been documented in detail for the human brain. In past studies, U-fibers have been characterized in the human brain with diffusion tensor imaging (DTI). However, the validity of such findings remains unclear. In this study, DTI of the macaque brain was performed, and the anatomy of U-fibers was compared with that of the human brain reported in a previous study. The macaque brain was chosen because it is the most commonly used animal model for exploring cognitive functions and the U-fibers of the macaque brain have been already identified by axonal tracing studies, which makes it an ideal system for confirming the DTI findings. Ten U-fibers found in the macaque brain were also identified in the human brain, with a similar organization and topology. The delineation of these species-conserved white matter structures may provide new options for understanding brain anatomy and function.

The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC50’s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12 hours following infection. Twenty-nine #13-like and twelve #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post entry.

Purpose

This study aims to explore gene expression signatures and serum biomarkers to predict intrinsic chemoresistance in epithelial ovarian cancer (EOC).

Patients and Methods

Gene expression profiling data of 322 high-grade EOC cases between 2009 and 2010 in The Cancer Genome Atlas project (TCGA) were used to develop and validate gene expression signatures that could discriminate different responses to first-line platinum/paclitaxel-based treatments. A gene regulation network was then built to further identify hub genes responsible for differential gene expression between the complete response (CR) group and the progressive disease (PD) group. Further, to find more robust serum biomarkers for clinical application, we integrated our gene signatures and gene signatures reported previously to identify secretory protein-encoding genes by searching the DAVID database. In the end, gene-drug interaction network was constructed by searching Comparative Toxicogenomics Database (CTD) and literature.

Results

A 349-gene predictive model and an 18-gene model independent of key clinical features with high accuracy were developed for prediction of chemoresistance in EOC. Among them, ten important hub genes and six critical signaling pathways were identified to have important implications in chemotherapeutic response. Further, ten potential serum biomarkers were identified for predicting chemoresistance in EOC. Finally, we suggested some drugs for individualized treatment.

Conclusion

We have developed the predictive models and serum biomarkers for platinum/paclitaxel response and established the new approach to discover potential serum biomarkers from gene expression profiles. The potential drugs that target hub genes are also suggested.

Exposure to interparental violence is associated with negative outcomes, such as depression, post-traumatic stress disorder and reduced cognitive abilities. However, little is known about the potential effects of witnessing domestic violence during childhood on gray matter volume (GMV) or cortical thickness. High-resolution 3.0 T volumetric scans (Siemens Trio Scanner) were obtained on 52 subjects (18–25 years) including 22 (6 males/16 females) with a history of visually witnessing episodes of domestic violence, and 30 (8 males/22 females) unexposed control subjects, with neither a current nor past DSM-IV Axis I or II disorder. Potential confounding effects of age, gender, level of parental verbal aggression, parental education, financial stress, full scale IQ, and total GMV, or average thickness were modeled using voxel based morphometry and FreeSurfer. Witnessing domestic violence subjects had a 6.1% GMV reduction in the right lingual gyrus (BA18) (P = 0.029, False Discovery Rate corrected peak level). Thickness in this region was also reduced, as was thickness in V2 bilaterally and left occipital pole. Theses regions were maximally sensitive to exposure to witnessing domestic violence between 11–13 years of age. Regional reductions in GMV and thickness were observed in both susceptible and resilient witnessing domestic violence subjects. Results in subjects witnessing domestic violence were similar to previously reported results in subjects with childhood sexual abuse, as the primary region affected was visual cortex. Brain regions that process and convey the adverse sensory input of the abuse may be specifically modified by this experience, particularly in subjects exposed to a single type of maltreatment. Exposure to multiple types of maltreatment is more commonly associated with morphological alterations in corticolimbic regions. These findings fit with preclinical studies showing that visual cortex is a highly plastic structure.

HOXA9, and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

Introduction

The aim of the study was to assess the association between attention deficit/hyperactivity disorder (ADHD) symptoms and potentially obesogenic behaviors.

Methods

Data of 11,676 German children and adolescents (6–17 years) were analyzed. Television/video exposure, physical activity, food frequency and portion size were assessed using questionnaires. A dietary quality index, energy density and volumes of consumed food, and total energy intake were calculated. The parent-rated hyperactivity/inattention subscale of the Strengths and Difficulties Questionnaire (SDQ-HI) was used as a continuous measure of ADHD symptoms. Associations were analyzed with general linear models adjusting for sex, age, socioeconomic status, migrant status, parental BMI, and parental smoking.

Results

SDQ-HI scores correlated positively with physical activity, average energy density of food, volume of beverages, total energy intake, and television exposure and negatively with the nutritional quality score (HuSKY) even after adjustment for parental variables (BMI, smoking, socioeconomic status, migrant status), age, sex, as well as the other SDQ subscales. The adjusted association of the SDQ-HI scores with the nutritional quality score was stronger in girls and the associations with food volume, food energy, and total energy intake was significant only in girls.

Conclusions

Poor nutritional quality, high energy intake and television exposure appear to be independently associated with ADHD symptoms. The relationship between food energy intake and ADHD symptoms was especially pronounced in girls and this may help to explain the reported association of ADHD symptoms with overweight in adolescent girls.

There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

Narrative Abstract

Many clinical investigators feel that the burden of institutional review board (IRB) requirements has been consistently increasing over recent years, though there are few objective data describing these trends. Over a period of 7 years the Reproductive Medicine Network observed a significant increase in the size and requirements of IRB submissions, and significant variability of IRB performance in reviewing multicenter trials. These additional regulatory and administrative demands represent substantial burdens to researchers and to the IRBs themselves. It is timely to consider whether these changes better protect the interests and safety of human research participants.

White matter provides anatomic connections among brain regions and has received increasing attention in understanding brain intrinsic networks and neurological disorders. Despite significant progresses made in characterizing the white matter’s structural properties using post-mortem techniques and in vivo diffusion-tensor-imaging (DTI) methods, its physiology remains poorly understood. In the present study, cerebral blood flow (CBF) of the white matter was investigated on a fiber-tract-specific basis using MRI (N=10, 25-33 years old). It was found that CBF in the white matter varied considerably, up to a factor of two between fiber groups. Furthermore, a paradoxically inverse correlation was observed between white matter CBF and structural and functional connectivities (P<0.001). Fiber tracts that had a higher CBF tended to have a lower fractional anisotropy in water diffusion, and the gray matter terminals connected to the tract also tended to have a lower temporal synchrony in resting-state BOLD signal fluctuation. These findings suggest a clear association between white matter perfusion and gray matter activity, but the nature of this relationship requires further investigations given that they are negatively, rather than positively, correlated.

Protein-bound dinitrosyl iron complexes (DNICs) have been observed in prokaryotic and eukaryotic cells under nitric oxide (NO) stress. The identity of proteins that bind DNICs, however, still remains elusive. Here we demonstrate that iron-sulfur proteins are the major source of protein-bound DNICs formed in Escherichia coli cells under NO stress. Expression of recombinant iron-sulfur proteins, but not the proteins without iron-sulfur clusters, almost doubles the amount of protein-bound DNICs formed in E. coli cells after NO exposure. Purification of recombinant proteins from the NO-exposed E. coli cells further confirms that iron-sulfur proteins, but not the proteins without iron-sulfur clusters, are modified forming protein-bound DINCs. Deletion of the iron-sulfur cluster assembly proteins IscA and SufA to block the [4Fe-4S] cluster biogenesis in E. coli cells largely eliminates the NO-mediated formation of protein-bound DNICs, suggesting that iron-sulfur clusters are mainly responsible for the NO-mediated formation of protein-bound DNICs in cells. Furthermore, depletion of “chelatable iron pool” in the wild-type E. coli cells effectively removes iron-sulfur clusters from proteins and concomitantly diminishes the NO-mediated formation of protein-bound DNICs, indicating that iron-sulfur clusters in proteins constitute at least part of “chelatable iron pool” in cells.

Quantifying the connectivity between arbitrary surface patches in the human brain cortex can be used in studies on brain function and to characterize clinical diseases involving abnormal connectivity. Cortical regions of human brain in their natural forms can be represented in surface formats. In this paper, we present a framework to quantify connectivity using cortical surface segmentation and labeling from structural magnetic resonance images, tractography from diffusion tensor images, and nonlinear inter-subject registration. For a single subject, the connectivity intensity of any point on the cortical surface is set to unity if the point is connected and zero if it is not connected. The connectivity proportion is defined as the ratio of the total connected surface area to the total area of the surface patch. By nonlinearly registering the connectivity data of a group of normal controls into a template space, a population connectivity metric can be defined as either the average connectivity intensity of a cortical point or the average connectivity proportion of a cortical region. In the template space, a connectivity profile and a connectivity histogram of an arbitrary cortical region of interest can then be derived from these connectivity quantification values. Results from the application of these quantification metrics to a population of schizophrenia patients and normal controls are presented, revealing connectivity signatures of specified cortical regions and detecting connectivity abnormalities.

Alterations in white matter integrity of several cortical and subcortical circuits have been reported in relation to unipolar major depressive disorder. It is not clear whether these white matter changes precede the onset of illness. In all, 13 adolescent volunteers with no personal or family history of a psychiatric disorder (controls) and 18 adolescent volunteers with no personal history of a psychiatric illness including depression, but who were at high risk for developing unipolar depression by virtue of parental depression (high-risk youth), underwent diffusion tensor imaging studies. An automated tract-based spatial statistics method, a whole-brain voxel-by-voxel analysis, was used to analyze the scans. Population average diffusion parameter values were also calculated for each tract. Adolescents at high risk for unipolar depression had lower fractional anisotropy (FA) values in the left cingulum, splenium of the corpus callosum, superior longitudinal fasciculi, uncinate, and inferior fronto-occipital fasciculi than did controls. Altered white matter integrity in healthy adolescents at familial risk for unipolar depression suggests that it might serve as a vulnerability marker for the illness.

High temperatures alter the physical properties of the plasma membrane and cause loss-of-function in the embedded proteins. Effective membrane and protein recycling through intracellular vesicular traffic is vital to maintain the structural and functional integrity of the plasma membrane under heat stress. However, in this regard, little experimental data is available. Our characterization of the Arabidopsis hit1-1 mutant, linking a subunit of a vesicle tethering complex to plasma membrane thermostability, provided valuable information to this end. We further dissected the effect of the hit1-1 mutation on plasma membrane properties and found that even at optimal growth temperature (23°C), the hit1-1 mutant exhibited a plasma membrane protein profile distinct from that of wild-type plants. This result implies that the hit1-1 mutation essentially alters vesicle trafficking and results in changes in the plasma membrane components under non-stress conditions. Such changes do not affect normal plant growth and development, but is significant for plant survival under heat stress.

Summary

Synaptotagmin 1 (syt1) functions as the Ca2+-sensor for neuronal exocytosis. Here site-directed spin labeling was used to examine the complex formed between a soluble fragment of syt1, which contains its two C2 domains, and the neuronal core SNARE complex. Changes in EPR lineshape and accessibility for spin-labeled syt1 mutants indicate that in solution, the assembled core SNARE complex contacts syt1 in several regions. For the C2B domain, contact occurs in the polybasic face and sites opposite the Ca2+-binding loops. For the C2A domain, contact is seen with the SNARE complex in a region near loop 2. Double electron-electron resonance was used to estimate distances between the two C2 domains of syt1. These distances have broad distributions in solution, which do not significantly change when syt1 is fully associated with the core SNARE complex. The broad distance distributions indicate that syt1 is structurally heterogeneous when bound to the SNAREs and does not assume a well-defined structure. Simulated annealing using EPR-derived distance restraints produces a family of syt1 structures where the Ca2+-binding regions of each domain face in roughly opposite directions. The results suggest that when associated with the SNAREs, syt1 is configured to bind opposing bilayers, but that the syt1/SNARE complex samples multiple conformational states.

MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Intragenic miRNAs account for ∼50% of mammalian miRNAs. Classic studies reported that they are usually coexpressed with host genes. Here, using genome-wide miRNA and gene expression profiles from five sample sets, we show that evolutionarily conserved (‘old’) intragenic miRNAs tend to be coexpressed with host genes, but non-conserved (‘young’) ones rarely do so. This result is robust: in all sample sets, the coexpression rate of young miRNAs is significantly lower than that of conserved ones even after controlling for abundance. As a result, although young miRNAs dominate in human genome, the majority of intragenic miRNAs that show coexpression with host genes are phylogenetically old ones. For younger miRNAs, extrapolation of their expression profiles from those of their host genes should be treated with caution. We propose a model to explain this phenomenon in which the majority of young miRNAs are unlikely to be coexpressed with host genes; however, for some fraction of young miRNAs coexpression with their host genes, initially imbued by chromatin level effects, is advantageous and these are the ones likely to embed into the system and evolve ever higher levels of coexpression, possibly by evolving piggybacking mechanisms.

SYNOPSIS

IscA is a key member of the iron-sulfur cluster assembly machinery in prokaryotic and eukaryotic organisms; however, the physiological function of IscA still remains elusive. Here we report the in vivo evidence demonstrating the iron binding activity of IscA in Escherichia coli cells. Supplement of exogenous iron (1μM) in the M9 minimal medium is sufficient to maximize the iron binding in IscA expressed in E. coli cells under aerobic growth conditions. In contrast, IscU, an iron-sulfur cluster assembly scaffold protein, or CyaY, a bacterial frataxin homologue, fails to bind any iron in E. coli cells under the same experimental conditions. Interestingly, the strong iron binding activity of IscA is greatly diminished in E. coli cells under anaerobic growth conditions. Additional studies reveal that oxygen in medium promotes the iron binding in IscA and that the iron binding in IscA in turn prevents formation of biologically inaccessible ferric hydroxide under aerobic conditions. Consistent with the differential iron binding activity of IscA under aerobic and anaerobic conditions, we find that IscA and its paralog SufA are essential for the iron-sulfur cluster assembly in E. coli cells under aerobic growth conditions but not under anaerobic growth conditions. The results provide the in vivo evidence that IscA may act as an iron chaperone for the biogenesis of iron-sulfur clusters in E. coli cells under aerobic conditions.

Human papillomaviruses (HPV) are common sexually transmitted pathogens that in women predispose them to cervical and other anogenital cancers. HPV vaccines can prevent infection by some but not other sexually transmitted HPVs, but are too costly for use in much of the world at greatest risk to HPV-associated cancers. Microbicides provide an inexpensive alternative to vaccines. In a high throughput screen, drugs that inhibit the cellular protein complex known as gamma secretase were identified as potential HPV microbicides. Gamma secretase inhibitors (GSIs) inhibited the infectivity of HPV pseudoviruses both in human keratinocytes and in mouse cells, with IC50s in the picomolar to nanomolar range. Using a mouse model, we observed that a GSI could inhibit HPV infection to the same degree as its effectiveness in inhibiting gamma secretase activity in vivo. We conclude that gamma secretase activity is required for HPV infection, and that GSIs are effective microbicides against anogenital HPVs.

BACKGROUND

Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables.

METHODS

The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses.

RESULTS

Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin.

CONCLUSIONS

Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.

The G1/S transition is a critical control point for cell proliferation and involves essential transcription complexes termed SBF and MBF in Saccharomyces cerevisiae or MBF in Schizosaccharomyces pombe. In the fungal pathogen Candida albicans, G1/S regulation is not clear. To gain more insight into the G1/S circuitry, we characterized Swi6p, Swi4p and Mbp1p, the closest orthologues of SBF (Swi6p and Swi4p) and MBF (Swi6p and Mbp1p) components in S. cerevisiae. The mbp1Δ/Δ cells showed minor growth defects, whereas swi4Δ/Δ and swi6Δ/Δ yeast cells dramatically increased in size, suggesting a G1 phase delay. Gene set enrichment analysis (GSEA) of transcription profiles revealed that genes associated with G1/S phase were significantly enriched in cells lacking Swi4p and Swi6p. These expression patterns suggested that Swi4p and Swi6p have repressing as well as activating activity. Intriguingly, swi4Δ/Δ swi6Δ/Δ and swi4Δ/Δ mbp1Δ/Δ strains were viable, in contrast to the situation in S. cerevisiae, and showed pleiotropic phenotypes that included multibudded yeast, pseudohyphae, and intriguingly, true hyphae. Consistently, GSEA identified strong enrichment of genes that are normally modulated during C. albicans-host cell interactions. Since Swi4p and Swi6p influence G1 phase progression and SBF binding sites are lacking in the C. albicans genome, these factors may contribute to MBF activity. Overall, the data suggest that the putative G1/S regulatory machinery of C. albicans contains novel features and underscore the existence of a relationship between G1 phase and morphogenetic switching, including hyphal development, in the pathogen.

Alterations in white matter integrity of several cortical and sub-cortical circuits have been reported in relation to unipolar major depressive disorder. It is not clear whether these white matter changes precede the onset of illness. Thirteen adolescent volunteers with no personal or family history of a psychiatric disorder (controls) and 18 adolescent volunteers with no personal history of a psychiatric illness including depression, but who were at high risk for developing unipolar depression by virtue of parental depression (high-risk youth), underwent diffusion tensor imaging studies. An automated tract-based spatial statistics (TBSS) method, a whole-brain voxel-by-voxel analysis, was used to analyze the scans. Population average diffusion parameter values also were calculated for each tract. Adolescents at high risk for unipolar depression had lower fractional anisotropy (FA) values in the left cingulum, splenium of the corpus callosum, superior longitudinal fasciculi, uncinate and inferior fronto-occipital fasciculi than controls. Altered white matter integrity in healthy adolescents at familial risk for unipolar depression suggests that it might serve as a vulnerability marker for the illness.

To study the temporal and spatial dynamics of carbon fixation by Moso bamboo (Phyllostachys pubescens) in subtropical China, carbon fixation of leaves within the canopy of P. pubescens was measured with a LI-6400 portable photosynthesis system. The results showed that the capability of carbon fixation of P. pubescens leaves had obvious temporal and spatial dynamic variations. It was revealed that there were two peak periods and two low periods in the season variation of carbon fixation capability. Data also revealed that the capability of carbon fixation by five-year-old P. pubescens was more than that of one-year-old and three-year-old. Daily and seasonal carbon fixation showed a negative correlation with the CO2 concentration. The temporal and spatial dynamics of carbon fixation by P. pubescens described above provided a scientific basis for development of technologies in bamboo timber production.

This study developed portable, non-invasive flexible humidity and temperature microsensors and an in situ wireless sensing system for a proton exchange membrane fuel cell (PEMFC). The system integrated three parts: a flexible capacitive humidity microsensor, a flexible resistive temperature microsensor, and a radio frequency (RF) module for signal transmission. The results show that the capacitive humidity microsensor has a high sensitivity of 0.83 pF%RH−1 and the resistive temperature microsensor also exhibits a high sensitivity of 2.94 × 10−3 °C−1. The established RF module transmits the signals from the two microsensors. The transmission distance can reach 4 m and the response time is less than 0.25 s. The performance measurements demonstrate that the maximum power density of the fuel cell with and without these microsensors are 14.76 mW·cm−2 and 15.90 mW·cm−2, with only 7.17% power loss.

The hippocampus governs memory formation and emotional regulation and there is widespread evidence of hippocampal dysfunction in psychiatric disorders including schizophrenia and autism. There is abundant evidence that prenatal viral infection may play a role in the development of these two disorders. In the current study we have examined gene expression and structural changes of the hippocampi of exposed neonates following maternal infection at E16 (middle second trimester). We observed significant changes in gene expression at P0 (birth), P14 (childhood), and P56 (adulthood) including a number of candidate genes for autism and schizophrenia. qRT-PCR, verified the direction and magnitude of change for 5 of the genes from the microarray data set revealed mRNA changes for additional genes associated with schizophrenia and autism. MRI revealed a decrease in hippocampal volume at P35 (adolescence). Our results demonstrate altered gene expression and reduced hippocampal volume following prenatal viral infection at E16.

In the human brain, different regions of the cortex communicate via white matter tracts. Investigation of this connectivity is essential for understanding brain function. It has been shown that trajectories of white matter fiber bundles can be estimated based on orientational information that is obtained from diffusion tensor imaging (DTI). By extrapolating this information, cortical regions associated with a specific white matter tract can be estimated. In this study, we created population-averaged cortical maps of brain connectivity for 4 major association fiber tracts, the corticospinal tract (CST), and commissural fibers. It is shown that these 4 association fibers interconnect all 4 lobes of the hemispheres. Cortical regions that were assigned based on association with the CST and the superior longitudinal fasciculus (SLF) agreed with locations of their known (CST: motor) or putative (SLF: language) functions. The proposed approach can potentially be used for quantitative assessment of the effect of white matter abnormalities on associated cortical regions.

Summary

Synaptotagmin 1 (syt1) is a synaptic vesicle membrane protein that functions as the Ca2+-sensor in neuronal exocytosis. Here, site-directed spin labeling was used to generate models for the solution and membrane bound structures of a soluble fragment of syt1 containing its two C2 domains, C2A and C2B. In solution, distance restraints between the two C2 domains of syt1 were measured using double electron-electron resonance (DEER) and used in a simulated annealing routine to generate models for the structure of the tandem C2A-C2B fragment. The data indicate that the two C2 domains are flexibly linked and do not interact with each other in solution, with or without Ca2+. However, the favored orientation is one where the Ca2+-binding loops are oriented in opposite directions. A similar approach was taken for membrane associated C2A–C2B, combining both distances and bilayer depth restraints with simulated annealing. The restraints can only be satisfied if the Ca2+ and membrane binding surfaces of the domains are oriented in opposite directions so that C2A and C2B are docked to opposing bilayers. The result suggests that syt1 functions to bridge across the vesicle and plasma membrane surfaces in a Ca2+-dependent manner.