Data-driven brain network models differentiate variability across language tasks

The relationship between brain structure and function has been probed using a variety of approaches, but how the underlying structural connectivity of the human brain drives behavior is far from understood. To investigate the effect of anatomical brain organization on human task performance, we use a data-driven computational modeling approach and explore the functional effects of naturally occurring structural differences in brain networks. We construct personalized brain network models by combining anatomical connectivity estimated from diffusion spectrum imaging of individual subjects with a nonlinear model of brain dynamics. By performing computational experiments in which we measure the excitability of the global brain network and spread of synchronization following a targeted computational stimulation, we quantify how individual variation in the underlying connectivity impacts both local and global brain dynamics. We further relate the computational results to individual variability in the subjects’ performance of three language-demanding tasks both before and after transcranial magnetic stimulation to the left-inferior frontal gyrus. Our results show that task performance correlates with either local or global measures of functional activity, depending on the complexity of the task. By emphasizing differences in the underlying structural connectivity, our model serves as a powerful tool to assess individual differences in task performances, to dissociate the effect of targeted stimulation in tasks that differ in cognitive demand, and to pave the way for the development of personalized therapeutics

Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor negative breast cancer

Calcium signaling is a critical regulator of cell proliferation. Elevated expression of calcium channels and pumps is a characteristic of some cancers, including breast cancer. We show that the plasma membrane calcium channel TRPV6, which is highly selective for Ca(2+), is overexpressed in some breast cancer cell lines. Silencing of TRPV6 expression in a breast cancer cell line with increased endogenous TRPV6 expression lead to a reduction in basal calcium influx and cellular proliferation associated with a reduction in DNA synthesis. TRPV6 gene amplification was identified as one mechanism of TRPV6 overexpression in a sub-set of breast cancer cell lines and breast tumor samples. Analysis of two independent microarray expression datasets from breast tumor samples showed that increased TRPV6 expression is a feature of estrogen receptor negative breast tumors encompassing the basal-like molecular subtype, as well as HER2-positive tumors. Breast cancer patients with high TRPV6 levels had decreased survival compared to patients with low or intermediate TRPV6 expression. Our findings suggest that inhibitors of TRPV6 may offer a novel therapeutic strategy for the treatment of estrogen receptor-negative breast cancers

The SAMI Galaxy Survey : mass as the driver of the kinematic morphology - density relation in clusters

We examine the kinematic morphology of early-type galaxies (ETGs) in eight galaxy clusters in the Sydney-AAO Multi-object Integral-field spectrograph Galaxy Survey. The clusters cover a mass range of 14.2log(M200/M☉) <15.2 and we measure spatially resolved stellar kinematics for 315 member galaxies with stellar masses 10.0 < log(M*/M☉) ≤ 11.7 within 1 R 200 of the cluster centers. We calculate the spin parameter, λ R , and use this to classify the kinematic morphology of the galaxies as fast or slow rotators (SRs). The total fraction of SRs in the ETG population is F SR = 0.14 ± 0.02 and does not depend on host cluster mass. Across the eight clusters, the fraction of SRs increases with increasing local overdensity. We also find that the slow-rotator fraction increases at small clustercentric radii (R cl < 0.3 R 200), and note that there is also an increase in the slow-rotator fraction at R cl ~ 0.6 R 200. The SRs at these larger radii reside in the cluster substructure. We find that the strongest increase in the slow-rotator fraction occurs with increasing stellar mass. After accounting for the strong correlation with stellar mass, we find no significant relationship between spin parameter and local overdensity in the cluster environment. We conclude that the primary driver for the kinematic morphology–density relationship in galaxy clusters is the changing distribution of galaxy stellar mass with the local environment. The presence of SRs in the substructure suggests that the cluster kinematic morphology–density relationship is a result of mass segregation of slow-rotating galaxies forming in groups that later merge with clusters and sink to the cluster center via dynamical friction.Publisher PDFPeer reviewe

The support and information needs of adolescents and young adults with cancer when active treatment ends

Background: The end of active treatment is a period of high stress for young people with cancer, but limited literature exists about their information and support needs during this phase. This study aimed to understand the needs of young people with cancer, how these needs are currently being met, and how best to provide information and support at the end of active treatment. Methods: This was a multi-stage, mixed methods study exploring the end of treatment experience from the perspectives of young people, and the healthcare professionals caring for them. Semi-structured interviews were undertaken with healthcare professionals, which informed a survey administered nationally. Subsequently, semi-structured interviews were conducted with young people. These combined results informed a co-design workshop to develop recommendations. Results: Telephone interviews were conducted with 12 healthcare professionals and 49 completed the online survey. A total of 11 young people aged 19-26 years (female = 8; 73%) were interviewed. The stakeholder workshop was attended by both healthcare professionals (n = 8) and young people (n = 3). At the end of treatment young people experience numerous ongoing physical issues including pain, fatigue and insomnia; in addition to a range of psychosocial and emotional issues including anxiety, fear of recurrence and isolation. The top three priorities for end of treatment care were: earlier provision and preparation around on-going impact of cancer and cancer treatment; standardised and continued follow-up of young people's emotional well-being; and development of more information and resources specific to young people. Conclusion: The access and availability of appropriate information and sources of support at the end of treatment is variable and inequitable. Young people's needs would be more effectively met by timely, structured and accessible information, and support provision at the end of treatment to both prepare and enable adaptation across their transition to living with and beyond cancer. This will require both organisational and practical adjustments in care delivery, in addition to a renewed and updated understanding of what the 'end of treatment' transition process means

High rate of loss to clinical follow up among African HIV-infected patients attending a London clinic: a retrospective analysis of a clinical cohort

<p>Abstract</p> <p>Background</p> <p>Long-term regular clinic follow up is an important component of HIV care. We determined the frequency and characteristics of HIV-infected patients lost to follow up from a London HIV clinic, and factors associated with loss to all HIV follow up in the UK.</p> <p>Methods</p> <p>We identified 1859 HIV-infected adults who had registered and attended a London clinic on one or more occasions between January 1997 and December 2005. Loss to follow up was defined as clinic non-attendance for one or more years. Through anonymized linkage with the Survey of Prevalent HIV Infections Diagnosed and Health Protection Scotland, national databases of all HIV patients in care in the UK up to December 2006, loss-to-follow-up patients were categorized as Transfers (subsequently received care at another UK HIV clinic) or UKLFU (no record of subsequent attendance at any HIV clinic in the UK). Logistic regression analysis was used to identify factors associated with UKLFU for those both on highly active antiretroviral therapy (HAART) and not on HAART.</p> <p>Results</p> <p>In total, 722 (38.8%) of 1859 patients were defined as lost to follow up. Of these, 347 (48.1%) were Transfers and 375 (51.9%), or 20.2% of all patients, were UKLFU. Overall, 11.9% of all patients receiving HAART, and 32.2% not receiving HAART were UKLFU. Among those on HAART, risk factors for UKLFU were: African heterosexual female (OR = 2.22, 95% CI: 1.11-4.56) versus white men who have sex with men; earlier year of HIV clinic registration (1997-1999 OR: 3.51, 95% CI: 1.97-6.26; 2000-02 OR: 2.49, 95% CI: 1.43-4.32 vs. 2003-2005); CD4 count of < 200 versus > 350 cells/mm³(OR = 1.99, 95% CI:1.05-3.74); and a detectable viral load of > 400 copies/ml (OR = 5.03, 95% CI: 2.95-8.57 vs. ≤ 400 copies/ml) at last clinic visit.</p> <p>Among those not receiving HAART, factors were: African heterosexual male (OR = 3.91, 95% CI: 1.77-8.64) versus white men who have sex with men; earlier HIV clinic registration (2000-2002 OR: 2.91, 95% CI: 1.77-4.78; 1997-1999: OR: 5.26, 95% CI: 2.71-10.19); and a CD4 count of < 200 cells/mm³(OR: 3.24, 95% CI: 1.49-7.04).</p> <p>Conclusions</p> <p>One in five HIV-infected patients (one in three not on HAART and one in nine on HAART) from a London clinic were lost to all clinical follow up in the UK. Black African ethnicity, earlier year of clinic registration and advanced immunological suppression were the most important predictors of UKLFU. There is a need for all HIV clinics to establish systems for monitoring and tracing loss-to-follow-up patients, and to implement strategies for improving retention in care.</p

Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2

The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental gene regulation in multicellular organisms. PRC1 and PRC2 modify chromatin by catalysing histone H2A lysine 119 ubiquitylation (H2AK119u1), and H3 lysine 27 methylation (H3K27me3), respectively. Reciprocal crosstalk between these modifications is critical for the formation of stable Polycomb domains at target gene loci. While the molecular mechanism for recognition of H3K27me3 by PRC1 is well defined, the interaction of PRC2 with H2AK119u1 is poorly understood. Here we demonstrate a critical role for the PRC2 cofactor Jarid2 in mediating the interaction of PRC2 with H2AK119u1. We identify a ubiquitin interaction motif at the amino-terminus of Jarid2, and demonstrate that this domain facilitates PRC2 localization to H2AK119u1 both in vivo and in vitro. Our findings ascribe a critical function to Jarid2 and define a key mechanism that links PRC1 and PRC2 in the establishment of Polycomb domains

Rapid Molecular Detection of Rifampicin Resistance Facilitates Early Diagnosis and Treatment of Multi-Drug Resistant Tuberculosis: Case Control Study

Multi-drug resistant tuberculosis (MDR-TB) is a major public health concern since diagnosis is often delayed, increasing the risk of spread to the community and health care workers. Treatment is prolonged, and the total cost of treating a single case is high. Diagnosis has traditionally relied upon clinical suspicion, based on risk factors and culture with sensitivity testing, a process that can take weeks or months. Rapid diagnostic molecular techniques have the potential to shorten the time to commencing appropriate therapy, but have not been put to the test under field conditions.This retrospective case-control study aimed to identify risk factors for MDR-TB, and analyse the impact of testing for rifampicin resistance using RNA polymerase B (rpoB) mutations as a surrogate for MDR-TB. Forty two MDR-TB cases and 84 fully sensitive TB controls were matched by date of diagnosis; and factors including demographics, clinical presentation, microbiology findings, management and outcome were analysed using their medical records. Conventionally recognised risk factors for MDR-TB were absent in almost half (43%) of the cases, and 15% of cases were asymptomatic. A significant number of MDR-TB cases were identified in new entrants to the country. Using rpoB mutation testing, the time to diagnosis of MDR-TB was dramatically shortened by a median of 6 weeks, allowing patients to be commenced on appropriate therapy a median of 51days earlier than those diagnosed by conventional culture and sensitivity testing.MDR-TB is frequently an unexpected finding, may be asymptomatic, and is particularly prevalent among TB infected new entrants to the country. Molecular resistance testing of all acid fast bacilli positive specimens has the potential to rapidly identify MDR-TB patients and commence them on appropriate therapy significantly earlier than by conventional methods

Functional Brain Network Modularity Captures Inter- and Intra-Individual Variation in Working Memory Capacity

Cognitive abilities, such as working memory, differ among people; however, individuals also vary in their own day-to-day cognitive performance. One potential source of cognitive variability may be fluctuations in the functional organization of neural systems. The degree to which the organization of these functional networks is optimized may relate to the effective cognitive functioning of the individual. Here we specifically examine how changes in the organization of large-scale networks measured via resting state functional connectivity MRI and graph theory track changes in working memory capacity.Twenty-two participants performed a test of working memory capacity and then underwent resting-state fMRI. Seventeen subjects repeated the protocol three weeks later. We applied graph theoretic techniques to measure network organization on 34 brain regions of interest (ROI). Network modularity, which measures the level of integration and segregation across sub-networks, and small-worldness, which measures global network connection efficiency, both predicted individual differences in memory capacity; however, only modularity predicted intra-individual variation across the two sessions. Partial correlations controlling for the component of working memory that was stable across sessions revealed that modularity was almost entirely associated with the variability of working memory at each session. Analyses of specific sub-networks and individual circuits were unable to consistently account for working memory capacity variability.The results suggest that the intrinsic functional organization of an a priori defined cognitive control network measured at rest provides substantial information about actual cognitive performance. The association of network modularity to the variability in an individual's working memory capacity suggests that the organization of this network into high connectivity within modules and sparse connections between modules may reflect effective signaling across brain regions, perhaps through the modulation of signal or the suppression of the propagation of noise

Voluntary HIV counselling and testing among men in rural western Uganda: Implications for HIV prevention

<p>Abstract</p> <p>Background</p> <p>Voluntary HIV counselling and testing (VCT) is one of the key strategies in the prevention and control of HIV/AIDS in Uganda. However, the utilization of VCT services particularly among men is low in Kasese district. We therefore conducted a study to determine the prevalence and factors associated with VCT use among men in Bukonzo West health sub-district, Kasese district.</p> <p>Methods</p> <p>A population-based cross-sectional study employing both quantitative and qualitative techniques of data collection was conducted between January and April 2005. Using cluster sampling, 780 men aged 18 years and above, residing in Bukonzo West health sub-district, were sampled from 38 randomly selected clusters. Data was collected on VCT use and independent variables. Focus group discussions (4) and key informant interviews (10) were also conducted. Binary logistic regression was performed to determine the predictors of VCT use among men.</p> <p>Results</p> <p>Overall VCT use among men was 23.3% (95% CI 17.2–29.4). Forty six percent (95% CI 40.8–51.2) had pre-test counselling and 25.9% (95%CI 19.9–31.9) had HIV testing. Of those who tested, 96% returned for post-test counselling and received HIV results. VCT use was higher among men aged 35 years and below (OR = 2.69, 95%CI 1.77–4.07), the non-subsistence farmers (OR = 2.37, 95%CI 2.37), the couple testing (OR = 2.37, 95%CI 1.02–8.83) and men with intention to disclose HIV test results to sexual partners (OR = 1.64, 95%CI 1.04–2.60). The major barriers to VCT use among men were poor utilization of VCT services due to poor access, stigma and confidentiality of services.</p> <p>Conclusion</p> <p>VCT use among men in Bukonzo West, Kasese district was low. In order to increase VCT use among men, the VCT programme needs to address HIV stigma and improve access and confidentiality of VCT services. Among the more promising interventions are the use of routine counselling and testing for HIV of patients seeking health care in health units, home based VCT programmes, and mainstreaming of HIV counselling and testing services in community development programmes.</p

Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal rTMS in major depression

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain’s emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection