Altered Cortico-Striatal Connectivity in Offspring of Schizophrenia Patients Relative to Offspring of Bipolar Patients and Controls

Schizophrenia (SZ) and bipolar disorder (BD) share clinical features, genetic risk factors and neuroimaging abnormalities. There is evidence of disrupted connectivity in resting state networks in patients with SZ and BD and their unaffected relatives. Resting state networks are known to undergo reorganization during youth coinciding with the period of increased incidence for both disorders. We therefore focused on characterizing resting state network connectivity in youth at familial risk for SZ or BD to identify alterations arising during this period. We measured resting-state functional connectivity in a sample of 106 youth, aged 7-19 years, comprising offspring of patients with SZ (N = 27), offspring of patients with BD (N = 39) and offspring of community control parents (N = 40). We used Independent Component Analysis to assess functional connectivity within the default mode, executive control, salience and basal ganglia networks and define their relationship to grey matter volume, clinical and cognitive measures. There was no difference in connectivity within any of the networks examined between offspring of patients with BD and offspring of community controls. In contrast, offspring of patients with SZ showed reduced connectivity within the left basal ganglia network compared to control offspring, and they showed a positive correlation between connectivity in this network and grey matter volume in the left caudate. Our findings suggest that dysconnectivity in the basal ganglia network is a robust correlate of familial risk for SZ and can be detected during childhood and adolescence

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

Brain-age prediction:Systematic evaluation of site effects, and sample age range and size

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5–90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8–80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9–25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5–40 and 40–90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.</p

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

Brain‐age prediction: systematic evaluation of site effects, and sample age range and size

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain‐age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain‐age has highlighted the need for robust and publicly available brain‐age models pre‐trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain‐age model. Here we expand this work to develop, empirically validate, and disseminate a pre‐trained brain‐age model to cover most of the human lifespan. To achieve this, we selected the best‐performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain‐age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5–90 years; 53.59% female). The pre‐trained models were tested for cross‐dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8–80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9–25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age‐bins (5–40 and 40–90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain‐age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open‐science, web‐based platform for individualized neuroimaging metrics

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Using genealogical trees to examine admixture between modern humans and Neandertals

This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of &amp;Tilde;712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, revealing distinct bimodal distributions of estimated coalescence times between non-African and Neandertal haplotypes. A Neandertal population history is inferred, from the time of their split with humans up to &amp;Tilde;50,000 years ago (the fossil age), showing this archaic species to have suffered a bottleneck at this time, consistent with leaving Africa, followed by a further reduction to extinction. Contrasting African-Neandertal and Eurasian-Neandertal analyses are used to define admixture using genealogical trees, and test our procedures in CEPHi via coalescent-based simulations. This region-level definition of admixture is used to specify sets of introgressed coldspots across 13 modern human populations. These sets are compared between pairs of populations, revealing information about the possible timing of interactions between Neandertals and modern humans, and sharing of admixture events between human groups, especially with respect to the split time between European and Asian populations. Online sets of introgressed regions for each of the four continents in our dataset are provided: African, American, Asian, and European. Finally, in order to investigate the variation in time of contact between Neandertals and individual human populations, a novel method is described and implemented which dates admixture between individual human populations and Neandertals, using information from genealogical trees. Dates of admixture are estimated as ~50-60,000 years in the past in European populations, and &amp;Tilde;80-90,000 years in the past in Asian populations, suggestive of potentially somewhat distinct histories between European and Asian populations. This method can be applied to date any set of introgressed regions, including those shared between particular populations, enabling a clearer picture of the joint evolutionary history of modern humans, Neandertals, and other archaic species.</p

Using genealogical trees to examine admixture between modern humans and Neandertals

This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of &Tilde;712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, revealing distinct bimodal distributions of estimated coalescence times between non-African and Neandertal haplotypes. A Neandertal population history is inferred, from the time of their split with humans up to &Tilde;50,000 years ago (the fossil age), showing this archaic species to have suffered a bottleneck at this time, consistent with leaving Africa, followed by a further reduction to extinction. Contrasting African-Neandertal and Eurasian-Neandertal analyses are used to define admixture using genealogical trees, and test our procedures in CEPHi via coalescent-based simulations. This region-level definition of admixture is used to specify sets of introgressed coldspots across 13 modern human populations. These sets are compared between pairs of populations, revealing information about the possible timing of interactions between Neandertals and modern humans, and sharing of admixture events between human groups, especially with respect to the split time between European and Asian populations. Online sets of introgressed regions for each of the four continents in our dataset are provided: African, American, Asian, and European. Finally, in order to investigate the variation in time of contact between Neandertals and individual human populations, a novel method is described and implemented which dates admixture between individual human populations and Neandertals, using information from genealogical trees. Dates of admixture are estimated as ~50-60,000 years in the past in European populations, and &Tilde;80-90,000 years in the past in Asian populations, suggestive of potentially somewhat distinct histories between European and Asian populations. This method can be applied to date any set of introgressed regions, including those shared between particular populations, enabling a clearer picture of the joint evolutionary history of modern humans, Neandertals, and other archaic species.</p