Patterns Of Dysregulation Research Articles

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.

Construction of a long non‑coding RNA‑mediated transcription factor and gene regulatory triplet network reveals global patterns and biomarkers for ischemic stroke.

Ischemic stroke (IS) is a severe neurological disease and a major cause of death and disability throughout the world. A long non-coding (lnc)RNA, transcription factor (TF) and gene can form a lncRNA-mediated regulatory triplet (LncMRT), which is a functional network motif that regulates numerous aspects of human diseases. However, systematic identification and molecular characterization of LncMRTs and their roles in IS has not been carried out. In the present study, a global LncMRT network was constructed and the topological features were characterized based on experimentally verified interactions. An integrated approach was developed to identify significantly dysregulated LncMRTs in peripheral blood mononuclear cells of IS and these dysregulated LncMRT networks exhibited specific topological characteristics and a closer network structure than the global LncMRT network that was constructed. The variation of the risk score for LncMRTs indicated that there were multiple dysregulated patterns of LncMRTs in IS. Numerous core clusters were identified from dysregulated LncMRT networks and these core clusters could distinguish IS patient and matched control samples. Finally, functional analyses demonstrated that LncMRTs associated with IS participated in the regulation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway. In conclusion, the roles of the LncMRTs in IS were elucidated, which could be beneficial for understanding IS pathogenesis and treatment.

Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific changes in supraspinal mRNA expression of epigenetic- and stress-related genes in adulthood

Exposure to prenatal maternal stress impacts adult behavioral outcomes and has been suggested as a risk factor for chronic pain. However, the neurobiological mechanisms implicated are not well-characterized.In this study, we analyzed the effect of a prenatal maternal stress on the development of neuropathic pain-related behaviours and gene expression in the frontal cortex and hippocampus in adult offspring following chronic constriction injury of the sciatic nerve in male and female CD1 mice.Nerve injury-induced mechanical hypersensitivity was amplified in both male and female prenatally-stressed offspring, suggesting that prenatal stress exacerbates pain after injury. Analysis of mRNA expression of genes related to epigenetic regulation and stress responses in the frontal cortex and hippocampus, brain structures implicated in chronic pain, showed distinct sex and region-specific patterns of dysregulation. In general, mRNA expression was most frequently altered in the male hippocampus and effects of prenatal stress were more prevalent than effects of nerve injury in both supraspinal areas.These findings demonstrate the impact of prenatal stress on behavioral sensitivity to a painful injury. Changes in the expression of epigenetic- and stress-related genes suggest a possible mechanism by which the early life stress becomes embedded in the central nervous system. Increased understanding of the interactions among early-life stress, sex, and pain may lead to the identification of novel therapeutic targets and epigenetic drugs for the treatment of chronic pain disorders.

Composition of Immune Subpopulations Influence Multiple Myeloma Disease Progression

Immune dysfunction is an important feature of multiple myeloma (MM). Characterization of lymphocytic infiltrates, comparing precursor, early & later disease stages, indicate that the anti-myeloma immune response evolves in conjunction with the progression of disease, while distinctive patterns identified in the infiltrating immune population have prognostic relevance (Pessoa de Magalhaes, Vidriales et al. 2013, Paiva, Mateos et al. 2016).The primary objective of this project is to characterize the marrow-infiltrating lymphocytic and myeloid populations to identify specific patterns of immune dysregulation & a biomarker signature that will guide predictions of efficacy of different immunotherapeutic modalities.(Willenbacher et al. 2016, Kini Bailur, Mehta et al. 2017). Patient samples are identified for inclusion based on clinical assessment parameters: detection of a monoclonal gammopathy, the presence or absence of end-organ damage indicative of active/symptomatic MM, and <2 prior lines of therapy. 15 Healthy donor samples were acquired from volunteers with no evidence of hematologic malignancy. Disease status was categorized as precursor MGUS stage, newly diagnosed untreated MM (NDMM), pre-transplant MM (PreT-MM) and 90 days post-transplant MM (D90-MM).Infiltrating leukocyte populations are isolated from 20ml of fresh bone marrow aspirates and analyzed by multi-parameter flow cytometry. Lymphocytes are analyzed for subset composition, memory/effector maturation & exhaustion.The myeloid component analyzes the monocytic and granulocytic myeloid-derived suppressor cells, M1/M2 macrophages, dendritic cells and neutrophils. To date, 38 samples for lymphoid and 56 for the myeloid panel have been analyzed. All calculations and data analysis are performed in the industry standard bioinformatics platform, FlowJo v10.6.Dimensionality reduction is run for visualization of high parameter data using the t-distributed stochastic neighbor embedding (tSNE) algorithm. X-shift unsupervised clustering is employed to identify populations in an unbiased manner. Unsupervised clusters are compared and contrasted relative to known biomarkers of interest within the ClusterExplorer platform and batched across tSNE space in contrast to: subjects, conditions & manually defined gating. The immunologic parameters are compared to histologic, molecular and genetic features of disease as detailed by the biopsy report & to the extended longitudinal clinical course of the patient (disease progression & response to therapy). Classical flow analysis of the myeloid panel clearly reveals significant changes occurring in the G-MDSC population with disease progression. tSNE-based unsupervised analysis show increases in CD4 T effector cells in NDMM patients, but the differences in the CD4 memory compartment in MGUS suggest that these variations in T cells may originate during premalignancy. The expression of CD95 on CD4 cells is downregulated with disease progression. In addition to changes in T cells, we observe changes in innate cells- NDMM samples show an increase in a CD194+NK cell population which may represent a transitional population expanded during pathological tumor growth. With recent studies suggesting that innate cells could be targets for immune-modulatory drugs, this opens a new avenue. Taken together, this data illustrates complex alterations in the immune landscape from a premalignant to malignant stage, implicating that engaging the immune system early in the evolution of clinical MM may improve the potential of durable remissions. Kini Bailur, J., et al. (2017). "Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy." Blood Adv1(25): 2343-2347. Paiva, B., et al. (2016). "Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis." Blood127(9): 1151-1162. Pessoa de Magalhaes, R. J., et al. (2013). "Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry." Haematologica98(1): 79-86. Willenbacher, W., et al. (2016). "Bone marrow microenvironmental CD4 + and CD8 + lymphocyte infiltration patterns define overall- and progression free survival in standard risk multiple myeloma--an analysis from the Austrian Myeloma Registry." Leuk Lymphoma57(6): 1478-1481. Disclosures Shain: AbbVie: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Osteoclast-Induced Immunosuppression Occurs through Dysregulation of Immune Checkpoint Axes in Multiple Myeloma

Osteolytic bone disease has a significant impact on both quality of life and overall survival of patients with multiple myeloma (MM). Given that bone and immune cells share the same microenvironment and interact with each other via cytokines, signaling molecules and regulatory proteins in the bone marrow (Tsukasaki M et al., Nat Rev Immunol 2019), we sought to elucidate the effect of osteoclasts (OCs) on the immune microenvironment. Specifically, T cells significantly suppress differentiation of OCs through signaling crosstalk between RANKL and IFN-γ (Takayanagi H et al., Nature 2000). However, little is known regarding the effect of OCs on the immune system. Here we investigated the effect of OCs on immune cells, especially on T cells. Dysregulation of several checkpoint molecules has been shown in MM (Kwon M et al., J Immunol 2017). We, therefore, assessed the expression of various immune checkpoint receptors, such as PD-1, TIGIT, OX40 and CD137 on T cells in co-culture with or without autologous OCs by multi-color flow cytometry. OC co-culture significantly increased co-inhibitory checkpoint (PD-1 and TIGIT) through direct contact, while decreasing co-stimulatory checkpoint (OX40 and CD137) in CD3+ T cells. Expression of the checkpoint ligand, PD-L1 was significantly increased on MM cells in the presence of both T cells and OCs compared to the presence of T cells alone. Conversely, OCs in the absence of T cells did not induce significant increase of PD-L1 on MM cells. According to previous literature, PD-L1 expression on MM cells is induced in part by IFN-γ (Liu J et al., Blood 2007). Interestingly, our data demonstrated that OCs activated IFN-γ producing T cells in co-culture conditions. Furthermore, we observed that T cell and OC-mediated upregulation of PD-L1 on MM cells was partially reversed by using IFN-γ neutralizing antibody. This implies that OCs indirectly induce PD-L1 upregulation on MM cells by enhancing IFN-γ secretion from T cells. In addition, we found that naïve CD4+ T cells have a higher propensity to differentiate into Th17 lineage in the presence of Th17 differentiation cytokines when co-cultured with OCs. Moreover, we observed an increased expansion of Th17 cells in co-culture with OCs. Those Th17 cells also showed a similar pattern of dysregulation of immune checkpoint axes. Our study demonstrates that OCs positively regulate co-inhibitory checkpoint molecules and negatively regulate co-stimulatory molecules on T cells. These findings indicate that OCs play an important role in inhibiting T cell-mediated antitumor immunity. Targeting OCs may help restore impaired immune surveillance in MM in addition to their critical role in preventing lytic bone lesions in MM. These data may support the role of antiresorptives in immune surveillance with indirect anti-tumor effects. Disclosures No relevant conflicts of interest to declare.

Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity.

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.

Zoster patients on earth and astronauts in space share similar immunologic profiles

BackgroundOn long-duration spaceflight, most astronauts experience persistent immune dysregulation and the reactivation of latent herpesviruses, including varicella zoster virus (VZV). To understand the clinical risk of these perturbations to astronauts, we paralleled the immunology and virology work-up of astronauts to otherwise healthy terrestrial persons with acute herpes zoster. MethodsBlood samples from 42 zoster patients – confirmed positive by PCR for VZV DNA in saliva (range from 100 to >285 million copies/mL) were analyzed for peripheral leukocyte distribution, T cell function, and plasma cytokine profiles via multi-parametric flow cytometry and multiplex bead-based immune-array assays. Patient findings were compared to normal value ranges specific for each assay that were defined in-house previously from healthy adult test subjects. ResultsCompared to the healthy adult ranges, the zoster patients possess (1) a higher proportion of constitutively activated T-cells, (2) a T-cell population skewed towards a more experienced maturation state, (3) depressed general T-cell function, and (4) a higher concentration of 20 of 22 measured plasma cytokines. DiscussionThe pattern of immune dysregulation in zoster patients is similar to that of astronauts during spaceflight who shed VZV DNA in their saliva. Because future deep space exploration missions will be of an unprecedented duration, prolonged immune depression and chronic viral reactivation threaten to manifest overt disease in exploration class astronauts.

Neuronal network remodeling and Wnt pathway dysregulation in the intra-hippocampal kainate mouse model of temporal lobe epilepsy.

Mouse models of mesial temporal lobe epilepsy recapitulate aspects of human epilepsy, which is characterized by neuronal network remodeling in the hippocampal dentate gyrus. Observational studies suggest that this remodeling is associated with altered Wnt pathway signaling, although this has not been experimentally examined. We used the well-characterized mouse intrahippocampal kainate model of temporal lobe epilepsy to examine associations between hippocampal neurogenesis and altered Wnt signaling after seizure induction. Tissue was analyzed using immunohistochemistry and confocal microscopy, and gene expression analysis was performed by RT-qPCR on RNA extracted from anatomically micro-dissected dentate gyri. Seizures increased neurogenesis and dendritic arborization of newborn hippocampal dentate granule cells in peri-ictal regions, and decreased neurogenesis in the ictal zone, 2-weeks after kainate injection. Interestingly, administration of the novel canonical Wnt pathway inhibitor XAV939 daily for 2-weeks after kainate injection further increased dendritic arborization in peri-ictal regions after seizure, without an effect on baseline neurogenesis in control animals. Transcriptome analysis of dentate gyri demonstrated significant canonical Wnt gene dysregulation in kainate-injected mice across all regions for Wnt3, 5a and 9a. Intriguingly, certain Wnt genes demonstrated differential patterns of dysregulation between the ictal and peri-ictal zones, most notably Wnt5B, 7B and DKK-1. Together, these results demonstrate regional variation in Wnt pathway dysregulation early after seizure induction, and surprisingly, suggest that some Wnt-mediated effects might actually temper aberrant neurogenesis after seizures. The Wnt pathway may therefore provide suitable targets for novel therapies that prevent network remodeling and the development of epileptic foci in high-risk patients.

Profiling and bioinformatics analyses reveal differential circular RNA expression in ovarian cancer

Ovarian cancer (OC) is the deadliest form of gynecologic malignancy, with the majority of patients being diagnosed only once the disease reaches an advanced stage owing to a lack of available biomarkers capable of accurately detecting the disease. Stable circular RNAs (circRNAs) can be found at high levels in exosomes, and there is evidence to suggest that they may be viable diagnostic biomarkers for certain cancers. However, circRNAs in the serum of OC patients have rarely been evaluated to date. We therefore sought to investigate serum circRNA profiles of OC patients, and to explore whether these sorts of circRNAs could be used to detect early OC, serving as biomarkers of disease that may allow for the earlier treatment thereof. Second-generation sequencing was used to screen differentially expressed circRNAs in OC patient serum and also in the serum obtained from healthy controls, and circRNA expression was confirmed by qPCR. A bioinformatics-based approach was then used to assess what biological functions might be affected be the altered regulation of these RNA molecules. We further conducted GO, KEGG, and network analyses to further explore the expression of circRNAs. We detected 178 differentially expressed circRNAs in OC patient serum, of which 175 were up-regulated and 3 were down-regulated. We validated 5 of these identified circRNAs by qPCR to confirm their expression, and further found these RNAs to be closely linked with FC gamma R-mediated phagocytosis, VEGF signaling, Transcriptional misregulation in cancer, Chemokine signaling, ErbB signaling, and TNF signaling based on conducted analyses. This study provides a profile of circRNAs in OC patient serum, revealing a pattern of dysregulation of these RNAs associated with OC. Our bioinformatics analysis suggested that these circRNAs are likely related to OC development, and as such they may be viable novel OC biomarkers.

Novel Inter-omic Analysis Reveals Relationships Between Diverse Gut Microbiota and Host Immune Dysregulation in HLA-B27-Induced Experimental Spondyloarthritis.

To define inflammation-related host-microbe interactions in experimental spondyloarthritis (SpA) using novel inter-omic approaches. The relative frequency of gut microbes was determined by 16S ribosomal RNA (rRNA) gene sequencing, and gene expression using RNA-Seq of host tissue. HLA-B27/human β2 -microglobulin-transgenic (HLA-B27-transgenic) and wild-type rats from dark agouti, Lewis, and Fischer backgrounds were used. Inter-omic analyses using Cytoscape were employed to identify relevant relationships. PICRUSt was used to predict microbial functions based on known metagenomic profiles. Inter-omic analysis revealed several gut microbes that were strongly associated with dysregulated cytokines driving inflammatory response pathways, such as interleukin-17 (IL-17), IL-23, IL-17, IL-1, interferon-γ (IFNγ), and tumor necrosis factor (TNF). Many microbes were uniquely associated with inflammation in Lewis or Fischer rats, and one was relevant on both backgrounds. Several microbes that were strongly correlated with immune dysregulation were not differentially abundant in HLA-B27-transgenic compared to wild-type controls. A multi-omic network analysis revealed non-overlapping clusters of microbes in Lewis and Fischer rats that were strongly linked to overlapping dysregulated immune/inflammatory genes. Prevotella, Clostridiales, and Blautia were important in Lewis rats, while Akkermansia muciniphila and members of the Lachnospiraceae family dominated in Fischer rats. Inflammation-associated metabolic pathway perturbation (e.g., butanoate, propanoate, lipopolysaccharide, and steroid biosynthesis) was also predicted from both backgrounds. Inter-omic and network analysis of gut microbes and the host immune response in experimental SpA provides an unprecedented view of organisms strongly linked to dysregulated IL-23, IL-17, IL-1, IFNγ, and TNF. Functional similarities between these organisms may explain why animals of different genetic backgrounds exhibit common patterns of immune dysregulation, possibly through perturbation of similar metabolic pathways. These results highlight the power of linking analyses of gut microbiota with the host immune response to gain insights into the role of dysbiotic microbes in SpA beyond taxonomic profiling.

Boys with autism spectrum disorder have distinct cortical folding patterns underpinning impaired self-regulation: a surface-based morphometry study.

Although impaired self-regulation (dysregulation) in autism spectrum disorder (ASD) garnered increasing awareness, the neural mechanism of dysregulation in ASD are far from conclusive. To complement our previous voxel-based morphometry findings, we estimated the cortical thickness, surface area, and local gyrification index based on the surface-based morphometry from structural MRI images in 85 ASD and 65 typically developing control (TDC) boys, aged 7-17years. Levels of dysregulation were measured by the sum of T-scores of Attention, Aggression, and Anxiety/Depression subscales on the Child Behavior Checklist. We found both ASD and TDC shared similar relationships between dysregulation and cortical folding patterns in the left superior and inferior temporal gyri and the left premotor cortex. Significant diagnosis by dysregulation interactions in cortical folding patterns were identified over the right middle frontal and right lateral orbitofrontal regions. The statistical significance of greater local gyrification index in ASD than TDC in several brain regions disappeared when the level of dysregulation was considered. The findings of shared and distinct neural correlates underpinning dysregulation between ASD and TDC may facilitate the development of targeted interventions in the future. The present work also demonstrates that inter-subject variations in self-regulation may explain some extents of ASD-associated brain morphometric differences, likely suggesting that dysregulation is one of the yardsticks for dissecting the heterogeneity of ASD.

Expressive Suppression and Negative Affect, Pathways of Emotional Dysregulation in Psoriasis Patients.

The main goal of this study was to assess the emotion regulation (ER) mechanisms, such as expressive suppression and cognitive reappraisal, in patients with psoriasis, as compared with healthy persons not afflicted by dermatological diseases. Moreover, the study intended to carry on a multidimensional assessment of emotional mechanisms in persons with psoriasis, highlighting the differences between psoriasis patients and healthy participants, in order to identify the specific patterns of emotion dysregulation (ED) in psoriasis. Another goal of the study was to investigate the predictors of ED among different emotional patterns. We presumed that the maladaptive ER mechanisms are higher in psoriasis patients than in the control group and there are specific dysregulation patterns in psoriasis patients as negative emotions tendency. This cross-sectional study was performed on 192 individuals aged between 35 and 75 years (mean age 59). The sample was divided in two groups: the clinical group including 91 patients with a diagnosis of psoriasis vulgaris and the control group including 101 healthy persons. The results of the present study suggest that psoriasis patients more frequently used emotional suppression – a maladaptive ER mechanism – as well as ED patterns – i.e., impulse control difficulties, and nonacceptance of emotional responses. They also displayed trait tendency to a negative emotional response. In fact, in people with psoriasis, the presence of suppression mechanism and negative affect of trait could predict that 35% of patients will show emotional dysregulated patterns, while living with higher levels of ED. The results of our study are important in the clinical practice, helping clinicians to better understand the emotional vulnerability of people that live with psoriatic disease, and to optimize the disease management and patient care in an interdisciplinary approach.

Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets.

Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.

Behavioral and Neural Dysregulation to Social Rewards and Links to Internalizing Symptoms in Adolescents.

Adolescence is a time of unique sensitivity to socially salient stimuli such as social rewards. This period overlaps with the onset of psychopathology such as internalizing and externalizing symptoms. In the current studies, we examined behavioral and neural patterns of dysregulation to social rewards and threats, and links to internalizing and externalizing symptoms in youths. In study 1, we used a social Go/NoGo cognitive control task using peer faces to test for age-related behavioral differences in inhibitory failures in adolescents (N = 53, Mage = 13.37 years), and adults (N = 51, Mage = 43.71 years). In study 2, an independent adolescent sample (N = 51, Mage = 13.98 years) completed a similar social Go/NoGo cognitive control task during fMRI. Results show that adolescents had greater inhibitory failures – as measured by false alarm rate – to both social reward and threat cues than adults, and more so to social reward than threat cues. Greater inhibitory failures to social reward than threat cues were associated with greater internalizing symptoms, but were not significantly related to externalizing symptoms. At the neural level, greater inhibitory failures to social reward than threat cues as well as greater internalizing symptoms were both associated with heightened amygdala-ventral striatum connectivity. Our findings indicate that subcortico-subcortical connectivity, which is deemed to occur chronologically earlier and thus necessary for subcortico-cortical circuits, may serve as an early biomarker for emotion dysregulation and a risk factor for internalizing symptoms.

Aberrant DNA methylation defines isoform usage in cancer, with functional implications.

Alternative transcript isoforms are common in tumors and act as potential drivers of cancer. Mechanisms determining altered isoform expression include somatic mutations in splice regulatory sites or altered splicing factors. However, since DNA methylation is known to regulate transcriptional isoform activity in normal cells, we predicted the highly dysregulated patterns of DNA methylation present in cancer also affect isoform activity. We analyzed DNA methylation and RNA-seq isoform data from 18 human cancer types and found frequent correlations specifically within 11 cancer types. Examining the top 25% of variable methylation sites revealed that the location of the methylated CpG site in a gene determined which isoform was used. In addition, the correlated methylation-isoform patterns classified tumors into known subtypes and predicted distinct protein functions between tumor subtypes. Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways. These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome.

Master regulator analysis of paragangliomas carrying SDHx, VHL, or MAML3 genetic alterations

BackgroundSuccinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors. Although hypotheses propose that succinate accumulation after SDH loss poisons dioxygenases and activates pseudohypoxia and epigenomic hypermethylation, it remains unclear whether these mechanisms account for oncogenic transcriptional patterns. Additionally, MAML3 translocation has recently been identified as a genetic alteration in PPGL, but is poorly understood. We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes.MethodsWe leverage publicly-available human tumor gene expression profiling experiments (N = 179) to reconstruct a PPGL tumor-specific transcriptional network. We subsequently use the inferred transcriptional network to perform master regulator analyses nominating transcription factors predicted to control oncogenic transcription in specific PPGL molecular subtypes. Results are validated by analysis of an independent collection of PPGL tumor specimens (N = 188). We then perform a similar master regulator analysis in SDH-loss mouse embryonic fibroblasts (MEFs) to infer aspects of SDH loss master regulator response conserved across species and tissue types.ResultsA small number of master regulator transcription factors are predicted to drive the observed subtype-specific gene expression patterns in SDH loss and MAML3 translocation-positive PPGL. Interestingly, although EPAS1 perturbation is detectible in SDH-loss and VHL-loss tumors, it is by no means the most potent factor driving observed patterns of transcriptional dysregulation. Analysis of conserved SDH-loss master regulators in human tumors and MEFs implicated ZNF423, a known modulator of retinoic acid response in neuroblastoma. Subsequent functional analysis revealed a blunted cell death response to retinoic acid in SDH-loss MEFs and blunted differentiation response in SDH-inhibited SH-SY5Y neuroblastoma cells.ConclusionsThe unbiased analyses presented here nominate specific transcription factors that are likely drivers of oncogenic transcription in PPGL tumors. This information has the potential to be exploited for targeted therapy. Additionally, the observation that SDH loss or inhibition results in blunted retinoic acid response suggests a potential developmental etiology for this tumor subtype.

Emotion dysregulation as a dynamic process.

In this article we adopt the view that emotion dysregulation is characterized by emotion regulation dynamics that are defined as dysfunctional based on contextual criteria. We regard the construct of emotion regulation as valuable because it permits the integration of the classic view of emotions as interfering with human functioning and contemporary views of emotion as adaptive and beneficial. To define patterns that reflect emotion dysregulation, we explain our views of emotion as a dynamic process, and emotion regulation as the bidirectional interplay between emotions and actions/thoughts (extrinsic factors) and the contextual factors that constitute the criteria for that interplay reflecting dysregulation. This conceptualization of emotion regulation and dysregulation leads to methods for studying the intrinsic dynamics of emotion, extrinsic factors that change the intrinsic dynamics of emotion, and how emotion regulation changes over time at multiple time scales. We then apply this thinking to several emotion dysregulation patterns. Emotion regulation is a complex construct, embracing emotion as regulator and as regulated, as self- and other-regulated, and as incorporating both top-down and bottom-up regulatory processes. We highlight an emerging line of research on the development of emotion regulation in early childhood and indicate how this work can inform understanding of emotion dysregulation and the emergence of psychopathology.

Temperamental vulnerability to emotion dysregulation and risk for mental and physical health challenges.

Emotion dysregulation characterizes many forms of psychopathology. Patterns of dysregulation occur as a function of a developmental process in which normative and adaptive emotion regulation skills fail to become part of the child's behavioral repertoire due to biological, psychological, and contextual processes and experiences. Here we highlight the processes involved in the dysregulation of temperamental anger and frustration that become core features of externalizing problems and place children at risk for more serious forms of psychopathology. We imbed these processes in a larger self-regulatory framework, and we discuss how they influence mental as well as physical health, using data from our 20-year longitudinal study following a large cohort of children into young adulthood. Recommendations are made for future research involving the integration of biological systems with mental and physical health outcomes.

Next Generation Networks: Featuring the Potential Role of Emerging Applications in Translational Oncology.

Nowadays, networks are pervasively used as examples of models suitable to mathematically represent and visualize the complexity of systems associated with many diseases, including cancer. In the cancer context, the concept of network entropy has guided many studies focused on comparing equilibrium to disequilibrium (i.e., perturbed) conditions. Since these conditions reflect both structural and dynamic properties of network interaction maps, the derived topological characterizations offer precious support to conduct cancer inference. Recent innovative directions have emerged in network medicine addressing especially experimental omics approaches integrated with a variety of other data, from molecular to clinical and also electronic records, bioimaging etc. This work considers a few theoretically relevant concepts likely to impact the future of applications in personalized/precision/translational oncology. The focus goes to specific properties of networks that are still not commonly utilized or studied in the oncological domain, and they are: controllability, synchronization and symmetry. The examples here provided take inspiration from the consideration of metastatic processes, especially their progression through stages and their hallmark characteristics. Casting these processes into computational frameworks and identifying network states with specific modular configurations may be extremely useful to interpret or even understand dysregulation patterns underlying cancer, and associated events (onset, progression) and disease phenotypes.

Aging impairs mouse skeletal muscle macrophage polarization and muscle-specific abundance during recovery from disuse.

Impaired recovery of aged muscle following a disuse event is an unresolved issue facing the older adult population. Although investigations in young animals have suggested that rapid regrowth of skeletal muscle following a disuse event entails a coordinated involvement of skeletal muscle macrophages, this phenomenon has not yet been thoroughly tested as an explanation for impaired muscle recovery in aging. To examine this hypothesis, young (4-5 mo) and old (24-26 mo) male mice were examined as controls following 2 wk of hindlimb unloading (HU) and following 4 (RL4) and 7 (RL7) days of reloading after HU. Muscles were harvested to assess muscle weight, myofiber-specifc cross-sectional area, and skeletal muscle macrophages via immunofluorescence. Flow cytometry was used on gastrocnemius and soleus muscle (at RL4) single-cell suspensions to immunophenotype skeletal muscle macrophages. Our data demonstrated impaired muscle regrowth in aged compared with young mice following disuse, which was characterized by divergent muscle macrophage polarization patterns and muscle-specifc macrophage abundance. During reloading, young mice exhibited the classical increase in M1-like (MHC II+CD206-) macrophages that preceeded the increase in percentage of M2-like macrophages (MHC II-CD206+); however, old mice did not demonstrate this pattern. Also, at RL4, the soleus demonstrated reduced macrophage abundance with aging. Together, these data suggest that dysregulated macrophage phenotype patterns in aged muscle during recovery from disuse may be related to impaired muscle growth. Further investigation is needed to determine whether the dysregulated macrophage response in the old during regrowth from disuse is related to a reduced ability to recruit or activate specific immune cells.