Role and mechanism of PVN-sympathetic-adipose circuit in depression and insulin resistance induced by chronic stress.

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.

A signature based on neutrophil extracellular trap-related genes for the assessment of prognosis, immunoinfiltration, mutation and therapeutic response in hepatocellular carcinoma.

BACKGROUND: Liver cancer is a highly lethal and aggressive form of cancer that poses a significant threat to patient survival. Within this category, liver hepatocellular carcinoma (LIHC) represents the most common subtype of liver cancer. Despite decades of research and treatment, the overall survival rate for LIHC has not significantly improved. Improved models are necessary to differentiate high-risk cases and predict possible treatment options for LIHC patients. Recent studies have identified a set of genes associated with neutrophil extracellular traps (NETs) that may contribute to tumor growth and metastasis; however, their prognostic value in LIHC has yet to be established. This study aims to construct a prognostic signature based on a set of NET-related genes (NRGs) for patients diagnosed with LIHC. METHODS: The transcriptomic data and clinical information concerning LIHC patients were procured from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium LIHC (ICLIHC) databases, respectively. To determine the NRG subtypes, the k-means algorithm was employed, along with consensus clustering. The aforementioned analysis aided the construction of a prognostic signature utilizing the last absolute shrinkage and selection operator Cox analysis. To validate the prognostic model, an external dataset, receiver operating characteristic curve, and principal component analysis were utilized. Moreover, the immune microenvironment and the proportion of immune cells between high- and low-risk cases were scrutinized by ESTIMATE and CIBERSORT algorithms. Finally, gene set enrichment analysis was executed to investigate the potential mechanism of NRGs in the pathogenesis and prognosis of LIHC. RESULTS: Two molecular subtypes of LIHC were identified based on the expression patterns of differentially expressed NRGs (DE-NRGs). The two subtypes demonstrated significant differences in survival rates and immune cell expression levels. The study results demonstrated the role of NRGs in antigen presentation, which led to the promotion of tumor immune escape. A risk model was developed and validated with strong overall survival prediction ability. The model, comprising 34 NRGs, showed a strong ability to predict prognosis. CONCLUSION: We built a dependable prognostic signature based on NRGs for LIHC. We identified that NRGs could have a significant interaction in LIHC's immune microenvironment and therapeutic response. This finding offers insight into the molecular mechanisms and targeted therapy for LIHC.

RNAi-based modulation of IFN-γ signaling in skin.

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.

Follicular Helper CD4+ T Cells, Follicular Regulatory CD4+ T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Follicular helper CD4+ T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class-switch recombination of B cells, and facilitate production of long-lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl-6), the chemokine (C-X-C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein-1 (PD-1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin-21 (IL-21) and IL-4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4), and IL-10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4+ effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.

Development of a Laser Gas Analyzer for Fast CO2 and H2O Flux Measurements Utilizing Derivative Absorption Spectroscopy at a 100 Hz Data Rate.

We report the development of a laser gas analyzer that measures gas concentrations at a data rate of 100 Hz. This fast data rate helps eddy covariance calculations for gas fluxes in turbulent high wind speed environments. The laser gas analyzer is based on derivative laser absorption spectroscopy and set for measurements of water vapor (H2O, at wavelength ~1392 nm) and carbon dioxide (CO2, at ~2004 nm). This instrument, in combination with an ultrasonic anemometer, has been tested experimentally in both marine and terrestrial environments. First, we compared the accuracy of results between the laser gas analyzer and a high-quality commercial instrument with a max data rate of 20 Hz. We then analyzed and compared the correlation of H2O flux results at data rates of 100 Hz and 20 Hz in both high and low wind speeds to verify the contribution of high frequency components. The measurement results show that the contribution of 100 Hz data rate to flux calculations is about 11% compared to that measured with 20 Hz data rate, in an environment with wind speed of ~10 m/s. Therefore, it shows that the laser gas analyzer with high detection frequency is more suitable for measurements in high wind speed environments.

Diversity of immune cell types in multiple sclerosis and its animal model: Pathological and therapeutic implications.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with an autoimmune attack on the components of the myelin sheath and axons. The etiology of the disease remains largely unknown, but it is commonly acknowledged that the development of MS probably results from the interaction of environmental factors in conjunction with a genetic predisposition. Current therapeutic approaches can only ameliorate the clinical symptoms or reduce the frequency of relapse in MS. Most drugs used in this disease broadly suppress the functions of immune effector cells, which can result in serious side effects. Thus, new therapeutic methods resulting in greater efficacy and lower toxicity are needed. Toward this end, cell-based therapies are of increasing interest in the treatment of MS. Several immunoregulatory cell types, including regulatory T cells, regulatory B cells, M2 macrophages, tolerogenic dendritic cells, and stem cells, have been developed as novel therapeutic tools for the treatment of MS. In this Review, we summarize studies on the application of these cell populations for the treatment of MS and its animal model, experimental autoimmune encephalomyelitis, and call for further research on applications and mechanisms by which these cells act in the treatment of MS. © 2017 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders.

This study analyzed the populations of three different subsets of regulatory B cells (Bregs) in the peripheral blood mononuclear cells (PBMCs) of patients with neuromyelitis optica spectrum disorders (NMOSDs) and explored the relationship between the changes in these subsets of Bregs and the severity of NMOSD. A total of 22 patients with relapsed NMOSDs before treatment were recruited in our study, along with 20 age and gender-matched healthy controls, from May 2015 to March 2016. The percentages and numbers for three different subsets of Bregs including the CD19+CD24hiCD38hi, CD19+CD24hiCD27+, and CD19+CD5+CD1dhi populations were evaluated in parallel by flow cytometry. Afterwards, correlations between the change of three different subsets of Bregs and disease severity were analyzed. We found significantly lower percentages of CD19+CD24hiCD38hi and CD19+CD5+CD1dhi Bregs in NMOSDs patients than in healthy individuals. In contrast, the CD19+CD24hiCD27+ Bregs population was significantly higher in NMOSDs patients than in healthy individuals. However, the three different Bregs subsets showed no significant correlation with expanded disability status scale (EDSS) or annualized relapse rate (ARR). Our findings suggest that the subsets of Bregs may play complex roles in the pathogenesis of NMOSDs and are not correlated with clinical disease severity. Further insights into the potential role of subsets of Bregs could increase our basic knowledge of NMOSDs pathogenesis.

Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene.

The E7 oncoprotein of high-risk human papillomavirus (HPV) types induces DNA re-replication that contributes to carcinogenesis; however, the mechanism is not fully understood. To better understand the mechanism by which E7 induces re-replication, we investigated the expression and function of cell division cycle 6 (Cdc6) in E7-expressing cells. Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We found that in E7-expressing cells, the steady-state level of Cdc6 protein was upregulated and its half-life was increased. Cdc6 was localized to the nucleus and associated with chromatin, especially upon DNA damage. Importantly, downregulation of Cdc6 reduced E7-induced re-replication. Interestingly, the level of Cdc6 phosphorylation at serine 54 (S54P) was increased in E7-expressing cells. S54P was associated with an increase in the total amount of Cdc6 and chromatin-bound Cdc6. DNA damage-enhanced upregulation and chromatin binding of Cdc6 appeared to be due to downregulation of cyclin-dependent kinase 1 (Cdk1) as Cdk1 knockdown increased Cdc6 levels. Furthermore, Cdk1 knockdown or inhibition led to re-replication. These findings shed light on the mechanism by which HPV induces genomic instability and may help identify potential targets for drug development.

Role of regulatory b cells in neuroimmunologic disorders.

B lymphocytes augment the immune response by producing antibodies and activating T cells by antigen presentation. Recent studies have highlighted a specific and functionally significant B-cell subset that could downregulate excessive immune and inflammatory responses through a vast array of inhibitory cytokines, such as interleukin (IL)-10 and transforming growth factor-ß (TGF-ß). This subset of B cells is generally referred to as regulatory B cells (Bregs). In addition, recent studies have shown that IL-35-producing Bregs also play a role in downregulation of immunity. Diverse phenotypes of Bregs have been proposed to underlie human disorders and their animal models. Most studies have focused on the role of different subsets of Bregs and Bregs-associated molecules such as IL-10, TGF-ß, and IL-35 in the pathogenesis of neuroimmunologic disorders. Furthermore, Bregs exert regulatory function mainly through suppressing the differentiation of Th1/Th17 cells and promoting regulatory T-cell expansion. Reduced presence of Bregs is reportedly associated with progression of several neuroimmunologic disorders. This Review summarizes the current knowledge on the role of Bregs in neuroimmunologic disorders, including multiple sclerosis, neuromyelitis optica, and myasthenia gravis. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Double Roles of Macrophages in Human Neuroimmune Diseases and Their Animal Models.

Macrophages are important immune cells of the innate immune system that are involved in organ-specific homeostasis and contribute to both pathology and resolution of diseases including infections, cancer, obesity, atherosclerosis, and autoimmune disorders. Multiple lines of evidence point to macrophages as a remarkably heterogeneous cell type. Different phenotypes of macrophages exert either proinflammatory or anti-inflammatory roles depending on the cytokines and other mediators that they are exposed to in the local microenvironment. Proinflammatory macrophages secrete detrimental molecules to induce disease development, while anti-inflammatory macrophages produce beneficial mediators to promote disease recovery. The conversion of the phenotypes of macrophages can regulate the initiation, development, and recovery of autoimmune diseases. Human neuroimmune diseases majorly include multiple sclerosis (MS), neuromyelitis optica (NMO), myasthenia gravis (MG), and Guillain-Barré syndrome (GBS) and macrophages contribute to the pathogenesis of these neuroimmune diseases. In this review, we summarize the double roles of macrophage in neuroimmune diseases and their animal models to further explore the mechanisms of macrophages involved in the pathogenesis of these disorders, which may provide a potential therapeutic approach for these disorders in the future.

Circulating Memory T Follicular Helper Cells in Patients with Neuromyelitis Optica/Neuromyelitis Optica Spectrum Disorders.

OBJECTIVE: This study aimed to examine the potential role of memory T follicular helper (Tfh) cells in patients with neuromyelitis optica/neuromyelitis optica spectrum disorders (NMO/NMOSD). METHODS: The percentages of different subsets of circulating memory Tfh cells in 25 NMO/NMOSD patients before and after treatment as well as in 17 healthy controls were examined by flow cytometry. The levels of IL-21 and AQP4 Ab in plasma and CSF were measured by ELISA. RESULTS: The percentages and numbers of circulating memory Tfh cells, ICOS(+), CCR7(-), CCR7(-)ICOS(+), CCR7(+), CCR7(+)ICOS(+) memory Tfh cells, and the levels of IL-21 in plasma and CSF were significantly increased in NMO/NMOSD patients. The percentages of CCR7(-) and CCR7(-)ICOS(+) memory Tfh cells were positively correlated with ARR, plasma IL-21, and AQP4 Ab levels. The percentages of CCR7(+) and CCR7(+)ICOS(+) memory Tfh cells were positively correlated with CSF white blood cell counts, proteins, and IL-21 levels. Treatment with corticosteroids significantly reduced the numbers of CCR7(-)ICOS(+) and CCR7(+)ICOS(+) memory Tfh cells as well as plasma IL-21 levels in patients with partial remission. CONCLUSIONS: Our findings indicate that circulating memory Tfh cells may participate in the relapse and development of NMO/NMOSD and may serve as a new therapeutic target.

Follicular Helper CD4+ T Cells in Human Neuroautoimmune Diseases and Their Animal Models.

Follicular helper CD4(+) T (TFH) cells play a fundamental role in humoral immunity deriving from their ability to provide help for germinal center (GC) formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21. It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells. A balance of TFH cell generation and function is critical for protective antibody response, whereas overactivation of TFH cells or overexpression of TFH-associated molecules may result in autoimmune diseases. Emerging data have shown that TFH cells and TFH-associated molecules may be involved in the pathogenesis of neuroautoimmune diseases including multiple sclerosis (MS), neuromyelitis optica (NMO)/neuromyelitis optica spectrum disorders (NMOSD), and myasthenia gravis (MG). This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

Human papillomavirus E7 induces rereplication in response to DNA damage.

Human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis. Genomic instability caused by HPV allows cells to acquire additional mutations required for malignant transformation. Genomic instability in the form of polyploidy has been demonstrated to play an important role in cervical carcinogenesis. We have recently found that HPV-16 E7 oncogene induces polyploidy in response to DNA damage; however, the mechanism is not known. Here we present evidence demonstrating that HPV-16 E7-expressing cells have an intact G(2) checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G(2) checkpoint and then undergo rereplication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces rereplication in human cancer cells, is upregulated in E7-expressing cells. Moreover, downregulation of Cdt1 impairs the ability of E7 to induce rereplication. These results demonstrate an important role for Cdt1 in HPV E7-induced rereplication and shed light on mechanisms by which HPV induces genomic instability.

A case of Trousseau syndrome: Screening, detection and complication.

Trousseau syndrome (TS) is a malignant tumor-mediated complication of the hypercoagulable state with an unknown etiology. Laboratory testing results in patients with TS have indicated elevated D-dimer levels. The imaging analysis in patients who had undergone stroke has shown the presence of several cerebral infarction lesions in multiple regions. Since patients have had malignant tumors for a long time when they suffer from a secondary stroke, the optimum time for radical tumor treatment is usually missed. This study reports a case to improve the early screening and detection of TS and reduce the risk of recurrence of cerebral infarction.

Image quality assessment and feasibility of three-dimensional amide proton transfer-weighted imaging for hepatocellular carcinoma.

Background: With the continuous innovation of magnetic resonance imaging (MRI) hardware and software technology, amide proton transfer-weighted (APTw) imaging has been applied in liver cancer. However, to our knowledge, no study has evaluated the feasibility of a three-dimensional amide proton transfer-weighted (3D-APTw) imaging sequence for hepatocellular carcinoma (HCC). This study thus aimed to conduct an image quality assessment of 3D-APTw for HCC and to explore its feasibility. Methods: 3D-APTw MRI examinations were completed in 134 patients with clinically suspected HCC. According to the uniformity of APTw signal in the liver and within the lesion and the proportion of artifact and missing signal regions, APTw images were subjectively scored using a 5-point scale. The scanning success rate of liver APTw imaging was calculated as the ratio of the number of cases with a quality assurance measurement of more than 3 to the total number of HCC cases. The intra- and interobserver quality assurance measurements for APTw images were compared via the Kappa consistency test. Within the HCC cases with a minimum image quality threshold of 3 points, the APT values of HCC and the liver parenchyma, signal-to-noise ratio of APT-weighted images (SNRAPTw), and contrast-to-noise ratio of HCC (CNRHCC) were measured by two observers. The intra- and interobserver agreement was assessed using the intraclass correlation coefficient (ICC). The differences in APT values between HCC and liver parenchyma was determined using the Mann-Whitney test. Results: Sixty-six HCC cases with a quality assurance measurement of APTw imaging were included in the final analysis, and the calculated success rate was 70.21% (66/94). The subjective APT image quality scores of the two observers were consistent (3.66±1.18, 3.50±1.19, and 3.68±1.18), and no intergroup or intragroup statistical differences were found (P=0.594, and P=0.091), but the consistency of inter- and intraobserver was not as satisfactory (κ=0.594 and κ=0.580). The APT values in HCC lesion were significantly higher than those in liver parenchyma (2.73%±0.91% vs. 1.62%±0.55%; P<0.001). The APT values in HCC showed favorable intra- and interobserver consistency between the two observers (ICC =0.808 and ICC =0.853); the APT values in liver parenchyma, SNRAPTw, and CNRHCC values had moderate intraobserver consistency (ICC =0.578, ICC =0.568, and ICC =0.508) and interobserver consistency (ICC =0.599, ICC =0.199, and ICC =0.650). The coefficients of variation of the APTw values in the HCC lesion and in liver parenchyma were 33.4% and 34.4%, respectively. The SNRAPTw and CNRHCC were 30.75±18.74 and 3.56±3.19, with a coefficient of variation of 60.9% and 74.9%, respectively. Conclusions: Liver 3D-APTw imaging was preliminarily demonstrated to be clinically feasible for evaluating HCC.

TGF-ß/Smads signaling pathway, Hippo-YAP/TAZ signaling pathway, and VEGF: Their mechanisms and roles in vascular remodeling related diseases.

Vascular remodeling is a basic pathological process in various diseases characterized by abnormal changes in the morphology, structure, and function of vascular cells, such as migration, proliferation, hypertrophy, and apoptosis. Various growth factors and pathways are involved in the process of vascular remodeling. The transforming growth factor-ß (TGF-ß) signaling pathway, which is mainly mediated by TGF-ß1, is an important factor in vascular wall enhancement during vascular development and regulates the vascular response to injury by promoting the accumulation of intimal tissue. Vascular endothelial growth factor (VEGF) has an important effect on initiating the formation of blood vessels. The Hippo-YAP/TAZ signaling pathway also plays an important role in angiogenesis. In addition, studies have shown that there is a certain interaction between the TGF-ß/Smads signaling pathway, Hippo-YAP/TAZ signaling pathway, and VEGF. Many studies have shown that in the development of atherosclerosis, hypertension, aneurysm, vertebrobasilar dolichoectasia, pulmonary hypertension, restenosis after percutaneous transluminal angioplasty, and other diseases, various inflammatory reactions lead to changes in vascular structure and vascular microenvironment, which leads to vascular remodeling. The occurrence of vascular remodeling changes the morphology of blood vessels and thus changes the hemodynamics, which is the cause of further development of the disease process. Vascular remodeling can cause vascular smooth muscle cell dysfunction and vascular homeostasis regulation. This review aims to explore the mechanisms of the TGF-ß/Smads signaling pathway, Hippo-YAP/TAZ signaling pathway, and vascular endothelial growth factor in vascular remodeling and related diseases. This paper is expected to provide new ideas for research on the occurrence and development of related diseases and provide a new direction for research on the treatment of related diseases.

The role of the gut microbiota and fecal microbiota transplantation in neuroimmune diseases.

The gut microbiota plays a key role in the function of the host immune system and neuroimmune diseases. Alterations in the composition of the gut microbiota can lead to pathology and altered formation of microbiota-derived components and metabolites. A series of neuroimmune diseases, such as myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), Guillain-Barré syndrome (GBS), and autoimmune encephalitis (AIE), are associated with changes in the gut microbiota. Microecological therapy by improving the gut microbiota is expected to be an effective measure for treating and preventing some neuroimmune diseases. This article reviews the research progress related to the roles of gut microbiota and fecal microbiota transplantation (FMT) in neuroimmune diseases.

Microglia in the context of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease that commonly results in nontraumatic disability in young adults. The characteristic pathological hallmark of MS is damage to myelin, oligodendrocytes, and axons. Microglia provide continuous surveillance in the CNS microenvironment and initiate defensive mechanisms to protect CNS tissue. Additionally, microglia participate in neurogenesis, synaptic refinement, and myelin pruning through the expression and release of different signaling factors. Continuous activation of microglia has been implicated in neurodegenerative disorders. We first review the lifetime of microglia, including the origin, differentiation, development, and function of microglia. We then discuss microglia participate in the whole processes of remyelination and demyelination, microglial phenotypes in MS, and the NF-κB/PI3K-AKT signaling pathway in microglia. The damage to regulatory signaling pathways may change the homeostasis of microglia, which would accelerate the progression of MS.

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.

Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure.

Inherited or non-inherited dilated cardiomyopathy (DCM) patients develop varied disease phenotypes leading to death after developing congestive heart failure (HF) or sudden death with mild or no overt HF symptoms, suggesting that environmental and/or genetic factors may modify the disease phenotype of DCM. In this study, we sought to explore unknown genetic factors affecting the disease phenotype of monogenic inherited human DCM. Knock-in mice bearing a sarcomeric protein mutation that causes DCM were created on different genetic backgrounds; BALB/c and C57Bl/6. DCM mice on the BALB/c background showed cardiac enlargement and systolic dysfunction and developed congestive HF before died. In contrast, DCM mice on the C57Bl/6 background developed no overt HF symptoms and died suddenly, although they showed considerable cardiac enlargement and systolic dysfunction. BALB/c mice have brain serotonin dysfunction due to a single nucleotide polymorphism (SNP) in tryptophan hydroxylase 2 (TPH2). Brain serotonin dysfunction plays a critical role in depression and anxiety and BALB/c mice exhibit depression- and anxiety-related behaviors. Since depression is common and associated with poor prognosis in HF patients, we examined therapeutic effects of anti-depression drug paroxetine and anti-anxiety drug buspirone that could improve the brain serotonin function in mice. Both drugs reduced cardiac enlargement and improved systolic dysfunction and symptoms of severe congestive HF in DCM mice on the BALB/c background. These results strongly suggest that genetic backgrounds involving brain serotonin dysfunction, such as TPH2 gene SNP, may play an important role in the development of congestive HF in DCM.