One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency.

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

Robo4-mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes.

In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.

RNA-seq analysis of LPS-induced transcriptional changes and its possible implications for the adrenal gland dysregulation during sepsis.

Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. In the present study, we have used RNA Sequencing (RNA-Seq) technology to analyze changes in adrenal transcriptome elucidated by bacterial LPS. We aimed to find particularly alterations in genes that were previously not reported to be involved in the adrenal gland dysregulation in contexts of sepsis. Our results demonstrate that systemic administration of LPS significantly altered expression of 8458 genes as compared to saline injected animals. The subsequent quality and functional analysis of these gene signatures revealed that LPS-induced highly homogenous transcriptional response in total upregulating 4312 and downregulating 4146 genes. Furthermore, functional annotation analysis together with gene enrichment set analysis (GSEA) clearly demonstrated that adrenal response to LPS involved alterations in multiple pathways related to the inflammatory response along with previously unexplored activation of the hypoxia pathway. In addition, LPS strongly downregulated genes involved in the adrenal homeostasis, development, and regeneration. Those alterations were subsequently verified in clinically relevant cecal ligation and puncture (CLP)-induced sepsis model. Collectively, our study demonstrates that RNA-seq is a very useful method that can be applied to search for new unexplored pathways potentially involved in adrenal gland dysregulation during sepsis.

State-Dependent Pulse Vaccination and Therapeutic Strategy in an SI Epidemic Model with Nonlinear Incidence Rate.

In this paper, the state-dependent pulse vaccination and therapeutic strategy are considered in the control of the disease. A pulse system is built to model this process based on an SI ordinary differential equation model. At first, for the system neglecting the impulse effect, we give the classification of singular points. Then for the pulse system, by using the theory of the semicontinuous dynamic system, the dynamics is analyzed. Our analysis shows that the pulse system exhibits rich dynamics and the system has a unique order-1 homoclinic cycle, and by choosing p as the control parameter, the order-1 homoclinic cycle disappears and bifurcates an orbitally asymptotical stable order-1 periodic solution when p changes. Numerical simulations by maple 18 are carried out to illustrate the theoretical results.

Transcriptional Analysis of Sepsis-Induced Activation and Damage of the Adrenal Endothelial Microvascular Cells.

Bacterial sepsis is a serious threat to the body homeostasis and is often associated with high mortality in non-coronary intensive stations. In order to survive sepsis, rapid activation of the hypothalamus-pituitary-adrenal gland axis and sympathomedullary system is necessary. In many patients with sepsis, the function of those two arms of the stress system is dysregulated with underlying mechanisms remaining unknown. In our previous experimental studies, we have demonstrated that LPS-induced systemic inflammation and CLP-induced peritonitis can result in adrenal gland damage. Histological and transcriptomic analysis revealed a potential involvement of the adrenal microvascular endothelium in this process. However, our knowledge about the function of adrenal microvascular cells during sepsis is scarce. In the present study, we have characterized transcriptomic alterations in isolated mouse adrenal microvascular endothelial cells induced by systemic administration of bacterial LPS. Our results revealed that LPS induced a distinct transcriptomic profile in the adrenal microvascular cells, including multiple genes regulating inflammation, activation of the coagulation cascade and vascular permeability. Activation of those genes may be potentially involved in the damage to the microvascular endothelium and altogether contribute to the sepsis-mediated adrenal dysregulation.

State feedback impulsive therapy to SIS model of animal infectious diseases.

Controlling animal infectious diseases and its related infra microbes is of great significance to public health, since a lot of infectious diseases originate from animal epidemics and they often threaten human health. A state feedback impulsive model is constructed to depict the transmission and treatment of animal epidemics. Basing on the impulsive model, the existence of order-1 periodic solution and its stability are proved with a novel method. The theoretical results indicate that the impulsive treatment triggered by the number of infectious is an efficient approach to control animal infectious disease from breakout. Numerical simulation is presented to support the theoretical conclusion in the end.

DEL-1 promotes macrophage efferocytosis and clearance of inflammation.

Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

State feedback impulsive control of computer worm and virus with saturated incidence.

A state feedback impulsive model is set up to discuss the spreading and control of the computer worm and virus. Considering the transmission features, saturated infectious is adopted to describe the spreading in the model, and all the treatment measures, such as patching operating system and updating antivirus software, are assumed to take effect instantly. Then the model is analyzed with a novel method, and the existence and stability of order-1 limit cycle are discussed. Finally, the numerical simulation is listed to verify the result of the paper.

Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity.

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of ß-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by ß3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.

Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.

Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release.

The transcription factor Hes3 is a component of a signaling pathway that supports the growth of neural stem cells with profound consequences in neurodegenerative disease models. Here we explored whether Hes3 also regulates pancreatic islet cells. We showed that Hes3 is expressed in human and rodent pancreatic islets. In mouse islets it co-localizes with alpha and beta cell markers. We employed the mouse insulinoma cell line MIN6 to perform in vitro characterization and functional studies in conditions known to modulate Hes3 based upon our previous work using neural stem cell cultures. In these conditions, cells showed elevated Hes3 expression and nuclear localization, grew efficiently, and showed higher evoked insulin release responses, compared with serum-containing conditions. They also exhibited higher expression of the transcription factor Pdx1 and insulin. Furthermore, they were responsive to pharmacological treatments with the GLP-1 analog Exendin-4, which increased nuclear Hes3 localization. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed cell growth and affected gene expression as revealed by DNA microarrays. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Hes3 overexpression (using a Hes3-GFP fusion construct) confirmed a role of Hes3 in regulating Pdx1 expression. Hes3 RNA interference reduced evoked insulin release. Mice lacking Hes3 exhibited increased islet damage by streptozotocin. These data suggest roles of Hes3 in pancreatic islet function.

The geometrical analysis of a predator-prey model with two state impulses.

Using successor functions and Poincaré-Bendixson theorem of impulsive differential equations, the existence of periodical solutions to a predator-prey model with two state impulses is investigated. By stability theorem of periodic solution to impulsive differential equations, the stability conditions of periodic solutions to the system are given. Some simulations are exerted to prove the results.

Theoretical approach to modelling and analysis of the bioprocess with product inhibition and impulse effect.

This work presents the first mathematical model of a bioprocess with product inhibition and impulse effect. To begin with, an exemplary mathematical bioprocess model with product inhibition and impulse effect is formulated. Then, according to the model, the analysis of bioprocess stability is presented. The article expresses the product oscillation period, which provides the precise feeding time frame for the regulator bioprocess to achieve an equivalent stable output as that of a bioprocess with impulse effect in the same production environment. Moreover, in this work, the optimization of the production process with respect to the tunable parameters is investigated, and analytical expressions of their optimal values are provided. Numerical simulations using biological data are presented to illustrate the main results.

Endogenous KLF4 expression in human fetal endothelial cells allows for reprogramming to pluripotency with just OCT3/4 and SOX2--brief report.

OBJECTIVE: The introduction of 4 transcription factors-c-MYC, OCT3/4, SOX2, and KLF4--can reprogram somatic cells back to pluripotency. However, some of the factors used are oncogenic, making therapeutic application unfeasible. Although the use of adult stem cells expressing high endogenous levels of some of these factors allows for reprogramming with fewer exogenous genes, such cells are rare and may have accumulated genetic mutations. Our goal was to reprogram human somatic cells without oncogenic factors. We found that high endogenous expression of KLF4 in human umbilical vein endothelial cells (HUVECs) allows for generation of induced pluripotent stem cells (iPSCs) with just 2 nononcogenic factors, OCT3/4 and SOX2. METHODS AND RESULTS: HUVECs were infected with lentivirus containing OCT4 and SOX2 for generation of iPSCs. These 2-factor HUVEC iPSCs were morphologically similar to embryonic stem cells, express endogenous pluripotency markers postreprogramming, and can differentiate toward lineages of all 3 germ layers both in vitro and in vivo. CONCLUSIONS: iPSCs can be generated from HUVECs with only 2 nononcogenic factors. The use of fetal cells for reprogramming without oncogenic factors may provide an efficient in vitro model for human iPSC research, as well as a novel source for possible therapeutic use.

Periodic solution of a chemostat model with Beddington-DeAnglis uptake function and impulsive state feedback control.

In this paper, a chemostat model with Beddington-DeAnglis uptake function and impulsive state feedback control is considered. We obtain sufficient conditions of the global asymptotical stability of the system without impulsive state feedback control. We also obtain that the system with impulsive state feedback control has periodic solution of order one. Sufficient conditions for existence and stability of periodic solution of order one are given. In some cases, it is possible that the system exists periodic solution of order two. Our results show that the control measure is effective and reliable.

Periodic solution of a chemostat model with Monod growth rate and impulsive state feedback control.

In this paper, we develop a mathematical model concerning a chemostat with impulsive state feedback control to investigate the periodicity of bioprocess. By the existence criteria of periodic solution of a general planar impulsive autonomous system, the conditions under which the model has a periodic solution of order one are obtained. Furthermore, we estimate the position of the periodic solution of order one and discuss the existence of periodic solution of order two. The theoretical results and numerical simulations indicate that the chemostat system with impulsive state feedback control either tends to a stable state or has a periodic solution, which depends on the feedback state, the control parameter of the dilution rate and the initial concentrations of microorganisms and substrate.