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We present HiGlass, an open source visualization tool built on web technologies that provides a rich interface for rapid, multiplex, and multiscale navigation of 2D genomic maps alongside 1D genomic tracks, allowing users to combine various data types, synchronize multiple visualization modalities, and share fully customizable views with others. We demonstrate its utility in exploring different experimental conditions, comparing the results of analyses, and creating interactive snapshots to share with collaborators and the broader public. HiGlass is accessible online at http://higlass.io and is also available as a containerized application that can be run on any platform.

A unique strain of Staphylococcus epidermidis , AIT01 (AIT, Airway Immune Trainer), identified in our previous research, has demonstrated immune-boosting properties. This study aimed to evaluate the systemic immune-modulatory effects and potential anti-tumor properties of this immune-enhancing skin microbiota strain. A series of ex vivo and in vivo experiments were conducted to assess immune cell proliferation, cytokine production, and anti-tumor efficacy. In ex vivo studies, splenocytes treated with the bacterial lysate or culture supernatant of the strain showed significantly increased viability in a concentration-dependent manner. Flow cytometry analysis revealed increased populations of dendritic cells, NK cells (Natural killer cells), and γδ T cells, with enhanced cytokine production, particularly IFN-γ (Interferon-γ) and perforin, in the lysate-treated group. When administered via intraperitoneal and intravenous routes in vivo, mice showed significant inhibition of melanoma growth upon receiving the bacterial lysate. Notably, pre-treatment demonstrated superior efficacy compared to post-treatment. Furthermore, the combination of the bacterial lysate with anti-PD-1 (anti-Programmed cell death protein-1) monoclonal antibody further suppressed tumor growth compared to anti-PD-1 monotherapy. These findings suggest that the AIT01 lysate enhances immune cell proliferation and cytokine production, contributing to its potent anti-tumor effects. The systemic delivery of this immune-boosting skin microbiota strain, particularly in combination with anti-PD-1 therapy, holds promise as an effective immunotherapeutic strategy against melanoma.

Boolean networks have been widely used to model biological processes lacking detailed kinetic information. Despite their simplicity, Boolean network dynamics can still capture some important features of biological systems such as stable cell phenotypes represented by steady states. For small models, steady states can be determined through exhaustive enumeration of all state transitions. As the number of nodes increases, however, the state space grows exponentially thus making it difficult to find steady states. Over the last several decades, many studies have addressed how to handle such a state space explosion. Recently, increasing attention has been paid to a satisfiability solving algorithm due to its potential scalability to handle large networks. Meanwhile, there still lies a problem in the case of large models with high maximum node connectivity where the satisfiability solving algorithm is known to be computationally intractable. To address the problem, this paper presents a new partitioning-based method that breaks down a given network into smaller subnetworks. Steady states of each subnetworks are identified by independently applying the satisfiability solving algorithm. Then, they are combined to construct the steady states of the overall network. To efficiently apply the satisfiability solving algorithm to each subnetwork, it is crucial to find the best partition of the network. In this paper, we propose a method that divides each subnetwork to be smallest in size and lowest in maximum node connectivity. This minimizes the total cost of finding all steady states in entire subnetworks. The proposed algorithm is compared with others for steady states identification through a number of simulations on both published small models and randomly generated large models with differing maximum node connectivities. The simulation results show that our method can scale up to several hundreds of nodes even for Boolean networks with high maximum node connectivity. The algorithm is implemented and available at http://cps.kaist.ac.kr/∼ckhong/tools/download/PAD.tar.gz.

We present HiGlass, an open source visualization tool built on web technologies that provides a rich interface for rapid, multiplex, and multiscale navigation of 2D genomic maps alongside 1D genomic tracks, allowing users to combine various data types, synchronize multiple visualization modalities, and share fully customizable views with others. We demonstrate its utility in exploring different experimental conditions, comparing the results of analyses, and creating interactive snapshots to share with collaborators and the broader public. HiGlass is accessible online at http://higlass.io and is also available as a containerized application that can be run on any platform. Footnotes * The results describing the off-diagonal contacts were updated to include findings in recent publications. We added an extra section listing the locations of the source code as well as the data used. New references were added to cite work that has appeared since the previous revision. The abstract was shortened.

High temperatures (30–36 °C) inhibited astaxanthin accumulation in Haematococcus pluvialis under photoautotrophic conditions. The depression of carotenogenesis was primarily attributed to excess intracellular less reactive oxygen species (LROS; O₂⁻and H₂O₂) levels generated under high temperature conditions. Here, we show that the heat stress-driven inefficient astaxanthin production was improved by accelerating the iron-catalyzed Haber–Weiss reaction to convert LROS into more reactive oxygen species (MROS; O₂and OH·), thereby facilitating lipid peroxidation. As a result, during 18 days of photoautotrophic induction, the astaxanthin concentration of cells cultured in high temperatures in the presence of iron (450 μM) was dramatically increased by 75 % (30 °C) and 133 % (36 °C) compared to that of cells exposed to heat stress alone. The heat stress-driven Haber–Weiss reaction will be useful for economically producing astaxanthin by reducing energy cost and enhancing photoautotrophic astaxanthin production, particularly outdoors utilizing natural solar radiation including heat and light for photo-induction of H. pluvialis.

Background In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. Methods To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. Results CD244 fl/fl LysM cre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244 fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244 fl/fl LysM cre mice also showed higher percentages of Ly6C low macrophages, along with elevated gp100 + IFN-γ + CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6C low macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244 −/− bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Conclusion Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.

Despite the established comorbidity between mood disorders and abnormal eating behaviors, the underlying molecular mechanism and therapeutics remain to be resolved. Here, we show that a spexin-based galanin receptor type 2 agonist (SG2A) simultaneously normalized mood behaviors and body weight in corticosterone pellet-implanted (CORTI) mice, which are underweight and exhibit signs of anhedonia, increased anxiety, and depression. Administration of SG2A into the lateral ventricle produced antidepressive and anxiolytic effects in CORTI mice. Additionally, SG2A led to a recovery of body weight in CORTI mice while it induced significant weight loss in normal mice. In Pavlovian fear-conditioned mice, SG2A decreased contextual and auditory fear memory consolidation but accelerated the extinction of acquired fear memory without altering innate fear and recognition memory. The main action sites of SG2A in the brain may include serotonergic neurons in the dorsal raphe nucleus for mood control, and proopiomelanocortin/corticotropin-releasing hormone neurons in the hypothalamus for appetite and body weight control. Furthermore, intranasal administration of SG2A exerted the same anxiolytic and antidepressant-like effects and decreased food intake and body weight in a dose-dependent manner. Altogether, these results indicate that SG2A holds promise as a clinical treatment for patients with comorbid mood disorders and abnormal appetite/body weight.

Background Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays an important role in diverse cellular processes by regulating Rho guanosine triphosphate (GTP)ases activity. RhoGDI1 phosphorylation regulates the spatiotemporal activation of Rho GTPases during cell migration. In this study, we identified polo-like kinase 1 (PLK1) as a novel kinase of RhoGDI1 and investigated the molecular mechanism by which the interaction between RhoGDI1 and PLK1 regulates cancer cell migration. Methods Immunoprecipitation, GST pull-down assay, and proximity ligation assay (PLA) were performed to analyze the interaction between RhoGDI1 and PLK1. In vitro kinase assay and immunoprecipitation were performed with Phospho-(Ser/Thr) antibody. We evaluated RhoA activation using RhoGTPases activity assay. Cell migration and invasion were analyzed by transwell assays. Results GST pull-down assays and PLA showed that PLK1 directly interacted with RhoGDI1 in vitro and in vivo. Truncation mutagenesis revealed that aa 90-111 of RhoGDI1 are critical for interacting with PLK1. We also showed that PLK1 phosphorylated RhoGDI1 at Thr7 and Thr91, which induces cell motility. Overexpression of the GFP-tagged RhoGDI1 truncated mutant (aa 90-111) inhibited the interaction of PLK1 with RhoGDI1 and attenuated RhoA activation by PLK1. Furthermore, the overexpression of the RhoGDI1 truncated mutant reduced cancer cell migration and invasion in vitro and suppressed lung metastasis in vivo. Conclusions Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. This study connects the interaction between PLK1 and RhoGDI1 to the promotion of cancer cell behavior associated with malignant progression, thereby providing opportunities for cancer therapeutic interventions.

Background: Acute bronchiolitis is a common cause of hospitalization during infancy that carries significant morbidity and mortality rates.Purpose: This study compared the efficacy of different treatment modalities for infants with bronchiolitis in terms of hospital stay and clinical severity scores.Methods: The PubMed database was searched for relevant studies. Eligibility criteria included double-blind randomized controlled trial design, assessment of the effect of treatment on bronchiolitis in infants under 2 years of age, and publication in English from inception through July 31, 2020. The primary efficacy outcome was the length of hospital stay, while the secondary outcome was the clinical severity score. The standardized treatment effect and standard error of the effect size were calculated.Results: We identified 45 randomized controlled trials of 24 pairwise comparisons. These 45 trials included 5,061 participants and investigated 13 types of interventions (12 active, 1 placebo). Inhalation therapy with epinephrine (standard mean difference [SMD], -0.41; 95% confidence interval [CI], -0.8 to -0.03) and hypertonic saline (SMD, -0.29; 95% CI, -0.55 to -0.03) reduced the length of hospital stay compared with normal saline. Hypertonic saline was the most effective at improving the clinical severity score (SMD, -0.52; 95% CI, -0.95 to -0.10).Conclusion: Inhalation therapy with epinephrine and hypertonic saline reduced the length of hospital stay and the clinical severity of bronchiolitis among infants under 2 years of age.

Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a critical role in regulating the activity of Rho guanosine triphosphatases (GTPases). Phosphorylation of RhoGDI1 dynamically modulates the activation of Rho GTPases, influencing cell proliferation and migration. This study explored the involvement of Never In Mitosis A (NIMA)-related serine/threonine protein kinase 2 (NEK2) in phosphorylating RhoGDI1 and its implications in cancer cell behavior associated with tumor progression. We employed GST pull-down assays and immunoprecipitation to investigate the interaction between NEK2 and RhoGDI1. Truncation fragments identified the region of RhoGDI1 responsible for binding with NEK2. Phosphorylation assays determined the site of NEK2-mediated phosphorylation on RhoGDI1. Functional assays were conducted using overexpression of the RhoGDI1 substitution mutant to assess their impact on cancer cell behavior. NEK2 directly bound to RhoGDI1 and phosphorylated it at Ser174. This phosphorylation event facilitated cancer cell proliferation and motility by activating RhoA and Rac1. The RhoGDI1 aa 112–134 region was critical for the binding to NEK2. Disruption of the NEK2–RhoGDI1 interaction through overexpression of a RhoGDI1 truncated fragment (aa 112–134) led to diminished RhoGDI1 phosphorylation and RhoA/Rac1 activation induced by NEK2, resulting in reduced cancer cell proliferation and migration. Moreover, in vivo studies showed reduced tumor growth and lung metastasis when the NEK2–RhoGDI1 interaction was disrupted. This study indicates that NEK2 promotes the metastatic behaviors of cancer cells by activating RhoA and Rac1 by phosphorylating RhoGDI1.