Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif ...cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.
The lack of a convenient high-resolution strain-typing method has hampered the application of molecular epidemiology to the surveillance of bacteria of the Mycobacterium tuberculosis complex, ...particularly the monitoring of strains of Mycobacterium bovis. With the recent availability of genome sequences for strains of the M. tuberculosis complex, novel PCR-based M. tuberculosis-typing methods have been developed, which target the variable-number tandem repeats (VNTRs) of minisatellite-like mycobacterial interspersed repetitive units (MIRUs), or exact tandem repeats (ETRs). This paper describes the identification of seven VNTR loci in M. tuberculosis H37Rv, the copy number of which varies in other strains of the M. tuberculosis complex. Six of these VNTRs were applied to a panel of 100 different M. bovis isolates, and their discrimination and correlation with spoligotyping and an established set of ETRs were assessed. The number of alleles varied from three to seven at the novel VNTR loci, which differed markedly in their discrimination index. There was positive correlation between spoligotyping, ETR- and VNTR-typing. VNTR-PCR discriminates well between M. bovis strains. Thirty-three allele profiles were identified by the novel VNTRs, 22 for the ETRs and 29 for spoligotyping. When VNTR- and ETR-typing results were combined, a total of 51 different profiles were identified. Digital nomenclature and databasing were intuitive. VNTRs were located both in intergenic regions and annotated ORFs, including PPE (novel glycine-asparigine-rich) proteins, a proposed source of antigenic variation, where VNTRs potentially code repeating amino acid motifs. VNTR-PCR is a valuable tool for strain typing and for the study of the global molecular epidemiology of the M. tuberculosis complex. The novel VNTR targets identified in this study should additionally increase the power of this approach.
AbstractThis article discusses the limitations of democracy. Democracy substantively recognizes the existence of minority rights and the rights of the majority. The establishment of majority rights ...can give rise to the tyranny of the majority which is harmful to the interests of the minority. However, minorities can also be in power and control the politics of a country, so the majority vote is also ignored. Majority and minority discourse becomes important in the relationship between politics and power.Keywords: Majority, Minority, Democracy. Abstrak Artikel ini membahas mengenai masalah keterbatasan demokrasi. Demokrasi secara substansif mengakui eksistensi hak minoritas dan hak mayoritas. Pengutamaan hak mayoritas dapat memunculkan tirani mayoritas yang berbahaya bagi kepentingan minoritas. Walaupun demikian, minoritas juga dapat kelompok yang berkuasa dan mengontrol politik suatu negara, sehingga suara mayoritas juga terabaikan. Diskursus mayoritas dan minoritas menjadi hal penting dalam relasi antara politik dan kekuasaanKata Kunci : Mayoritas, Minoritas, Demokrasi.
AbstrakPenelitian ini mengkaji proses Politik Internasional dimana Negara-negara ditandai bersaing dalam kebijakan antariksanya, kemudian bekerjasama, dan melibatkan actor negara dalam mengembangkan ...eksplorasi Antariksa sebagai bagian kesadaran akan kepentingan umat manusia dibumi dan keberlangsungannya, dan tranformasi Globalisme menuju Planetisme telah mengubah Konfigurasi Kekuasaan Internasional, Aktor, dan relasinya. Key Word, Politik Internasional, Politik Antariksa, Globalisme, PlanetismeAbstractThis study examines the process of international politics in which countries are marked to compete in their space policies, then develop, and involve state actors in developing space exploration as part of awareness of the interests of mankind on earth and its sustainability, towards the transformation of globalism planetism changes international power, actors, and relations.Key Word, International Politics, Space Politics, Globalism, Planetism
ABSTRACTThis study describes the existence of Indonesian diplomats in answering Vanuatu's questions regarding human rights violations in Papua in the UN General Assembly forum. The ethnic closeness ...that Vanuatu has with Papua, namely the Melanesian race, is one of the reasons Vanuatu is increasingly massive in supporting the independence of West Papua. This study uses a qualitative descriptive analysis research methodology accompanied by interview data collection techniques as primary data and literature study as secondary data. The conclusion of this study is that the success of Indonesia's diplomacy in the UN General Assembly forum cannot be separated from the ability of Indonesian diplomats to answer and analyze problems that occur in the forum. The attitude and behavior of diplomats is something that is indispensable in the process of diplomacy at the UN General Assembly. Keywords: Existence of Diplomats, Diplomacy, and Neo-realists
Summary
Immunological memory was long considered a trait exclusive to cells of the adaptive immune system. However, recent studies have shown that after activation of the innate immune system, innate ...immune cells may undergo long‐term functional reprogramming characterized by the ability to mount either a stronger or attenuated inflammatory response upon reactivation. This phenomenon, which has been termed trained immunity and is a de facto innate immune memory, is regulated by a network of integrated metabolic and epigenetic rewiring. The endogenous mediators that modulate trained immunity in the host are only partially understood, but increasing evidence supports the concept that the interleukin (IL)‐1 family of cytokines plays an important role. In this review, we will highlight key findings from studies that provide insight into the multifaceted roles of members of the IL‐1 family for trained immunity. Finally, we will discuss how the recent advances of our understanding on the role of IL‐1 cytokines in this field may lead to new therapeutic strategies for treatment of common conditions, such as IL‐1‐driven autoinflammatory diseases.
Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate immune cells upon stimulation with ...heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8+ T cells show heterologous transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription factors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon-related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.
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•IFN-γ plays an important role in amplifying trained immunity response•Monocytes show heterogeneous trained immunity capacity after in vivo BCG vaccination•Trained monocytes are regulated by different transcription factors including STAT1•A developed tool for user to test trained immunity signatures in transcriptome data
Li et al. show that BCG vaccination induces an enhanced antimicrobial response upon secondary stimulation, and this effect is heterogeneous at single-cell level. These findings provide comprehensive insights into the molecular mechanism of trained immunity and its role in immune-mediated diseases.
Background
Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological ...mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.
Objective
We combined functional immunological assays and an omics-based approach to investigate the
in vitro
and
in vivo
effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.
Methods
Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2
ex vivo
in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.
Results
Dexamethasone efficiently inhibited SARS-CoV-2-induced
in vitro
expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated
ex vivo
with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.
Conclusion
We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.
Despite the clinical success of BRAF inhibitors like vemurafenib in treating metastatic melanoma, resistance has emerged through “paradoxical MEK/ERK signaling” where transactivation of one protomer ...occurs as a result of drug inhibition of the other partner in the activated dimer. The importance of the dimerization interface in the signaling potential of wild-type BRAF in cells expressing oncogenic Ras has recently been demonstrated and proposed as a site of therapeutic intervention in targeting cancers resistant to adenosine triphosphate competitive drugs. The proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signaling in malignant melanoma cells occurring through this drug target. The lead compounds identified are type-IV kinase inhibitors and represent an ideal framework for conversion into next-generation BRAF inhibitors through macrocyclic drug discovery.
The measles, mumps, and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically ...investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized, placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. Using single-cell RNA-Seq, we found that MMR caused transcriptomic changes in CD14+ monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFN-γ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.
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