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Chikungunya Virus Vaccines: Viral Vector-Based Approaches.

In 2013, a major chikungunya virus (CHIKV) epidemic reached the Americas. In the past 2 years, >1.7 million people have been infected. In li … as modified vaccinia virus Ankara, complex adenovirus, vesicular stomatitis virus, alphavirus-based chimeras, and measles vaccine Schwarz strain (MV/Schw) have been described as potential vaccines. We summarize here the recent data on these experimental vaccines, with a focus on the preclinical and clinical activities on the MV/Schw-based candidate, which …

The E glycoprotein plays an essential role in the high pathogenicity of European-Mediterranean IS98 strain of West Nile virus.

West Nile virus (WNV) is the most widespread arbovirus in the world. Several recent outbreaks and epizootics have been reported in Europe and the Mediterranean basin with increased virulence. In contrast to the well-characterized American and Australian strains, little is known about the virulence determinants of the WNV European-Mediterranean strains. To investigate the viral factors involved in the virulence of these strains, we generated chimeras between the highly neuropathogenic Israel 1998 (IS-98-ST1, IS98) strain and the non-pathogenic Malaysian Kunjin virus (KJMP-502). In vivo analyses…

The bile acid-sensitive ion channel (BASIC) is activated by alterations of its membrane environment.

The bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC family of ion channels. Channels of this family are characterized by … that BASIC is sensitive for changes in its membrane environment. Furthermore based on results from chimeras between BASIC and ASIC1a, we show that the extracellular and the transmembrane domains are important for membrane sensitivity.

Отрицательно заряженные остатки в эндодомене имеют решающее значение для конкретного соединения белка шипа в муринный коронавирус.

Протеин коронавируса (S) соединяется с вирионами через карбокситермин, который состоит из трансмембранной области и эндодомена. Здесь было установлено, что движущая сила, богатая зарядом в эндодомене, имеет решающее значение для специфичности S-комбинации в вирусе гепатита мыши (MHV). Рекомбинантные MHV продемонстрировали ряд возможностей для размещения гомологовых S-эндоводов из бета-коронавирусов говяжьего коронавируса и человека, связанного с SARS, коронавируса, альфакоронавирусного трансмиссивного гастроэнтерита (TGEV) и гаммакоронавируса птичьего инфекционного бронхита, соответственно. Ин

Совпадение в аннотации оригинала
Coronavirus spike (S) protein assembles into virions via its carboxy-terminus, which is composed of a transmembrane domain and an endodomain … gammacoronavirus avian infectious bronchitis virus respectively. Interestingly, in TGEV endodomain chimeras the reverting mutations resulted in stronger S incorporation into virions, and a net gain of negatively charged residues in the charge-rich motif accounted for the improvement. Additionally, MHV S assembly could also be rescued by the acidic carbox …

DNA damage and repair in epithelium after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans, following hematoablative treatment, results in biological chimeras. In this case, the transplanted hematopoietic, immune cells and their derivatives can be considered the donor genotype, while the other tissues are the recipient genotype. The first sequel, which has been recognized in the development of chimerical organisms after allo-HSCT, is the graft versus host (GvH) reaction, in which the new developed immune cells from the graft recognize the host's epithelial cells as foreign and mount an inflammatory response to …

Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse.

Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and poste … oration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.

A polymeric bacterial protein activates dendritic cells via TLR4.

The enzyme lumazine synthase from Brucella spp. (BLS) is a highly immunogenic protein that folds as a stable dimer of pentamers. It is possible to insert foreign peptides and proteins at the 10 N terminus of BLS without disrupting its general folding, and these chimeras are very efficient to elicit systemic and oral immunity without adjuvants. In this study, we show that BLS stimulates bone marrow dendritic cells from mice in vitro to up-regulate the levels of costimulatory molecules (CD40, CD80, and CD86) and major histocompatibility class II Ag. Furthermore, the mRNA levels of several chemok…

Analysis of an ethylnitrosourea-generated mouse mutation defines a cell intrinsic role of nuclear factor kappaB2 in regulating circulating B cell numbers.

The number of circulating follicular B lymphocytes is normally kept within a precise range despite their dispersion through the body and daily overproduction of precursors in the bone marrow. By establishing a genome wide recessive mutation screen in C57BL/6 mice to identify critical components of immune system regulation, we identified a mutant strain with selective deficiency in recirculating B cells but not immature or peritoneal B1 cells. Analysis of mixed bone marrow chimeras established that the mutation affects a cell autonomous process within B cells that is required for their accumula…

T-cell tolerance and autoimmune diabetes.

Herein we describe the major signaling events that occur in T-cells upon T-cell receptor (TCR) engagement, and the mechanisms responsible fo … further development of antigen-specific immunotherapeutic agents such as human-like MHC lI/peptide chimeras endowed with efficient down-regulatory effects in CD4 T-cell-mediated autoimmune diseases such as Type 1 diabetes, multiple sclerosis, primary biliary cirrhosis, and rheumatoid arthritis.

Heritable germ and somatic cell lineage competitions in chimeric colonial protochordates.

Theories of evolution that state natural selection acts on individuals have been modified to include multiple levels of selection. Here we demonstrate in chimeric protochordates that primitive germ cell (pgc) and somatic cell (psc) lineages have traits that also make them likely units of natural selection. Specifically, by using microsatellites to determine the genetic identity of various somatic and gametic tissues within vascularly fused Botryllus schlosseri chimeras, we show that genetically distinct pgc and psc can compete for access to developing gonads and somatic organs, and that this c…

Haematopathology of 'Sjögren-mice': histopathological changes in spleens after semiallogeneic cell transfer.

Haematopoietic transplantation chimeras may be readily produced in adult mice, using F1-hybrids of selected inbred strains as recipients and mice from one of the parental strains as donors. We transplanted spleen cells from BALB/c donors into nonirradiateded F1-hybrids of BALB/c and CBA/H-T6. Both female and male recipients developed a primary Sjögren's syndrome-like exocrinopathy without signs of kidney disease. At long-term follow-up, 7(1/2) months after cell transfer, lymph nodes were enlarged, and spleens were diminished and irregular in shape. In general, changes in haematopoietic organs …

Surgical fusion between incompatible colonies of the compound ascidian, Botrylloides fuscus.

In the compound ascidian Botrylloides fuscus, allorecognition responses were observed at the colonial margin (natural growing edge) as necrotic reactions in the subcuticular region of the facing tunic. However, artificial cut surface contacts between incompatible colonies resulted in the formation of chimeras with common vascular systems, termed "surgical fusion." The occurrence of surgical fusion in B. fucus contrasts with rejection occurring under the same conditions in other botryllids. Together the two observations suggest that self-nonself recognition may be a specialized function of tuni…

Immunosuppression prior to marrow transplantation for sensitized aplastic anemia patients: comparison of TLI with TBI.

From May 1980 through July 1986, 26 patients with severe aplastic anemia, sensitized with multiple transfusions of blood products, were trea … cells, whereas 6/11 with TLI had 100% donor cells. Of the five who did not, three were stable mixed chimeras with greater than or equal to 70% donor cells, one became a mixed chimera with about 50% donor cells, but became aplastic again after Cyclosporine A cessation 5 mo post-transplant, and the fifth reverted to all host cells by d. 18 post-transplant. …

Graft-versus-host disease in dog and man: the Seattle experience.

In dog and in man a marrow graft from a donor genetically identical for the major histocompatibility complex is followed by significant graf … HD but at the price of a higher likelihood of subsequent graft failure. Studies of canine and human chimeras are in agreement with murine data indicating a principal role for T cells in the pathogenic mechanism of GvHD. Chimera lymphocytes (of donor origin) from dogs and patients with acute GvHD proliferate in response to previously stored host cells, and …

Targeting the nonenzymatic scaffold function of RIPK1 via a VHL-recruiting PROTAC synergizes with immunotherapy in melanoma.

Receptor-interacting protein kinase 1 (RIPK1) mediates cell survival, inflammation, and cell death, and its kinase-independent scaffolding function drives tumor progression and therapeutic resistance, which cannot be eliminated by conventional RIPK1 kinase inhibitors. To overcome this limitation, we adopted proteolysis-targeting chimera (PROTAC) technology to achieve complete RIPK1 protein depletion. Through linker structural optimization with a rigid phenyl ring incorporation, we successfully identified a potent RIPK1 degrader, compound B11. In A375 and B16F10 melanoma cells, B11 exhibited ro…

Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics.

Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men, fundamentally driven by gain-of-function altera … medicine-based drug delivery, poly-(ADP ribose) polymerase (PARP) inhibition, proteolysis-targeting chimera (PROTAC) technologies, and RNA-based approaches, with emphasis on their translational potential and current limitations. By integrating the existing literature with targeted in silico insights, this perspective presents a forward-looking perspective …

Targeting the ubiquitin-proteasome system and drug therapy in colorectal cancer.

Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths, posing a … impeding tumor progression. Moreover, emerging therapeutic strategies such as proteolysis-targeting chimera (PROTAC) and molecular glue technologies selectively degrade specific oncogenic proteins, thereby offering new avenues and promising opportunities for CRC treatment.

Intracellular LRG1 recruits MARCH2 to ubiquitinate and degrade endothelial VE-cadherin in septic lung injury.

Endothelial barrier dysfunction and consequent vascular injury are central contributors to acute lung injury (ALI) during sepsis. However, t … r disruption. Genetic deletion of Lrg1 or pharmacological intervention with a proteolysis targeting chimera (PROTAC)-based degradation strategy significantly reduced VE-cadherin loss, alleviated endothelial hyperpermeability, and mitigated ALI in septic mice. Collectively, our study elucidates a previously unrecognized role of endothelial LRG1 in disrupti …

VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α.

Acute kidney injury (AKI) impairs renal function in the short term and may eventually progress to chronic kidney disease (CKD) in the long term. The activation of Smad3 and an imbalance in hypoxia-inducible factors-α (HIF-α) expression constitute vital mechanisms leading to the AKI-CKD transition. We have designed a Smad3-targeted Proteolysis-Targeting Chimera (PROTAC) named P1705434, which recruited VHL to degrade Smad3 and meanwhile stable HIF-2α levels. We established a cisplatin nephrotoxicity model and folic acid nephropathy (FAN) model to explore its role and possible mechanisms in the e…

Control of airway basal stem cell-mediated lung repair by TGF-β signaling.

Airway basal stem cells (BCs) are recognized as resident stem cells responsible for reconstituting epithelial barriers and differentiating into multiple epithelial cell types following severe lung injury. However, the mechanism that the injured lung microenvironment uses to modulate BC-mediated lung repair remains unclear. Here, we showed that the profibrotic transforming growth factor-β (TGF-β) gradient from the injured lung immune microenvironment can be sensed by BCs. Targeted degradation of Smad2/3 in human BCs via proteolysis targeting chimera (PROTAC) disrupted TGF-β signaling, causing c…