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Агенты болезни Креуцфельдта-Якоба могут скрывать более вирулентные инфекции.

Ранее мы показали, что медленный инфекционный штамм болезни Креуцфельдт-Якоб (CJD) может резко подавить выражение быстрых вирулентных агентов, впрыскиваемых внутриутробно через 80 дней. В то время как медленный агент SY в конце концов вызвал болезнь примерно 400 дней, было мало доказательств быстрого агента FU. Однако у двух из 18 суперинфицированных мышей наблюдалось незначительное увеличение патологических изменений. Чтобы определить, был ли FU частично или полностью подавлен, или были ли агенты FU и SY образуют "химера" с промежуточными свойствами инкубации, как предсказывалось теорией прио

Совпадение в аннотации оригинала
We previously showed that a slow infectious strain of Creutzfeldt-Jakob Disease (CJD) can dramatically suppress the expression of a fast vir … hanges. To determine if FU was partially or completely suppressed, or if FU and SY agents formed a 'chimera' with intermediate incubation properties as predicted by prion theory, we passaged representative brains. All traces of FU were obliterated in typical brains of suppressed mice. The two aberrant mice however had mixed SY and FU infections, with FU r …

c-Myc induces cellular susceptibility to the cytotoxic action of TNF-alpha.

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine which is cytotoxic for some tumor cells and transformed cells. The molecular mechanisms which render transformed and tumor cells sensitive to the cytotoxic action of TNF are unclear. We show here that an increased expression of the c-Myc oncoprotein strongly increases cellular sensitivity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone-inducible c-Myc-estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c-Myc overexpress…

PhenoDEL: A Novel Screening Strategy Based on Intracellular Protein Degradation Activity.

Targeted protein degradation (TPD), including proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs), is a promising therapeutic approach. However, systematic discovery of such small molecules remains a major challenge. Here, we present PhenoDEL, a novel phenotypic DNA-encoded library (DEL) screening platform that integrates one-bead one-compound DEL (OBOC-DEL) with the Beacon optofluidic system for single-cell analysis. By coculturing individual OBOC-DEL beads and engineered reporter cells in nanoliter-scale chambers, PhenoDEL enables time-resolved, single-cell phenotypi…

Tumor-confined delivery via syringeable hydrogels for reinforced immunomodulatory intervention.

Syringeable hydrogels have emerged as transformative tools for precise drug delivery and controlled release, capitalizing on their exception … including adoptive cell therapy, catalytic immunotherapy, cancer vaccination, proteolysis-targeting chimeras, and immunometabolic intervention. To achieve a high therapeutic index while minimizing systemic side effects, the underlying mechanisms governing the spatiotemporal release of immunomodulators are presented as well. Finally, this review systematic …

Proteolysis Targeting Chimeric-Based Technology in Myeloma and Lymphoma.

Proteolysis-targeting chimeras (PROTAC) leverage the ubiquitin-proteasome system to selectively degrade oncogenic proteins, including those previously seen as undruggable. Recent preclinical studies indicate that PROTACs may represent a novel therapeutic strategy in lymphoma and myeloma. Indeed, preclinically, PROTACs have shown high efficacy and remarkable selectivity, a favorable safety profile, and lower toxicity compared with conventional therapies. Their catalytic, reusable mechanism enables drug dosing and offers the perspective of long-term low-dose treatment. PROTACs have demonstrated …

Structure-guided discovery of HIV-1 capsid inhibitors: From diverse binding sites to resistance-resilient antiviral strategies.

HIV-1 capsid (CA) protein is a key target for next-generation antiretrovirals, driving multiple stages of the viral life cycle. This review … lso briefly discuss emerging approaches such as AI-driven design and PROTACs (Proteolysis-Targeting Chimeras), and highlight long-acting combination regimens as a promising path toward an HIV-1 functional cure.

Injectable PROTAC-loaded hydrogel remodels the tumor microenvironment to potentiate radio-immunotherapy.

Radiotherapy (RT) is a key component of comprehensive cancer treatment regimens; nevertheless, its concomitant immunosuppression may diminish therapeutic efficacy. In this study, we developed an injectable hydrogel system for the local delivery of PROteolysis TArgeting Chimeras (PROTACs), achieved by loading tumor cell membrane-fused liposome nanoparticles to enhance the anti-tumor effect. The system targeted Bromodomain-containing protein 4 (BRD4), and combined treatment with RT promoted DNA damage, reduced DNA repair and decreased tumor cell proliferation and survival. Additionally, this str…

CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer.

Breast cancer is one of the most prevalent malignancies affecting women worldwide, underscoring the urgent need for more effective and specific treatments. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy to develop new lead compounds by selectively targeting oncoproteins for degradation. In this study, we designed, synthesized and evaluated a CRBN-based PROTAC, L055, which targets CDK9. Our findings demonstrate that L055 effectively inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells in vitro. L055 …

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Zinc-finger ubiquitin-binding domains (ZnF-UBDs) are noncatalytic domains mostly found in deubiquitylases (DUBs) such as USP3. They represent an underexplored opportunity for the development of deubiquitylase-targeting chimeras (DUBTACs) to pharmacologically induce the deubiquitylation of target proteins. We previously showed that ZnF-UBDs are ligandable domains. Here, a focused small molecule library screen against a panel of 11 ZnF-UBDs led to the identification of compound 59, a ligand engaging the ZnF-UBD of USP3 with a KD of 14 μM. The compound binds the expected C-terminal ubiquitin bind…

Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin.

Ivermectin (IVM) is an antiparasitic drug that is used worldwide and rescues hundreds of millions of people from onchocerciasis and lymphati … dentification of IVM targets, as well as their modulation mechanisms, through molecular structures, chimeras and site-directed mutagenesis, and molecular docking and modelling studies.

Aminoglycoside antibiotics: structure, functions and effects on in vitro plant culture and genetic transformation protocols.

Plant transformation protocols generally involve the use of selectable marker genes for the screening of transgenic material. The bacterial gene nptII, coding for a neomycin phosphotransferase, and the hpt gene, coding for a hygromycin phosphotransferase, are frequently used. These enzymes detoxify aminoglycoside antibiotics by phosphorylation, thereby permitting cell growth in the presence of antibiotics. Nevertheless, the screening for transgenic regenerated shoots is often partial and difficult due to regeneration of escapes and chimeras. These difficulties can be caused, in part, by an inc…

Two cases of bovine male pseudohermaphrodites with different endocrinological and pathological findings.

Two cases of bovine male pseudohermaphrodites (PH) were subjected for clinical investigation with transrectal ultrasonography, endocrinology with adoption of hCG-stimulation test, cytogenetics with analysis of sex chromosome and Y-specific DNA, and finally histological examination. Results were compared with normal calves. Case 1 was a 10-month-old calf with XX/XY chimeras, showing elevation of testosterone (T) levels, but no change in progesterone (P(4)) after hCG test, and possessed atrophied testes in the cavitas pelvis. Case 2 was an 18-month-old calf with SRY positive-XY chromosome, showi…

A combined artificial chromosome-stem cell therapy method in a model experiment aimed at the treatment of Krabbe's disease in the Twitcher mouse.

Mammalian artificial chromosomes (MACs) are safe, stable, non-integrating genetic vectors with almost unlimited therapeutic transgene-carryi … acterized and used to produce chimeric mice on the mutant genetic background. The lifespan of these chimeras was increased twofold, verifying the feasibility of the development of MAC-stem cell systems for the delivery of therapeutic genes in stem cells to treat genetic diseases and cancers, and to produce cell types for cell replacement therapies.

Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos.

In blastocyst chimeras, embryonic stem (ES) cells contribute to embryonic tissues but not extraembryonic trophectoderm. Conditional activation of HRas1(Q61L) in ES cells in vitro induces the trophectoderm marker Cdx2 and enables derivation of trophoblast stem (TS) cell lines that, when injected into blastocysts, chimerize placental tissues. Erk2, the downstream effector of Ras-mitogen-activated protein kinase (MAPK) signaling, is asymmetrically expressed in the apical membranes of the 8-cell-stage embryo just before morula compaction. Inhibition of MAPK signaling in cultured mouse embryos comp…

Impaired virus control and severe CD8+ T-cell-mediated immunopathology in chimeric mice deficient in gamma interferon receptor expression on both parenchymal and hematopoietic cells.

Bone marrow chimeras were used to determine the cellular target(s) for the antiviral activity of gamma interferon (IFN-gamma). By transfusing such mice with high numbers of naive virus-specific CD8(+) T cells, a system was created in which the majority of virus-specific CD8(+) T cells would be capable of responding to IFN-gamma, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-gamma receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic vir…

Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels.

Hanatoxin (HaTx) binds to multiple sites on the surface of the drk1 voltage-gated K+ channel and modifies channel gating. We set out to identify channel residues that contribute to form these HaTx binding sites. Chimeras constructed using the drk1 and shaker K+ channels suggest that the S3-S4 linker may contain influential residues. Alanine scanning mutagenesis of the region extending from the C terminal end of S3 through S4 identified a number of residues that likely contribute to form the HaTx binding sites. The pore blocker Agitoxin2 and the gating modifier HaTx can simultaneously bind to i…

Perceptual asymmetry for chimeric faces across the life span.

Perceptual asymmetries for processing chimeric faces were investigated in dextral subjects, ranging in age from 5 years to elderly adults. The task involved deciding which member of a pair of face chimeras presented in free vision looks happier, the one with the smile to the left or its mirror image with the smile to the right (Levy, Heller, Banich, & Burton, 1983a, Brain and Cognition, 2, 404-419). A leftward bias was found for all age groups. However, kindergarteners' mean asymmetry score was lower than that of all other groups combined, most likely due to noise in their data. The direction …

Graft-versus-host reactions and abrogation of allotype suppression following histoincompatible lymphoid cell transfers in rabbits.

Noninbred rabbits that were characterized for antigens of the major histocompatibility complex (MHC) by serological (RLA) typing were used a … in this and in earlier publications, recipients of RLA-compatible cells become stable B lymphocyte chimeras without detectable T cells or erythrocytes of donor type. In the latter case allotype suppression is neither established in the recipient nor abrogated in the donor's cells.

Chitosan-rapamycin carbon dots rejuvenate autologous Sca-1⁺ stem cells paracrine function for neuroprotection in normal tension glaucoma.

BACKGROUND: Normal tension glaucoma (NTG) causes progressive retinal ganglion cell (RGC) loss without elevated intraocular pressure, and cur … y elevated neurotrophic factor expression in retinal tissues compared to RAPA-treated and untreated chimeras. Functional assessments further confirmed superior visual performance in CRCD-Sca-1+ chimeras, correlating with improved RGC survival. CONCLUSION: These findings suggest that CRCD improved paracrine neurotrophic support of autologous BM stem cells …

Identification of Novel Acylthiourea-Based PROTACs Exhibiting Broad-Spectrum Antiviral Activity against Enteroviruses.

Enteroviruses are the primary cause of hand, foot, and mouth disease (HFMD). The absence of broad-spectrum antivirals, due to high serotypic and genetic diversity, greatly hampers effective treatment. In this study, we developed a novel type of acylthiourea-based proteolysis-targeting chimeras (PROTACs) to induce targeted protein degradation. Compound X14 was identified as a potent candidate. X14 showed strong anti-EV71 activity by inhibiting viral replication. It directly binds to the EV71 3D polymerase with higher affinity than ribavirin and causes proteasome-dependent degradation of the 3D …