Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors

A preliminary review of the cultural heritage and emerging pilgrimage tourism in Tamil Nadu / V. Sivakumar ... [et al.]

Pilgrimage Tourism has become an emergent form of domestic tourism with the expanding demand for religious travel along with the accomplishment of other religious obligations. It can also be considered as a catalyst for socio-economic development of the neighbourhood community involved directly and indirectly for the pilgrims during their sojourns at the sacred sites. Though Pilgrimage Tourism is considered as the bottom of the tourism business pyramid, much value can be added through numerous attractive and affordable packages. This paper deals with the concern and challenges of pilgrimage tourism and the impact of cultural heritage in southern districts of Tamil Nadu. Prospects of religious tourists and the impact of cultural heritage are also explored in this research paper

Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation

\ua9 2023 The Authors. Published under the terms of the CC BY 4.0 license. Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in “gain-of-function” conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1−/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1−/− and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1−/− mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders

Immunotherapeutic targeting of aging-associated isoDGR motif in chronic lung inflammation

\ua9 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo

Immunotherapeutic targeting of aging-associated isoDGR motif in chronic lung inflammation

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo

The connected vertex monophonic number of a graph

For a connected graph G of order p ≥ 2 and a vertex x of G, a set S ⊆ V (G) is an x-monophonic set of G if each vertex v ∈ V (G) lies on an x − y monophonic path for some element y in S. The minimum cardinality of an x-monophonic set of G is defined as the x-monophonic number of G, denoted by mx(G). A connected x-monophonic set of G is an x-monophonic set S such that the subgraph G[S] induced by S is connected. The minimum cardinality of a connected x-monophonic set of G is defined as the connected x-monophonic number of G and is denoted by cmx(G). We determine bounds for it and find the same for some special classes of graphs. If p, a and b are positive integers such that 2 ≤ a ≤ b ≤ p − 1, then there exists a connected graph G of order p, mx(G) = a and cmx(G) = b for some vertex x in G. Also, if p, dm and n are positive integers such that 2 ≤ dm ≤ p − 2 and 1 ≤ n ≤ p, then there exists a connected graph G of order p, monophonic diameter dm and cmx(G) = n for some vertex x in G