Cardiac vagal control and inflammation are upregulated in exceptional human longevity.

We investigated the interplay of cardiovascular autonomic and inflammatory profiles in persons with extreme longevity (PEL), their direct offsprings (DO), and a group of controls matched for age and sex with the DO. Cardiac autonomic control was assessed through the heart rate variability (HRV) using spectral and symbolic analysis. The plasma concentration and gene expression of interleukin (IL)-10, IL-6, and TNF-α were quantified.

Clinical research on extreme longevity: The FACET experience.

People with extreme longevity represent a unique model to study the biology of aging. Unfortunately, their inclusion in research projects is challenging with the consequent lack of evidence and the need to rely on small convenience samples. Given the growing global aging population, especially in the segment of the oldest old (i.

Fatigue in older persons: the role of nutrition.

Fatigue is defined as a symptom leading to the inability to continue functioning at the expected activity level. It is a highly prevalent symptom, challenging to frame into monodimensional pathophysiological mechanisms. As a result, fatigue is often underestimated in the clinical setting and is wrongly considered an unavoidable consequence of ageing.

MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression.

The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination. However, it also sustains the progression of DNA replication forks, even in the absence of functional p53. Here, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1 (PARP1).

MDM2-Driven Ubiquitination Rapidly Removes p53 from Its Cognate Promoters.

MDM2 is the principal antagonist of the tumor suppressor p53. p53 binds to its cognate DNA element within promoters and activates the transcription of adjacent genes. These target genes include MDM2.

The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models.

The search for successful therapies of infections with the coronavirus SARS-CoV-2 is ongoing. We tested inhibition of host cell nucleotide synthesis as a promising strategy to decrease the replication of SARS-CoV-2-RNA, thus diminishing the formation of virus progeny. Methotrexate (MTX) is an established drug for cancer therapy and to induce immunosuppression.

Correction: The integrated stress response induces R-loops and hinders replication fork progression.

In the original version of this Article, the figures were not in the correct sequence, and the references and legends did not match with the figures. This has now been corrected in the PDF and HTML versions of the Article.

The integrated stress response induces R-loops and hinders replication fork progression.

The integrated stress response (ISR) allows cells to rapidly shutdown most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within 1 h, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis.

Mdm4 supports DNA replication in a p53-independent fashion.

The Mdm4 (alias MdmX) oncoprotein, like its paralogue and interaction partner Mdm2, antagonizes the tumor suppressor p53. p53-independent roles of the Mdm proteins are emerging, and we have reported the ability of Mdm2 to modify chromatin and to support DNA replication by suppressing the formation of R-loops (DNA/RNA-hybrids). We show here that the depletion of Mdm4 in p53-deficient cells compromises DNA replication fork progression as well.