Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19.

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

Comparison of the repair of potentially lethal damage after low- and high-LET radiation exposure, assessed from the kinetics and fidelity of chromosome rejoining in normal human fibroblasts.

Potentially lethal damage (PLD) and its repair (PLDR) were studied in confluent human fibroblasts by analyzing the kinetics of chromosome break rejoining after X-ray or heavy-ion exposures. Cells were either held in the non-cycling G0 phase of the cell cycle for 12 h, or forced to proliferate immediately after irradiation. Fusion premature chromosome condensation (PCC) was combined with fluorescence in situ hybridization (FISH) to study chromosomal aberrations in interphase. The culture condition had no impact on the rejoining kinetics of PCC breaks during the 12 h after X-ray or heavy-ion irradiation. However, 12 h after X-ray and silicon irradiation, cycling cells had more chromosome exchanges than non-cycling cells. After 6 Gy X-rays, the yield of exchanges in cycling cells was 2.8 times higher than that in non-cycling cells, and after 2 Gy of 55 keV/µm silicon ions the yield of exchanges in cycling cells was twice that of non-cycling cells. In contrast, after exposure to 2 Gy 200-keV/µm or 440-keV/µm iron ions the yield of exchanges was similar in non-cycling and cycling cells. Since the majority of repair in G0/G1 occurs via the non-homologous end joining process (NHEJ), increased PLDR in X-ray and silicon-ion irradiated cells may result from improved cell cycle-specific rejoining fidelity through the NHEJ pathway, which is not the case in high-LET iron-ion irradiated cells.

Expression of a thyroglobulin (Tg) variant in mouse kidney glomerulus.

Thyroglobulin (Tg) is an essential substrate for thyroid hormone biosynthesis whose production is primarily limited to the thyroid follicular cell. We have previously identified an approximately 1.2 kb fragment of Tg mRNA in cultured mouse mesangial cells, and in the present study provide evidence showing that this transcript is transcribed and translated into a unique protein (kTg) in the kidney, but not the thyroid gland. Cloning of kTg from a mouse kidney cDNA library showed that transcription starts in the middle of intron 41 of the Tg gene and continues in-frame with the remaining coding sequence of thyroid-derived Tg beginning with exon 42. Translation of this mRNA is predicted to yield a protein of 367 amino acids (40 kDa) containing a unique 13 amino acid sequence serving as a signal peptide followed by a 354 amino acid segment identical to the carboxy-terminal end of thyroid Tg. Western blot analysis with an antibody directed against the C-terminus of thyroid Tg detected a 40 kDa protein expressed in the kidney. Immunohistochemistry with this antibody showed that immunoreactive Tg was localized in podocytes and the mesangial area of the renal glomerulus. A part of a homologous transcript was also detected in human kidney, and the kTg protein was recognized by sera from Hashimoto's thyroiditis but not from controls. Together these results suggest that a unique low molecular weight variant of Tg is expressed in the kidney, where it could serve both physiological and pathological roles, including that of an autoantigen.

[Molecular mechanisms for intracellular parasitisation and exclusion in macrophage infected with Mycobacterium leprae].

It was previously demonstrated that TLR2 and CORO1A (TACO, Coronin 1, p57) localize phagosome membrane of macrophage. However, the functional relationship between TLR2 and CORO1A was not known. We show here that there is a functional counteraction between TLR2 and CORO1A.