Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism.

The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.

Sir Victor Horsley's contributions to the study and treatment of gunshot wounds of the head.

Sir Victor Horsley'S many contributions to neurological surgery include experimental and clinical studies of gunshot wounds (GSW) of the head. Horsley's publications from 1894 to 1897 and 1914 to 1915 on GSWs were reviewed. Horsley described GSWs in animal and clay models, illustrating characteristics of the primary missile tract and secondary cavitation. A transcranial GSW model in 67 dogs related intracranial damage to the projectile's velocity and sectional area, producing a marked sudden increase in intracranial pressure that presumably "tunneled" to the medullary respiratory and cardiac centers. If the resultant sudden apnea was treated with artificial respiration and prompt surgical decompression, the animal often survived. In these animal experiments, Horsley clearly described increased intracranial pressure, hypertension, and bradycardia-later recognized as the Cushing response or triad. With the onset of World War I, Horsley again reviewed the ballistics of military weaponry, emphasizing projectile spin and velocity as the main wounding mechanisms. He was outspoken against the "wicked tradition" of neglecting cranial GSWs and personally treated cases with aggressive respiratory support and prompt decompression of devitalized tissue. Horsley's contributions to the experimental and clinical aspects of GSWs to the head are consistent with his other important contributions to neurosurgery and have largely stood the test of time.