Direct observation of electron dynamics in the attosecond domain

Dynamical processes are commonly investigated using laser pump-probe experiments, with a pump pulse exciting the system of interest and a second probe pulse tracking its temporal evolution as a function of the delay between the pulses. Because the time resolution attainable in such experiments depends on the temporal definition of the laser pulses, pulse compression to 200 attoseconds (1 as = 10(-18) s) is a promising recent development. These ultrafast pulses have been fully characterized, and used to directly measure light waves and electronic relaxation in free atoms. But attosecond pulses can only be realized in the extreme ultraviolet and X-ray regime; in contrast, the optical laser pulses typically used for experiments on complex systems last several femtoseconds (1 fs = 10(-15) s). Here we monitor the dynamics of ultrafast electron transfer--a process important in photo- and electrochemistry and used in solid-state solar cells, molecular electronics and single-electron devices--on attosecond timescales using core-hole spectroscopy. We push the method, which uses the lifetime of a core electron hole as an internal reference clock for following dynamic processes, into the attosecond regime by focusing on short-lived holes with initial and final states in the same electronic shell. This allows us to show that electron transfer from an adsorbed sulphur atom to a ruthenium surface proceeds in about 320 as.     

Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis

Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. In approximately one-third of all cases, no aetiological factor can be found, and these patients are classified as having idiopathic disease. Pathophysiologically, autodigestion and inflammation may be caused by either increased proteolytic activity or decreased protease inhibition. Several studies have demonstrated mutations in the cationic trypsinogen gene (PRSS1) in patients with hereditary or idiopathic CP. It is thought that these mutations result in increased trypsin activity within the pancreatic parenchyma. Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor. We found mutations in 23% of the patients. In 18 patients, 6 of whom were homozygous, we detected a missense mutation of codon 34 (N34S). We also found four other sequence variants. Our results indicate that mutations in SPINK1 are associated with chronic pancreatitis.     

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.     

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.