Beating crystallization in glass-forming metals by millisecond heating and processing

The development of metal alloys that form glasses at modest cooling rates has stimulated broad scientific and technological interest. However, intervening crystallization of the liquid in even the most robust bulk metallic glass-formers is orders of magnitude faster than in many common polymers and silicate glass-forming liquids. Crystallization limits experimental studies of the undercooled liquid and hampers efforts to plastically process metallic glasses. We have developed a method to rapidly and uniformly heat a metallic glass at rates of 10(6) kelvin per second to temperatures spanning the undercooled liquid region. Liquid properties are subsequently measured on millisecond time scales at previously inaccessible temperatures under near-adiabatic conditions. Rapid thermoplastic forming of the undercooled liquid into complex net shapes is implemented under rheological conditions typically used in molding of plastics. By operating in the millisecond regime, we are able to "beat" the intervening crystallization and successfully process even marginal glass-forming alloys with very limited stability against crystallization that are not processable by conventional heating.     

Seawater sulfur isotope fluctuations in the Cretaceous

The exogenic sulfur cycle is tightly coupled with the carbon and oxygen cycles, and therefore a central component of Earth's biogeochemistry. Here we present a high-resolution record of the sulfur isotopic composition of seawater sulfate for the Cretaceous. The general enrichment of isotopically light sulfur that prevailed during the Cretaceous may have been due to increased volcanic and hydrothermal activity. Two excursions toward isotopically lighter sulfur represent periods of lower rates of pyrite burial, implying a shift in the location of organic carbon burial to terrestrial or open-ocean settings. The concurrent changes in seawater sulfur and inorganic carbon isotopic compositions imply short-term variability in atmospheric oxygen partial pressure.     

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.     

Transfer of biologically derived nanometer-scale patterns to smooth substrates

Atomic force microscopy has been used to measure the surface profile of a periodic array of 10-nanometer (nm)-diameter holes fabricated by fast-atom beam milling of a smooth graphite surface in which a 3.5-nm-thick titanium oxide screen was used as a mask. The nanostructured titanium oxide mask was itself derived from a protein crystal template. Pattern transfer from the biological crystal to the metal oxide film and finally to the graphite substrate was accomplished entirely by parallel processing.     

Causal protein-signaling networks derived from multiparameter single-cell data

Machine learning was applied for the automated derivation of causal influences in cellular signaling networks. This derivation relied on the simultaneous measurement of multiple phosphorylated protein and phospholipid components in thousands of individual primary human immune system cells. Perturbing these cells with molecular interventions drove the ordering of connections between pathway components, wherein Bayesian network computational methods automatically elucidated most of the traditionally reported signaling relationships and predicted novel interpathway network causalities, which we verified experimentally. Reconstruction of network models from physiologically relevant primary single cells might be applied to understanding native-state tissue signaling biology, complex drug actions, and dysfunctional signaling in diseased cells.     

Kilimanjaro ice core records: evidence of holocene climate change in tropical Africa

Six ice cores from Kilimanjaro provide an approximately 11.7-thousand-year record of Holocene climate and environmental variability for eastern equatorial Africa, including three periods of abrupt climate change: approximately 8.3, approximately 5.2, and approximately 4 thousand years ago (ka). The latter is coincident with the "First Dark Age," the period of the greatest historically recorded drought in tropical Africa. Variable deposition of F- and Na+ during the African Humid Period suggests rapidly fluctuating lake levels between approximately 11.7 and 4 ka. Over the 20th century, the areal extent of Kilimanjaro's ice fields has decreased approximately 80%, and if current climatological conditions persist, the remaining ice fields are likely to disappear between 2015 and 2020.     

TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.