Obliquity pacing of the late Pleistocene glacial terminations

The 100,000-year timescale in the glacial/interglacial cycles of the late Pleistocene epoch (the past approximately 700,000 years) is commonly attributed to control by variations in the Earth's orbit. This hypothesis has inspired models that depend on the Earth's obliquity (approximately 40,000 yr; approximately 40 kyr), orbital eccentricity (approximately 100 kyr) and precessional (approximately 20 kyr) fluctuations, with the emphasis usually on eccentricity and precessional forcing. According to a contrasting hypothesis, the glacial cycles arise primarily because of random internal climate variability. Taking these two perspectives together, there are currently more than thirty different models of the seven late-Pleistocene glacial cycles. Here we present a statistical test of the orbital forcing hypothesis, focusing on the rapid deglaciation events known as terminations. According to our analysis, the null hypothesis that glacial terminations are independent of obliquity can be rejected at the 5% significance level, whereas the corresponding null hypotheses for eccentricity and precession cannot be rejected. The simplest inference consistent with the test results is that the ice sheets terminated every second or third obliquity cycle at times of high obliquity, similar to the original proposal by Milankovitch. We also present simple stochastic and deterministic models that describe the timing of the late-Pleistocene glacial terminations purely in terms of obliquity forcing.     

Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis

Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.     

The Precautionary Principle: Scientific Uncertainty and Type I and Type II Errors

We provide examples of the extent and nature of environmental and human health problems and show why in the United States prevailing scientific and legal burden of proof requirements usually cannot be met because of the pervasiveness of scientific uncertainty. We also provide examples of how may assumptions, judgments, evaluations, and inferences in scientific methods are value-laden and that when this is not recognized results of studies will appear to be more factual and value-neutral than warranted. Further, we show that there is a "tension" between the use of the 95 percent confidence rule as a normative basis to reduce speculation in scientific knowledge and other public policy and moral concerns embodied by the adoption of a precautionary principle. Finally, although there is no precise agreement regarding what a precautionary principle might entail, we make several recommendations regarding the placement of the burden of proof and the standard of proof that ought to be required in environmental and human health matters. This revised version was published online in July 2006 with corrections to the Cover Date.     

Single mimivirus particles intercepted and imaged with an X-ray laser

X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000?K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.     

The role of evolution in the emergence of infectious diseases

It is unclear when, where and how novel pathogens such as human immunodeficiency virus (HIV), monkeypox and severe acute respiratory syndrome (SARS) will cross the barriers that separate their natural reservoirs from human populations and ignite the epidemic spread of novel infectious diseases. New pathogens are believed to emerge from animal reservoirs when ecological changes increase the pathogen's opportunities to enter the human population and to generate subsequent human-to-human transmission. Effective human-to-human transmission requires that the pathogen's basic reproductive number, R(0), should exceed one, where R(0) is the average number of secondary infections arising from one infected individual in a completely susceptible population. However, an increase in R(0), even when insufficient to generate an epidemic, nonetheless increases the number of subsequently infected individuals. Here we show that, as a consequence of this, the probability of pathogen evolution to R(0) > 1 and subsequent disease emergence can increase markedly.     

Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3

Normal sensory transduction requires the efficient disposal of acid (H+) generated by neuronal and sensory receptor activity. Multiple highly sensitive transport mechanisms have evolved in prokaryotic and eukaryotic organisms to maintain acidity within strict limits. It is currently assumed that the multiplicity of these processes provides a biological robustness. Here we report that the visual and auditory systems have a specific requirement for H+ disposal mediated by the sodium bicarbonate cotransporter NBC3 (refs. 7,8). Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome. Our results indicate that in certain sensory organs, in which the requirement to transduce specific environmental signals with speed, sensitivity and reliability is paramount, the choice of the H+ disposal mechanism used is limited.