The exocrine pancreas, liver, and submandibular glands of the rat were used to express and secrete two exogenous, human protein hormones (growth hormone and insulin) into blood at physiological concentrations. Transfection, expression, and secretion were achieved by the in vivo retrograde injection of plasmid DNA into the secretory ducts of these glands. Pancreatic acinar cells secreted physiological concentrations of growth hormone into the circulation, and its secretion was enhanced by cholinergic stimulation. A human insulin gene was engineered to allow normal processing of insulin in non-beta cells. With this gene, the secretion of human insulin by the exocrine pancreas normalized elevated blood glucose levels in diabetic rats. These in vivo observations demonstrate the utility of retrograde ductal administration of naked DNA into exocrine organs as a novel method for the regulated systemic delivery of protein-based pharmaceuticals.

The traditional understanding is that an entirely new complement of digestive enzymes is secreted by the pancreas into the small intestines with each meal. This is thought to be necessary because, like food itself, these enzymes are degraded during digestion. In this review we discuss experiments that bring this point of view into question. They suggest that digestive enzymes can be absorbed into blood, reaccumulated by the pancreas, and reutilized, instead of being reduced to their constituent amino acids in the intestines. This is called an enteropancreatic circulation of digestive enzymes.

The exocrine pancreas and certain salivary glands of mammals secrete a variety of enzymes into the gastrointestinal tract, where they digest food. The same glands also release these enzymes into the bloodstream. This latter process has commonly been assumed to occur solely as the result of a pathological condition or as an inadvertent by-product of exocrine secretion due to the leakage of trace quantities of the enzymes into blood. However, a variety of evidence suggests that the endocrine secretion of digestive enzymes is a normal occurrence that can be of substantial magnitude in healthy individuals, is responsive to various physiological stimuli, and is distinct from exocrine secretion. Recent research has focused attention on this process as a promising means for the delivery of engineered proteins into the systemic circulation for pharmaceutical purposes. In this review, we survey research in this area and consider the evidence for the existence of an endocrine secretion of digestive enzymes, the cause of enzyme release into the bloodstream, its source within the tissue, and, finally, the physiological purposes that this secretion process might serve.

Gabor x-ray holograms of biological specimens and of test objects that display <56-nm resolution are presented. This spatial resolution is more than an order of magnitude smaller than what has been achieved previously in x-ray holography. The holograms were recorded on photoresist using 2.57-nm soft x rays from the X-17t undulator at the National Syncrotron Light Source at Brookhaven National Laboratory. The processed photoresists were enlarged with an electron microscope and digitized using a scanning microdensitometer; the digitized holograms were reconstructed numerically. The exposure requirements were in good agreement with simple theory. The method offers promise as a technique for soft-x-ray microscopy.

Abstract-2 -It has long been known that x-ray holography offered the possibility of three-dimensional microscopy with resolution higher than the light microscope and with special forms of contrast based on x-ray edges. In principle, the

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Unlike most substances that cells manufacture, proteins are not produced and broken down by a common series of chemical reactions, but by completely different (independent and disconnected) mechanisms that possess no intrinsic means of making the rates of the two processes equal and attaining steady state concentrations. Balance between them is achieved extrinsically and is often imagined today to be the result of the actions of chemical feedback agents. But however instantiated, chemical feedback or any similar mechanism can only rectify induced imbalances in a system previously balanced by other means. Those "other means" necessarily involve reversible mass action or equilibrium-based interactions between native and altered forms of protein molecules somewhere in time and space between their synthesis and degradation.

Intact digestive enzymes can be absorbed by the intestine and resecreted by the pancreas. The pancreas, therefore, appears to be able to recycle proteins much as the liver recycles bile salts, although the magnitude of this process remains uncertain.