Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke

Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal’s recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DRα1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females

Law, Liberty and the Rule of Law (in a Constitutional Democracy)

In the hunt for a better--and more substantial--awareness of the “law,” The author intends to analyze the different notions related to the “rule of law” and to criticize the conceptions that equate it either to the sum of “law” and “rule” or to the formal assertion that “law rules,” regardless of its relationship to certain principles, including both “negative” and “positive” liberties. Instead, he pretends to scrutinize the principles of the “rule of law,” in general, and in a “constitutional democracy,” in particular, to conclude that the tendency to reduce the “democratic principle” to the “majority rule” (or “majority principle”), i.e. to whatever pleases the majority, as part of the “positive liberty,” is contrary both to the “negative liberty” and to the “rule of law” itself

FAPRI 2000 U.S. Agricultural Outlook

Crop Production/Industries, Livestock Production/Industries,

FAPRI 2000 World Agricultural Outlook

The Food and Agricultural Policy Research Institute (FAPRI) prepares a preliminary agricultural outlook on world agricultural production, consumption, and trade every fall. This is followed by an outside review, re-evaluation of projections, and completion of the final baseline in January. The FAPRI 2000 World Agricultural Outlook presents these final projections for world agricultural markets. A companion volume, the FAPRI 2000 U.S. Agricultural Outlook, presents the U.S. component of the baseline. FAPRI projections assume average weather patterns worldwide, existing policy, and policy commitments under current trade agreements. FAPRI projections do not include conjectures on potential policy changes, such as those resulting from the likely eastward enlargement of the European Union (EU). The baseline predicts recovery of world agricultural production, consumption, and trade, but with remaining price weakness for crops. Stock-to-use ratios in world crop markets remain high despite the strong recovery of Asian and Latin American economies. Above-average yields kept world production high relative to demand in 1999. In contrast, pork and beef prices are increasing significantly above their 1999 level. The physical volume of U.S. agricultural exports is projected to reverse the downward trend of fiscal year (FY) 1999, whereas the value of agricultural exports continue to decline for one more year before recovering because of low crop prices in 2000/01. World crop trade is projected to increase by 55 million metric tons (mmt) in the coming decade, with the United States capturing 49 percent of the expanded market, but still unable to increase its market share by a large percentage. Following this expansion of the market, grain prices increase by 35 percent in the projection period, but still stay well below the peak of 1995/96. The increase in world crop trade reflects the increasing specialization occurring in world agriculture. Increased market access and land scarcity in many Asian economies induce them to import grains and oilseeds to meet their feed demand. Developing Asia remains the fastest growing market for corn in the next decade. With implementation of Agenda 2000 reforms, the EU will reduce its wheat domestic price relative to the world price and will export wheat without subsidies after 2004, constraining gains in market shares for the United States. EU barley exports will expand significantly in the coming years but are likely to be constrained by General Agreement on Tariffs and Trade (GATT) commitments on export subsidies after 2004. World meat trade will increase by 31 percent over the next decade. The United States has become a competitive producer and exporter of meat products. In the coming decade, the United States will experience the largest meat export growth rates among major exporters of beef, pork, and broilers. U.S. exporters capture more than 70 percent of the growth in trade, increasing their share of the combined meat markets from 23 percent in 1999 to 37 percent in 2009. Meat imports are recovering and expanding rapidly in Japan, South Korea, and Taiwan. In Japan, the share of imports in consumption increases from 38 percent in the 1990s to 49 percent at the end of the next decade. Taiwan meat imports will triple from 1990-1999 levels to 2000-2009 levels, driven by imports of beef, non muscle pork products, and the opening of the poultry market. Recovery of Asian food demand will prompt dairy prices to grow by about 1 percent per year over the next decade. Total milk production is projected to increase, with particularly strong growth in the United States, Mexico, Argentina, and Brazil. Most of the growth occurs through yield increases. Per capita cheese consumption is expected to grow by 1 to 2 percent a year in most countries.Crop Production/Industries, Livestock Production/Industries,

FAPRI 2001 U.S. and World Agricultural Outlook

Crop Production/Industries, Livestock Production/Industries,

FAPRI 2002 World Agricultural Outlook

Crop Production/Industries, Livestock Production/Industries,

Resonance Effects in the Nonadiabatic Nonlinear Quantum Dimer

The quantum nonlinear dimer consisting of an electron shuttling between the two sites and in weak interaction with vibrations, is studied numerically under the application of a DC electric field. A field-induced resonance phenomenon between the vibrations and the electronic oscillations is found to influence the electronic transport greatly. For initially delocalization of the electron, the resonance has the effect of a dramatic increase in the transport. Nonlinear frequency mixing is identified as the main mechanism that influences transport. A characterization of the frequency spectrum is also presented.Comment: 7 pages, 6 figure

FAPRI 1999 U.S. Agricultural Outlook

Crop Production/Industries, Livestock Production/Industries,

Temperature- and Touch-Sensitive Neurons Couple CNG and TRPV Channel Activities to Control Heat Avoidance in Caenorhabditis elegans

Background: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding,35uC and also senses changes in its environmental temperature in the range between 15 and 25uC. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. Methodology/Principal Findings: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicinsensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. Conclusions/Significance: Our results identify distinct thermal responses mediated by a single neuron, but also show tha

A Survey of New Temperature-Sensitive, Embryonic-Lethal Mutations in C. elegans: 24 Alleles of Thirteen Genes

To study essential maternal gene requirements in the early C. elegans embryo, we have screened for temperature-sensitive, embryonic lethal mutations in an effort to bypass essential zygotic requirements for such genes during larval and adult germline development. With conditional alleles, multiple essential requirements can be examined by shifting at different times from the permissive temperature of 15°C to the restrictive temperature of 26°C. Here we describe 24 conditional mutations that affect 13 different loci and report the identity of the gene mutations responsible for the conditional lethality in 22 of the mutants. All but four are mis-sense mutations, with two mutations affecting splice sites, another creating an in-frame deletion, and one creating a premature stop codon. Almost all of the mis-sense mutations affect residues conserved in orthologs, and thus may be useful for engineering conditional mutations in other organisms. We find that 62% of the mutants display additional phenotypes when shifted to the restrictive temperature as L1 larvae, in addition to causing embryonic lethality after L4 upshifts. Remarkably, we also found that 13 out of the 24 mutations appear to be fast-acting, making them particularly useful for careful dissection of multiple essential requirements. Our findings highlight the value of C. elegans for identifying useful temperature-sensitive mutations in essential genes, and provide new insights into the requirements for some of the affected loci