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Recent recognition of the soluble form of the amyloid-beta (A[beta]) peptide as a neurotoxic agent in Alzheimer's disease (AD) has spurred the development of agents to target this species. Because A[beta] is known to chelate metal ions in solution, metal-based therapeutics are uniquely suited to exploit this affinity, where coordination to A[beta] has been shown to impact the neurotoxicity of the peptide. Ruthenium(II)-arene complexes are unique candidates for evaluation, as one face of the molecule is blocked by the hydrophobic arene ring, while coordination to the A[beta] peptide can occur on the other side of the molecule. We have prepared and evaluated two Ru(II)-arene complexes with chelating quinoline-based ligands, Ru1 and Ru2, for their respective anti-amyloid abilities. Although both complexes decreased the aggregation of soluble A[beta], Ru1 displayed promise in disrupting formed aggregates of the peptide. These findings represent an exciting new avenue for therapeutic development in AD, where both sides of the aggregation equilibrium are affected. Key words: Alzheimer's disease, amyloid-beta, ruthenium(II) therapeutics, peptide aggregation. Le fait que le peptide beta-amyloide (A[beta]) sous sa forme soluble a recemment ete reconnu comme agent neurotoxique dans la maladie d'Alzheimer (alzheimer) a suscite un interet pour la recherche d'agents ciblant cette espece. Puisque l'on sait que l'A[beta] chelate les ions metalliques en solution, les agents therapeutiques a base de metaux sont particulierement adaptes pour exploiter cette affinite. La coordination de tels agents avec l'A[beta] a d'ailleurs montre un effet sur la neurotoxicite du peptide. Les complexes de ruthenium(II)arene sont des candidats tout indiques pour l'evaluation de cet effet, car une face de la molecule est bloquee par le noyau arene hydrophobe. La coordination avec le peptide A[beta] peut ainsi s'effectuer de l'autre cote de la molecule. Nous avons prepare et evalue deux complexes de Ru(II)arene avec des ligands chelatants a base de quinoleine, Ru1 et Ru2, pour leurs proprietes anti-amyloides respectives. Bien que les deux complexes diminuent l'agregation de l'A[beta] soluble, le complexe Ru1 s'est montre prometteur pour detruire les agregats du peptide deja formes. Ces resultats representent pour la recherche d'agents therapeutiques contre l'alzheimer une nouvelle avenue fort interessante, ou l'agregation est influencee des deux cotes de l'equilibre. [Traduit par la Redaction] Mots-cles : maladie d'Alzheimer, beta-amyloide, agents therapeutiques a base de ruthenium(II), agregation de peptides., Introduction Alzheimer's disease (AD) is the most common form of dementia, and prior to the COVID-19 pandemic, it was the sixth leading cause of death in the United States. (1) [...]

Author(s): Kyle Beloy [sup.1] [sup.1] , Martha I. Bodine [sup.1] , Tobias Bothwell [sup.2] , Samuel M. Brewer [sup.1] [sup.5] , Sarah L. Bromley [sup.2] [sup.6] , Jwo-Sy Chen [sup.1] [...], Atomic clocks are vital in a wide array of technologies and experiments, including tests of fundamental physics.sup.1. Clocks operating at optical frequencies have now demonstrated fractional stability and reproducibility at the 10.sup.-18 level, two orders of magnitude beyond their microwave predecessors.sup.2. Frequency ratio measurements between optical clocks are the basis for many of the applications that take advantage of this remarkable precision. However, the highest reported accuracy for frequency ratio measurements has remained largely unchanged for more than a decade.sup.3-5. Here we operate a network of optical clocks based on .sup.27Al.sup.+ (ref. .sup.6), .sup.87Sr (ref. .sup.7) and .sup.171Yb (ref. .sup.8), and measure their frequency ratios with fractional uncertainties at or below 8 × 10.sup.-18. Exploiting this precision, we derive improved constraints on the potential coupling of ultralight bosonic dark matter to standard model fields.sup.9,10. Our optical clock network utilizes not just optical fibre.sup.11, but also a 1.5-kilometre free-space link.sup.12,13. This advance in frequency ratio measurements lays the groundwork for future networks of mobile, airborne and remote optical clocks that will be used to test physical laws.sup.1, perform relativistic geodesy.sup.14 and substantially improve international timekeeping.sup.15. A network of optical atomic clocks based on three different atomic species is reported and their frequency ratios are measured with uncertainties at or below 8 × 10.sup.-18.

Author(s): Qian Xiao [1]; Jibo Wu [2]; Wei-Jia Wang [1]; Shiyang Chen [3]; Yingxia Zheng [1]; Xiaoqing Yu [4]; Katrina Meeth [5]; Mahnaz Sahraei [1]; Alfred L M Bothwell [6, [...], Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-[beta]-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8[sup.+] T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.

Author(s): D. P. Marrone (corresponding author) [1]; J. S. Spilker [1]; C. C. Hayward [2, 3]; J. D. Vieira [4]; M. Aravena [5]; M. L. N. Ashby [3]; M. B. [...]

As the penetration of variable renewable energy in electricity markets grows, there is increasing need for capacity markets to account for the contribution of renewables to system adequacy. An important issue is the inconsistent industry definition of capacity credits for resources whose availability may be limited, such as renewable generation. Inaccurate credits can subsidize or penalize different resources, and consequently distort investment between renewables and non-renewables, and also among different types and locations of renewables. Using Electric Reliability Council of Texas (ERCOT) data, we use a market equilibrium model to quantify the resulting loss of efficiency due to capacity credits alone and in combination with renewable tax subsidies and portfolio standards. Layering inaccurate capacity credits with existing US federal tax subsidies decreases efficiency as much as 6.3% compared to optimal capacity crediting under those subsidies. Compensating producers based on their marginal contributions to system adequacy, considering how renewable penetration affects the timing of net load peaks, can yield an efficient capacity market design. Keywords: Electricity Markets, Capacity Mechanisms, Renewable Generation, Wind, Solar, 1. INTRODUCTION Electric system adequacy is defined as the ability of generation, storage, demand-side and other resources to meet the demand for electricity, as measured by static indices such as [...]

Blooms of the river benthic diatom Didymosphenia geminata are an enigma because they occur under phosphorus-poor conditions. A recent proposal that ferric-ferrous iron redox shifts sequester the additional phosphorus needed to stimulate and sustain D. geminata blooms does not agree with published experimental data showing that blooms only occur when cells are phosphorus-limited. The 'iron hypothesis' also infers that blooms would be favoured in rivers with elevated iron, and management should target iron. Surveys of rivers around the world affected by D. geminata show that blooms most often occur in iron-poor rivers. Phosphorus uptake experiments conducted under realistic environmental conditions with living D. geminata colonies showed no effect of iron enrichment on phosphorus uptake. Iron does not solve the mystery of D. geminata growth causing nuisance blooms worldwide. Les proliferations de la diatomee benthique de riviere Didymosphenia geminata constituent une enigme puisqu'elles se produisent dans des conditions d'appauvrissement en phosphore. Il a recemment ete propose que des changements d'oxydoreduction du fer ferrique au fer ferreux retiennent le phosphore supplementaire necessaire pour stimuler et soutenir les proliferations de D. geminata. Ce postulat ne concorde toutefois pas avec les donnees experimentales publiees qui demontrent que les proliferations ne se produisent que quand le phosphore est restreint. Il decellsle egalement de cette << hypothese du fer >> que les rivieres presentant de fortes teneurs en fer favoriseraient ces proliferations et que les mesures d'amenagement devraient cibler le fer. Les etudes de rivieres affectees par D. geminata aux quatre coins du monde montrent que les proliferations se produisent le plus souvent dans des rivieres pauvres en fer. Des experiences de mobilisation du phosphore menees dans des conditions ambiantes realistes avec des colonies de D. geminata vivantes n'ont montre aucun effet d'un enrichissement en fer sur la mobilisation du phosphore. Le fer ne resout pas l'enigme des formes de croissance de D. geminata qui entrainent des proliferations nefastes partout sur la planete., Sundareshwar et al. (2011) have proposed that complexes between iron (Fe) and phosphorus (P) that occur on the polysaccharide stalks of the benthic diatom Didymosphenia geminata play a central role [...]

Wildfire impacts on ecological and socioeconomic systems are regulated, in part, by climate. Association between hemispheric-scale climate patterns and annual wildfire activity can be obscured by local factors that also control the initiation and spread of fires. Vegetation, topography, and fire suppression can be expected to influence conventional measures of annual wildfire activity such as area burned, effectively concealing evidence of broad-scale climate influences. This study investigates alternatives to area-burned statistics for quantifying annual wildfire activity in Canada in relation to Northern Hemisphere climate variability represented by the Atlantic Multidecadal Oscillation (AMO). We depart from conventional approaches by including socioeconomic measures of wildfire activity and by assessing spatially referenced wildfire data over units of observation chosen explicitly to diminish variability caused by factors unrelated to broad-scale climate. Our datacentred approach, combined with linear regression modelling, revealed that the AMO was positively correlated with national time series of very large fires (≥10 000 ha), wildfire-related evacuations, and fire suppression expenditures over the period 1975-2007. The AMO and wildfire activity were most closely coupled during a period of predominantly positive-phase Arctic Oscillation (AO) and Pacific Decadal Oscillation (PDO) between 1989 and 2001. Positive correlation between maximum evacuation wind speed and the AMO suggests that wind may be a causal factor in the AMO-wildfire relation-ship. Les impacts des feux de foret sur les systemes ecologiques et socio-economiques sont determines en partie par le climat. La relation entre les patrons climatiques a l'echelle de l'hemisphere et l'activite annuelle des feux de foret peut etre embrouillee par des facteurs locaux qui regissent egalement l'initiation et la propagation des feux. La vegetation, la topogra-phie et la suppression du feu devraient influencer les mesures conventionnelles de l'activite annuelle des feux de foret, telles que la superficie brulee, dissimulant ainsi les indices de l'influence exercee par le climat a plus grande echelle. Cette etude porte sur des alternatives aux statistiques de superficies brulees pour quantifier l'activite annuelle des feux de foret au Canada en relation avec la variabilite du climat de l'hemisphere Nord, representee par l'oscillation multidecennale de l'Atlan-tique (OMA). Nous nous demarquons des approches traditionnelles en incluant des mesures socio-economiques de l'activite des feux de foret et en evaluant des donnees georeferencees sur les feux de foret pour des unites d'observation choisies ex-plicitement dans le but de diminuer la variabilite due a des facteurs non relies au climat. Notre approche centree sur les don-nees, combinee a la modelisation par regression lineaire, a revele que l'OMA etait positivement correlee avec des series temporelles nationales des tres grands feux (≥10 000 ha), les evacuations reliees aux feux de foret et les couts de suppression du feu au cours de la periode 1975-2007. L'OMA et l'activite des feux de foret etaient le plus etroitement reliees du-rant une periode ou l'oscillation arctique (OA) et l'oscillation decennale du Pacifique (ODP) ont connu une phase essentiellement positive, entre 1989 et 2001. La correlation positive entre la vitesse maximale du vent qui justifie une evacuation et l'AMO indique que le vent pourrait etre responsable de la relation entre l'OMA et les feux de foret. [Traduit par la Redaction], Introduction The impact of wildfires on ecological and socioeconomic systems in any given year will be influenced, in part, by broad-scale climate patterns. In Canada, interannual variability in wildfire activity [...]

THE POLITICS OF LINKAGE Power, Interdependence, and Ideas in Canada-US Relations Brian Bow Vancouver: UBC Press, 2010. 232 pp, $32.95 paper ISBN 978-0774816960 It used to be, in the not [...]

In the summer of 1988, Robert Bothwell and Jack Granatstein were pursuing their research for the final volume in the Canadian Institute of International Affairs' series Canada in World Affairs. [...]

Foxp3 is a key transcription factor for differentiation and function of regulatory T (Treg) cells that is critical for maintaining immunological self-tolerance. Therefore, increasing Treg function by Foxp3 transduction to regulate an inflammatory immune response is an important goal for the treatment of autoimmune and allergic diseases. Here we have generated a cell-permeable Foxp3 protein by fusion with the unique human HHph-1-PTD (protein transduction domain), examined its regulatory function in T cells, and characterized its therapeutic effect in autoimmune and allergic disease models. HHph-1-Foxp3 was rapidly and effectively transduced into cells within 30 min and conferred suppressor function to [CD4.sup.+] [CD25.sup.-] cells as well as directly inhibiting T-cell activation and proliferation. Systemic delivery of HHph-1 Foxp3 remarkably inhibited the autoimmune symptoms of scurfy mice and the development of colitis induced by scurfy or wild-type CD4 T cells. Moreover, intranasal delivery of HHph-1-Foxp3 strongly suppressed ovalbumin-induced allergic airway inflammation. These results demonstrate the clinical potential of the cell-permeable recombinant HHph-1-Foxp3 protein in autoimmune and hypersensitive allergic diseases. protein transduction domain | immunotherapy | autoimmunity | allergy doi/ 10.1073/pnas.1000400107

The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene ([Apc.sup.Min/+] mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in [Apc.sub.Min/+] mice. CD4 T cells from [Apc.sub.Min/+] mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from [Apc.sup.Min/+] mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in [Apc.sup.Min/+] mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in [Apc.sup.Min/+] mice. inflammation | T cells | colon cancer www.pnas.org/cgi/doi/10.1073/pnas.0912675107

Tricia Rose. 2008. The Hip Hop Wars: What We Talk About When We Talk About Hip Hop--And Why It Matters. New York: Basic/Civitas Books. As hip hop slowly settles into [...]

CTLA-4 (CD152) negatively regulates T cell activation signaling, and the cytoplasmic domain of CTLA-4 (ctCTLA-4) itself has the capacity to inhibit T cell activation in vitro and in vivo. In this study, the inhibitory mechanisms of the cell-permeable recombinant protein Hph-1-ctCTLA-4 on T cell activation and its ability to prevent collagen-induced arthritis were analyzed. Hph-1-ctCTLA-4 prevented human and mouse T cell activation and proliferation by inhibition of T cell receptor-proximal signaling and the arrest of the cell cycle. Furthermore, Hph-1-ctCTLA-4 protected human umbilical vein endothelial cells (HUVEC) from the human CTL allo-response. The incidence and severity of collagen-induced arthritis were significantly reduced and the erosion of cartilage and bone was effectively prevented by i.v. injection and transdermal administration of Hph-1-ctCTLA-4. Inflammatory cytokine production (IL-1[beta], IL-6, TNF-[alpha], IL-17A) and collagen-specific antibody levels were significantly reduced, and the numbers of activated T cells and infiltrating granulocytes were substantially decreased. These results demonstrate that systemic or transdermal application of a cell-permeable form of the cytoplasmic domain of CTLA-4 offers an effective therapeutic approach for autoimmune diseases such as rheumatoid arthritis. autoimmune disease | costimulatory molecule

BACKGROUND: School-based study recruitment efforts are both time consuming and challenging. This paper highlights the recruitment strategies employed by the national, multisite Trial of Activity for Adolescent Girls (TAAG), a study designed to measure the effectiveness of an intervention to reduce the decline of physical activity levels among middle school-aged girls. TAAG provided a unique opportunity to recruit large cohorts of randomly sampled girls within 36 diverse middle schools across the United States. METHODS: Key elements of the formative planning, coordination, and design of TAAG's recruitment efforts included flexibility, tailoring, and the use of incentives. Various barriers, including a natural disaster, political tension, and district regulations, were encountered throughout the recruitment process, but coordinated strategies and frequent communication between the 6 TAAG sites were helpful in tailoring the recruitment process at the 36 intervention and control schools. RESULTS: Progressively refined recruitment strategies and specific attention to the target audience of middle school girls resulted in overall study recruitment rates of 80%, 85%, and 89%, for the baseline, posttest, and follow-up period, respectively. DISCUSSION: The steady increase in recruitment rates over time is attributed to an emphasis on successful strategies and a willingness to modify less successful methods. Open and consistent communication, an increasingly coordinated recruitment strategy, interactive recruitment presentations, and participant incentives resulted in an effective recruitment campaign. Keywords: recruitment; TAAG; adolescent girls; school-based research; physical activity., Research efforts among children and adolescents in schools require careful attention to recruitment and retention rates. Recruiting students in school-based studies requires more than basic motivational efforts. One review of [...]

The new Canadian War Museum should be a triumph. Its stunning building beside the Ottawa River houses excellent exhibits which trace the history of warfare from the earliest recorded Canadian [...]

Abstract: The behaviour of juvenile coho salmon (Oncorhynchus kisutch) was observed in outdoor experimental flumes in which three different spectral regimes were created by plastic covers that selectively blocked all [...]

Abstract: We designed and developed an internet mapping application to collect data on the locations of forest landscape values across a 2.4 million hectare study area in the province of [...]

Abstract: Dissolved organic carbon (DOC) in Mackenzie Delta lakes varies in composition and concentration, ranging from low concentrations and high colour in frequently flooded lakes to high concentrations in clear [...]

Mock jurors (college students and prospective jurors) made individual decisions regarding liability and damages (before and after deliberation) in response to a case of sexual harassment. There were no significant differences in damage awards from college students and prospective jurors. There was evidence of racial bias among White mock jurors against plaintiffs who accused a Black supervisor of sexual harassment: Lower damages were recommended for plaintiffs who accepted an offer to meet for drinks in a Black supervisor's room than for plaintiffs who accepted the same offer from a White supervisor. There was also evidence of racial bias among White mock jurors against Black plaintiffs: Lower damages were recommended for Black plaintiffs than for White plaintiffs. These effects were present in the individual judgments of college students and prospective jurors. However, these forms of racial bias did not carry over into the decisions made by juries comprised of college students or prospective jurors. Subtle racial biases operating primarily at a subconscious level may get washed out in the complex task of coming to agreement on an appropriate award. The effects of manipulated variables on damage awards probably are overestimated in general in mock juror studies that do not examine group verdicts.

Regulatory T cells that express the Foxp3 transcription factor play important roles in preventing autoimmune diseases. Although several studies have demonstrated that the lack of the forkhead DNA-binding domain of Foxp3 caused severe autoimmune disease in scurfy mutant mice, the other functional domains of Foxp3 are less well characterized. Here, we show that the deletion of glutamic acid ([DELTA]E250) in the leucine-zipper domain of Foxp3 causes a loss of hyporesponsiveness when compared with wild-type Foxp3 upon antigenic stimulation. CD4 T cells that ectopically express the glutamic acid mutant show significant losses of suppressor activity both in vitro and in vivo. We also demonstrate that regulation of both Th1- and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid. Defects are also observed in the expression of adhesion molecules, such as L-selectin (CD62L) and CD103, suggesting an important role of glutamic acid in the migratory behavior of regulatory T cells. Finally, this mutation reduces transcriptional repressor activity and impairs the homodimerization of Foxp3. Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3. autoimmunity

The SOS response in bacteria includes a global transcriptional response to DNA damage. DNA damage is sensed by the highly conserved recombination protein RecA, which facilitates inactivation of the transcriptional repressor LexA. Inactivation of LexA causes induction (derepression) of genes of the LexA regulon, many of which are involved in DNA repair and survival after DNA damage. To identify potential RecA-LexA-regulated genes in Bacillus subtilis, we searched the genome for putative LexA binding sites within 300 bp upstream of the start codons of all annotated open reading frames. We found 62 genes that could be regulated by putative LexA binding sites. Using mobility shift assays, we found that LexA binds specifically to DNA in the regulatory regions of 54 of these genes, which are organized in 34 putative operons. Using DNA microarray analyses, we found that 33 of the genes with LexA binding sites exhibit RecA-dependent induction by both mitomycin C and UV radiation. Among these 33 SOS genes, there are 22 distinct LexA binding sites preceding 18 putative operons. Alignment of the distinct LexA binding sites reveals an expanded consensus sequence for the B. subtilis operator: 5'-CGAACATATGTTCG-3'. Although the number of genes controlled by RecA and LexA in B. subtilis is similar to that of Escherichia coli, only eight B. subtilis RecA-dependent SOS genes have homologous counterparts in E. coli.

The effects of solar ultraviolet radiation (UVR), both mid-ultraviolet (UVB; 280-320 nm) and near-ultraviolet (UVA; 320-400 nm), on benthic algal and invertebrate communities were compared in three reaches of a British Columbia coastal stream that differed in the degree of shading by riparian canopy (a full canopy, a partial canopy, and no canopy). At each of the three sites benthic communities were exposed to three different radiation treatments: photosynthetically active radiation alone (PAR; 400-700 nm), PAR+UVA, and PAR+UVA+UVB. Relative to the site with no canopy, UVR was 88% and 66% lower, and PAR was 83% and 49% lower at sites with full and partial canopy, respectively. Late summer increases in UVR to the streambed caused by declines in water level and dissolved organic carbon (DOC) were also lower at sites with high canopy. Sites with less canopy shading had greater algal accrual, decreased biomass of total invertebrates, mayflies, and stoneflies, and reduced invertebrate community diversity compared to the heavily shaded reach of the stream. UVR produced taxon-specific community responses that varied across sites and increased with increasing UVR as summer progressed. At the full canopy site UVR had no impact, and the final (day 91) biomass and diversity of invertebrates was highest, and algal biomass lowest. Higher UVA radiation under reduced canopies inhibited algal accrual but had little effect on algal community composition. The biomass of several invertebrate taxa (e.g., Dicosmoecus spp., Limnephilidae) and community diversity were reduced by both UVA and UVB. Less sensitive taxa (e.g., Paraleptophlebia spp., Paraleptophlebidae) were inhibited only by the highest UVB levels in late summer when water transparency to UVR was greatest. Inhibition of grazers by UVR appeared to indirectly increase algal accrual, particularly at the partial canopy site. Our results indicate that riparian shading may moderate UVR effects on benthic communities, mainly through impacts on invertebrates with indirect effects on algae. By reducing UVR exposure of streambeds, riparian canopies may be important for ameliorating UVR effects on shallow lotic systems, especially during late-summer, low-flow periods when DOC concentrations are reduced. Key words: epilithon; lotic system; photoinhibition; riparain canopy; stream benthic invertebrates; stream shading; trophic interactions; ultraviolet radiation.

Author(s): Julia Foreman [1, 2]; Vadim Demidchik [2, 3]; John H. F. Bothwell [2, 4]; Panagiota Mylona [1]; Henk Miedema [3]; Miguel Angel Torres [5, 6]; Paul Linstead [1]; Silvia [...]

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory cytokines, including tumor necrosis factor [alpha] and IFN-[gamma], are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-[kappa]B activation. Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.

Research has been conducted on Pax5-deficient progenitor B cells. The assembly of the IgH locus in these cells has been investiogated and the results demonstrate that 3' IgH V gene segments recombine efficiently and that progressively more distal V gene segments recombine less efficiently.

Fortification of cereal flours may be a useful public health strategy to combat iron deficiency. Cereal flours that are used shortly after production (e.g., baking flour) can be fortified with soluble iron compounds, such as ferrous sulfate, whereas the majority of flours stored for longer periods is usually fortified with elemental iron powders to avoid unacceptable sensory changes. Elemental iron powders are less well absorbed than soluble iron compounds and--they vary widely in their absorption depending on manufacturing method and physicochemical characteristics. Costs vary with powder type, but elemental iron powders are generally less expensive than ferrous sulfate. This review evaluates the usefulness of the different elemental iron powders based on results from in vitro studies, rat assays, human bioavailability studies, and efficacy studies monitoring iron status in human subjects. It concludes that, at the present time, only electrolytic iron powder can be recommended as an iron fortificant. Because it is only approximately half as well absorbed as ferrous sulfate, it should be added to provide double the amount of iron. Key Words: elemental iron, iron bioavailability, cereal fortification, wheat flour fortification

Tautomycetin (TMC) was identified as an immunosuppressor of activated T cells. Inhibition of T cell proliferation with TMC was observed at concentrations 100-fold lower than those needed to achieve maximal inhibition with cyclosporin A (CsA). TMC specifically blocked tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosine kinases in a T cell-specific manner, leading to apoptosis due to cleavage of Bcl-2, caspase-9, caspase-3, and poly(ADP-ribose) polymerase, but not caspase-1. In TMC-treated rats that received a heterotopic cardiac allograft, the graft survived more than 160 days, comparable to graft survival in allografted rats treated with CsA. Thus, TMC, whose mechanism of action is different from that of CsA or FK506, can be used as a potent T cell-specific immunosuppressor.

Ground processing of data from the Multi-angle Imaging SpectroRadiometer (MISR) instrument, part of NASA's Earth Observing System (EOS), exploits new and unique science algorithms not previously used operationally. A range of data products from Level 1 through Level 3 is being produced. Because of MISR's unprecedented design, extensive prototyping was required from a relatively early stage. The data throughput is large, necessitating an innovative software design approach that maximizes performance. The systematic science processing software was developed at the Jet Propulsion Laboratory (JPL), with data processing occurring at the NASA Langley Research Center using the EOS Core System (ECS), a collaborative arrangement that works we!!. With the availability of actual mission data following launch on the Terra spacecraft in December 1999, MISR's computational needs have become better known, and many improvements have been made to both the science software and the production system to achieve a successful overall data processing capability. This paper provides information about MISR data for the science user, and describes the nature and scope of implementation and operations activities. Index Terms--Algorithms, data processing, data products, ground system.

The Multi-angle Imaging SpectroRadiometer, one of five science instruments aboard NASA's Terra spacecraft, was launched into earth orbit in December 1999. Acquisition of earth imagery began in February 2000, and the quality of the data is excellent. Overall, MISR has been performing superbly, though the instrument exhibits several idiosyncrasies, some of which were anticipated prior to launch. Details regarding the in-flight performance of the instrument system are presented. Index Terms--Earth, imaging, multiangle, remote sensing.

Author(s): S. Kolkowitz (corresponding author) [1]; S. L. Bromley (corresponding author) [1]; T. Bothwell [1]; M. L. Wall [1]; G. E. Marti [1]; A. P. Koller [1]; X. Zhang [1]; [...]

By using antisense RNA, Lck-deficient transfectants of a T helper 2 (Th2) clone have been derived and shown to have a qualitative defect in the T cell receptor signaling pathway. A striking feature observed only in Lck-deficient T cells was the presence of a constitutively tyrosine-phosphorylated 32-kDa protein. In the present study, we provide evidence that this aberrantly hyperphosphorylated protein is p[34.sup.cdc2] (cdc2) a key regulator of cell-cycle progression. Lck-deficient transfectants expressed high levels of cdc2 protein and its regulatory units, cyclins A and B. The majority of cdc2, however, was tyrosine-phosphorylated and therefore enzymatically inactive. The transfectants were significantly larger than the parental cells and contained 4N DNA. These results establish that a deficiency in Lck leads to a cell-cycle arrest in [G.sub.2]. Moreover, transfected cells were hypersusceptible to apoptosis when activated through the T cell receptor. Importantly, however, this hypersusceptibility was largely reversed in the presence of T cell growth factors. These findings provide evidence that, in mature T lymphocytes, cell-cycle progression through the [G.sub.2]-M check point requires expression of the Src-family protein tyrosine kinase, Lck. This requirement is Lck-specific; it is observed under conditions in which the closely related Fyn kinase is expressed normally, evincing against a redundancy of function between these two kinases.

The theoretical concept, based on modern photogrammetric methods, underlying the design of the Multi-angle Imaging SpectroRadiometer (MISR) science data processing system, responsible for the autonomous and continuous georectification of multiangle imagery, is the subject of this paper. The algorithm partitions effort between the MISR Science Computing Facility and the Earth Observing System (EOS) Distributed Active Archive Center (DAAC) in a way that minimizes the amount of processing required at the latter location to rectify and map project remotely sensed data online, as it comes from the instrument. The algorithm deals with the following issues: 1) removal of the errors introduced by inaccurate navigation and attitude data; 2) removal of the distortions introduced by surface topography; 3) attainment of a balance between limited hardware resources, huge data volume and processing requirements, and autonomous and nonstop aspects of the production system. Index Terms - Calibration, mapping, photogrammetry, rectification.

Edward III was the first ruler of England during his reign in the 14th century to change the trend of membership of parliamentary peerage which was then determined by a mixture of nobility. His attempt to influence the composition of parliamentary peerage could be attributed to the problems he faced in his relation with the nobility when he acquired the royal throne. A mixture of nobility in parliamentary peerage would have made the control of such institution difficult for King Edward III.

Split-thickness pig skin was transplanted on severe combined immunodeficient mice so that pig dermal microvessels spontaneously inosculated with mouse microvessels and functioned to perfuse the grafts. Pig endothelial cells in the healed grafts constitutively expressed class I and class II major histocompatibility complex molecules. Major histocompatibility complex molecule expression could be further increased by intradermal injection of pig interferon-[Gamma] (IFN-[Gamma]) but not human IFN-[Gamma] or tumor necrosis factor. Grafts injected with pig IFN-[Gamma] also developed a sparse infiltrate of mouse neutrophils and eosinophils without evidence of injury. Introduction of human peripheral blood mononuclear cells into the animals by intraperitoneal inoculation resulted in sparse perivascular mononuclear cell infiltrates in the grafts confined to the pig dermis. Injection of pig skin grafts on mice that received human peripheral blood mononuclear cells with pig IFN-[Gamma] (but not human IFN-[Gamma] or heat-inactivated pig IFN-[Gamma]) induced human CD[4.sup.+] and CD[8.sup.+] T cells and macrophages to more extensively infiltrate the pig skin grafts and injure pig dermal microvessels. These findings suggest that human T cell-mediated rejection of xenotransplanted pig organs may be prevented if cellular sources of pig interferon (e.g., passenger lymphocytes) are eliminated from the graft.