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As many of us know from our clinical practice, there is an urgent need for more research to guide and inform shared clinical decision making in patients with multiple chronic [...]

The American Geriatrics Society (AGS) Annual Scientific Meeting has a long history of celebrating innovation, cutting-edge research in geriatrics, and encouraging professional excellence. Now is a time like no other [...]

Flu season is just around the corner, and data from the southern hemisphere is sending warning signs that after 2 years of low transmission rates, the United States may be [...]

Experts' discussions and recommendations addressing the interface between cancer and heart disease were published in the Journal of the American Geriatrics Society (JAGS), summarizing sessions from a virtual bench to [...]

The American Geriatrics Society (AGS) has long recognized how crucial the direct care workforce is to improving the quality of care for older adults. Together with the eldercare workforce and [...]

IntroductionThere is still uncertainty around the impact of combat exposure on the life span of war veterans. Therefore we made use of a natural experiment to study the impact on veteran life span of combat versus non-combat exposure in World War II (WW2).MethodsThe combat-exposed military personnel were derived from a random (10%) sample of the military roll of the 28th (Māori) Battalion from New Zealand. One non-combat cohort was the 15th Reinforcements of this same Battalion, since the war ended before they reached the front line. The other non-combat cohort were Māori personnel who were only involved in Jayforce, which occupied Japan at the end of the WW2. Data on life span were mainly derived from an official repository of birth and death records, but supplemented with other sources, including military files.ResultsWhen comparing life spans of service veterans, there was no statistically significant reduction for the average life span of the 234 combat-exposed veterans in our sample from the 28th (Māori) Battalion (66.7 years), relative to the Māori veterans from two non-combat cohorts: the 132 personnel in the 15th Reinforcements (67.2 years) and the 147 personnel in Jayforce (66.9 years).ConclusionsDespite a very high level of wounding in the combat-exposed group (48%), there were no statistically significant reductions in life span between this group and comparable non-combat exposed veterans. This finding contrasts to life span reductions found in a similar study of New Zealand veterans of WW1.

A study of nursing homes finds that most, motivated by a mixture of common sense and compassion for those very near death, do not follow the standard paradigm for attempted cardiopulmonary resuscitation. Nursing home staff are, after all, the ones who take care of the patients daily and who know them best.

The Prospectors and Developers Assn. of Canada (PDAC) has been collecting statistics about exploration expenditures by Canadian junior exploration and mining companies since 1991. It has developed a profile of [...]

Intracranial metastases are a common cause of morbidity and mortality in patients with advanced NSCLC, and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established.

Context. The solar mid-infrared metallic emission lines have already been observed and analyzed well, and the formation scenario of the Mg I 12 $\rm\mu$m lines has been known for more than a decade. Detections of stellaremission at 12 $\rm\mu$m have, however, been limited to Mg I in very few objects. Previous modeling attempts have been made only for Procyonand two cool evolved stars, with unsatisfactory results for the latter. This prevents the lines' long predicted usage as probes of stellar magnetic fields.

Numerous barriers to clinic-based HIV testing exist (e.g., stigmatization) for African American youth. These barriers may be addressed by new technology, specifically HIV self-implemented testing (SIT). We conducted a series of formative phase 3 translation studies (49 face-to-face interviews, 9 focus groups, 1 advisory panel review) among low-income African American youth (15–19 years) and providers of adolescent services in two US cities to identify potential translation difficulties of the OraQuick SIT. Based on content analysis, we found that providers and African American youth viewed SITs positively compared to clinic-based testing. Data suggest that SITs may reduce social stigma and privacy concerns and increase convenience and normalization of HIV testing. Challenges with SIT implementation include difficulties accessing confirmatory testing, coping with adverse outcomes, and instructional materials that may be inappropriate for low socioeconomic status (SES) persons. Study results underscore the need for translation studies to identify specific comprehension and implementation problems African American youth may have with oral SITs.

Cuntz ([CITE]) suggested that apparent velocity shifts in Fe II emission lines observed in Betelgeuse (αOrionis: M2 Iab) indicate that non-magnetic wave modes are relevant for the heating and dynamics of αOri's chromosphere. This claim was based on the similarity of computed stochastic velocities in 1-D short-period acoustic wave models and velocity shifts in profile fits to Fe II emission lines (Carpenter & Robinson [CITE]), which is now identified as coincidental. While acoustic waves may indeed be important for the heating and dynamics of αOri's chromosphere, the interpretation of the Fe II emission line profiles does not provide evidence for this possibility. The line formation of optically thick scattering lines in an extended outflow makes Fe II emission lines poorly suited as a diagnostic for small-scale structure in hydrodynamical models. Better diagnostics include electron density sensitive, low opacity lines such as C II] . In the view of these findings, we discuss directions of future research.

Regulatory T cells (Tregs) are CD4+T cells that maintain immune homeostasis and prevent autoimmunity. Like all CD4+T cells, Tregs require antigen-specific signals via T cell receptor-major histocompatibility complex class II (TCR-MHCII) interactions for their development. However, the requirement for MHCII in Treg homeostasis in tissues such as intestinal lamina propria (LP) is unknown. We examined LP Treg homeostasis in a transgenic mouse model that lacks peripheral TCR-MHCII interactions and generation of extrathymic Tregs (iTregs). Thymically generated Tregs entered the LP of weanlings and proliferated independently of MHCII to fill the compartment. The adult LP was a closed niche; new thymic Tregs were excluded, and Tregs in parabiotic pairs were LP resident. The isolated LP niche was interleukin-2 (IL-2) independent but dependent on commensal bacteria. Thus, an LP Treg niche can be filled, isolated, and maintained independently of antigen signals and iTregs. This niche may represent a tissue-specific mechanism for maintaining immune tolerance.

Pediatricians will often find depressed adolescents difficult to engage. The physician assessing such patients must be prepared for a challenging presentation. [ABSTRACT FROM AUTHOR]

This study determined the extent to which bovine longissimus lumborum muscle (LLM) myofibers are influenced by nutrition for 120 d from weaning and the time-course of recovery after severe postweaning nutritional restriction. After weaning, 3 groups of Belmont Red cattle, a tropically adapted breed, were fed to achieve rapid growth (RG, ≥0.6 kg of BW gain/d; n = 16), slow growth (SG, 0.2 kg of BW gain/d; n = 17), or BW loss (WL, 10% loss of weaning weight; n = 17) over 120 d. They were then grazed as 1 group at pasture with forage supplementation for 600 d until slaughter at approximately 500 kg of BW. Samples of LLM were taken from 8 to 12 animals per treatment 6 d before (baseline) and 115, 204, 324, and 476 d after commencement of the study and from all cattle at slaughter (d 721). Myofiber characteristics were determined by immunocytochemical staining of myosin heavy chains. Cross-sectional areas (CSA) of the major myofiber types 1, 2A, and 2X in WL were reduced at d 115 compared with baseline and with the growth groups (all P< 0.001); however, there was little difference in the percentage of the different myofiber types (all P> 0.10). Differences in CSA of the major myofiber types between WL and the growth groups at 115 d were smallest for type 1 (slow oxidative) and greatest for type 2X (fast glycolytic). Consequently, the relative area (percentage of total myofiber area) of type 1 myofibers in WL was significantly greater at 115 d than in the growth groups (P< 0.001). During recovery from postweaning nutritional restriction, significant differences in major myofiber type percentages were not evident (all P> 0.10), and by 721 d CSA of myofiber types differed little between the treatment groups, although SG had greater CSA of type 1 (P< 0.05) and type 2A (P< 0.01) myofibers than WL and RG. At 721 d, the relative area of type 2A myofibers was less in WL compared with SG (P< 0.01) and RG (P< 0.05) and of type 2X myofibers greater (P< 0.05) in WL compared with SG. It is concluded that in the LLM of cattle undergoing severe nutritional restriction immediately postweaning, the size of the more glycolytic fiber types is more adversely affected than the more oxidative types, resulting in an increased relative area of type 1, slow oxidative myofibers. However, given adequate time and nutriment at pasture, LLM myofiber characteristics of cattle recovered to near normal after severe, chronic nutritional restriction immediately postweaning, consistent with earlier findings for beef quality.

Context. The solar mid-infrared metallic emission lines have already been observed and analyzed well, and the formation scenario of the Mg?I 12??m lines has been known for more than a decade. Detections of stellar emission at 12??m have, however, been limited to Mg?I in very few objects. Previous modeling attempts have been made only for Procyon and two cool evolved stars, with unsatisfactory results for the latter. This prevents the lines' long predicted usage as probes of stellar magnetic fields.Aims. We want to explain our observed Mg?I emission lines at 12??m in the K?giants Pollux, Arcturus, and Aldebaran and at 18??m in Pollux and Arcturus. We discuss our modeling of these lines and particularly how various aspects of the model atom affect the emergent line profiles.Methods. High-resolution observational spectra were obtained using TEXES at Gemini North and the IRTF. To produce synthetic line spectra, we employed standard one-dimensional, plane-parallel, non-LTE modeling for trace elements in cool stellar atmospheres. We computed model atmospheres with the MARCS code, applied a comprehensive magnesium model atom, and used the radiative transfer code MULTI to solve for the magnesium occupation numbers in statistical equilibrium.Results. The Mg?I emission lines at 12??m in the K?giants are stronger than in the dwarfs observed so far. We present the first observed stellar emission lines from Mg?I at 18??m and from Al?I, Si?I, and presumably Ca?I at 12??m. We successfully reproduce the observed Mg?I emission lines simultaneously in the giants and in the Sun, but show how the computed line profiles depend critically on atomic data input and how the inclusion of energy levels with n ? 10 and collisions with neutral hydrogen are necessary to obtain reasonable fits.

Gene expression profiles of LM from beef cattle that underwent significant postweaning undernutrition were studied using complementary DNA (cDNA) microarrays. After 114 d of undernutrition, the RNA from LM showed 2- to 6-fold less expression of many genes from the classes of muscle structural proteins, muscle metabolic enzymes, and extracellular matrix compared with animals on a rapid growth diet. The expression levels of these genes had mostly returned to pretreatment levels after 84 d of realimentation. The gene expression changes associated with undernutrition and BW loss showed an emphasis on downregulation of gene expression specific to fast-twitch fibers, typical of starving mammals, with a preferential atrophy of glycolytic fast-twitch fibers. We also identified a small group of genes that showed 2- to 5-fold elevated expression in LM after 114 d of undernutrition. Putative roles for these genes in atrophying skeletal muscle are regulation of myogenic differentiation (CSRP3), maintenance of mesenchymal stem cells (CYR61), modulation of membrane function (TM4SF2), prevention of oxidative damage (SESN1), and regulation of muscle protein degradation (SQSTM1). A significant increase in stearoyl-CoA desaturase (SCD) gene expression was observed in atrophying muscle, suggesting either that increased fatty acid synthesis is part of the tissue response to caloric restriction, or that SCDplays another role in energy metabolism in the mixed cellular environment of bovine skeletal muscle.

The effects of post-weaning nutrient restriction on growth, carcass characteristics and beef quality were determined. Belmont Red weaner steers (n = 100) were allocated to an initial slaughter group and 3 treatment groups of 120 days duration: rapid growth, slow growth and weight loss. The average daily gain of the groups were (mean s.e.): 0.81 0.02, 0.29 0.02 and ?0.22 0.01 kg/day, for the rapid growth, slow growth and weight loss groups, respectively. At the end of the treatment period, rapid growth steers had significantly (P<0.05) heavier carcasses, higher dressing percentages and greater bone mineral contents than those from the weight loss group. Steers from each group were realimented for 192 days at pasture. Average daily gains during this period were 0.39 0.03, 0.52 0.04 and 0.61 0.05 kg/day for the rapid growth, slow growth and weight loss groups, respectively. Ten animals from the rapid growth group were then slaughtered to determine carcass characteristics. The remaining steers were finished at pasture for a further 409 days. During this period there was no significant difference in average daily gain between treatment groups. Steers from the rapid growth group had a significantly greater final weight (531 16.8 kg) compared with weight loss steers (481 14.0 kg). Carcass characteristics, eye muscle area, bone mineral content and objective measures of meat quality for the M. longissimus dorsi and M. semitendinosus did not differ significantly between groups. Shear peak force values for cooked M. longissimus dorsi samples were not significantly different between groups. Clipped meat quality scores for M. longissimus dorsi samples, as assessed by Meat Standards Australia, were not significantly different between treatment groups and indicated consumer acceptability. It was concluded that nutrient restriction in the immediate post-weaning period followed by pasture realimentation did not influence final carcass characteristics or beef quality.

To determine factors associated with fetal growth, preterm delivery and stillbirth in an area of high malaria transmission in Southern Malawi, a cross-sectional study of pregnant women attending and delivering at two study hospitals was undertaken. A total of 243 (17·3%) babies were preterm and 54 (3·7%) stillborn. Intra-uterine growth retardation (IUGR) occurred in 285 (20·3%), of whom 109 (38·2%) were low birthweight and 26 (9·1%) preterm. Factors associated with IUGR were maternal short stature [adjusted odds ratio (AOR) 1·6, 95% confidence interval (CI) 1·0–2·5] primigravidae (AOR 1·9, 95% CI 1·4–2·7); placental or peripheral malaria at delivery (AOR 1·4, 95% CI 1·0–1·9) and maternal anaemia at recruitment (Hb <8 g/dl) (AOR 1·9, 95% CI 1·3–2·7). Increasing parasite density in the placenta was associated with both IUGR (P=0·008) and prematurity (P=0·02). Factors associated with disproportionate fetal growth were maternal malnutrition [mid-upper arm circumference (MUAC) <23 cm, AOR 1·9, 95% CI 1·0–3·7] and primigravidae (AOR 1·8, 95% CI 1·0–3·1). Preterm delivery and stillbirth were associated with <5 antenatal care visits (AOR 2·2, 95% CI 1·3–3·7 and AOR 3·1, 95% CI 1·4–7·0 respectively) and stillbirth with a positive Venereal Disease Research Laboratory (VDRL) test (AOR 4·7, 95% CI 1·5–14·8). Interventions to reduce poor pregnancy outcomes must reduce the burden of malaria in pregnancy, improve antenatal care and maternal malnutrition.

The purpose of this study was to determine if estimated breeding value (EBV) of an animal's sire and or the animal's nutrition affected the structure of its M. longissimus thoracis et lumborum (LL) and, hence, the eating quality of meat derived from its carcass. Lambs were chosen based on the EBV of their sires in terms of post-weaning live weight (PWWT), post weaning fat at the C-site (PFAT), and post-weaning eye muscle depth (PEMD). Morphometric techniques were used to characterise muscle structure in terms of the distribution of intramuscular connective tissue; the variables together are called fascicular structure. Perimysial seam thickness and fascicular width were both influenced by sire estimated breeding values for PWWT, PFAT, and PEMD. Variation in fascicular structure was associated with an interaction between PEMD-EBV and PFAT-EBV of the sire. Fascicular width decreased with increased PEMD-EBV and increased with PFAT-EBV, but was not affected by PWWT-EBV. When the total seam thickness was adjusted to a common fascicular width, the lambs on a low plane of nutrition had relatively more intramuscular connective tissue than those on a high plane. The total seam thickness was negatively associated with PFAT-EBV and positively associated with PEMD-EBV. Warner Bratzler shear (WBS) peak force (PF) and initial yield were not associated with differences in sire EBV. The residual WBS shear force, peak force minus initial yield (PFIY), and compression values were negatively associated with nutrition but were positively associated with PWWT-EBV and PEMD-EBV of the sires. These latter 2 effects were moderated by nutrition. The data support the hypothesis that morphological characteristics of perimysium are genetically determined and nutritionally responsive. Variance in morphology accounted for some variance in the biophysical attributes of meat and may help explain why sheep with high muscling potential have tougher meat.

Japanese Black cattle are characterised by a unique ability to deposit intramuscular fat with lower melting temperature. In this study, 3 consecutive biopsies from Longissimus muscle tissue were taken and RNA isolated from 3 Japanese Black (Tajima strain) and 3 Holstein animals at age 11?20 months. The gene expression changes in these samples were analysed using a bovine fat/muscle cDNA microarray. A mixed-ANOVA model was fitted to the intensity signals. A total of 335 (4.8%) array elements were identified as differentially expressed genes in this breed time comparison study. Genes preferentially expressed in Japanese Black are associated with mono-unsaturated fatty acid synthesis, fat deposition, adipogenesis development and muscle regulation, while examples of genes preferentially expressed in Holstein come from functional classes involved in connective tissue and skeletal muscle development. The gene expression differences detected between the Longissimus muscle of the 2 breeds give important clues to the molecular basis for the unique features of the Japanese Black breed, such as the onset and rate of adipose tissue development, metabolic differences, and signalling pathways involved in converting carbohydrate to lipid during lipogenesis. These findings will impact on industry management strategies designed to manipulate intramuscular adipose development at different development stages to gain maximum return for beef products.

We propose a data-driven reverse engineering approach to isolate the components of a gene interaction and regulatory network. We apply this method to the construction of a network for bovine skeletal muscle. Key nodes in the network include muscle-specific genes and transcription factors. muscle-specific genes are identified from data mining the USA National Cancer Institute, Cancer Genome Anatomy Project database, while transcription factors are predicted by accurate function annotation. A total of 5 microarray studies spanning 78 hybridisations and 23 different experimental conditions provided raw expression data. A recently-reported analytical method based on multivariate mixed-model equations is used to compute gene co-expression measures across 624 genes. The resulting network included 102 genes (of which 40 were muscle-specific genes and 7 were transcription factors) that clustered in 7 distinct modules with clear biological interpretation.

Expression profiling using microarrays allows for the detailed characterization of the gene networks that regulate an animal's response to environmental stresses. During nutritional restriction, processes such as protein turnover, connective tissue remodeling, and muscle atrophy take place in the skeletal muscle of the animal. These processes and their regulation are of interest in the context of managing livestock for optimal production efficiency and product quality. Here we expand on recent research applying complementary DNA (cDNA) microarray technology to the study of the effect of nutritional restriction on bovine skeletal muscle. Using a custom cDNA microarray of 9,274 probes from cattle muscle and s.c. fat libraries, we examined the differential gene expression profile of the LM from 10 Brahman steers under three different dietary treatments. The statistical approach was based on mixed-model ANOVA and model-based clustering of the BLUP solutions for the gene × diet interaction effect. From the results, we defined a transcript profile of 156 differentially expressed array elements between the weight loss and weight gain diet substrates. After sequence and annotation analyses, the 57 upregulated elements represented 29 unique genes, and the 99 downregulated elements represented 28 unique genes. Most of these co-regulated genes cluster into groups with distinct biological function related to protein turnover and cytoskeletal metabolism and contribute to our mechanistic understanding of the processes associated with remodeling of muscle tissue in response to nutritional stress.

In functional genomic laboratories, it is common to use the same microarray slide across studies, each investigating a unique biological question, and each analyzed separately due to computational limitations and/or because there is no hybridization of samples from different studies on one slide. However, the question of analyzing data from multiple studies is a major current issue in microarray data analysis because there are gains to be made in the accuracy of estimated effects by exploiting a covariance structure between gene expression data across studies. We propose an approach for combining multiple studies using multivariate mixed models, with the assumption of a nonzero correlation among genes across experiments, while imposing a null residual covariance. We applied this method to jointly analyze three experiments in genetics of cattle with a total of 54 arrays, each with 19,200 spots and 7,638 elements. The resulting seven-variate model contains 752,476 equations and 56 covariances. To identify differentially expressed genes, we applied model-based clustering to a linear combination of the random gene × variety interaction effect. We enhanced the biological interpretation of the results by applying an iterative algorithm to identify the gene ontology classes that significantly changed in each experiment. We found 118 elements with coordinate expression that clustered into distinct biological functions such as adipogenesis and protein turnover. These results contribute to our understanding of the mechanistic processes involved in adipogenesis and nutrient partitioning.

Virtual screening and high-throughput screening are two major components of lead discovery within the pharmaceutical industry. In this paper we describe improvements to previously published methods for similarity searching with reduced graphs, with a particular focus on ligand-based virtual screening, and describe a novel use of reduced graphs in the clustering of high-throughput screening data. Literature methods for reduced graph similarity searching encode the reduced graphs as binary fingerprints, which has a number of issues. In this paper we extend the definition of the reduced graph to include positively and negatively ionizable groups and introduce a new method for measuring the similarity of reduced graphs based on a weighted edit distance. Moving beyond simple similarity searching, we show how more flexible queries can be built using reduced graphs and describe a database system that allows iterative querying with multiple representations. Reduced graphs capture many important features of ligand−receptor interactions and, in conjunction with other whole molecule descriptors, provide an informative way to review HTS data. We describe a novel use of reduced graphs in this context, introducing a method we have termed data-driven clustering, that identifies clusters of molecules represented by a particular whole molecule descriptor and enriched in active compounds.

In this paper we introduce a quantitative model that relates chemical structural similarity to biological activity, and in particular to the activity of lead series of compounds in high-throughput assays. From this model we derive the optimal screening collection make up for a given fixed size of screening collection, and identify the conditions under which a diverse collection of compounds or a collection focusing on particular regions of chemical space are appropriate strategies. We derive from the model a diversity function that may be used to assess compounds for acquisition or libraries for combinatorial synthesis by their ability to complement an existing screening collection. The diversity function is linked directly through the model to the goal of more frequent discovery of lead series from high-throughput screening. We show how the model may also be used to derive relationships between collection size and probabilities of lead discovery in high-throughput screening, and to guide the judicious application of structural filters.

This review describes the pattern of intramuscular fat accretion in cattle and the potential for its manipulation during both the pasture (or backgrounding) and intensive grain-finishing phases of development. A growth curve for the development of marbling in British and Japanese Black type breeds is discussed with the conclusion that 3 phases of development exist: (i) a period of growth up to ~200 kg hot carcass weight where intramuscular fat does not increase; (ii) a period of linear development as carcass weight increases from 200 to 450kg; and (iii) the attainment of mature body size (~500 kg carcass weight depending on genotype) at which intramuscular fat content appears to reachea maximum. Data are also presented to show that the intramuscular and other fat depots develop at similar rates indicating that intramuscular fat is not a late maturing depot. Pre-finishing growth checks reduce the initial intramuscular fat at the start of finishing and this is translated into lower levels at the end of finishing. It is argued that the greatest potential for the manipulation of intramuscular fat accretion during fattening is via an increase in the net energy of the ration. Increasing net energy can be achieved by increasing the cereal grain content of the diet (grain v. grass); by feeding processed cereal grain, which allows both maximal rumen fermentation and small intestinal digestion of starch, and by increasing the lipid content of the diet. In addition it is proposed that the substrate supply or hormonal milieu can also be optimised, along with the availability of net energy to maximise fat accretion. The role of lipolysis (fat turnover) as a regulator of fat accretion is also discussed.

Marbling is an important meat quality trait, in that it contributes directly to the value of beef on international markets. The development of marbling is not well understood, though there have been some significant recent discoveries regarding adipogenesis in general. This article describes a working hypothesis around the early events of marbling. It attempts to rationalise findings from several mammalian experimental systems on hyperplastic growth of adipocyte precursor cells.

This paper describes the development of a drug rings database and Web-based search tools. The database contains ring structures from both corporate and commercial databases, along with characteristic descriptors including frequency of occurrence as an indicator of synthetic accessibility and calculated property and geometric parameters. Analysis of the rings in several major databases is described, with illustrations of applications of the database in lead discovery programs where bioisosteres and geometric isosteres are sought.

The distal radius and its articulations clearly have a vital role in the functional abilities of the hand and wrist. The treatment of tumours of the radius, therefore, needs to achieve satisfactory clearance of the lesions while also preserving as much wrist function as possible. We have employed osteoarticular autologous fibula grafts to reconstitute the distal radius after tumour excision. Since 1992, 13 patients have been treated by this technique for tumours of the distal radius. The group comprised patients with primary and recurrent giant cell tumours of bone, osteosarcoma, chondrosarcoma and Ewing's tumour. This technique achieves a satisfactory functional result without compromise of the prognosis for the tumour.

The influence of soil type, location, and sclerotial condition on survival of sclerotia of Sclerotium cepivorum Berk, was examined under field conditions. There was no significant difference in sclerotial survival in the two soil types tested (Patumahoe clay loam and Wakanui silt loam). Experiments were conducted at two locations (Auckland and Lincoln, New Zealand), which differed substantially in both average soil temperature and rainfall. Location had little effect on sclerotial survival over time. The condition of the sclerotia, related to structural damage caused by desiccation and re-wetting in the field, was an important influence on survival. A significant proportion of sclerotia (40-60%) decayed after just 2 months in soil, after which numbers declined slowly over a period of 2 years. The sudden drop in viability over the first few months in soil was attributed to damage caused by adverse environmental conditions and subsequent attack by microbes.

High-throughput screening has made a significant impact on drug discovery, but there is an acknowledged need for quantitative methods to analyze screening results and predict the activity of further compounds. In this paper we introduce one such method, binary kernel discrimination, and investigate its performance on two datasets; the first is a set of 1650 monoamine oxidase inhibitors, and the second a set of 101 437 compounds from an in-house enzyme assay. We compare the performance of binary kernel discrimination with a simple procedure which we call “merged similarity search”, and also with a feedforward neural network. Binary kernel discrimination is shown to perform robustly with varying quantities of training data and also in the presence of noisy data. We conclude by highlighting the importance of the judicious use of general pattern recognition techniques for compound selection.

The intrinsic properties (those extant at the time of slaughter) of bovine skeletal muscle as they relate to the subsequent quality attributes of beef are reviewed here. Attributes of bovine skeletal muscle that ultimately affect toughness, colour, fat content, flavour, juiciness, and nutritive value of beef are discussed. The dynamic nature of muscle development, particularly with regard to structure and composition, is highlighted. Variation in development of muscle structure and composition due to inherited (genetic) factors and environment (particularly nutrient supply) are described. Examples are given of the implications of sources of variation due to animal genotype, age, nutrient supply, and hormonal environment on muscle cellularity and growth, fibre type, connective tissue composition and structure as they affect meat quality attributes. Key intrinsic properties of muscle include muscle type, cellularity, size, myofibre type, connective tissue composition and structure, glycogen and fat content and proteolytic activity. Activity of the calpain system at slaughter is seen as an important attribute. Regulation of myofibrillar and connective tissue proteolysis in vivo are discussed together with implications for subsequent meat quality. Amongst the on-farm environmental factors, nutritional history and developmental pathway are identified as factors that can be responsible for significant variation in the intrinsic properties of muscle that contribute to variation in toughness, colour and fat content, and thus consumer liking of beef. meat, tenderness, toughness, colour, flavour, juiciness.

Using a simple model of ligand−receptor interactions, the interactions between ligands and receptors of varying complexities are studied and the probabilities of binding calculated. It is observed that as the systems become more complex the chance of observing a useful interaction for a randomly chosen ligand falls dramatically. The implications of this for the design of combinatorial libraries is explored. A large set of drug leads and optimized compounds is profiled using several different properties relevant to molecular recognition. The changes observed for these properties during the drug optimization phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An extreme example of the use of simple molecules for directed screening against thrombin is provided.

Sorted muscle cells, cultured from a patient with nephropathic cystinosis, stored 100 times normal amounts of cystine. Subcellular fractionation and density-gradient centrifugation confirmed that the cystine was located in a lysosomal compartment. 2. Myoblasts from cystinotic patients in culture underwent fusion to myotubes in a normal fashion. 3. The free thiol cysteamine effectively depleted cystinotic-muscle cells of cystine. 4. Cultured myoblast and myotubes offered a unique system for investigating the effects of lysosomal storage on differentiated cell functions.

Transgenic potato roots have been produced usingAgrobacterium rhizogenesand a chimeric transgene consisting of the wound-induciblewun1gene promoter and the β-glucuronidase (uidA) reporter coding region. Transgenic hairy roots were challenged in sterile tissue culture with the cyst nematode,Globodera pallida, and the root-knot nematodeMeloidogyne javanica. Strong expression of β-glucuronidase occurred during intracellular migration byG. pallidabut the area of responsive tissue was later restricted to the immediate vicinity of the feeding nematode. In contrast,M. javanicainfection induced only weak expression during its intercellular migration, but the gall which subsequently developed showed transgene expression. This study shows that nematode-inducible expression of a transgene can be analyzed in plant tissue culture and demonstrates differential response to two nematodes that can be correlated with different host-parasite interactions. The early expression of the transgene following invasion byG. pallidais correlated with a phase of wounding and intracellular migration and involves a local, systemic response that extends beyond directly damaged plant cells.

Diffusion in multicomponent solutions containing proteoglycan is shown to result in the formation of coherent, fluid structures (known as dissipative structures) and induction of rapid polymer transport. These phenomena occur over a wide range of conditions (i.e. varying solute distribution, concentration, size, and chemical composition) which are envisaged to occur in the extracellular matrix of connective tissues. A concentration gradient of chondroitin sulfate in a proteoglycan matrix of uniform concentration yields dissipative structures which transport the proteoglycan up to 300-fold faster than its transport in the absence of the gradient component. Similar behavior was observed with other polysaccharide and monosaccharide concentration gradient components. Amplification of structure formation and rapid transport was achieved by 1) increasing the concentration of proteoglycan matrix, 2) increasing the magnitude of the concentration gradient, 3) decreasing the molecular weight of the gradient-forming component, and 4) decreasing the concentration gradient of proteoglycan in the matrix. Dissipative structure morphology exhibits a marked dependence on the initial component distribution. Non-specific, excluded volume interactions between the proteoglycan and the gradient component are believed to induce coupled diffusive transport of the proteoglycan. This leads to microscopic density inversions which nucleate and develop into macroscopic convective flows. These results are similar to those previously observed in ternary solutions of uncharged polymers (i.e. dextran/polyvinylpyrrolidone). We have demonstrated that dissipative structures may transport Micrococcus luteus cells as well as various solutes. Flows were also observed in proteoglycan solutions after localized addition of small amounts of either a proteolytic enzyme or hyaluronic acid. It is likely that the prerequisites for this spontaneous macroscopic self-organization, as manifested by the flow phenomenon, are present in the extracellular matrix of connective tissues.

Cultured fibroblasts from patients with I-cell disease (mucolipidosis II) accumulate excessive amounts of free cystine, similarly to cells from patients with nephropathic cystinosis, a disorder of lysosomal cystine transport. To clarify whether the intralysosomal accumulation of cystine in I-cell-disease fibroblasts was due to a defective disposal mechanism, we measured the rates of clearance of free [35S]cystine from intact normal, cystinotic and I-cell-disease fibroblasts. Loss of radioactivity from the two mutant cell types occurred slowly (t 1/2 = 500 min) compared with the rapid loss from normal cells (t 1/2 = 40 min). Lysosome-rich granular fractions isolated from three different cystine-loaded normal, cystinotic and I-cell-disease fibroblast strains were similarly examined for non-radioactive cystine egress. Normal granular fractions lost cystine rapidly (mean t 1/2 = 43 min), whereas cystinotic granular fractions did not lose any cystine (mean t 1/2 = infinity). I-cell-disease granular fractions displayed prolonged half-times for cystine disposal (mean = 108 min), suggesting that I-cell-disease fibroblasts, like cystinotic cells, possess a defective carrier mechanism for cystine transport.