Incorporating hydrology into climate suitability models changes projections of malaria transmission in Africa.

Continental-scale models of malaria climate suitability typically couple well-established temperature-response models with basic estimates of vector habitat availability using rainfall as a proxy. Here we show that across continental Africa, the estimated geographic range of climatic suitability for malaria transmission is more sensitive to the precipitation threshold than the thermal response curve applied. To address this problem we use downscaled daily climate predictions from seven GCMs to run a continental-scale hydrological model for a process-based representation of mosquito breeding habitat availability. A more complex pattern of malaria suitability emerges as water is routed through drainage networks and river corridors serve as year-round transmission foci. The estimated hydro-climatically suitable area for stable malaria transmission is smaller than previous models suggest and shows only a very small increase in state-of-the-art future climate scenarios. However, bigger geographical shifts are observed than with most rainfall threshold models and the pattern of that shift is very different when using a hydrological model to estimate surface water availability for vector breeding.

The effects of land use and topographic changes on sediment connectivity in mountain catchments.

Understanding the evolution of sediment connectivity associated with different land use and topographic changes is a prerequisite for a better understanding of sediment budgets and sediment transport processes. We used the Index of Sediment Connectivity (IC) developed by Cavalli et al. (2013) based on the original approach by Borselli et al. (2008) to study the effects of decadal-scale land use and topographic changes on sediment connectivity in mountain catchments. The input variables of the IC (i.e. land cover and topography) were derived from historical aerial photos using Structure from Motion-Multi View Stereo algorithms (SfM-MVS). The method was applied in different sub-catchments of the Upper River Cinca Catchment (Central Pyrenees), representative of three scenarios: (a) Land cover changes; (b) Topographic changes in agricultural fields (terracing); and (c) Topographic changes associated with infrastructure (road construction). In terms of land cover changes, results show that although connectivity is increased in some areas due to the establishment of new field crops, for most of the study area connectivity decreased due to afforestation caused by rural abandonment. Topographic changes due to the establishment of agricultural terraces affected connectivity to a larger degree than land cover changes. Terracing generally reduced connectivity due to the formation of flat areas in step-slopes, but in certain points, an increase in connectivity caused by the topographic convergence produced by terraces was observed. Finally, topographic changes associated with road construction greatly modified surface flow directions and the drainage network, resulting in changes in connectivity that may affect erosional processes nearby. The methodology used in this paper allows to study the effects of real decadal-scale land use and topographic changes on sediment connectivity and also evaluating and disentangling those changes. Furthermore, this approach can be a useful tool to identify potential risks associated with morphological and land use changes, involving road infrastructures.

Gone with the heat: a fundamental constraint on the imaging of dust and molecular gas in the early Universe.

Images of dust continuum and carbon monoxide (CO) line emission are powerful tools for deducing structural characteristics of galaxies, such as disc sizes, H2 gas velocity fields and enclosed H2 and dynamical masses. We report on a fundamental constraint set by the cosmic microwave background (CMB) on the observed structural and dynamical characteristics of galaxies, as deduced from dust continuum and CO-line imaging at high redshifts. As the CMB temperature rises in the distant Universe, the ensuing thermal equilibrium between the CMB and the cold dust and H2 gas progressively erases all spatial and spectral contrasts between their brightness distributions and the CMB. For high-redshift galaxies, this strongly biases the recoverable H2 gas and dust mass distributions, scale lengths, gas velocity fields and dynamical mass estimates. This limitation is unique to millimetre/submillimetre wavelengths and unlike its known effect on the global dust continuum and molecular line emission of galaxies, it cannot be addressed simply. We nevertheless identify a unique signature of CMB-affected continuum brightness distributions, namely an increasing rather than diminishing contrast between such brightness distributions and the CMB when the cold dust in distant galaxies is imaged at frequencies beyond the Raleigh-Jeans limit. For the molecular gas tracers, the same effect makes the atomic carbon lines maintain a larger contrast than the CO lines against the CMB.

Association of variants in genes related to the immune response and obesity with BPH in CLUE II.

BACKGROUND: Chronic inflammation and obesity may contribute to the genesis or progression of BPH and BPH-associated lower urinary tract symptoms (LUTS). The influence of variants in genes related to these states on BPH has not been studied extensively. Thus, we evaluated the association of 17 single-nucleotide polymorphisms (SNPs) in immune response genes (IL1B, IL6, IL8, IL10, TNF, CRP, TLR4 and RNASEL) and genes involved in obesity, including insulin regulation (LEP, ADIPOQ, PPARG and TCF7L2), with BPH. METHODS: BPH cases (N = 568) and age-frequency matched controls (N=568) were selected from among adult male CLUE II cohort participants who responded in 2000 to a mailed questionnaire. BPH was defined as BPH surgery, use of BPH medications or symptomatic BPH (American Urological Association Symptom Index Score ⩾ 15). Controls were men who had not had BPH surgery, did not use BPH medications and whose symptom score was ⩽ 7. Age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: None of the candidate SNPs was statistically significantly associated with BPH. However, we could not rule out possible weak associations for CRP rs1205 (1082C>T), ADIPOQ rs1501299 (276C>A), PPARG rs1801282 (-49C>G) and TCF7L2 rs7903146 (47833T>C). After summing risk alleles, men with ⩾ 4 had an increased BPH risk compared with those with ⩽ 1 (OR, 1.78; 95% CI, 1.10-2.89; P(trend) = 0.006). CONCLUSIONS: SNPs in genes related to immune response and obesity, especially in combination, may be associated with BPH.

A simple, rapid, cost-effective and sensitive method for detection of Salmonella in environmental and pecan samples.

AIMS: PCR is widely used in the routine detection of foodborne human pathogens; however, challenges remain in overcoming PCR inhibitors present in some sample matrices. The objective of this study was to develop a simple, sensitive, cost-effective and rapid method for processing large numbers of environmental and pecan samples for Salmonella detection. This study was also aimed at validation of a new protocol for the detection of Salmonella from in-shell pecans. METHODS AND RESULTS: Different DNA template preparation methods, including direct boiling, prespin, multiple washing and commercial DNA extraction kits, were evaluated with pure cultures of Salmonella Typhimurium and with enriched soil, cattle feces and in-shell pecan each spiked individually with Salmonella Typhimurium. PCR detection of Salmonella was conducted using invA and 16S rRNA gene (internal amplification control) specific primers. The effect of amplification facilitators, including bovine serum albumin (BSA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and gelatin on PCR sensitivity, was also evaluated. Conducting a prespin of sample matrices in combination with the addition of 0·4% (w/v) BSA and 1% (w/v) PVP in PCR mix was the simplest, most rapid, cost-effective and sensitive method for PCR detection of Salmonella, with up to 40 CFU Salmonella per reaction detectable in the presence of over 10(9 ) CFU ml(-1) of background micro-organisms from enriched feces soil or pecan samples. CONCLUSIONS: The developed method is rapid, cost-effective and sensitive for detection of Salmonella from different matrices. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a method with broad applicability for PCR detection of Salmonella in complex sample matrices. This method has a potential for its application in different research arenas and diagnostic laboratories.

BNNT-mediated irreversible electroporation: its potential on cancer cells.

Irreversible lethal electroporation (IRE) is a new non-thermal ablation modality that uses short pulses of high amplitude static electric fields (up 1000 V/cm) to create irreversible pores in the cell membrane, thus, causing cell death. Recently, IRE has emerged as a promising clinical modality for cancer disease treatment. Here, we investigated the responses of tumour human HeLa cells when subjected to IRE in the presence of BNNTs. These consist of tiny tubes of B and N atoms (arranged in hexagons) with diameters ranging from a 1 to 3 nanometres and lengths < 2 µm. BNNTs have attracted wide attention because of their unique electrical properties. We speculate that BNNTs, when interacting with cells exposed to static electrical fields, amplify locally the electric field, leading to cell death. In this work, electroporation assays were performed with a commercial electroporator using the cell- specific protocol suggested by the supplier (exponential decay wave, time constant 20 ms) with the specific aim to compare IRE in absence and in presence of BNNTs. We observed that BNNTs have the capacity to decrease substantially the voltage required for IRE. When cells were pulsed at 800 V/cm, we observed a 2,2-fold reduction in cell survival in the presence of BNNTs compared to controls. We conclude that the death of the tumour cells exposed to IRE is strongly enhanced in the presence of BNNTs, indicating their potential therapeutic application.

Extended IL10 haplotypes and their association with HIV progression to AIDS.

Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around 'classic' 'proximal' promoter polymorphisms: -592, -819 and -1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.

Detecting AIDS restriction genes: from candidate genes to genome-wide association discovery.

The screening of common genetic polymorphisms among candidate genes for AIDS pathology in HIV exposed cohort populations has led to the description of 20 AIDS restriction genes (ARGs), variants that affect susceptibility to HIV infection or to AIDS progression. The combination of high-throughput genotyping platforms and the recent HapMap annotation of some 3 million human SNP variants has been developed for and applied to gene discovery in complex and multi-factorial diseases. Here, we explore novel computational approaches to ARG discovery which consider interacting analytical models, various genetic influences, and SNP-haplotype/LD structure in AIDS cohort populations to determine if these ARGs could have been discovered using an unbiased genome-wide association approach. The procedures were evaluated by tracking the performance of haplotypes and SNPs within ARG regions to detect genetic association in the same AIDS cohort populations in which the ARGs were originally discovered. The methodology captures the signals of multiple non-independent AIDS-genetic association tests of different disease stages and uses association signal strength (odds ratio or relative hazard), statistical significance (p-values), gene influence, internal replication, and haplotype structure together as a multi-facetted approach to identifying important genetic associations within a deluge of genotyping/test data. The complementary approaches perform rather well and predict the detection of a variety of undiscovered ARGs that affect different stages of HIV/AIDS pathogenesis using genome-wide association analyses.

A nucleic acid sequence-based amplification assay for real-time detection of norovirus genogroup II.

AIMS: To use molecular beacon based nucleic acid sequence-based amplification (NASBA) to develop a rapid, sensitive, specific detection method for norovirus (NV) genogroupII (GII). METHODS AND RESULTS: A method to detect NV GII from environmental samples using real-time NASBA was developed. This method was routinely sensitive to 100 copies of target RNA and intermittent amplification occurred with as few as 10 copies. Quantitative estimates of viral load were possible over at least four orders of magnitude. CONCLUSIONS: The NASBA method described here is a reliable and sensitive assay for the detection of NV. This method has the potential to be linked to a handheld NASBA device that would make this real-time assay a portable and inexpensive alternative to bench-top, lab-based assays. SIGNIFICANCE AND IMPACT OF THE STUDY: The development of the real-time NASBA assay described here has resulted in a simple, rapid (<1 h), convenient testing format for NV. To our knowledge, this is the first example of a molecular beacon based NASBA assay for NV.

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans.

BACKGROUND: The extent which universally common or population-specific alleles can explain between-population variations in phenotypes is unknown. The heritable coronary heart disease risk factor lipoprotein(a) (Lp(a)) level provides a useful case study of between-population variation, as the aetiology of twofold higher Lp(a) levels in African populations compared with non-African populations is unknown. OBJECTIVE: To evaluate the association between LPA sequence variations and Lp(a) in European Americans and African Americans and to determine the extent to which LPA sequence variations can account for between-population variations in Lp(a). METHODS: Serum Lp(a) and isoform measurements were examined in 534 European Americans and 249 African Americans from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. In addition, 12 LPA variants were genotyped, including 8 previously reported LPA variants with a frequency of >2% in European Americans or African Americans, and four new variants. RESULTS: Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three single-nucleotide polymorphisms (SNPs) were independently associated with Lp(a) level (p<0.02 in both populations). The Lp(a)-increasing SNP (G-21A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of <20% in one or both populations. Together, they reduced the isoform-adjusted African American Lp(a) increase from 2.23 to 1.37-fold(a 60% reduction) and the between-population Lp(a) variance from 5.5% to 0.5%. CONCLUSIONS: Multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma.

OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance.

Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

Evaluating association and transmission of eight inflammatory genes with Viliuisk encephalomyelitis susceptibility.

Since the discovery of Viliuisk encephalomyelitis (VE) in 1887, scientists have tried to understand the natural history and aetiology of this endemic neurological disorder among the native Sakha population of Central Siberia. Familial aggregation and segregation analysis suggested a genetic influence on VE incidence. However, recent studies have implicated an unknown virus, possibly from the alpha herpesvirus family, as a possible cause for this disease. As VE is a neurological disease characterized by the inflammatory reactions systematically observed in the spinocerebellar fluid and in the brain tissue of deceased patients, we examined 17 single nucleotide polymorphisms (SNPs) across seven inflammation-related candidate gene regions, including chemokine receptors type 2 and 5 (CCR2/CCR5), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, IL-10, stromal cell-derived factor (SDF) and chemokine regulated upon activation, normal T-cell expressed and presumably secreted (RANTES). Our main objective was to analyse the degree of genetic association between VE and candidate genes that have been previously implicated in other inflammatory diseases. Samples were collected from 83 affected families comprising 88 verified VE cases, 156 family members, and an additional 69 unrelated, unaffected inhabitants of the same geographical area. This collection included substantially all of the cases that are currently on the VE Registry. The experimental design included both case-control and transmission/disequilibrium test (TDT)-based familial association analyses. None of 17 SNPs analysed was significantly associated with VE occurrence. Exclusion of these eight genes based on the lack of association has important implications for identifying the disease agent, as well as prescribing therapy and understanding Viliuisk encephalomyelitis.

Prospective risk of cancer in CDKN2A germline mutation carriers.

BACKGROUND: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family's CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment. METHODS: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained (that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4-26 years starting in the 1970s. RESULTS: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/Exp = 12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks. CONCLUSIONS: Differences in CDKN2A-non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences.

Fraction of cases of acquired immunodeficiency syndrome prevented by the interactions of identified restriction gene variants.

Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984-1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Delta 32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Delta 32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 'A and CCR5 promoter P1/approximately P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.

Vehicle-Mounted Optical Sensing: An Objective Means for Evaluating Turf Quality.

Visual evaluation of turfgrass quality is a subjective process that requires experienced personnel. Optical sensing of plant reflectance provides objective, quantitative turf quality evaluation and requires no turf experience. This study was conducted to assess the accuracy of optical sensing for evaluating turf quality, to compare the rating consistency among human evaluators and optical sensing, and to develop a model that describes a relationship between optically sensed measurements and visual turf quality. Visual evaluations for turf color, texture, percent live cover (PLC), and optically sensed measurements were collected on the National Turfgrass Evaluation Program (NTEP) tall fescue (Festuca arundinacea Schreb) and creeping bentgrass (Agrostis palustris Huds.) trials at Stillwater, OK. Measurements were made monthly for 12 consecutive months from June 1999 through May 2000. Red (R) and near infrared (NIR) reflectance were collected with sensors and converted to normalized difference vegetative indices (NDVI). The NDVI were closely correlated with visual evaluations for turf color, moderately correlated with percent live cover (PLC), and independent of texture. Measurements of turf color and PLC were evaluated more consistently with optical sensors than by visual ratings. Normalized difference vegetation index (Y) could be reliably predicted by the following generalized model for turf color (X) and PLC (Z): Y = B(0) + B(1)log10X + B(2)Z(3). Optical sensing provided fast, reliable turf assessment and deserves consideration as a supplemental or replacement technique for evaluating turf quality.

Range of motion after arthroplasty for the stiff osteoarthritic knee.

In 28 of 1656 total knee arthroplasties (TKAs) (1.7%) performed for osteoarthritis at this institution, the preoperative arc of motion was 60 degrees or less (average 47.5 degrees; range, 20-60 degrees). The outcome of 22 of the 28 TKAs (21 patients) is reported at a mean follow-up of 52.9 months (range, 24-144 months). Eighty-two percent of the cases were managed with standard soft-tissue releases and posterior cruciate-retaining implants and 18% with a cruciate-substituting design. The joint score rose from 28.8 to 82.2 and the Knee Society Score from 24.6 to 77 points. The mean postoperative arc of motion improved by 46 degrees-93.5 degrees. At latest follow-up, 68.2% of knees achieved maximal flexion of 90 degrees or more. Manipulation was performed in 22.7%. Complications were minimal. A functionally useful range of motion is possible after total knee arthroplasty in the majority of stiff osteoarthritic knees, often without the need for posterior cruciate substitution.

Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

Saturation mutagenesis of 5S rRNA in Saccharomyces cerevisiae.

rRNAs are the central players in the reactions catalyzed by ribosomes, and the individual rRNAs are actively involved in different ribosome functions. Our previous demonstration that yeast 5S rRNA mutants (called mof9) can impact translational reading frame maintenance showed an unexpected function for this ubiquitous biomolecule. At the time, however, the highly repetitive nature of the genes encoding rRNAs precluded more detailed genetic and molecular analyses. A new genetic system allows all 5S rRNAs in the cell to be transcribed from a small, easily manipulated plasmid. The system is also amenable for the study of the other rRNAs, and provides an ideal genetic platform for detailed structural and functional studies. Saturation mutagenesis reveals regions of 5S rRNA that are required for cell viability, translational accuracy, and virus propagation. Unexpectedly, very few lethal alleles were identified, demonstrating the resilience of this molecule. Superimposition of genetic phenotypes on a physical map of 5S rRNA reveals the existence of phenotypic clusters of mutants, suggesting that specific regions of 5S rRNA are important for specific functions. Mapping these mutants onto the Haloarcula marismortui large subunit reveals that these clusters occur at important points of physical interaction between 5S rRNA and the different functional centers of the ribosome. Our analyses lead us to propose that one of the major functions of 5S rRNA may be to enhance translational fidelity by acting as a physical transducer of information between all of the different functional centers of the ribosome.

Culture and psychopharmacology.

In this brief review the authors strive to provide a broad overview of various factors that impinge on psychopharmacotherapeutic practices. The literature revealed an impressive progress in research focusing on the delineation of the biologic mechanisms responsible for cross-ethnic variations in psychotropic metabolism and effects. With the field progressing at an accelerating pace, there is little doubt that in the coming decade clinicians will be provided with a detailed map showing the prevalence and distribution of genetic polymorphisms of most, if not all, of the drug-metabolizing enzymes, and clinicians also will have an overall picture on what these polymorphisms mean clinically. At the same time, clinicians should also start to have a good grasp on the meaning of the variations of the genes that encode therapeutic targets of psychotropics (e.g., neurotransmitter transporters and receptors). Such genetic fingerprinting, which will soon become a clinical reality, will provide tremendous help in ensuring that pharmacotherapies are increasingly more individually tailored, taking into consideration each patients genetic makeups that vary substantially across ethnic groups. As exciting as these new developments will be, they are dwarfed by the challenges ahead on the cultural side of the equation. Issues that are still awaiting further clarification include the following: How do we assess patients' beliefs and expectations related to psychotropic treatment? How do we minimize the communication gaps between patients and clinicians who are often from divergent sociocultural backgrounds? To what extent, and in what ways, do cultural (environmental) factors interact with biologic factors, and what might be the most efficient way to systematically assess such interactions? Data that have emerged in the past several decades clearly indicate the importance of culture and ethnicity in influencing patients' psychopharmacological response. It is expected that continuing progress in the near future will bring a better understanding on the way these cultural and biologic processes, separately and in interaction with each other, mediate treatment responses. Such knowledge will be crucial for the optimal pharmacotherapeutic care of for the majority of patients who will increasingly be of diverse ethnic and cultural backgrounds and will represent a significant contribution to the field of psychopharmacology as a whole.