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PubMed2002

Stereointegrity of thalidomide: gas-chromatographic determination of the enantiomerization barrier.

Enantioselective chromatographic methods, representing the most commonly used techniques for the determination of enantiomeric ratios, can also be used for the evaluation of stereochemical integrity. In the present study, two chromatographic methods, dynamic gas chromatography (DGC) and stopped-flow gas chromatography (SFGC) were used to determine the enantiomerization barrier of thalidomide. In the presence of a chiral stationary phase (CSP), the enantiomers of thalidomide produced characteristic elution profiles exhibiting plateaus and/or peak broadening which were observed between 190 and 220 degrees C in DGC. To obtain the enantiomerization barrier of thalidomide from experimental data, the fast and efficient simulation program ChromWin was used to simulate the elution profiles and obtain kinetic activation parameters. From temperature-dependent measurements the rate constants k(1) and k(-1) and the kinetic activation parameters DeltaG#, DeltaH# and DeltaS# of the enantiomerization of thalidomide were obtained by DGC. The enantiomerization barrier DeltaG# was determined to be 154+/-2 kJ/mol with DGC and 150+/-3 kJ/mol with the sfGC technique at 200 degrees C, respectively. The concept of the retention increment R' has been applied to separate the enantiomerization barrier of thalidomide in the dissolved and complexed state of the CSP.

Chromatography, Gas↗
PubMed1992

A contig assembly program based on sensitive detection of fragment overlaps.

An effective computer program for assembling DNA fragments, the contig assembly program (CAP), has been developed. In the CAP program, a filter is used to eliminate quickly fragment pairs that could not possibly overlap, a dynamic programming algorithm is applied to compute the maximal-scoring overlapping alignment between each remaining pair of fragments, and a simple greedy approach is employed to assemble fragments in order of alignment scores. To identify the true fragment overlaps, the dynamic programming algorithm uses specially chosen sets of alignment parameters to tolerate sequencing errors and to penalize "mutational" changes between different copies of a repetitive sequence. The performance tests of the program on fragment data from genomic sequencing projects produced satisfactory results. The CAP program is efficient in computer time and memory; it took about 4 h to assemble a set of 1015 fragments into long contigs on a Sun workstation.

Algorithms↗
PubMed1997

What is the relationship between osteoarthritis and ageing?

The relationship between osteoarthritis and ageing raises important questions about what exactly defines 'normal' ageing and whether the pathogenesis of osteoarthritis shares common pathways with other age-associated dysfunctions, or whether osteoarthritis is a time-dependent disorder distinct from normal ageing with a separate causative mechanism at work. Theories of ageing now emphasize the stochastic nature of the ageing process, that is the role played by accumulation of essentially random cell and tissue damage, such as somatic mutations, oxidative damage and the formation of aberrant proteins. The role of genetic factors in determining longevity and predisposition to age-associated diseases is probably in programming the efficiency of somatic maintenance functions and in influencing the development of a durable soma. Gene-environment interactions, for example through lifestyle, can also be important. Many of the risk factors and mechanisms that are thought to contribute to osteoarthritis can be accommodated within this framework.

Aged↗
PubMed1999

Mutations in the MOF2/SUI1 gene affect both translation and nonsense-mediated mRNA decay.

Recent studies have demonstrated that cells have evolved elaborate mechanisms to rid themselves of aberrant proteins and transcripts. The nonsense-mediated mRNA decay pathway (NMD) is an example of a pathway that eliminates aberrant mRNAs. In yeast, a transcript is recognized as aberrant and is rapidly degraded if a specific sequence, called the DSE, is present 3' of a premature termination codon. Results presented here show that strains harboring the mof2-1, mof4-1, mof5-1, and mof8-1 alleles, previously demonstrated to increase the efficiency of programmed -1 ribosomal frameshifting, decrease the activity of the NMD pathway. The effect of the mof2-1 allele on NMD was characterized in more detail. Previous results demonstrated that the wild-type MOF2 gene is identical to the SUI1 gene. Studies on the mof2-1 allele of the SUI1 gene indicate that in addition to its role in recognition of the AUG codon during translation initiation and maintenance of the appropriate reading frame during translation elongation, the Mof2 protein plays a role in the NMD pathway. The Mof2p/Sui1 p is conserved throughout nature and the human homolog of the Mof2p/Sui1p functions in yeast cells to activate NMD. These results suggest that factors involved in NMD are general modulators that act in several aspects of translation and mRNA turnover.

Alleles↗
PubMed2002

Development and evaluation of an immunoassay for biological monitoring chlorophenols in urine as potential indicators of occupational exposure.

Trichlorophenols (TCP) eliminated by the urine can be considered as potential biomarkers of exposure of many chemicals (chlorophenols, chlorophenoxy acid herbicides, prochloraz, lindane, hexachlorobenzene, etc). High-throughput screening methods are necessary to carry out efficient monitoring programs that may help to prevent certain occupational health diseases. For this purpose, an indirect enzyme-linked immunosorbent assay (ELISA) for 2,4,6-trichlorophenol detection has been developed using polyclonal antisera raised against 3-(3-hydroxy-2,4,6-trichlorophenyl)propanoic acid (hapten 5) covalently coupled by the mixed anhydride (MA) method to keyhole limpet hemocyanin (KLH). The indirect ELISA uses a heterologous coating antigen prepared by conjugation of 3-(2-hydroxy-3,6-dichlorophenyl)propanoic acid (hapten 4) to bovine serum albumin (BSA) using the active ester (AE) method. The optimum hapten density for the coating antigen was found to be 3 mol of hapten/mol of protein. The assay shows a limit of detection of 0.245 +/- 0.116 microg L(-1), and it is performed on 96-well microtiter plates in about 1.5 h. The ELISA reported recognizes on a much less extent other chlorinated phenols, such as 2,3,4,6-tetrachlorophenol (2,3,4,6-TtCP, 21%), 2,4,5-TCP (12%) and 2,3,5-TCP (15%); however, brominated phenols (BP) are even more recognized than the corresponding chlorinated analogues (ex. 2,4,6-TBP, 710%; 2,4-DBP, 119%). With the aim of finding an explanation for this behavior, theoretical calculations have been performed for those and other halogenated phenols (2,4,6-triiodophenol and 2,4,6-trifluorophenol) to clarify which physicochemical parameter can explain better the recognition pattern observed. Finally, the assay has been adapted to the analysis of urine samples. The studies have shown that a limit of detection of 1 microg L(-1) can be accomplished on this biological matrix by combining the ELISA procedure with a C18 solid-phase extraction method.

Chlorophenols↗
PubMed2001

Genetic methods and strategies for secondary metabolite yield improvement in actinomycetes.

The foundation for any strain improvement program is efficient random chemically-induced mutagenesis coupled with highly reproducible fermentation and product assays. The broad spectrum of spontaneous mutations can be leveraged in some cases by direct selection of mutants with desired traits. Transposons containing outward-reading promoter activity might be used to enhance yields by inducing promoter fusions, disrupting negative regulatory elements, or disrupting genes involved in competing pathways. Transposons might also be used to identify and clone positive regulatory genes. As knowledge of the key elements in the fermentation process and secondary metabolite biosynthesis grows, gene cloning and targeted gene duplication becomes an important tool. Duplication of genes involved in rate limiting steps can be achieved to improve product yields by inserting the desired gene(s) into neutral sites in the chromosome by homologous recombination or by site-specific integration. The probabilities and frequencies of success of the molecular genetic approaches should increase with an increasing knowledge of key factors influencing product yields. This knowledge can be broadened dramatically by a combination of structural and functional genomics, gene disruption analysis and metabolic modeling. Protoplast fusion can be used to recombine beneficial traits from any of the other approaches.

Actinomycetales↗
PubMed2005

[Efficiency of a herd health program in Swiss dairy herds].

A retrospective analysis of the reproductive parameters was conducted in 15 dairy farms using a herd health monitoring system between 1995 and 1998. Five of these farms have used this monitoring process for many years (group 1) while 10 of them only initiated the process in 1996 (group 2). It was the aim of this study to evaluate the economic gain of the farms in each group due to the herd health monitoring program throughout the three year study period, by using Value Based Management (VBM), a model from the economic sciences. The mean calving to conception interval decreased from 93.3 to 84.0 days and from 104.9 to 86.7 days throughout the study period in groups 1 (P>0.05) and 2 (P < 0.05), respectively. The mean percentage of cows with calving to conception intervals below 115 days varied between 68.2% and 82.0% in group 1, while there was an increase form 65.2% to 78.6% in group 2 (P<0.05). There were no apparent trends in the reproductive culling rate throughout the study period (P>0.05), and the majority fell below 10%. Likewise, the first service conception rate varied between 52.7% and 56.6% and between 41.2% and 50.0%, in group 1 and 2, respectively. The number of services per conception varied between 1.6 and 1.8 and between 1.8 and 1.9, in groups 1 and 2, respectively. The number of days between calving and first service varied between 62.7 and 64.8 days in group 1, while it decreased significantly from 69.2 to 59.2 in group 2 (P<0.05). The time between first service and conception decreased from 30.6 to 22.0 days, and from 35.7 to 28.0 days in groups 1 and 2, respectively (P<0.05). Although there was an apparent increase of the detection rate of oestrus from 57.8% to 68.2% throughout the study period in group 1, it was not significant (P > 0.05). In group 2, however, the oestrus detection rate increased significantly from 53.0% to 69.9% (P < 0.05). The percent of detected oestrus within 42 days post partum increased from 33.1% to 38.1%, and from 24.1% to 40.9% in groups 1 and 2, respectively (P < 0.05). By 1998, four out of five farms in group 1, and five out of the eight farms where information was avail- year study period of CHF 25.- to CHF 609.- per cow and year. The calving to conception interval and the reproductive culling rate were the two most important parameters to determine the reproductive performance of the herd and the economic benefit of the herd health monitoring program. These findings support the implementation of a herd health monitoring program.

Animal Welfare↗
PubMed1992

Optimizing nucleotide mixtures to encode specific subsets of amino acids for semi-random mutagenesis.

In random mutagenesis, synthesis of an NNN triplet (i.e. equiprobable A, C, G, and T at each of the three positions in the codon) could be considered an optimal nucleotide mixture because all 20 amino acids are encoded. NN(G,C) might be considered a slightly more intelligent "dope" because the entire set of amino acids is still encoded using only half as many codons. Using a general algorithm described herein, it is possible to formulate more complex doping schemes which encode specific subsets of the twenty amino acids, excluding others from the mix. Maximizing the equiprobability of amino acid residues contributing to such a subset is suggested as an optimal basis for performing semi-random mutagenesis. This is important for reducing the nucleotide complexity of combinatorial cassettes so that "sequence space" can be searched more efficiently. Computer programs have been developed to provide tables of optimized dopes compatible with automated DNA synthesizers.

Amino Acid Sequence↗
PubMed1995

The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance.

As genetic marker maps have improved, multipoint linkage analysis has become a crucial part of all disease mapping studies. Paradoxically, multipoint lod scores become increasingly difficult to compute, particularly as the numbers of markers, marker alleles and untyped people increase. We have solved this problem by using a novel set-recording scheme to recode each person's genotype and 'fuzzy inheritance' to infer transmission probabilities. Our approach is implemented in a memory-efficient computer program, VITESSE, for extremely rapid computation of exact multipoint likelihoods. VITESSE enables fast and precise multipoint mapping of disease loci with highly polymorphic markers.

Algorithms↗
PubMed2003

Effects of an exercise program on muscle performance in patients undergoing allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has been successfully used for the treatment of several hematological malignancies; however, it is associated with transplant-related toxicities such as functional impairment and muscle weakness. In order to analyze how an exercise program may influence muscle strength in patients undergoing BMT, we carried out a prospective study assessing patients from the pre-BMT phase to 16 weeks post-BMT. In all, 18 patients underwent three trials: (1) pre-BMT, (2) after marrow engraftment, and (3) 6 weeks after trial 2. After trial 2, the patients were randomized in a control group (CG) or treatment group (TG), which received a 6-week exercise program with active exercise, muscle stretching and treadmill walking. The results obtained in trial 1 showed similar values for CG and TG, as both groups had muscle strength lower than normal patterns based on data concerning age, sex and weight. In trial 2, CG and TG showed similarly decreased values. In trial 3, TG showed values higher than CG for all muscle groups tested. These results suggest that the exercise program was efficient in promoting an increase of muscle strength after allogeneic BMT.

Adolescent↗
PubMed2000

Primary HIV-1 infection of human CD4+ T cells passaged into SCID mice leads to selection of chronically infected cells through a massive fas-mediated autocrine suicide of uninfected cells.

We have recently shown that a human CD4+ T cell line (CEM-SS) acquires the permissiveness to M-tropic strains and primary isolates of HIV-1 after transplantation into SCID mice. This permissiveness was associated with the acquisition of a memory (CD45RO+) phenotype as well as of a functional CCR5 coreceptor. In this study, we have used this model for invest-igating in vivo the relationships between HIV-1 infection, apoptosis and T cell differentiation. When an in vivo HIV-1 infection was performed, the CEM cell tumors grew to a lower extent than the uninfected controls. CEM cells explanted from uninfected SCID mice (ex vivo CEM) underwent a significant level of spontaneous apoptosis and proved to be CD45RO+, Fas+ and Fas-L+, while Bcl-2 expression was significantly reduced as compared to the parental cells. Acute HIV-1 infection markedly increased apoptosis of uninfected ex vivo CEM cells, through a Fas/Fas-L-mediated autocrine suicide/fratricide, while parental cells did not undergo apoptosis following viral infection. The susceptibility to apoptosis of ex vivo CEM cells infected with the NSI strain of HIV-1, was progressively lost during culture, in parallel with the loss of Fas-L and marked changes in the Bcl-2 cellular distribution. On the whole, these results are strongly reminiscent of a series of events possibly occurring during HIV-1 infection. After an initial depletion of bystander CD4+ memory T cells during acute infection, latently or chronically infected CD4+ T lymphocytes are progressively selected and are protected against spontaneous apoptosis through the development of an efficient survival program. Studies with human cells passaged into SCID mice may offer new opportunities for an in vivo investigation of the mechanisms involved in HIV-1 infection and CD4+ T cell depletion.

Animals↗
PubMed2003

Control of apoptosis by p53.

The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. p53 apparently promotes apoptosis through transcription-dependent and -independent mechanisms that act in concert to ensure that the cell death program proceeds efficiently. Moreover, the apoptotic activity of p53 is tightly controlled, and is influenced by a series of quantitative and qualitative events that influence the outcome of p53 activation. Interestingly, other p53 family members can also promote apoptosis, either in parallel or in concert with p53. Although incomplete, our current understanding of p53 illustrates how apoptosis can be integrated into a larger tumor suppressor network controlled by different signals, environmental factors, and cell type. Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment.

Apoptosis↗
PubMed2006

Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation.

In order to analyse the relationships between regulation of apoptosis and homologous recombination (HR), we overexpressed proapoptotic Bax or only-BH3 Bid proteins or antiapoptotic Bcl-2 or Bcl-XL, in hamster CHO cells or in SV40-transformed human fibroblasts. We measured HR induced by gamma-rays, UVC or a specific double-strand cleavage targeted in the recombination substrate by the meganuclease I-SceI. We show here that the induction of both recombinant cells and recombinant colonies was impaired when expressing Bcl-2 family members, in hamster as well as in human cells. Moreover, the pro- as well as antiapoptotic Bcl-2 family members inhibited HR, independently of degradation of the RAD51 recombination protein and of their impact on apoptosis. These data reveal a mechanism of HR downregulation by potentially proapoptotic proteins, distinct from and parallel to degradation of recombination proteins, a situation that should also optimize the efficiency of programmed cell death.

Animals↗
PubMed1998

Effect of aerobic training on ventilatory muscle endurance of spinal cord injured men.

The functional consequences of ventilatory muscle impairment of spinal cord injured (SCI) subjects has been evaluated through spirometric and maximal respiratory pressure tests. Nevertheless, underlying functional abnormalities may be evident only under dynamic conditions, such as with a ventilatory muscle endurance test (VME). In order to evaluate the VME of thoracic SCI men and the effect of physical training on it we evaluated 12 SCI subjects (Group I) and 12 able-bodied controls (Group II). The subjects were submitted to clinical evaluation, spirometry, maximum voluntary ventilation in 12 s (MVV-12 sec) and a test of VME-the highest time of sustained ventilation at 70% of the maximum voluntary ventilation in isocapnic conditions (MVV-70% time). Gr. II was evaluated before and after an arm cranking aerobic training program (30 min/session, three times/week, 6 weeks) with training target heart rate corresponding to ventilatory anaerobic threshold. On the initial evaluation, Gr. I subjects presented a significantly reduced forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and MVV-12 sec when compared to controls (P < 0.05). Also, the VME was severely reduced in Group I (median, ranges; 1.15, 0.61-12.22) when compared to Group II (14.60, 1.20-15.00) - P < 0.001. When Gr. I subjects were separated by the level of lesion, the VME was lower in high injured (T1-T7) than intermediate (T8-T10) and low injured patients (T11-T12)-P < 0.05. After aerobic training, Group I subjects incremented significantly the FVC (P < 0.05) and the VME (P < 0.001), so that MVV-70% time values post-training were not different from the initial values of the Gr. II. In conclusion, (i) the VME of thoracic SCI men was severely reduced when compared to able-bodied controls; (ii) a 6-weeks arm cranking aerobic training program was efficient to normalize the VME of SCI subjects.

Adult↗
PubMed2006

Growing multiconfigurational potential energy surfaces with applications to X + H2 (X = C,N,O) reactions.

A previously developed method, based on a Shepard interpolation procedure to automatically construct a quantum mechanical potential energy surface (PES), is extended to the construction of multiple potential energy surfaces using multiconfigurational wave functions. These calculations are accomplished with the interface of the PES-building program, GROW, and the GAMESS suite of electronic structure programs. The efficient computation of multiconfigurational self-consistent field surfaces is illustrated with the C + H2, N + H2, and O + H2 reactions.

Journal Article↗
PubMed1998

Reaching the global minimum in docking simulations: a Monte Carlo energy minimization approach using Bezier splines.

The docking problem faces two major challenges: the global optimization of a multivariable function, such as the energy, and the ability to discriminate between true and false positive results, i.e., native from nonnative structures based on the input energy function. Among all energy evaluation tools, only a local energy-minimization method using an accurate enough potential function is able to discriminate between native and nonnative structures. To meet these requirements, a Monte Carlo with energy-minimization method has been incorporated into a new ECEPP/3 docking program. The efficiency of the simulation results from the use of an energy-grid technique based on Bezier splines and from a simplification of the receptor by switching on the energy of only important residues of the active site. Simulations of a thrombin-inhibitor complex show that the global minimum of the energy function was reached in every independent run within less than 3 min of time on an IBM RX 6000 computer. For comparison, 10 standard independent Monte Carlo simulations with 10(6) steps in each were carried out. Only three of them led to a conformation close to the x-ray structure. The latter simulations required an average of 24 min and about 10 hr with and without the grid, respectively. Another important result is that the Bezier spline technique not only speeds up the calculation by reducing the number of operations during the energy evaluation but also helps in reaching the global minimum by smoothing out the potential energy surface.

Animals↗
PubMed2006

First trimester Down syndrome screening: distribution of markers and comparison of assays for quantification of pregnancy-associated plasma protein-A.

OBJECTIVE: First trimester screening for fetal chromosomal disease is now possible using the maternal serological markers pregnancy-associated plasma protein-A (PAPP-A) and the free ss-form of human chorionic gonadotrophin (sshCG) in combination with the ultrasound marker nuchal translucency (NT) thickness. The availability of well-defined analytical methods and reference ranges for the involved parameters, and knowledge of the correlation between markers and clinical parameters, e.g. maternal weight, parity and age, are important for the design of efficient screening programs. MATERIAL AND METHODS: Women (n = 2702), with singleton pregnancies, participating in the Copenhagen First Trimester Screening Study had PAPP-A and sshCG values determined and NT measured at a gestational age of 11 to 14 weeks, as determined from crown rump length (CRL). The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and reference intervals established. Three methods for determination of PAPP-A, one manual in-house poly-monoclonal ELISA and two commercial semi-automatic double-monoclonal methods, i.e. PAPP-A for the AutoDelfia platform and PAPP-A for the Kryptor platform, were compared in 260 women. RESULTS: All markers had log-normally distributed MoMs. Gestational age independent reference intervals were established. Maternal weight should be included in risk algorithms. The semi-automated PAPP-A assays (AutoDelfia and Kryptor) gave similar values, mean difference 10.5 %, whereas the manual assay gave higher values, mean differences 50.4 % and 41.0 %, respectively, CONCLUSIONS: This calls for better standardization and a uniform quality control scheme that is focused on discriminatory ability rather than adherence to mean values from a large number of laboratories.

Biomarkers↗
PubMed1995

Handling Techniques: The Influence of Weight and Height for Experts and Novices.

The purpose of this study was to evaluate the influence of the weight of the load (12 kg, 22 kg) and of the height of the grasp (high: 126 cm; middle: 64 cm and 95 cm; low: 33 cm) on the handling techniques adopted by six experienced handlers and six novices having only limited handling experience during a free box-handling task. Each subject had to transfer two sets of 16 boxes from a platform to a four-wheel cart. The observations dealt with the position of the subject at the beginning of transfer and at deposit (position of the back, knees and feet, pelvic orientation, position of the hands), his way of moving during the transfer (position of the feet), and his way of positioning and moving the box during handling (tilt of the box, impulse given to the box, grip change). The results show that the weight and the height of grasp/deposit had an influence on the techniques adopted by expert handlers and novices. Some of these variations are common to both groups but many of them are not, such as the position of the knees, the grips and the position of the box. This study suggests that there is not one method that is suitable for all situations, and that expert handlers may have learned how to adjust their methods to the working environment. A better understanding of the experts' techniques could help in redesigning efficient training programs.

experienced handlers↗