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History in the interpretation of the pattern of p49a,f TaqI RFLP Y-chromosome variation in Egypt: a consideration of multiple lines of evidence.

The possible factors involved in the generation of p49a,f TaqI Y-chromosome spatial diversity in Egypt were explored. The object was to consider explanations beyond those that emphasize gene flow mediated via military campaigns within the Nile corridor during the dynastic period. Current patterns of the most common variants (V, XI, and IV) have been suggested to be primarily related to Middle Kingdom and New Kingdom political actions in Nubia, including occasional settler colonization, and the conquest of Egypt by Kush (in upper Nubia, northern Sudan), thus initiating the Twenty-Fifth Dynasty. However, a synthesis of evidence from archaeology, historical linguistics, texts, distribution of haplotypes outside Egypt, and some demographic considerations lends greater support to the establishment, before the Middle Kingdom, of the observed distributions of the most prevalent haplotypes V, XI, and IV. It is suggested that the pattern of diversity for these variants in the Egyptian Nile Valley was largely the product of population events that occurred in the late Pleistocene to mid-Holocene through the First Dynasty, and was sustained by continuous smaller-scale bidirectional migrations/interactions. The higher frequency of V in Ethiopia than in Nubia or upper (southern) Egypt has to be taken into account in any discussion of variation in the Nile Valley.

Chromosomes, Human, Y↗

[The cribriform fossa of the sacrum. A source of abusive interpretation of osteolysis].

A number of X-ray pictures have been taken of a 29 years old man suffering from low back pains. The profile negative of these pictures imply an erosion on the forewall of the sacral canal, which is similar to a tumor destruction. The tomography refutes any bone destruction. On the contrary, it proves that there are some very deep riddled fossae of the sacrum, a frequent anatomic variant.

Adult↗

[Mathematical express interpretation of the results of biochemical typing for identification of representatives of Enterobacteriaceae].

With the aid of Ypapi-14A computer the authors studied the sets of biochemical tests to assess the differential significance of each of the tests in identification of representative of the Enterobactericeae family. The sequence of the tests under study in the order of interpriorty by the differential significance was determined. The test sets providing the best identification variants were demonstrated. Complete identification of enterobacteriae was possible in all the cases with the use of 6 to 9 tests.

Bacteriological Techniques↗

How to avoid spurious cluster validation? A methodological investigation on simulated and fMRI data.

This paper presents an evaluation of a common approach that has been considered as a promising option for exploratory fMRI data analyses. The approach includes two stages: creating from the data a sequence of partitions with increasing number of subsets (clustering) and selecting the one partition in this sequence that exhibits the clearest indications of an existing structure (cluster validation). In order to achieve that the selected partition is actually the best characterization of the data structure, previous studies were directed to find the most appropriate validity function(s). In our analysis protocol, we first optimize the sequence of partitions according to the given objective function. Our study showed that an insufficient optimization of the partition, for one or more numbers of clusters, can easily yield a spurious validation result which, in turn, may lead the analyst to a misleading interpretation of the fMRI experiment. However, a sufficient optimization, for each included number of clusters, provided the basis for a reliable, adequate characterization of the data Furthermore, it enabled an adequate evaluation of the validity functions. These findings were obtained independently for three clustering algorithms (representing the hard and fuzzy clustering variant) and three up-to-date cluster validity functions. The findings were derived from analyses of Gaussian clusters, simulated data sets that mimic typical fMRI response signals, andreal fMRI data. Based on our results we propose a number of options of how to configure improved clustering tools.

Algorithms↗

DNA synthesis during meiosis of eight-spored strains of Chlamydomonas reinhardi.

In strain 137F of Chlamydomonas reinhardi, the zygospores undergo one round of nuclear DNA replication followed by three divisions to produce octospores. The third division without replication has been interpreted by Sueoka et al. (1967, 1969) to mean that the gametes and vegetative cells have at least binemic chromosomes. We have repeated their experiments using the same strain. However, the meiotic products were inviable--unable to undergo postmeiotic vegetative growth, DNA replication or division. On the other hand, using a variant of strain 137C which also has three divisions during germination we have shown that meiosis is normal. Zygospores from this strain undergo two rounds of nuclear DNA replication prior to the formation of octospores. These meiotic products are viable and capable of postmeiotic vegetative growth, replication and division. Since the third division without DNA replication subsequent to the two meiotic divisions leads to inviable products, and the strain which has viable products after three divisions does not lack the additional replication, meiosis in Chlamydomonas reinhardi provides no evidence of a bineme chromosome structure.

Chlamydomonas↗

The effect on anterior column loading due to different vertebral augmentation techniques.

BACKGROUND: Vertebral compression fractures are a significant cause of morbidity amongst the elderly, resulting in pain, kyphosis, decreased mobility, and often depression. The two most popular operative treatments of compression wedge fractures are vertebroplasty and kyphoplasty, however, which method leads to restoration of normal spinal loading is unknown. METHODS: A cadaveric thoracolumbar spine model was fractured and then treated using one of two techniques: vertebroplasty or kyphoplasty. Three non-destructive loading regimes were applied to the intact, fractured and treated cases. Sub-adjacent nuclear pressure, used as a measure of anterior column loading, was determined for each experimental variant and loading case. FINDINGS: The data indicate that nuclear pressure was substantially reduced after the spine was fractured. These pressures were minimally increased after treatment, however, not to the level of the pre-fractured condition. In all loading cases, there were no significant differences between the two treatment types. INTERPRETATION: While our data show that both vertebroplasty and kyphoplasty allow the disc to generate higher nuclear pressures, neither treatment increased nucleus pulposus pressure above the level of the intact state. This directly relates to the clinical condition in that adjacent segment fractures sustained subsequent to either treatment is likely the result of overall disease progression, and not a direct result of the intervention.

Adult↗

Phenotypic-karyotypic localization of the human Rh-locus on chromosome 1.

Statistical evaluation of between homologue differences and cytogenetic banding techniques were utilized to identify a small but significant homologue difference in Alp. An inherited chromosome variant characterized by an apparent deletion of the region delimited by the band pia3 and the telomeric end (t1) of chromosome A1, with telomeric conservation, was found to be consistently present in 3 familial pedigree members who expressed the highly infrequent -D-blood group type (-D/-D-). The most likely interpretation is that both the difference in length and the difference in banding characteristics reflect a real difference in DNA content of these homologues.

Antigens↗

Complex evolution of a salmonid microsatellite locus and its consequences in inferring allelic divergence from size information.

Sequence analysis of 78 alleles of a microsatellite locus was resolved at various taxonomic levels among salmonid fishes to test for congruence between size and sequence information. Allelic variability of this locus involved changes in number of dinucleotide repeats as expected for microsatellite loci. However, additional mutational events involving large indels and base substitutions also occurred frequently among and within species. These caused the evolution of different imperfect microsatellite variants, from an ancestral perfect one, which was undetectable from allelic size information only. Alleles of the same length resulting from different mutational events were also observed among and within species. Altogether, these results revealed the incongruence between size and number of mutation events, implying that it may be imprecise to interpret mutational rates and relationships on the basis of size information alone in interspecific comparisons and, to a lesser extent, within species.

Alleles↗

Multimerization behaviour of single chain Fv variants for the tumour-binding antibody B72.3.

A systematic study has been performed on the relationship between linker length, relative orientation of variable domains, multimerization behaviour and antigen binding activity for single chain Fvs (scFvs) of the tumour-binding antibody B72.3. Thirteen scFv variants with linkers comprising up to six repeats of the motif Gly-Gly-Gly-Gly-Ser were studied. All these scFvs showed a tendency to form dimers or higher molecular weight species, and this tendency decreased with increasing linker length. The dimers and higher molecular weight forms may arise from head to tail intermolecular association of VH and VL domains. For each linker length, scFvs with the organization VL-linker-VH showed greater binding activity than those with the organization VH-linker-VL. In fact, for the latter organization only the variant with a 30 amino acid linker showed good binding activity, suggesting that (i) for B72.3 the C-terminus of VH or the N-terminus of VL makes a structural contribution to antigen binding, and (ii) shorter linkers interfere with this contribution. Antigen binding studies on scFvs should be interpreted with caution because of their tendency to multimerize. Such multimerization can be minimized by using linkers longer than those in common use.

Amino Acid Sequence↗

Analysis of the catalytic mechanism of a fungal lipase using computer-aided design and structural mutants.

Both an active enzyme conformation and stabilization of tetrahedral transition states are essential for the catalysis of ester bond hydrolysis by lipases. X-ray structural data and results from site-directed mutagenesis experiments with proteases have been used as a basis for predictions of amino acid residues likely to have key functions in lipases. The gene encoding a lipase from Rhizopus oryzae was cloned and expressed in Escherichia coli. Site-directed mutagenesis of this gene was used to test the validity of computer-aided predictions of the functional roles of specific amino acids in this enzyme. Examination of the kinetic constants of the Rhizopus oryzae lipase variants allowed us to identify amino acid residues which are directly involved in the catalytic reaction or which stabilize the active geometry of the enzyme. The combination of these results with molecular mechanics simulations, based on a homology-derived structural model, provided new information about structure-function relationships. The interpretation of the data is consistent with results obtained with other hydrolases, such as proteases.

Amino Acid Sequence↗

The antigenic structure of poliovirus.

We have solved the structure of the Mahoney strain of type 1 and the Sabin (attenuated vaccine) strain of type 3 poliovirus by X-ray crystallographic methods. By providing a three-dimensional framework for the interpretation of a wealth of experimental data, the structures have yielded insight into the architecture and assembly of the virus particle, have provided information regarding the entry of virus into susceptible cells, and defined the sites on the virus particle that are recognized by neutralizing monoclonal antibodies. Thus locating mutations in variants selected for resistance to neutralizing monoclonal antibodies has defined three antigenic sites of the surface of the virion, and provided clues as to the mechanisms by which viruses escape neutralization. Finally, comparison of the structures of the two strains, together with analysis of sequences of many poliovirus strains, have begun to define the structural changes associated with serotypic differences between polioviruses.

Antigens, Viral↗

Case report: asymmetrical development of the gyri recti presenting as a suprasellar mass: case report and description of six further cases.

Asymmetrical appearances of normal anatomical structures can sometimes mimic pathology. We present a case where asymmetry of the gyri recti was interpreted as a suprasellar mass on axial CT scanning. The true nature of the apparent abnormality was revealed by coronal magnetic resonance imaging (MRI). We also present six further cases where asymmetrical gyri recti were noted as incidental findings on coronal MRI scans. This is a common, but important, normal anatomical variant, which should not be mistaken for pathology.

Adult↗

A new, reliable, and simple-to-use method for the analysis of a population of values of a random variable using the Weibull probability distribution: application to acrylic bone cement fatigue results.

In cases where the Weibull probability distribution is being investigated as a possible fit to experimentally obtained results of a random variable (V), there is, currently, no accurate and reliable but simple-to-use method available for simultaneously (a) establishing if the fit is of the two- or three-parameter variant of the distribution, and/or (b) estimating the minimum value of the variable (V(0)), in cases where the three-parameter variant is shown to be applicable. In the present work, the details of such a method -- which uses a simple nonlinear regression analysis -- are presented, together with results of its use when applied to 4 sets of number-of-cycles-to-fracture results from fatigue tests, performed in our laboratory, using specimens fabricated from 3 different acrylic bone cement formulations. The key result of the method is that the two- or three-parameter variant of the probability distribution is applicable if the estimate of V(0) obtained is less than or greater than zero, respectively.

Algorithms↗

The importance of functional testing in the genetic assessment of Muir-Torre syndrome, a clinical subphenotype of HNPCC.

A majority of families with hereditary nonpolyposis colorectal cancer (HNPCC) are attributable to germline mutations in three DNA mismatch repair (MMR) genes, MLH1, MSH2 and MSH6. However, the clinical phenotype appears to reflect a complex interplay between the predisposing mutation and putative constitutional and somatic modifiers. Certain MMR gene mutations predispose to combined occurrence of cutaneous sebaceous gland neoplasms and visceral malignancies, which is known as Muir-Torre syndrome (MTS) and regarded as a phenotypic variant of HNPCC. The sebaceous tumors associated with MTS appear in many patients before visceral malignancies providing important predictability of HNPCC-related integral cancers in mutation carriers. Since most sebaceous skin tumors are, however, sporadic, the contribution of non-truncating mutations found in skin cancer patients is difficult to interpret and genetic assessment of MTS requires a functional test. Here, we studied the repair efficiency of the two MSH2 missense mutations, L187P and C697F, found in HNPCC families including a few mutation carriers with sebaceous skin tumors. Both mutations were completely deficient in an MMR assay, which together with tumor findings suggested their predisposing role in both internal and skin malignancies in the families.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

[Investigation of human papillomavirus, its types and variants].

Cervical cancer is one of the most common cancers in Lithuania. It is the fourth cancer in women according to the morbidity. The incidence rate of cervical cancer has been increasing in Lithuania since 1992. One of the important risk factor for cervical cancer is human papillomavirus (HPV) infection. The aim of this study is to compare the prevalence of human papillomavirus among cervical cancer patients and women with cervical intraepithelial lesions and healthy women, to determine its types and HPV 16 variants. Polymerase chain reaction and DNA sequencing were used for analysis of specimens taken from cervix uteri. Human papillomavirus was detected in 92.7% of cervical cancer patients and in 26.7% of control women (p<0.0001). It is important to notice that prevalence of HPV in women with high-grade squamous intraepithelial lesions was higher than in the control group. HPV 16 (55.8% in squamous cell carcinoma patients and 35.3% in cervical adenocarcinoma patients) and its European HPV 16 L83V variant were detected more frequently in cervical cancer patients. Studies on HPV, prevalence of its types and variants are very important for HPV based preventive strategies, especially for the vaccination.

Adenocarcinoma↗

Gene specific therapy for cardiac disease: the case of long QT syndrome.

Molecular genetics is progressively entering clinical practice. This new approach is modifying medical thinking as it becomes possible to diagnose diseases in their presymptomatic phase. It is therefore important for physicians to become acquainted with the "language" and the "methodology" of molecular biologists in order to balance opposite attitudes of the novice, i.e. skepticism and over-expectation, and to establish a fruitful interaction with the molecular diagnostic laboratories. Long QT syndrome is an inherited disease that few years ago was still called "idiopathic" as the underlying causes were unknown. Clinicians are now becoming aware that what was considered as one disease is actually the common phenotype of defects in at least five different LQT-related genes and that therefore clinical heterogeneity is likely to parallel genetic heterogeneity. The first steps have been undertaken to define the relative prevalence of the molecular variants of LQTS, to develop gene-specific therapy and to perform risk stratification based on the molecular defect. In this article, current knowledge of the molecular bases of LQTS is reviewed and criteria are proposed to help defining 1) when it is appropriate to attempt molecular diagnosis, 2) how to interpret results of the diagnostic laboratory and 3) how molecular diagnosis may affect patients management.

Genetic Counseling↗

[Superacute lethal liver necrosis in monkeys infected with highly pathogenic variants of enteroviruses (ECHO 11 and ECHO 19 viruses)].

The authors studied the phenomenon of superhigh virulence for monkeys of viruses ECHO 11 (E11) and ECHO 19 (E19) isolated in 1981-1991 in Russia and Tadzhikistan from children with acute enterovirus uveitis or severe enterovirus infection. In 21 morphologically examined animals after coma, macrofocal or total necrosis of hepatocytes in weak inflammation was seen as early as experiment day 1-6. Hepatic lesion interpreted as hepatosis underlies acute hepatic failure with lethal outcome. The most intensive reproduction of viruses E11 and E19 occurred in the liver. Changes in the kidneys, lungs, spleen, adrenals, CNS detected in many animals aggravated the disease, but were not the primary cause of death. The disease in monkey was similar by the main criteria to superacute lethal diseases (acute hepatic failure against massive hepatic necrosis, hemorrhagic syndrome) registered in outbreaks of E11 and E19-virus infection in children in the USA, Great Britain, Israel, Russia and Ukraine. Monkeys can be used as man-adequate model for study of enterovirus superacute lethal necrosis of the liver.

Animals↗

Analysis of the mouse proteome. (I) Brain proteins: separation by two-dimensional electrophoresis and identification by mass spectrometry and genetic variation.

The total protein of the mouse brain was fractionated into three fractions, supernatant, pellet extract and rest pellet suspension, by a procedure that avoids any loss of groups or classes of proteins. The supernatant proteins were resolved to a maximum by large-gel two-dimensional electrophoresis. Two-dimensional patterns from ten individual mice of the commonly used inbred strain C57BL/6 (species: Mus musculus) were prepared. The master pattern was subjected to densitometry, computer-assisted image analysis and treatment with our spot detection program. The resulting two-dimensional pattern, a standard pattern for mouse brain supernatant proteins, was divided into 40 squares, calibrated, and specified by providing each spot with a number. The complete pattern and each of the 40 squares are shown in our homepage (http://www.charite.de/ humangenetik). The standard pattern comprises 8767 protein spots. To identify the proteins known so far in the brain fraction investigated, a first set of 200 spots was analyzed by matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) after in-gel digestion. By screening protein databases 115 spots were identified; by extending the analysis to selected, genetically variant protein spots, 166 spots (including some spot series) were identified in total. This number was increased to 331 by adding protein spots identified indirectly by a genetic approach. By comparing the two-dimensional patterns from C57BL/6 mice with those of another mouse species (Mus spretus), more than 1000 genetically variant spots were detected. The genetic analysis allowed us to recognize spot families, i.e., protein spots that represent the same protein but that are post-translationally modified. If some members of the family were identified, the whole family was considered as being identified. Spot families were investigated in more detail, and interpreted as the result of protein modification or degradation. Genetic analysis led to the interesting finding that the size of spot families, i.e., the extent of modification or degradation of a protein, can be genetically determined. The investigation presented is a first step towards a systematic analysis of the proteome of the mouse. Proteome analysis was shown to become more efficient, and, at the same time, linked to the genome, by combining protein analytical and genetic methods.

Animals↗