Anchoring the Late Devonian mass extinction in absolute time by integrating climatic controls and radio-isotopic dating.

The Devonian Frasnian-Famennian (F-F) boundary marks one of the five main extinction intervals of the Phanerozoic Aeon. This time was characterized by two pulses of oceanic anoxia, named the Lower and Upper Kellwasser events, during which massive marine biodiversity losses occurred. This paper presents high-resolution magnetic susceptibility, X-ray fluorescence elemental geochemistry and carbon isotope datasets obtained from the Steinbruch Schmidt F-F boundary section (Germany). These records lead to an astronomical time calibration of the environmental changes associated with the two ocean anoxia pulses. Cyclostratigraphic interpretation indicates deposition of the black argillaceous Lower and Upper Kellwasser horizons over ~ 90 and ~ 110 kyr, respectively; approximately equivalent to the duration of one short eccentricity cycle. This study confirms that the succession of events within the Upper Kellwasser event is paced by obliquity, under a low-eccentricity orbit. Hence, astronomical insolation forcing likely contributed to the expansion of ocean anoxia and other environmental perturbations associated with these two crises. The new floating chronology established for the Steinbruch Schmidt section is anchored in numerical time by means of a radio-isotopic date, obtained from a bentonite layer interbedded between the two Kellwasser horizons. After anchoring, this time scale gives a high-precision age of 371.870 ± 0.108 Ma for the F-F boundary.

Precisely dating the Frasnian-Famennian boundary: implications for the cause of the Late Devonian mass extinction.

The Frasnian-Famennian boundary records one of the most catastrophic mass extinctions of the Phanerozoic Eon. Several possible causes for this extinction have been suggested, including extra-terrestrial impacts and large-scale volcanism. However, linking the extinction with these potential causes is hindered by the lack of precise dating of either the extinction or volcanic/impact events. In this study, a bentonite layer in uppermost-Frasnian sediments from Steinbruch Schmidt (Germany) is re-analysed using CA-ID-TIMS U-Pb zircon geochronology in order to constrain the date of the Frasnian-Famennian extinction. A new age of 372.36 ± 0.053 Ma is determined for this bentonite, confirming a date no older than 372.4 Ma for the Frasnian-Famennian boundary, which can be further constrained to 371.93-371.78 Ma using a pre-existing Late Devonian age model. This age is consistent with previous dates, but is significantly more precise. When compared with published ages of the Siljan impact crater and basalts produced by large-scale volcanism, there is no apparent correlation between the extinction and either phenomenon, not clearly supporting them as a direct cause for the Frasnian-Famennian event. This result highlights an urgent need for further Late Devonian geochronological and chemostratigraphic work to better understand the cause(s) of this extinction.

Conserved and variable residues within the Bw4 motif of HLA-B make separable contributions to recognition by the NKB1 killer cell-inhibitory receptor.

Allotypes from four divergent HLA-B families (B8, B15, B16, and B27) were compared for their inhibition of cytolysis by NK cells expressing the NKB1 receptor. Allotypes differing solely at the Bw4/Bw6 region were examined as were a more divergent subset of B15 allotypes. The capacity to interact with NKB1 correlated precisely with possession of a Bw4 sequence motif at residues 77-83, whereas no correlation was made with the peptide-binding specificities of two Bw4 and four Bw6 allotypes of the B15 family. HLA-B allotypes having four different Bw4 motifs were examined and all interact with NKB1. In contrast, HLA-A allotypes, which have a Bw4 motif identical with one of those present in HLA-B, do not. Mutation at leucine 82 and arginine 83, the residues common to Bw4 motifs, shows they contribute to NKB1 interaction but are not essential. Three types of polymorphism are implicated in formation of the ligand recognized by NKB1: ones shared by Bw4 motifs; ones distinguishing Bw4 motifs; and ones outside the Bw4/Bw6 region that distinguish HLA-B from HLA-A.

HLA class I genotyping by cDNA sequence of a Vietnamese family expressing a weak B46 antigen.

Serological heterogeneity in HLA-B46 antigens has been described. Previous studies have identified B*4601 as the allele encoding the "strong" B46 antigen found in Chinese populations. Serological characterization of a Vietnamese family revealed a "weak" B46 antigen. Complementary DNA for the HLA-A, B and C alleles of three family members were cloned and the coding regions sequenced. The allele encoding the weak B46 antigen has the same coding sequence as B*4601, demonstrating that the antigenic differences are not due to polymorphism in the amino acid sequence of the HLA-B heavy chain. The recently described HLA-B*1525 and HLA-Cw*0403 alleles were also found to segregate in this Vietnamese family.

Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.

Previously, we reported overlap in the repertoires of peptides endogenously bound by a group of HLA-B allotypes related to HLA-B7. Extending such analysis to four members of the B17 family and seven members of the B15 family shows that allotypes that share sequence identity in the alpha 1 helix of the class I heavy chain possess markedly similar peptide-binding specificities. Members of the B17 family share a preference for peptides with serine, threonine, or alanine at position 2 and aromatic residues at the carboxyl terminus. Strikingly, the presence of a segment of the B17 alpha 1 helix in B*1516 and B*1517 confers the B17-like peptide-binding motif. The strong influence of natural variation in the alpha 1 helix is exemplified by the differences in peptide-binding specificity of B15 allotypes related by conversion events that replaced segments of the alpha 1 helix. In contrast, evolutionary changes that are confined to the alpha 2 domain confer less dramatic change. They do not perturb the primary anchors of the peptide-binding motif but can modulate the specificity through development and diversification of secondary anchors. Our results, in combination with those obtained previously for other HLA-B allotypes, suggest a general trend whereby polymorphism in the alpha 1 helix is the overriding influence on peptide-binding specificity of HLA-B allotypes, while amino acid substitutions in the alpha 2 domain play a more modulatory role.

Peptides bound endogenously by HLA-Cw*0304 expressed in LCL 721.221 cells include a peptide derived from HLA-E.

The peptide-binding specificity of HLA-Cw*0304 was determined. Sequence analysis of endogenously-bound peptides isolated from Cw*0304 expressed by LCL 721.221 (221 for short) cells transfected with Cw*0304 cDNA revealed this class I allotype preferentially binds peptides possessing alanine at position 2 and leucine or methionine at the C-terminus. One peptide isolated from Cw*0304 expressed by 221 cells has sequence identity to residues 116-126 of HLA-E. Expression of HLA-E by 221 cells was confirmed by isolation of mRNA transcripts for HLA-E*0101 and detection of beta 2-microglobulin (beta 2-m)-associated HLA-E protein.

The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C.

The vast majority of new human HLA class I alleles are formed by conversions between existing alleles of the same locus. A notable exception to this rule is HLA-B*4601 formed by replacement of residues 66-76 of the alpha 1 helix of B*1501 by the homologous segment of Cw*0102. This inter-locus recombination, which brings together characteristic elements of HLA-B and HLA-C structure, is shown here to influence function dramatically. Naturally processed peptides bound by B*4601 are distinct from those of its parental allotypes B*1501 and Cw*0102 and dominated by three high abundance peptides. Such increased peptide selectivity by B*4601 is unique among HLA-A,B,C allotypes. For other aspects of function, presence of the small segment of HLA-C-derived sequence in an otherwise HLA-B framework converts B*4601 to an HLA-C-like molecule. Alloreactive cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and cellular glycosidases all recognize B*4601 as though it were an HLA-C allotype. These unusual properties are those of an allotype which has frequencies as high as 20% in south east Asian populations and is associated with predisposition to autoimmune diseases and nasopharyngeal carcinoma.

Characterization of the peptide-binding specificity of HLA-B*7301.

Previous studies showed the human MHC class I heavy chain HLA-B*7301 has a sequence very divergent from other class I alleles. Despite the unusual sequence, we predicted B*7301 would retain the peptide-binding function typical of other HLA-A, B and C glycoproteins, and sequence similarity to B*2705 in a region of the peptide-binding site known as the B pocket suggested B*7301 would bind peptides with Arg at position 2. To test this hypothesis, the peptide-binding specificity of B*7301 was investigated. Sequence analysis of peptides bound endogenously by B*7301 indeed found selectivity for nonamer peptides possessing Arg at position 2 and a preference for small nonpolar residues such as Pro or Ala at the C terminus was also revealed. B*7301 therefore possesses the potential to function as a conventional antigen presenting class I glycoprotein. Functional similarities between B*7301 and B*2705 are discussed in the context of the association of B*27 subtypes with susceptibility to ankylosing sponylitis and arthritic diseases.

Unusual uniformity of the N-linked oligosaccharides of HLA-A, -B, and -C glycoproteins.

MHC class I glycoproteins possess an invariant site for N-linked oligosaccharide addition at position 86 of the heavy chain. For human HLA-A, -B, and -C class I glycoproteins, position 86 is the only site of N-linked glycosylation. Comparison of the size and relative abundance of oligosaccharides associated with nine HLA-A, -B, or -C allotypes isolated from EBV-transformed B cell lines and mixtures of HLA-A, -B, and -C allotypes isolated from pooled PBLs revealed a very restricted set of structures. Allotypes encoded by the HLA-A and -B loci have two predominant glycan structures that were almost exclusively di-sialylated. In contrast, HLA-C allotypes have four glycan structures, comprising those associated with HLA-A and -B and two additional glycans. Identical oligosaccharides were present on different allotypes of a class I HLA locus, and in particular, HLA-C allotypes defining two inhibitory specificities for NK cells were shown to possess the same set of oligosaccharides. The uniformity of oligosaccharide structure associated with different HLA-A, -B, and -C products and the relative lack of heterogeneity for any given allotype are unusual features for a mammalian glycoprotein. Particularly striking is that such conserved oligosaccharide structures juxtapose the major regions of amino acid sequence variation within the Ag recognition site, including the polymorphisms of the alpha 1 helix that determine the inhibitory ligands for human NK cells.

A case study of dermatitis based on a collaborative approach between occupational physicians and industrial hygienists.

An example of interdisciplinary problem solving by occupational health professionals is presented. Approximately one dozen employees in an aircraft wire harness assembly line complained of dermatitis, alleging workplace exposures as causation. The plant's and consulting industrial hygienists prepared toxicology and exposure assessments for all process materials, manufacturing procedures, and protective equipment used. They identified no common elements in the work environment that may have caused the dermatitis, suggesting multiple causation and possible individual worker sensitivities. An investigative team composed of the industrial hygienists and physicians in outside practice, including dermatologists and occupational medicine physicians, conducted a review of plant operations and proposed that workers with dermatitis complaints receive diagnostic medical examinations. An initial examination medically documented each worker's complaint, and a follow-up included patch testing for selected process materials. The physicians diagnosed a variety of mainly nonoccupationally induced illnesses such as fungal infections, skin cancer (solar induced), acne, etc., confirming the industrial hygienists' original assessment. One case appeared directly work-related and to be a specific assembly component sensitivity. Although several cases with a nonoccupational origin could have been aggravated by working conditions, these workers showed no sensitivity to the component when patch tested.

Overlap in the repertoires of peptides bound in vivo by a group of related class I HLA-B allotypes.

BACKGROUND: Polymorphism among class I molecules of the major histocompatibility complex (MHC) confers allotypic specificity on the peptides that these molecules bind and present to cytotoxic T lymphocytes. Evolution of new human HLA class I alleles usually involves gene recombination events that replace a segment of one allele with the homologous region of another. In this study, the impact of these evolutionary changes has been assessed by comparison of the peptide-binding specificities of six related HLA-B allotypes. RESULTS: Endogenous peptides bound by HLA-B*5401, HLA-B*5501, HLA-B*5502, HLA-B*5601, HLA-B*6701 and HLA-B*0702 were characterized. Despite differing by 1-9 of the amino-acid residues comprising their peptide-binding sites, all these allotypes share a dominant preference for peptides that have proline at position 2. Polymorphism results in differing selection of carboxy-terminal and secondary anchor residues, but the peptide-binding specificities are sufficiently similar that there is overlap in the repertoires of peptides bound by these allotypes. Complete sequence determination of individual peptides revealed four that could be isolated from two or more allotypes. Members of the closely related HLA-B22 family--HLA-B*5401, HLA-B*5501, HLA-B*5502 and HLA-B*5601--show only minor differences in their peptide-binding specificities. This marked similarity is reflected at the functional level, as alloreactive cytotoxic T lymphocytes generated against HLA-B*5401 and HLA-B*5501 exhibited cross-reactive recognition. CONCLUSION: The isolation of identical endogenously bound peptides from six HLA-B allotypes demonstrates overlap in the repertoires of peptides bound in vivo by different allotypes. We speculate that the shared preference for binding peptides with proline at position 2 reflects a selective pressure to retain this specificity, which may be based upon peptide availability in vivo. Characterization of the overlap between the repertoires of peptides bound by HLA-B allotypes could simplify the development of peptide-based vaccines that are targeted to cytotoxic T cells, as single peptides would be effective for humans of different HLA types.

Performance-based assessment of oculomotor efficiency.

Acquisition of visual information from spatial points disparate enough to necessitate head and eye movement involves the vestibular and other oculomotor control systems in shifting and stabilizing gaze relative to those points. In the present study, a simple procedure to test oculomotor abilities was developed and evaluated; it uses performance (serial letter identification) to maintain initial gaze position and performance (number of digits correctly identified) to measure the efficiency of gaze-shift control. Number of digits acquired from briefly displayed digit sets was consistently and powerfully influenced by exposure duration of digit sets and to a lesser extent by the size of required gaze shift. The performance of normal subjects in eye movement and head-and-eye movement conditions is predictable from static performance of normals. Results suggest that the procedure will be sensitive to certain types of central nervous system and vestibular pathology. Substantial individual differences in performance dependent upon gaze-shift control were found among normal subjects. If some pilots operate at the lower extremes of the performance distribution, they may be subject to critical response deficiencies in emergency conditions requiring large gaze shifts.

Fitness level and health status: an analysis.

Physicians and physiologists agree that ability to utilize oxygen during effort is the most reliable indication of physical fitness. This article describes the findings of a study done at the Fitness Institute in Toronto on individuals before and during a fitness program. Results are categorized in nine-year sections and the fitness level of any given age group can be determined.