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Appendicular robusticity and the paleobiology of modern human emergence.

The emergence of modern humans in the Late Pleistocene, whatever its phylogenetic history, was characterized by a series of behaviorally important shifts reflected in aspects of human hard tissue biology and the archeological record. To elucidate these shifts further, diaphyseal cross-sectional morphology was analyzed by using cross-sectional areas and second moments of area of the mid-distal humerus and midshaft femur. The humeral diaphysis indicates a gradual reduction in habitual load levels from Eurasian late archaic, to Early Upper Paleolithic early modern, to Middle Upper Paleolithic early modern hominids, with the Levantine Middle Paleolithic early modern humans being a gracile anomalous outlier. The femoral diaphysis, once variation in ecogeographically patterned body proportions is taken into account, indicates no changes across the pre-30,000 years B.P. samples in habitual locomotor load levels, followed by a modest decrease through the Middle Upper Paleolithic.

Biological Evolution↗

Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells.

Skeletal formation is a fundamental element of body patterning and is strictly regulated both temporally and spatially by a variety of molecules. Among these, retinoic acid (RA) has been shown to be involved in normal skeletal development. However, its pleiotropic effects have caused difficulty in identifying its crucial target cells and molecular mechanisms for each effect. Development of cartilage primordia is an important process in defining the skeletal structures. To address the role of RA in skeletal formation, we have generated mice expressing a dominant-negative retinoic acid receptor (RAR) in chondrogenic cells by using the type II collagen alpha1 promoter, and we have analyzed their phenotypes. These mice exhibited small cartilage primordia during development and retarded skeletal formation in both embryonic and postnatal periods. They also showed selective degeneration in their cervical vertebrae combined with homeotic transformations, but not in their extremities. The cervical phenotypes are reminiscent of phenotypes involving homeobox genes. We found that the expression of Hoxa-4 was indeed reduced in the cartilage primordia of cervical vertebrae of embryonic day 12.5 embryos. These observations demonstrate that endogenous RA acts directly on chondrogenic cells to promote skeletal growth in both embryonic and growing periods, and it regulates the proper formation of cervical vertebrae. Furthermore, RA apparently specifies the identities of the cervical vertebrae through the regulation of homeobox genes in the chondrogenic cells. Great similarities of the phenotypes between our mice and reported RAR knockout mice revealed that chondrogenic cells are a principal RA target during complex cascades of skeletal development.

Animals↗

Ethnic differences in behavioural risk factors for stroke: implications for health promotion.

OBJECTIVES: Ethnic minority groups are at a higher risk of stroke and heart disease. However, designing effective prevention strategies requires responding to the needs of different ethnic groups. The aims of this study were to estimate the prevalence of four behavioural risk factors (smoking, drinking, exercise and weight) for stroke among Black Caribbeans, Black Africans and Whites, and also to examined reported willingness to change these behaviours. DESIGN: A random sample of 311 Black Caribbean, 300 White, and 105 Black Africans aged 45-74 registered with 16 practices in south London were surveyed in 1995. Information was obtained on smoking, drinking and exercise patterns, body mass index and perceptions of being at risk of stroke, and willingness to change risk behaviour. RESULTS: White respondents (31% age and sex standardised prevalence) were more likely to smoke than Black Caribbeans (23%) and Black Africans (10%) (p < 0.001). Self reported rates of drinking were higher than the government's 'sensible drinking levels' for 19% of Whites, 11% of Black Caribbeans and 4% Black Africans (p < 0.001). In contrast, fewer Whites (51%) were overweight (BMI > 27) than Black Caribbeans (60%) and Black Africans (68%) (p = 0.001). A high proportion of smokers wished to give up (89% Black African; 83% Black Caribbean; 74% White). A higher proportion of Black Caribbeans (35%) reported a willingness to reduce their alcohol intake compared to only 15% of Whites (p = 0.040). There was a difference between groups in attitudes to weight reduction with 69% Black Caribbean women expressing a desire to be thinner compared to 86% Whites and 82% Black Africans (p = 0.051). CONCLUSION: Strategies to reduce behavioural risk factors for heart attack and stroke need to emphasise different risk foctors among ethnic groups, especially in relation to alcohol use in the White population and weight in the Black Caribbean population. Influencing the change of these behaviours requires working in partnership with local community' groups.

Africa↗

Morphogenesis and tissue engineering of bone and cartilage: inductive signals, stem cells, and biomimetic biomaterials.

Morphogenesis is the developmental cascade of pattern formation, body plan establishment, and the architecture of mirror-image bilateral symmetry of many structures and asymmetry of some, culminating in the adult form. Tissue engineering is the emerging discipline of design and construction of spare parts for the human body to restore function based on principles of molecular developmental biology and morphogenesis governed by bioengineering. The three key ingredients for both morphogenesis and tissue engineering are inductive signals, responding stem cells, and the extracellular matrix. Among the many tissues in the human body, bone has considerable powers for regeneration and is a prototype model for tissue engineering based on morphogenesis. Implantation of demineralized bone matrix into subcutaneous sites results in local bone induction. This model mimics sequential limb morphogenesis and permitted the isolation of bone morphogens. Although it is traditional to study morphogenetic signals in embryos, bone morphogenetic proteins (BMPs), the inductive signals for bone, were isolated from demineralized bone matrix from adults. BMPs and related cartilage-derived morphogenetic proteins (CDMPs) initiate, promote, and maintain chondrogenesis and osteogenesis and have actions beyond bone. The symbiosis of bone inductive and conductive strategies are critical for tissue engineering, and is in turn governed by the context and biomechanics. The context is the microenvironment, consisting of extracellular matrix, which can be duplicated by biomimetic biomaterials such as collagens, hydroxyapatite, proteoglycans, and cell adhesion proteins including fibronectins. Thus, the rules of architecture for tissue engineering are an imitation of the laws of developmental biology and morphogenesis, and thus may be universal for all tissues, including bones and joints.

Adult↗

Quality of life studies and genito-urinary tumors.

BACKGROUND: Genitourinary (GU) tumors represent a large proportion of solid cancers (1 of 4) and a wide variety of natural histories, based on various prognostic factors and resulting in different treatment options and end points. In some cases, for the same stage of disease, different treatment strategies do not impact differently on overall survival (OS): surgery vs. radiation, or radical vs. conservative multidisciplinary approach, adjuvant or neoadjuvant, chemotherapy vs. BSC. Quality of life (QoL) is considered a reasonable end point when differences in OS do not seem to be striking. DESIGN: A review of the literature on different disease stages was undertaken to show where and when QoL was used as the end point of treatment efficacy. RESULTS: Very few studies have been performed in prostate, bladder and testicular cancer to show the impact of different treatment approaches on QoL. Although these studies might be considered as non-conclusive, some data may allow a better choice for the patients. CONCLUSIONS: QoL as the principal end point has not been used in clinical trials of GU tumors comparing different treatment approaches. This makes the choice between treatments offering similar survival but different toxicity patterns, body and behavioral consequences more difficult. We suggest that future prospective randomized studies should be planned taking into account the QoL as the main end point.

Carcinoma, Renal Cell↗

The Arabidopsis gene MONOPTEROS encodes a transcription factor mediating embryo axis formation and vascular development.

The vascular tissues of flowering plants form networks of interconnected cells throughout the plant body. The molecular mechanisms directing the routes of vascular strands and ensuring tissue continuity within the vascular system are not known, but are likely to depend on general cues directing plant cell orientation along the apical-basal axis. Mutations in the Arabidopsis gene MONOPTEROS (MP) interfere with the formation of vascular strands at all stages and also with the initiation of the body axis in the early embryo. Here we report the isolation of the MP gene by positional cloning. The predicted protein product contains functional nuclear localization sequences and a DNA binding domain highly similar to a domain shown to bind to control elements of auxin inducible promoters. During embryogenesis, as well as organ development, MP is initially expressed in broad domains that become gradually confined towards the vascular tissues. These observations suggest that the MP gene has an early function in the establishment of vascular and body patterns in embryonic and post-embryonic development.

Amino Acid Sequence↗

Evolution of the hedgehog gene family.

Effective intercellular communication is an important feature in the development of multicellular organisms. Secreted hedgehog (hh) protein is essential for both long- and short-range cellular signaling required for body pattern formation in animals. In a molecular evolutionary study, we find that the vertebrate homologs of the Drosophila hh gene arose by two gene duplications: the first gave rise to Desert hh, whereas the second produced the Indian and Sonic hh genes. Both duplications occurred before the emergence of vertebrates and probably before the evolution of chordates. The amino-terminal fragment of the hh precursor, crucial in long- and short-range intercellular communication, evolves two to four times slower than the carboxyl-terminal fragment in both Drosophila hh and its vertebrate homologues, suggesting conservation of mechanism of hh action in animals. A majority of amino acid substitutions in the amino- and carboxyl-terminal fragments are conservative, but the carboxyl-terminal domain has undergone extensive insertion-deletion events while maintaining its autocleavage protease activity. Our results point to similarity of evolutionary constraints among sites of Drosophila and vertebrate hh homologs and suggest some future directions for understanding the role of hh genes in the evolution of developmental complexity in animals.

Amino Acid Sequence↗

A selective screen reveals discrete functional domains in Drosophila Nanos.

The Drosophila protein Nanos encodes an evolutionarily conserved protein with two zinc finger motifs. In the embryo, Nanos protein function is required for establishment of the anterior-posterior body pattern and for the migration of primordial germ cells. During oogenesis, Nanos protein is involved in the establishment and maintenance of germ-line stem cells and the differentiation of oocyte precursor cells. To establish proper embryonic patterning, Nanos acts as a translational regulator of hunchback RNA. Nanos' targets for germ cell migration and development are not known. Here, we describe a selective genetic screen aimed at isolating new nanos alleles. The molecular and genetic analysis of 68 new alleles has allowed us to identify amino acids critical for nanos function. This analysis shows that the CCHC motifs, which coordinate two metal ions, are essential for all known functions of Nanos protein. Furthermore, a region C-terminal to the zinc fingers seems to constitute a novel functional domain within the Nanos protein. This "tail region" of Nanos is required for abdomen formation and germ cell migration, but not for oogenesis.

Alleles↗

Anti-fibrillarin antibodies in systemic sclerosis.

OBJECTIVES: To investigate the nature and extent of organ involvement in anti-fibrillarin antibody (AFA)-positive patients within a UK systemic sclerosis (SSc) population. METHODS: We investigated 1026 consecutive patients with SSc. AFA was identified by the characteristic clumpy nucleolar and coilin body pattern of staining in interphase cells and staining of fibrillarin in metaphase cells by indirect immunofluorescence using HEp-2 cells. Identity of the 34-kDa fibrillarin protein was confirmed by immunoprecipitation from [(35)S]methionine-labelled HeLa cell extract. RESULTS: AFA was detected in 42 patients (4.1%) with early disease onset (mean age 36 yr). Sixteen (38%) patients had limited cutaneous (lcSSc) and 26 (62%) diffuse cutaneous SSc (dcSSc). All eight Afro-Caribbean patients with AFA had dcSSc whereas the Caucasians were equally divided between dcSSc and lcSSc. Within the dcSSc subgroup, 54% had myositis, 35% had pulmonary hypertension, 15% had cardiac involvement and 23% had renal involvement. CONCLUSIONS: AFA identifies young SSc patients with frequent internal organ involvement, especially pulmonary hypertension, myositis and renal disease. In contrast to previous reports, AFA was not restricted to dcSSc patients in Caucasians.

Adult↗

Physical characteristics of patients with herniated intervertebral lumbar discs.

In an attempt to determine whether certain physical characteristics discriminated between people with and without herniated intervertebral lumbar discs, volunteers (N = 40) who were diagnosed as having a herniated lumbar disc were compared to control subjects (N = 40) who had been randomly selected and matched by age and sex. All subjects completed a questionnaire to determine the history of their back injury and a description of their exercise behavior patterns. Body composition was estimated by hydrostatic weighing. Maximum oxygen consumption was predicted using the Astrand-Ryhming nomogram. Strength scores were determined from a battery of cable tensiometer tests. Dependent variables were analyzed using a multiple analysis of variance (MANOVA). Using discriminant analysis, as a post hoc test, predicted maximum oxygen consumption was shown to account for the difference between the groups (P less than .002). The control subjects' values were higher than the patients' values. Subjects' exercise history indicated no differences between the groups relative to the time period preceding the onset of injury (P greater than .05). The exercise activity of patients was significantly reduced after injury (P less than .001). An average of 87 days elapsed between the onset of injury to the date of fitness testing.

Adipose Tissue↗

Dynamic mimicry in an Indo-Malayan octopus.

During research dives in Indonesia (Sulawesi and Bali), we filmed a distinctive long-armed octopus, which is new to science. Diving over 24 h periods revealed that the 'mimic octopus' emerges during daylight hours to forage on sand substrates in full view of pelagic fish predators. We observed nine individuals of this species displaying a repertoire of postures and body patterns, several of which are clearly impersonations of venomous animals co-occurring in this habitat. This 'dynamic mimicry' avoids the genetic constraints that may limit the diversity of genetically polymorphic mimics but has the same effect of decreasing the frequency with which predators encounter particular mimics. Additionally, our observations suggest that the octopus makes decisions about the most appropriate form of mimicry to use, allowing it to enhance further the benefits of mimicking toxic models by employing mimicry according to the nature of perceived threats.

Animals↗

Transmission of ocular media in labrid fishes.

Wrasses (Labridae) are the second largest family of fishes on the Great Barrier Reef (after the Gobiidae) and, in terms of morphology and lifestyle, one of the most diverse. They occupy all zones of the reef from the very shallow reef flats to deep slopes, feeding on a variety of fauna. Many wrasses also have elaborately patterned bodies and reflect a range of colours from ultraviolet (UV) to far red. As a first step to investigating the visual system of these fishes we measured the transmission properties of the ocular media of 36 species from the Great Barrier Reef, Australia, and Hawaii, California and the Florida Keys, USA. Transmission measurements were made of whole eyes with a window cut into the back, and also of isolated lenses and corneas. Based on the transmission properties of the corneas the species could be split into two distinct groups within which the exact wavelength of the cut-off was variable. One group had visibly yellow corneas, while the corneas of the other group appeared clear to human observers. Five species had ocular media that transmitted wavelengths below 400 nm, making a perception of UV wavelengths for those species possible. Possible functional roles for the different filter types are discussed.

Animals↗

Translational repressor bruno plays multiple roles in development and is widely conserved.

oskar (osk) mRNA is tightly localized to the posterior pole of the Drosophila oocyte, where the subsequent expression of Osk protein directs abdomen and germ-line formation in the developing embryo. Misplaced expression of Osk protein leads to lethal body patterning defects. The Osk message is translationally repressed before and during the localization process, ensuring that Osk protein is only expressed after the mRNA has reached the posterior. An ovarian protein, Bruno (Bru), has been implicated as a translational repressor of osk mRNA. Here we report the isolation of a cDNA encoding Bru using a novel approach to the expression cloning of an RNA-binding protein, and the identification of previously described mutants in the arrest (aret)-locus as mutants in Bru. The mutant phenotype, along with the binding properties of the protein and its pattern of accumulation within the oocyte, indicate that Bru regulates multiple mRNAs involved in female and male gametogenesis as well as early in embryogenesis. Genetic experiments provide further evidence that Bru functions in the translational repression of osk. Intriguingly, we find that Bru interacts physically with Vasa (Vas), an RNA helicase that is a positive regulator of osk translation. Bru belongs to an evolutionarily conserved family of genes, suggesting that Bru-mediated translational regulation may be widespread. Models for the molecular mechanism of Bru function are discussed.

Amino Acid Sequence↗

Isolation of the Drosophila segmentation gene runt and analysis of its expression during embryogenesis.

runt is one of the genes required for establishment of the segmented body pattern of the Drosophila embryo. We have isolated DNA sequences containing this gene using P-element transposon tagging. Southern blot analyses of six different DNA rearrangements that are associated with runt mutations revealed a minimal region of 8.5-kb of DNA that was important for function. In germ line transformation experiments, a 14.5-kb segment of DNA that spanned this minimal region provided significant, although not full, levels of runt activity. The runt gene encoded a 2.6-kb poly(A)+ RNA that underwent a series of dynamic changes in its spatial and temporal patterns of accumulation during embryogenesis. The runt RNA was most abundant at the blastoderm stage when it showed the seven stripes of expression characteristic of other Drosophila pair-rule genes.

Animals↗

The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system.

Generation of the anterior-posterior body pattern in the Drosophila embryo requires the activity of the segmentation genes. The segmentation gene runt has been classified as one of the primary pair-rule genes because of the pivotal role it plays in regulating the expression of other pair-rule genes. Here, we present the structure of this gene and describe the pattern of runt protein expression during embryogenesis. The deduced protein sequence shows no obvious overall homology with any sequences in the data base. The absence of an identifiable transcription factor motif (e.g., homeo box, zinc finger, leucine zipper, or helix-loop-helix) makes runt different from the other early-acting segmentation proteins. A runt-specific polyclonal antibody was generated and used to demonstrate that the subcellular location of the protein is in the nucleus. Double-staining immunolocalization experiments were used to determine the overlap of the runt protein pattern with the patterns of the pair-rule genes hairy (h), even-skipped (eve), and fushi tarazu (ftz). We found that the patterns of runt and hairy are complementary. Their phasing is shifted anteriorly by two cell diameters with respect to the complementary eve and ftz patterns. Experiments with the runt antibody also indicated that the protein is present throughout embryogenesis and is expressed extensively in the developing central and peripheral nervous system.

Amino Acid Sequence↗

Pacing impedance variability in tined steroid eluting leads.

The aim of the study was to investigate pacing impedance (PI) behavior in ambulatory patients. Eighteen atrial and 18 ventricular tined steroid eluting leads with 1.2-mm2 and 5.6-mm2 electrodes were implanted in 20 patients. At 9-27 months after implantation PI was measured automatically by means of additional algorithms downloaded via telemetry links into implanted Thera pulse generators. PI was determined based on the voltage drop on the output capacitor during the 5 V-1 ms pacing impulse, at the programmable sampling rates from 1 second to 30 minutes. The study examined in particular: (1) PI trends and variations associated with different breathing patterns, body postures, provocative maneuvers, bike exercise, and during 24 hours; (2) impact of pacing rate and AV-delay on PI; (3) correlation between PI variability and pacing threshold, lead configuration, absolute PI value, age, gender, disease, and cardiac chamber. The most important findings were: (1) large PI variations of up to 450 omega were observed in properly functioning leads, (2) PI variability exhibited a weak negative correlation with pacing thresholds as if electrode positional stability was not a major factor underlying PI variations, (3) unipolar and bipolar PI variations were equivalent to each other (correlation factor = 0.93) implying that PI was mostly dependent on the circumstances around the lead tip.

Aged↗

Spatial control of the gap gene knirps in the Drosophila embryo by posterior morphogen system.

The gap genes of Drosophila are the first zygotic genes to respond to the maternal positional signals and establish the body pattern along the anterior-posterior axis. The gap gene knirps, required for patterning in the posterior region of the embryo, can be activated throughout the wild-type embryo and is normally repressed from the anterior and posterior sides. These results provide direct molecular evidence that the posterior morphogen system interacts in a fundamentally different manner than do hunchback and bicoid, which are responsible for anterior pattern formation.

Animals↗

BSF binds specifically to the bicoid mRNA 3' untranslated region and contributes to stabilization of bicoid mRNA.

The early stages of Drosophila melanogaster development rely extensively on posttranscriptional forms of gene regulation. Deployment of the anterior body patterning morphogen, the Bicoid protein, requires both localization and translational regulation of the maternal bicoid mRNA. Here we provide evidence that the bicoid mRNA is also selectively stabilized during oogenesis. We identify and isolate a protein, BSF, that binds specifically to IV/V RNA, a minimal form of the bicoid mRNA 3' untranslated region that supports a normal program of mRNA localization during oogenesis. Mutations that disrupt the BSF binding site in IV/V RNA or substantially reduce the level of BSF protein lead to reduction in IV/V RNA levels, indicating a role for BSF in RNA stabilization. The BSF protein is novel and lacks all of the characterized RNA binding motifs. However, BSF does include multiple copies of the PPR motif, whose function is unknown but appears in other proteins with roles in RNA metabolism.

Amino Acid Sequence↗