Influence of the human blood serum on contractility and β-adrenoreactivity of the isolated human myocardium

Influence of adrenaline (10⁻⁹ to 10⁻⁴ g/ml) on the contraction amplitude caused by electrostimuli (1Hz, 5 ms, 25–30 V) and inotropic and adrenomodulation activities of blood serum of nonpregnant women (at dilutions of 1 : 10 000, 1 : 1000, 1 : 500, 1 : 100, 1 : 50, 1 : 10, and 1 : 5) have been studied. The study has been carried out on isolated myocardium strips of the right atrial auricle that were taken from 43 patients with ischemic illness of the heart and 9 patients with valvular heart diseases of various etiologies upon venous cannula insertion during an aortocoronary bypass. Direct dependence of the contraction amplitude on the cardiac output according to Teicholz has been found. This meant that strips of the right atrial auricle reflected the contractility of the left ventricle myocardium. Adrenaline has been shown to dose-dependently increase the amplitude of evoked contractions in the concentration interval from 10⁻⁷ to 10⁻⁶ g/ml and had no influence from 10⁻⁹ to 10⁻⁸ g/ml (dissociation constant, 2 × 10⁻⁷ g/ml), which proved a decrease in the β-adrenoreceptor’s (β-AR) activation. Blood serum in a dilution range from 1 : 10 000 to 1 : 50 had no effect on the contraction amplitude, but an enhanced effect has been found in a dilution range from 1 : 10 and 1 : 5. The presence of the endogenous activator of myocytes contractility (EAMC) has explained this enhanced effect. The β-adrenomodulation activity of blood serum has been explained by the presence of the endogenous sensitizer of β-AR (ESBAR) and the endogenous blocker of β-AR (EBBAR). The ESBAR activity of blood serum (dilutions: 1 : 1000, 1 : 500, 1 : 100, and 1 : 50) has been found in experiments with a subthreshold adrenaline concentration (10⁻⁸ g/ml). ESBAR (dilutions: 1 : 50 and 1 : 10) and EBBAR (dilution 1 : 500) activities of blood serum have been found in experiments with the maximum effective concentration of adrenaline (10⁻⁶ g/ml). Therefore, blood serum endogenous modulators of β-adrenergic reactivity, ESBAR and EBBAR, can modulate the activation of β-AR of human cardiomyocytes. These prove the prospects of the ESBAR analogue application in cardiology.     

Beyond the frog: the evolution of homology models of human IKKβ

Nuclear Factor κ B is implicated in tumor progression and chronic inflammatory diseases and is regulated by IκB kinase β (IKKβ). The crystal structure of IKKβ has been recently solved for Xenopus laevis. Homology models of human IKKβ have been developed prior to and after the crystal structure was solved. Here, we compare four models of human IKKβ and evaluate their performance in both broad and focused library docking studies.     

Origin of the multiple components of human α1-antitrypsin

Multiple components of human ₁-antitrypsin were separated by preparative starch gel electrophoresis, and the sialic acid contents of these components were determined. The acidic components contained more sialic acid per molecule than the basic components. The molecular sizes of these components were identical, excluding the possibility of polymerization of the inhibitor in the formation of the multiple components. Consequently, the multiple components of the inhibitor are primarily due to differences in the sialic acid content of each component. Three major components contain eight, seven, and six sialic acid residues per molecule, respectively.This work was supported by Grant HL-17535 from the National Institutes of Health.     

Are human beings part of the rest of nature?

Unified explanations seek to situate the traits of human beings in a causal framework that also explains the trait values found in nonhuman species. Disunified explanations claim that the traits of human beings are due to causal processes not at work in the rest of nature. This paper outlines a methodology for testing hypotheses of these two types. Implications are drawn concerning evolutionary psychology, adaptationism, and anti-adaptationism. This revised version was published online in July 2006 with corrections to the Cover Date.     

Determination of the structure of the carbohydrate chains of acid α-glucosidase from human placenta

Acid α-glucosidase (α-d-glucoside glucohydrolase, EC 3.2.1.20) from human placenta (70 and 76 kDa) was found to contain 4 N-glycosidic carbohydrate chains per molecule. Sugar analysis of purified enzyme revealed the presence of mannose, N-acetylglucosamine and fucose at a molar ratio of 5.0:2.0:0.6. In addition, trace amounts of galactose and N-acetylneuraminic acid were detected. The sugar chains were liberated from the polypeptides by the hydrazinolysis procedure and subsequently fractionated by gel filtration and HPLC. Purified compounds were investigated by 500-MHz ¹H-NMR spectroscopy. Oligomannoside-type chains of intermediate size, e.g., Man₅GlcNAcGlcNAc-ol and Man₇GlcNAcGlcNAc-ol, and N-type chains of smaller size e.g., Man_2–3GlcNAc[Fuc]_0–1GlcNAc-ol, were demonstrated to be present at a ratio of 2:3. In addition, a small amount of sialylated N-acetyllactosamine-type chains has been found. The possible biosynthetic route of the fucose-containing small-size chains is discussed.     

Structural organisation of the gene encoding the α-subunit of the human amiloride-sensitive epithelial sodium channel

The human amiloride-sensitive epithelial sodium channel (ENaC) is a member of the degenerin/ENaC family of ion channels and regulates fluid and electrolyte absorption across a number of epithelia, including kidney, colon and lung. Native ENaC has been shown to be a multimer made up of at least three homologous subunits (α, β, γ) and mutations affecting the channel complex have been identified in various human diseases. “Gain of function” mutations in one of the three ENaC subunits have been found to cause pseudoaldosteronism (Liddle’s syndrome) and ENaC “reduction of function” mutations are found in patients affected with the recessive form of pseudohypoaldosteronism (PHA) type 1. In this report, we describe the genomic organisation of the humanαENaC gene. Human αENaC consists of 13 exons spanning 17 kb on chromosome 12p13 and contains at least eight Alu sequences. In addition to the intron/exon boundaries, we have deciphered almost all the intron sequences and 475 bp of the CCAAT-less and TATA-less 5′ flanking region. Received: 23 December 1997 / Accepted: 5 March 1998     

Characterization of auto-regulation of the human cardiac α1 subunit of the L-type calcium channel: Importance of the C-terminus

The carboxyl terminal of the L-type calcium channel _1C subunit comprises approximately one third of the primary structure of the ₁ subunit (> 700 amino acids residues). This region is sensitive to limited posttranslational processing. In heart and brain the _1C subunits are found to be truncated but the C-terminal domain remains functionally present. Based on our previous data we hypothesized that the distal C-terminus (approximately residues 1650–1950) harbors an important, predominantly inhibitory domain. We generated C-terminal-truncated _1C mutants, and after expressing them in combination with a ₃ subunit in HEK-293 cells, electrophysiological experiments were carried out. In order to dissect the important inhibitory part of the C-terminus, trypsin was dialyzed into the cells. The data provide evidence that there are multiple residues within the inhibitory domain that are crucial to the inhibitory process as well as to the enhancement of expressed current by intracellular application of proteases. In addition, the expression of the chimeric mutant _1C1673-DRK₁ demonstrated that the C-terminal is specific for the heart channel.     

Ukhtomski? and the nature of the human "ego"]

A. Ukhtomski? is one of those Russian naturalists of the beginning of the 20th century (K. Tsiolkovski?, V. Vernadski?, K. Timiriazev, I. Pavlov), whose scientific work is characterized by a combination of the valuable contribution to a specific field of science and deep philosophical conceptualizations. Ukhtomski? enriched modern neurophysiology by the ideas on dominant--a stable focus of enhanced excitability, determining the organism reactions to the environmental stimuli. Unlike artificial experimental models, natural dominant--vector of the goal-directed behaviour--represents the needs of immediate satisfaction, dominating at the present moment. Formation of needs hierarchy, characteristic of the given personality, occurs during the process of people communication. Namely, another man serves to the subject a mirror, looking into which he realizes himself as a human being (K. Marx). By his teaching on the dominant, Ukhtomski? has revealed the dual nature of the personality's self-consciousness in the process of its perception of the surrounding people. He showed that involuntary projection of its dominating vital and social needs (motives, intentions) to the image of another man makes the latter only the "double" of the observer, which does not promote the development and enrichment of personality. Actually productive is only the perception which is motivated by the ideal need of learning another personality, sincere interest in him, what makes another person a "well-deserved colocutor", a source of new knowledge about people and himself. The ideas of Ukhtomski? on the nature of human "self" are close to ideological searchings of L. Tolsto? and F. Dostoevski?.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of the early stages of human γD-crystallin aggregation process

Cataract, a major cause of visual impairment worldwide, is a common disease of the eye lens related to protein aggregation. Several factors including the exposure of ultraviolet irradiation and possibly acidic condition may induce the unfolding and subsequent aggregation of the crystallin proteins leading to crystalline lens opacification. Human γD-crystallin (HγDC), a 173 residue monomeric protein, abundant in the nucleus of the human eye lens, has been shown to aggregate and form amyloid fibrils under acidic conditions and that this aggregation route is thought to be a potential initiation pathway for the onset of age-related nuclear cataract. However, the underlying mechanism of fibril formation remains elusive. This report is aimed at examining the structural changes and possible amyloid fibril formation pathway of HγDC using molecular dynamics and molecular docking simulations. Our findings demonstrated that incubation of HγDC under the acidic condition redistributes the protein surface charges and affects the protein interaction with its surrounding solvent environment. This brings about a twist motion in the overall tertiary structure that gives rise to newly formed anti-parallel β-strands in the C-terminal flexible loop regions. The change in protein structural conformation also involves an alteration in specific salt-bridge interactions. Altogether, these findings revealed a plausible mechanism for amyloid fibril formation of HγDC that is important to the early stages of HγDC aggregation involved in cataractogenesis.     

Does the occurrence of Harris lines affect the morphology of human long bones?

The purpose of the study is to check the relationship between the occurrence of Harris lines and the morphological differentiation of the long bones of the human skeleton as an indicator of living conditions. The bone material (233 adult individuals, including 120 males and 113 females) was collected at a mediaeval burial ground in Cedynia, Poland. Recommended methods were applied to estimate the sex and age of the individuals (Ferembach et al 1979; Buikstra & Ubelaker 1994). The results obtained indicate that there is no clear relationship between metric characteristics of the studied long bones and the occurrence of Harris lines. Adverse environmental factors, which triggered the occurrence of Harris lines did not strongly affect the growth of long bones and did not change their morphology. Regardless of the phase of ontogenetic development in which the arrested growth lines (HL) formed, no effect of this fact on the final length of bones was observed. Similarly, no statistically significant differences were found in the proportions of bones between individuals reacting to adverse living conditions with the formation of Harris lines and those, whose bones were free of Harris lines. One may assume that Harris lines are of significance in epidemiological research and when assessing the general health profile of a population, but they are less useful in research on morphological reactions of individuals to living conditions.     

Morphology of the “spindle-shaped body” in the developing tail of human spermatids

Summary At the beginning of the late cap phase of the normal differentiation of human spermatids, a unique structure, the spindle shaped body, occupies part of the future middlepiece. This spindle-shaped body was followed throughout its development, and its functional relationship to the formation of the fibrous sheath is discussed. The spindle-shaped body disappears when the fibrous sheath is completed and the annulus moves down, giving rise to the middle-piece.Supported by Grants from the Deutsche Forschungsgemeinschaft.     

Molecular cloning of the Ig-α subunit of the human B-cell antigen receptor complex

The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number M74721.     

The primary structure of the human ϵ-globin gene

We describe the complete nucleotide sequence of the human ?-globin gene including 387 nucleotides of 5′ flanking sequence and 301 nucleotides of 3′ flanking sequence. The arrangement of coding, noncoding and intervening sequences in this gene is entirely consistent with its identification as the embryonic β-like globin gene.     

Role of A-chain in functioning of the active site of human α-thrombin

This review summarizes current data suggesting that A-chain of the human alpha-thrombin molecule plays a role of allosteric effector in catalytic reactions with various substrates. Special attention is paid to the relationship between A-chain structure and catalytic activity of thrombin. The existence of this relationship is based on studies of natural mutation of A-chain of the alpha-thrombin molecule. Use of molecular and essential dynamics confirmed the role of A-chain in changes of conformation and catalytic properties of this enzyme; these changes involve residues located in the specificity sites and some inserting loops. Current knowledge on structure and properties of thrombin can be used for the development of new antithrombin agents.     

Nucleotide sequence of the humanθ 1-globin gene

We have cloned and sequenced the human ₁-globin gene. The nucleotide sequence and organization of the human ₁ gene (exons, introns, promoter, and polyadenylation signals) are similar to those reported for the orangutan ₁-globin gene. If these genes are functional, the sequences of their ₁-globin chains would differ by only one amino acid residue (at position 137).This research was supported by USPHS Research Grants HLB-05168 and HLB-15158. This is contribution No. 1085 from the Department of Cell and Molecular Biology at the Medical College of Georgia in Augusta.