Inhibition of HIV-1 by modification of a host membrane protease

While it is clear that CD4 Is the receptor for the gp120 envelopeprotein of HIV-1, substantial evidence suggests that other hostcell proteins are required for successful membrane fusion. Studieswere initiated to examine the potential for a protein receptorwhich has an elastase-like character to participate in fusionof HIV-1 with permissive host cells. A synthetic elastase inhibitorwas shown to significantly reduce HIV-1 infectivity when presentduring, but not after, the initial contact between virus andcells. A human T cell elastase-like membrane component was purifiedand shown to be lipid-associated. By competitive Inhibition,the purified protein was shown to bind gp160 within the HIV-1fusion domain. The binding parameters of whole T cell membraneextract, with a hydrophobic pentapeptide representative of thefusion domain, suggested an elastase-like protein is the single,secondary T cell receptor for HIV-1 (K = 1x10³ M^–1). Thepentapeptide interacted with porcine and human (epithelial andpolymorphonuclear leukocyte), but not murine, elastase isoforms,suggesting its participation In the permissiveness of host cellsto infection.     

Adenosine and adenine nucleotides are independently released from both the nerve terminals and the muscle fibres upon electrical stimulation of the innervated skeletal muscle of the frog

The independent release of adenosine and adenine nucleotides upon electrical stimulation was studied in the innervated sartorius muscle of the frog after blockade of the extracellular catabolism of adenosine monophosphate (AMP) through exo-AMP deaminase and ecto-5-nucleotidase. Nerve stimulation (30 min, 0.2Hz) induced the release of both adenosine (19±3 pmol) and adenine nucleotides (101±7 pmol). Experiments performed in the presence of tubocurarine (5 M) to prevent purine release due to nerve-evoked muscle twitching, or under direct stimulation of the muscle in low calcium solutions to prevent pre-synaptic release of purines, showed that there was an evoked release of adenosine and adenine nucleotides both from the nerve endings and from the twitching muscle fibres. Removal of ecto-5-nucleotidase inhibition shows that the catabolism of adenine nucleotides released during stimulation contributes in about 50% to the amount of endogenous extracellular adenosine. When only one of the enzymes catabolizing AMP (ecto-5-nucleotidase or exo-AMP deaminase) was inhibited, the evoked release of adenine nucleotides was undetectable, suggesting that each enzyme is able to catabolize all the AMP formed from adenine nucleotides released upon stimulation. It is concluded that the concentration of endogenous extracellular adenosine is under the control of the relative activities of exo-AMP deaminase and ecto-5-nucleotidase.Brief accounts of some of the results in this study have been published previously (refs. [6, 7]).     

Effect of amino acid derivatives of β-carboline-3-carboxylate on behavior in rats

Brain Research Institute, All-Union Mental Health Research Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR O. S. Adrianov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 5, pp. 586–587, May, 1989.     

Medikamentöse Therapie tachykarder Herzrhythmusstörungen

Zusammenfassung Tachykarde Herzrhythmusstörungen lassen sich im wesentlichen auf eine Störung der Erregungsbildung — Fokusgenese — oder der Erregungsleitung — begünstigend für eine Kreiserregung —, zurückführen. Antiarrhythmika wirken diesen beiden entscheidenden Störungen entgegen. Auf Grund ihrer Hauptwirkung auf das Aktionspotential isolierter Herzmuskelzellen in therapeutischen Dosen lassen sich die Antiarrhythmika in 4 Gruppen einteilen. Beim Menschen läßt die schwerpunktmäßige Beeinflussung der Erregungsleitung in den verschiedenen Anteilen des Erregungsleitungssystems Anwendungsschwerpunkte begründen und Nebenwirkungen voraussagen. Die Antiarrhythmikawirkung auf die elektrophysiologischen Vorgänge am kranken menschlichen Herzen sind bisher noch unzureichend untersucht, so daß für die klinische Therapie letztlich die Empirie, d.h. die systematische therapeutische Anwendung entscheidet. Für die wichtigsten Antiarrhythmika haben sich so bevorzugte Indikationen ergeben. Unter bestimmten Voraussetzungen ist in der Klinik aber auch eine pathogenetisch differenzierende Therapie möglich, wenn auf Grund der bekannten spezifischen Wirkung eines Antiarrhythmikums ein Rückschluß auf die Pathogenese möglich wird; so u.a. beim Ansprechen auf Kalziumantagonisten, Typ Verapamil, die offenbar spezifisch auf sogenannte slow response Aktionspotentiale wirken. Vorbestehende TU-Abnormitäten im EKG weisen auf eine inhomogene Repolarisation als prädisponierenden Faktor für ventrikuläre Tachykardien durch Kreiserregung hin. Beim akuten Herzinfarkt kommt es zu wechselnden elektrophysiologischen Voraussetzungen für die Entstehung von Herzrhythmusstörungen, die eine therapeutische Beeinflussung durch ein einziges Antiarrhythmikum unwahrscheinlich erscheinen lassen. In der Hospitalphase ist eine ausreichend dosierte prophylaktische Gabe von Lidokain sinnvoll, in der prähospitalen Phase ohne Überwachungsmöglichkeit jedoch von zweifelhaftem Wert. Die prophylaktische Gabe von Betarezeptorenblockern kann in der posthospitalen Nachbehandlungsphase das Risiko des plötzlichen Herztodes um 50% senken. Auch bei anderen Risikopatienten mit ventrikulären Herzrhythmusstörungen ist eine konsequente antiarrhythmische Behandlung notwendig.     

Investigations on integration of mossy fiber inputs to Purkyně cells in the anterior lobe

Summary The 275 Purkyn cells identified by the criteria of the previous paper have been investigated with respect to their role as units integrating the input to the anterior lobe from various limb nerves. The discharges from single Purkyn cells have been studied in lightly anesthetized (pentothal) or in decerebrate unanesthetized cats, there being averaging usually of 128 responses in the form of post-stimulus time histograms and cumulative frequency distributions.Single Purkyn cells exhibited a wide variation in their responses to the diverse inputs from the various afferent nerves. Attention was focussed on excitatory and inhibitory responses evoked by mossy fibers with a short latency, usually 10–15 msec for hindlimb afferents. With most Purkyn cells these responses were predominantly evoked from cutaneous nerves, low threshold fibers being particularly effective. A few Purkyn cells were preponderantly excited by afferent volleys from muscle nerves, but there was a large group with a mixed input from cutaneous and muscle nerves. Graded strengths of stimulation of muscle nerves showed that sometimes group I volleys were prepotent, but other Purkyn cells were selectively excited by group II volleys. Though sometimes the afferent volleys from antagonistic muscles had a reciprocal action on a Purkyn cell, as on a motoneurone, it was more common to find similar actions. Also convergence of inputs from forelimb and hindlirnb nerves, both cutaneous and muscular, was not uncommon, particularly in marginal areas between hindlimb and forelimb zones. A special design feature is the convergence onto a Purkyn cell of mossy fiber and climbing fiber inputs evoked by the same afferent volley. This convergence was of particular interest along the parasagittal strip of hindlimb climbing fiber distribution in lobule V.It was not possible to translate the observations into some map of the cerebellar cortex on which are marked the territorial distributions from the various limb afferent nerves. Rather, there was an ill-defined patchy character, closely adjacent Purkyn cells often receiving very different subsets of the total input from the various limb nerves. The unitary integrations accomplished by the individual Purkyn cells are further integrated when their axons converge onto and inhibit the neurones of the cerebellar nuclei, and this integration by convergence would occur in each successive relay on the output pathways from the cerebellum.It is pointed out that the experimental findings on the integrative action of the individual Purkyn cells provide basic information for attempts to construct models simulating cerebellar performance and control.Post-Doctoral Fellow NINDS (1F2NB40, 545101 NSRB).Post-Doctoral Fellow UHF Grant No. FTF-3-UB-70.     

Pigments of the Gastrointestinal Tract: A Comparison of Light Microscopic and Electron Microscopic Findings

It is now apparent that light microscopy and histochemistry failed to identify correctly the nature and composition of pigments in various gastrointestinal tract melanoses. In most instances it was thought that the pigment was melanin or a melanin-like substance. Electron microscopy (EM) and electron-probe energy dispersive x-ray analysis have rectified these errors and have shown the following: in melanosis coli the pigment granules contain lipofuscin; in melanoses ilei the pigment granules may contain either silicates and titanium or hemosiderin; and in melanosis duodeni the pigment granules contain iron sulfide. In melanosis esophagi it is not clear what the pigment is; it could be melanin or lipofuscin.     

Peripheral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-1β

Journal of Clinical Immunology - The objective of this study was to characterize interleukin-1 receptor antagonist (IL-1ra) and interleukin-1β (IL-1β) production by human peripheral blood...     

Primary sequence and functional expression of a novel β subunit of the P-ATPase gene family

The cortical collecting tubule (CCT) of the mammalian kidney reabsorbs sodium and potassium, processes that are mediated by Na/K-ATPase and H/K-ATPase. CCT is also an important site for proton secretion, which is driven, in part, by H/K-ATPase. Na/K-ATPase and H/K-ATPase are members of the ion-motive P-ATPase gene family. They are closely related plasma membrane proteins which consist of heterodimers. The urinary bladder of the toad Bufo marinus is the amphibian counterpart of mammalian CCT. We have previously characterized a ouabain-resistant Na/K-ATPase [see ref. 17], from TBM cells, a clonal cell line derived from the toad bladder, which expresses transepithelial sodium transport. In the present study, we report the primary sequence and functional expression of a novel subunit ( _bladder= _bl) isolated from a toad bladder epithelial cell cDNA library. The deduced polypeptide is 299 amino acids in length and has a predicted molecular mass of 33 kDa. The _bl protein exhibits 35% amino acid identity to the previously characterized ₁ of B. marinus Na/K-ATPase and 39% identity with ₃ of B. marinus Na/K-ATPase. It shares 38% identity with the mammalian gastric H/K-ATPase and 52% with the mammalian ₂ Na/K-ATPase. Northern blot analysis shows that a 1.4×10³-base mRNA is expressed at a high level in bladder epithelial cells and eye and at a trace level in kidney; it is not detectable in significant amounts in the stomach, colon and small intestine. The _bl subunit can associate with the ₁ subunit of B. marinus Na/K-ATPase to form a functional sodium pump in the Xenopus laevis oocyte. Our data indicate that, in addition to the known ₁ and ₃ isoforms, a third distinct isoform of the subunit is present in the bladder epithelium. This new isoform could be functionally associated with subunits of either Na/K- or H/K-ATPase.