The value of decreasing the duration of the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 [treating 25% of symptomatic cases, reducing by 0.5 days, reproductive number (R₀) 3.5, and starting treatment when 15% of the population has been exposed] to 44.4 million SARS-CoV-2 cases (treating 75% of all infected cases, reducing by 3.5 days, R₀ 2.0). With R₀ 2.5, reducing the average infectious period duration by 0.5 days for 25% of symptomatic cases averted 1.4 million cases and 99,398 hospitalizations; increasing to 75% of symptomatic cases averted 2.8 million cases. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R₀ 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study quantifies the potential effects of reducing the SARS-CoV-2 infectious period duration.     

Eye and head movements to visual and auditory targets

Coordinated eye-head movements evoked by the presentation of visual, auditory and combined audio-visual targets were studied in 24 human subjects. At 60 deg located targets latencies of eye and head movements were shorter for auditory than for visual stimuli. Latencies were shorter for bisensory than for monosensory targets. The eye and head latencies were differently influenced by the modality of the stimulus when the eccentricity of the target was changed, but not by the variation of the stimulus duration. The different responses of the eye and the head depending on target modality and target eccentricity can be partially attributed to perceptual and central processing mechanisms, and are important to answer the question about the initial event in coordinated eye-head orientation.     

Islet amyloid polypeptide (IAPP) competes for two binding sites of CGRP.

Two distinct binding sites for [125I]human calcitonin gene-related peptide (hCGRP) were found in rat brain, skeletal muscle, and liver. Each tissue had a high affinity site with an average Kd of 46 pM and a low affinity site with an average Kd of 22 nM. Islet amyloid polypeptide (IAPP), which has N- and C-terminal sequence homology to CGRP and is produced by islet beta-cells, bound to both sites but had a potency closer to that of CGRP at the low affinity binding site. A C-terminal fragment of IAPP competed for [125I]hCGRP binding at the low affinity site with potency comparable to that of hIAPP. No specific binding to membrane preparations was found in experiments using [125I]rIAPP, which was iodinated at the C-terminal tyrosyl residue. These results suggest that some of the previously reported biological effects occurring at nM or microM concentrations of IAPP may be mediated by IAPP binding to low affinity CGRP receptors. This study further indicates that the C-terminal region of IAPP is important for binding to low affinity CGRP receptors, and suggests that C-terminal fragments of IAPP may be of biological importance.     

Quantitative autoradiographic analysis of [I]-human CGRP binding sites in the dorsal horn of rat following chronic constriction injury or dorsal rhizotomy

Quantitative receptor autoradiography was used to examine the binding of [¹²⁵I]-human CGRP in the dorsal horn of the L4 spinal segment of rats with a chronic constriction injury (CCI) of the sciatic nerve or unilateral dorsal rhizotomies of spinal segments L1–L6. At the times selected for study, we found no change in the amount of CGRP binding in any areas examined following CCI. In contrast, our results showed a temporally related increase in the amount of CGRP binding in areas within laminae I–II and in lateral lamina V of the dorsal horn ipsilateral to the rhizotomies. These results indicate that CGRP binding sites are regulated, most likely, by changes in the release of CGRP. Further, our results suggest that the release of CGRP from primary afferent neurons is unchanged in animals with a CCI.     

Synthesis and phosphorylation of cytoskeleton components in foetal,regenerating and adult normal rat hepatocytes during culture

Summary Detergent insoluble material (DIM) was prepared by gentle treatment with detergent from foetal, regenerating and adult normal rat hepatocytes cultured for various times. It retained to some degree the morphology of the cells. After incubation of intact cells with ³⁵S-methionine, most of the labelled DIM proteins were found to be components of the cytoskeleton. They included several cytokeratins, vimentin and actin. The synthesis rate varied with the age of animals and culture conditions. The high synthetic rate of vimentin in foetal and regenerating hepatocytes could be associated with cell proliferation. No correlation was found between cytokeratin synthesis and hepatocyte growth. Most of the cytoskeleton proteins could be phosphorylated in intact cells and in DIM from cultured hepatocytes. However the degree of phosphorylation of these proteins was not related to their synthetic rate. The decreased phosphorylation level in cultured adult rat hepatocytes could be related to the rapid loss of specific functions.     

Mucociliary interaction in vitro: effects of physiological and inflammatory stimuli

Mucociliary transport in the airways is governed by the interaction between ciliary activity and the depth and rheological properties of the liquids (mucus) covering the epithelial surface. A change in one of these parameters may not predict the direction and magnitude of a concomitant change in mucociliary transport. We therefore determined the effects of physiological (neurotransmitters) and pathological (inflammatory mediators) stimuli on ciliary beat frequency (CBF), surface liquid velocity (SLV), surface liquid depth (SLD), and viscoelasticity of mucus in pieces of sheep trachea (n = 5 for each treatment) mounted in a chamber such that the submucosal side was bathed with Krebs-Henseleit perfusate (KH) and the luminal side was exposed to conditioned air. SLV, SLD, and CBF were measured with a microscope provided with an electronic micrometer and strobe light. Apparent viscosity and shear elastic modulus were measured with a microcapillary method using mucus collected at the downstream end of the preparation. Control CBF, SLV, and SLD were 11.6 +/- 0.4 (SE) Hz, 91 +/- 8 micron/s, and 33 +/- 5 microns, respectively, at base line and did not change during KH perfusion for 100 min. Perfusion with both acetylcholine and epinephrine (10(-5) to 10(-3) M) produced concentration-dependent increases in mean CBF (maximum increases at 10(-3) M of 16 and 9%, P less than 0.05), whereas only acetylcholine increased mean SLV (+56% at 10(-3) M, P less than 0.05). Perfusion with platelet-activating factor (10(-7) to 10(-5) M) decreased both mean CBF and SLV in a dose-dependent fashion (-6 and -63% at 10(-5) M, P less than 0.05), whereas antigen perfusion (1:60 dilution) increased mean CBF (+10%, P less than 0.05) but decreased SLV (-47%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interfacial and micellar behavior of glucose lipid

Summary Glucose lipid of notable surfactant properties was produced by using hydrocarbon assimilating bacterium of the bacterial strain MM1. Its surface active properties were notable in spite of ,-hydrophilic and bulky molecule. The critical micelle concentration (cmc) was small (0.165 M); surface and interfacial tension for hexadecane at 0.1 % (pH 7.35) solution, 24.6 and 13.3 mN/m, respectively. The emulsifying action was excellent and comparable to those of rhamnolipids. The micelle has the outer radius. 28.5 Å and inner core, 6.7 Å on the basis of the concentric spherical shell model by means of the small angle X-ray solution scattering measurement.Dedicated to Professor Fritz Wagner on the occasion of his 65th birthday.     

Crystal structure and conformational analysis of ampullosporin A.

Ampullosporin A is a 15-mer peptaibol type polypeptide that induces pigment formation by the fungus Phoma destructiva, forms voltage-dependent ion channels in membranes and exhibits hypothermic effects in mice. The structure of ampullosporin A has been determined by x-ray crystallography. This is the first three-dimensional (3D) structure of the peptaibol subfamily SF6. From the N-terminus to residue 13 the molecule adopts an approximate right-handed alpha-helical geometry, whereas a less regular structure pattern with beta-turn characteristics is found in the C-terminus. Even though ampullosporin A does not contain a single proline or hydroxyproline it is significantly bent. It belongs to both the shortest and the most strongly bent peptaibol 3D structures. The straight structure part encompasses residues Ac-Trp(1)-Aib(10) and is thus less extended than the alpha-helical subunit. The 3D structure of ampullosporin A is discussed in relation to other experimentally determined peptaibol structures and in the context of its channel-forming properties. As a part of this comparison a novel bending analysis based on a 3D curvilinear axis describing the global structural characteristics has been proposed and applied to all 3D peptaibol structures. A sampling of 2500 conformations using different molecular dynamics protocols yields, for the complete ampullosporin A structure, an alpha-helix as the preferred conformation in vacuo with almost no bend. This indicates that solvent or crystal effects may be important for the experimentally observed peptide backbone bending characteristics of ampullosporin A.     

Hydroxylation of 4-methylphenylalanine by rat liver phenylalanine hydroxylase

Rat liver phenylalanine hydroxylase that has been activated with lysolecithin catalyzes the hydroxylation of 4-methylphenylalanine in the presence of a pterin cofactor. Two products, 4-hydroxymethylphenylalanine and 3-methyltyrosine, can be detected. The total amount of amino acids hydroxylated is equal to the amount of tetrahydropterin oxidized. Isotopic labeling studies with 18O2 and H2(18)O show that the hydroxyl groups of both products are derived from molecular oxygen and not from water. Results obtained with 2H-labeled substrates support the conclusion that these products are formed via different mechanistic pathways. Our previous investigations on substrate analogs, as well as the present results, indicate that a highly reactive oxygen-containing intermediate, such as an enzyme-bound iron-oxo compound, must be the hydroxylating species. Our present results could stimulate further discussion of the possibility that the reaction mechanism for the "NIH-shift" of the methyl group may not involve the spontaneous opening of an epoxide intermediate.