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Molecular clocks do not support the Cambrian explosion.

The fossil record has long supported the view that most animal phyla originated during a brief period approximately 520 MYA known as the Cambrian explosion. However, molecular data analyses over the past 3 decades have found deeper divergences among animals (approximately 800 to 1,200 MYA), with and without the assumption of a global molecular clock. Recently, two studies have instead reported time estimates apparently consistent with the fossil record. Here, we demonstrate that methodological problems in these studies cast doubt on the accuracy and interpretations of the results obtained. In the study by Peterson et al., young time estimates were obtained because fossil calibrations were used as maximum limits rather than as minimum limits, and not because invertebrate calibrations were used. In the study by Aris-Brosou and Yang, young time estimates were obtained because of problems with rate models and other methods specific to the study, and not because Bayesian methods were used. This also led to many anomalous findings in their study, including a primate-rodent divergence at 320 MYA. With these results aside, molecular clocks continue to support a long period of animal evolution before the Cambrian explosion of fossils.

Animals↗

Prisoners of the proximate: loosening the constraints on epidemiology in an age of change.

"Modern epidemiology" has a primary orientation to the study of multiple risk factors for chronic noncommunicable diseases. If epidemiologists are to understand the determinants of population health in terms that extend beyond proximate, individual-level risk factors (and their biological mediators), they must learn to apply a social-ecologic systems perspective. The mind-set and methods of modern epidemiology entail the following four main constraints that limit engagement in issues of wider context: 1) a preoccupation with proximate risk factors; 2) a focus on individual-level versus population-level influences on health; 3) a typically modular (time-windowed) view of how individuals undergo changes in risk status (i.e., a life-stage vs. a life-course model of risk acquisition); and 4) the, as yet, unfamiliar challenge of scenario-based forecasting of health consequences of future, large-scale social and environmental changes. The evolution of the content and methods of epidemiology continues. Epidemiologists are gaining insights into the complex social and environmental systems that are the context for health and disease; thinking about population health in increasingly ecologic terms; developing dynamic, interactive, life-course models of disease risk acquisition; and extending their spatial-temporal frame of reference as they perceive the health risks posed by escalating human pressures on the wider environment. The constraints of "the proximate" upon epidemiology are thus loosening as the end of the century approaches.

Epidemiology↗

Recent clinical trials in superficial bladder cancer.

The present review addresses literature regarding the management of superficial bladder cancer published since March 2000. There is no definitive winner among urinary markers of bladder cancer, because they lack specificity or are insufficiently tested. Pathologists continue in their efforts to improve prediction of evolution of superficial bladder cancer to recurrent or infiltrative disease. A few studies have confirmed the value of previously described prognostic factors for recurrence and progression, and have added some refinements. Transurethral resection is not as complete as was believed. Fluorescence detection of flat bladder carcinoma has been demonstrated to improve diagnosis and treatment. The necessity to perform a repeat transurethral resection in high-grade superficial bladder cancer became evident. Identification of the working mechanisms of bacille Calmette-Guérin on superficial bladder cancer remains an important objective, and may help to improve treatment schedules and avoid the morbidity associated with bacille Calmette-Guérin administration. Patients who are at high risk may benefit from long-term maintenance bacille Calmette-Guérin therapy. Valrubicin and keyhole limpet haemocyanin appear to be promising agents in the treatment of superficial bladder cancer.

Antineoplastic Agents↗

Canonical functions for dispersal-induced synchrony.

Two processes are universally recognized for inducing spatial synchrony in abundance: dispersal and correlated environmental stochasticity. In the present study we seek the expected relationship between synchrony and distance in populations that are synchronized by density-independent dispersal. In the absence of dispersal, synchrony among populations with simple dynamics has been shown to echo the correlation in the environment. We ask what functional form we may expect between synchrony and distance when dispersal is the synchronizing agent. We formulate a continuous-space, continuous-time model that explicitly represents the time evolution of the spatial covariance as a function of spatial distance. Solving this model gives us two simple canonical functions for dispersal-induced covariance in spatially extended populations. If dispersal is rare relative to birth and death, then covariances between nearby points will follow the dispersal distance distribution. At long distances, however, the covariance tails off according to exponential or Bessel functions (depending on whether the population moves in one or two dimensions). If dispersal is common, then the covariances will follow the mixture distribution that is approximately Gaussian around the origin and with an exponential or Bessel tail. The latter mixture results regardless of the original dispersal distance distribution. There are hence two canonical functions for dispersal-induced synchrony

Animals↗

Innovations in the speciation of organolead compounds in water: towards a more rational, rapid, and simple analytical process.

Speciation analysis calls for rapid, simple systems for minimizing errors made in the most troublesome of all steps in the analytical process: sample preparation. In this context, continuous-flow systems are of great help. The evolution in the different methodologies enabled solutions to the main shortcomings occurring from the lack of selectivity of using RP-C18 as sorbent material. One solution was a shift to more sensitive and selective, but only partially automated, systems employing C60 fullerene and Grignard's reagent; another was a shift to completely automated systems employing sodium tetrapropylborate; and a final solution was to employ the simplest possible configuration by removing the reagent stream. The analytical methods developed allowed the identification and quantification of different organolead species at the pg/ml levels in rainwater samples, with precision (RSD) of about 5% and recoveries ranging from 92 to 100%.

Automation↗

Continued fraction representation of temporal multiscaling in turbulence.

It was shown recently that the anomalous scaling of simultaneous correlation functions in turbulence is intimately related to the breaking of temporal scale invariance, which is equivalent to the appearance of infinitely many times scales in the time dependence of time-correlation functions. In this paper we derive a continued fraction representation of turbulent time correlation functions which is exact and in which the multiplicity of time scales is explicit. We demonstrate that this form yields precisely the same scaling laws for time derivatives and time integrals as the "multi-fractal" representation that was used before. Truncating the continued fraction representation yields the "best" estimates of time correlation functions if the given information is limited to the scaling exponents of the simultaneous correlation functions up to a certain, finite order. It is worth noting that the derivation of a continued fraction representation obtained here for a time evolution operator which is not Hermitian or anti-Hermitian may be of independent interest.

Journal Article↗

Effect of slow compression on the linear stability of an accelerated shear layer

An analysis is given of the effect of a slow uniform anisotropic compression or expansion on the linear stability of a normally accelerated planar interface between two fluids with different densities and tangential velocities, i.e., a combined Kelvin-Helmholtz and Rayleigh-Taylor instability, but generalized to an arbitrary time-dependent acceleration history. The compression is presumed to be sufficiently slow that the density remains uniform within each fluid and hence depends only on time. The perturbation is taken to be sinusoidal with amplitude h(t). The time evolution of h is determined by requiring pressure continuity across the interface in the usual way. The resulting linearized stability equation is a second-order linear ordinary differential equation for h(t). Compared to the corresponding well-known result for incompressible fluids, it is found that normal compression has the effect of reducing the perturbation growth rate &hdot; by an obvious geometrical correction, while transverse compression does not directly affect the net growth rate but rather has the dynamical effect of increasing its time derivative. When attention is focused on the masses transported across the initial interface rather than h, the purely geometrical effects of compression no longer appear explicitly, while the dynamical effects remain. It is thereby shown that both normal and transverse compression dynamically enhance the mixing of material masses, in spite of the corresponding purely geometrical reduction in &hdot;.

Journal Article↗

Stream-stage response tests and their joint interpretation with pumping tests.

Hydraulic head response to stream-stage variations can be used to explore the hydraulic properties of stream-aquifer systems at a relatively large scale. These stream-stage response tests, also called flooding tests, are typically interpreted using one- or two-dimensional models that assume flow perpendicular to the river. Therefore, they cannot be applied to systems that are both horizontally and vertically heterogeneous. In this work, we use the geostatistical inverse problem to jointly interpret data from stream-stage response and pumping tests. The latter tests provide flow data (which are needed to resolve aquifer diffusivity into transmissivity and storage coefficient) and may supply supplementary small-scale information. Here, we summarize the methodology for the design, execution, and joint numerical interpretation of these tests. Application to the Aznalcóllar case study allows us to demonstrate that the proposed methodology may help in responding to questions such as the continuity of aquitards, the role and continuity of highly permeable paleochannels, or the time evolution of stream-aquifer interaction. These results expand the applicability and scope of stream-stage response tests.

Calibration↗

Hydrogen generation from artificial sea water in a semiconductor septum electrochemical photovoltaic cell.

Visible light of the solar spectrum is directly converted to stored chemical energy of hydrogen from artificial sea water in a novel electrochemical photovoltaic cell. The principal element of the cell, modeled after the photosynthetic thylakoid membrane, is a semiconductor septum made of polycrystalline n-CdSe thin film deposited on nickel foil, which separates two aqueous solutions. Under short-circuit conditions, vigorous hydrogen evolution was seen at the Ni surface and continued as long as the cell was operated. The novel cell, the concept of which was derived from pigmented bilayer lipid membrane studies, is easy to construct, simple to operate, and appears to be a practical approach to the photochemical conversion and storage of solar energy.

Electrochemistry↗

Baroreceptor function during exercise: resetting the record.

This paper briefly reviews the historical evolution of ideas about how baroreflexes operate and continue to regulate arterial blood pressure during exercise. Observations from studies conducted in conscious humans and animals are emphasized and three main questions are asked. First, do baroreflexes contribute to arterial blood pressure regulation during exercise? Second, if baroreflexes contribute to blood pressure regulation during exercise, how do they do it? Third, are there any pathophysiological conditions in which manipulation of baroreflexes or baroreflex 'dysfunction' might alter exercise responses? In this context, ideas related to baroreflex resetting during exercise are emphasized, and the potential improvement in exercise tolerance in cardiovascular disease that might be achieved by electrical stimulation of the carotid sinus nerve is highlighted. Additionally, the key contributions of John Shepherd and the late David Donald (along with their colleagues) on related issues are noted.

Animals↗

The clc element of Pseudomonas sp. strain B13, a genomic island with various catabolic properties.

Pseudomonas sp. strain B13 is a bacterium known to degrade chloroaromatic compounds. The properties to use 3- and 4-chlorocatechol are determined by a self-transferable DNA element, the clc element, which normally resides at two locations in the cell's chromosome. Here we report the complete nucleotide sequence of the clc element, demonstrating the unique catabolic properties while showing its relatedness to genomic islands and integrative and conjugative elements rather than to other known catabolic plasmids. As far as catabolic functions, the clc element harbored, in addition to the genes for chlorocatechol degradation, a complete functional operon for 2-aminophenol degradation and genes for a putative aromatic compound transport protein and for a multicomponent aromatic ring dioxygenase similar to anthranilate hydroxylase. The genes for catabolic functions were inducible under various conditions, suggesting a network of catabolic pathway induction. For about half of the open reading frames (ORFs) on the clc element, no clear functional prediction could be given, although some indications were found for functions that were similar to plasmid conjugation. The region in which these ORFs were situated displayed a high overall conservation of nucleotide sequence and gene order to genomic regions in other recently completed bacterial genomes or to other genomic islands. Most notably, except for two discrete regions, the clc element was almost 100% identical over the whole length to a chromosomal region in Burkholderia xenovorans LB400. This indicates the dynamic evolution of this type of element and the continued transition between elements with a more pathogenic character and those with catabolic properties.

Aminophenols↗

Strain variation in adenovirus serotypes 4 and 7a causing acute respiratory disease.

In order to determine the suitability of vaccine strains established in the 1960s for a new vaccine, a comprehensive study of strain variation of adenovirus serotype 4 (AV 4) and AV 7 was undertaken. A 1,500-bp region of the hexon gene containing the AV neutralization epitopes from prototype, vaccine, and community-acquired strains and from wild-type strains from military personnel that cause acute respiratory disease (ARD) was sequenced and analyzed. The whole hexon gene from prototype strains, vaccine strains, and selected isolates was sequenced. AV 7 and AV 7a were found to have distinct genotypes, and all vaccine and wild-type strains recovered from 1963 to 1997 had the AV 7a genotype. There was no significant strain variation in the neutralization epitopes of the AV 7a genotype over a 42-year period. The evolution of AV 4 was more complex, with continuous genetic drift punctuated by replacement with a new strain. The current strain of AV 4, which has been in circulation since 1995, is significantly different from the AV 4 prototype and the vaccine strains. Genetic differences were confirmed to be antigenic differences by neutralization tests, which define the new strain as an AV 4 variant. A type-specific PCR for AV 4, AV 7/7a, and AV 21 was developed, and this PCR facilitated the rapid identification of isolates from outbreaks of ARD.

Adenovirus Infections, Human↗

Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C.

Continual human immunodeficiency virus type 1 (HIV-1) evolution and expansion within the human population have led to unequal distribution of HIV-1 group M subtypes. In particular, recent outgrowth of subtype C in southern Africa, India, and China has fueled speculation that subtype C isolates may be more fit in vivo. In this study, nine subtype B and six subtype C HIV-1 isolates were added to peripheral blood mononuclear cell cultures for a complete pairwise competition experiment. All subtype C HIV-1 isolates were less fit than subtype B isolates (P < 0.0001), but intrasubtype variations in HIV-1 fitness were not significant. Increased fitness of subtype B over subtype C was also observed in primary CD4(+) T cells and macrophages from different human donors but not in skin-derived human Langerhans cells. Detailed analysis of the retroviral life cycle during several B and C virus competitions indicated that the efficiency of host cell entry may have a significant impact on relative fitness. Furthermore, phyletic analyses of fitness differences suggested that, for a recombined subtype B/C HIV-1 isolate, higher fitness mapped to the subtype B env gene rather than the subtype C gag and pol genes. These results suggest that subtype B and C HIV-1 may be transmitted with equal efficiency (Langerhans cell data) but that subtype C isolates may be less fit following initial infection (T-cell and macrophage data) and may lead to slower disease progression.

Cells, Cultured↗

Regulation of valine and alpha-ketoisocaproate metabolism in rat kidney mitochondria.

Activities of branched-chain amino acid (BCAA) aminotransferase (BCAT) and alpha-keto acid dehydrogenase (BCKD) were assayed in mitochondria isolated from kidneys of rats. Rates of transamination of valine and oxidation of keto acids alpha-ketoisocaproate (KIC) or alpha-ketoisovalerate (KIV) were estimated using radioactive tracers of the appropriate substrate from amounts of 14C-labeled products formed (14CO2 or [1-14C]-keto acid). Because of the high mitochondrial BCAT activity, an amino acceptor for BCAT, alpha-ketoglutarate (alpha-KG) or KIC, was added to the assay medium when valine was the substrate. Rates of valine transamination and subsequent oxidation of the KIV formed were determined with 0.5 mM alpha-KG as the amino acceptor; these rates were 5- to 50-fold those without added alpha-KG. Rates of CO2 evolution from valine also increased when KIC (0.01-0.10 mM) was present; however, with KIC concentrations above 0.2 mM, rates of CO2 evolution from valine declined although rates of transamination continued to rise. When 0.05 mM KIC was added to the assay medium, oxidation of KIC was suppressed by inclusion of valine or glutamate in the medium. When valine was present KIC was not oxidized preferentially, presumably because it was also serving as an amino acceptor for BCAT. These results indicate that as the supply of amino acceptor, alpha-KG or KIC, is increased in mitochondria not only is the rate of valine transamination stimulated but also the rate of oxidation of the KIV formed from valine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[Study of deferoxamine in subcutaneous profusion treatment of iron overload in myelodysplastic syndromes].

BACKGROUND AND OBJECTIVE: The progressive accumulation of iron in the organism contribute to one of the most important problems of morbidity and mortality in patients with myelodysplastic syndrome (MDS). We present an observational protocol, multicentre, open and non-aleatheorised, in patients diagnosed with MDS on transfusional regime with iron overload. The study was meant to prove the effectiveness of the parenteral treatment with desferrioxamine using continuous devices of subcutaneous profusion and evaluate the evolution of iron overload as well as transfusional requirements. PATIENTS AND METHOD: There were 28 patients (12 men and 16 women), 12 AR, 15 AS and 1 unknown. Average monitoring lasted 13.5 months and there was a gradual loss of patients. 11 of them had gone during the first year. RESULTS: After 12 months the average of ferritin decreased by 258.51 ng/dl (DE 1208.04; p = 9.4) and after 24 months, it decreased by 979.6 ng/dl (DE 810.31; p = 0.1). After 12 months the average of requirements increased by 60.57 gHb/month (DE 183.7; p = 0.029) and after 24 months, it increased by 167.3 g/Hb/month (DE 406.5; p = 0.36). CONCLUSIONS: Desferroxiamine treatment is effective at least to prevent an iron overload in these patients, and therefore should be incorporated in the clinical practice.

Aged↗

CO2 and Nd:YAG laser-induced pulmonary parenchymal lung injury in a rabbit model.

Laser exposure of the pulmonary parenchyma during treatment of emphysema and other clinical indications causes acute lung injury. Animal investigations are needed to understand and control laser-induced lung injury. We hypothesized that lung injury is deeper from Nd:YAG laser exposures than CO2 exposures because of deeper penetration of Nd:YAG wavelength light. We compared the temporal evolution of histologic injury in rabbits resulting from continuous mode shallow CO2 and Nd:YAG laser pulmonary parenchymal exposures applied in rabbits. Forty-six New Zealand white (NZW) rabbits underwent treatment with CO2 laser (n=18), Nd:YAG laser (n=18), or sham thoracotomy control (n=10) to the visceral pleural surface using 1 min of exposure (5 watts, defocused to 70 W/cm2 power density for both lasers). Animals were killed at 0, 4, 7, 21, and 49 d after exposure. Lung injury, similar to that seen clinically in humans, developed in all laser-treated animals. Injury progressed from ischemia and vascular congestion, to edema and necrosis, followed by pleural and parenchymal fibrosis. The acute injury was qualitatively distinct and slightly deeper in CO2 than Nd:YAG-treated animals (p<0.02) despite the shallower depth of penetration of the CO2 laser. These findings may imply that higher absorption coefficient for CO2 laser energy results in greater focal temperatures and injury in the areas of direct exposure, and suggest that Nd:YAG laser exposure at these settings may cause shallower injury than CO2 lasers in humans undergoing clinical treatment.

Absorption↗

Structural and functional characterization of a conserved cryptic epitope on SARS-CoV-2 spike S2 subunit.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone extensive evolution since its emergence in 2019, underscoring the continuous need for vaccines and therapeutics effective against multiple variants of concern (VOCs). The S2 subunit of the viral spike (S) glycoprotein is highly conserved among sarbecoviruses, making it an attractive target for broadly protective countermeasures. To elucidate the S2 antigenic landscape, we employed yeast surface display to isolate S2-targeted antibodies from COVID-19 convalescent donors. Biophysical characterization revealed that these S2 apex-directed antibodies preferentially bind to open spike conformations and a stabilized S2 construct but not to the closed, trimeric prefusion spike. Cryo-electron microscopy structures defined a cryptic epitope encompassing the upper helix and fusion peptide proximal region on S2. This epitope is conserved among sarbecoviruses but remains largely occluded in the closed prefusion conformation of the spikes. As a result, the antibodies exhibited weak neutralization activity against SARS-CoV-2 pseudoviruses, failed to neutralize authentic viruses, and did not provide protection in a lethal mouse challenge model using a mouse-adapted SARS-CoV-2 strain. These findings highlight a non-neutralizing epitope on S2 capable of eliciting antibodies during SARS-CoV-2 infection in humans and provide valuable reagents for probing S2 conformational dynamics and optimizing S2-based vaccine antigens.

Spike Glycoprotein, Coronavirus↗

Current concepts and controversies in the treatment of alcoholic hepatitis.

The treatment of alcoholic hepatitis remains one of the most debated topics in medicine and a field of continued research. In this review, we discuss the evolution of scoring systems, including the recent development of the Glasgow alcoholic hepatitis score, role of liver biopsy and current treatment interventions. Studies of treatment interventions with glucocorticoids, pentoxifylline, infliximab, s-adenosyl-methionine, and colchicine are reviewed with discussion on quality. Glucocorticoids currently remain the mainstay of treatment for severe alcoholic hepatitis.

Biopsy↗