A Bayesian Approach to Surrogacy Assessment Using Principal Stratification in Clinical Trials

Summary A surrogate marker (S) is a variable that can be measured earlier and often more easily than the true endpoint (T) in a clinical trial. Most previous research has been devoted to developing surrogacy measures to quantify how well S can replace T or examining the use of S in predicting the effect of a treatment (Z). However, the research often requires one to fit models for the distribution of T given S and Z. It is well known that such models do not have causal interpretations because the models condition on a postrandomization variable S. In this article, we directly model the relationship among T, S, and Z using a potential outcomes framework introduced by Frangakis and Rubin (2002, Biometrics 58 , 21–29). We propose a Bayesian estimation method to evaluate the causal probabilities associated with the cross‐classification of the potential outcomes of S and T when S and T are both binary. We use a log‐linear model to directly model the association between the potential outcomes of S and T through the odds ratios. The quantities derived from this approach always have causal interpretations. However, this causal model is not identifiable from the data without additional assumptions. To reduce the nonidentifiability problem and increase the precision of statistical inferences, we assume monotonicity and incorporate prior belief that is plausible in the surrogate context by using prior distributions. We also explore the relationship among the surrogacy measures based on traditional models and this counterfactual model. The method is applied to the data from a glaucoma treatment study.     

Transport of heterocyclic acids across rat small intestinein Vitro

Summary A study has been made of the steady-state fluxes of barbituric acid, six of its substituted derivatives, and 5,5-dimethyloxazolidinedione (DMO) across the wall of rat jejunumin vitro. For each of the compounds tested the mucosal (M) to serosal (S) flux was significantly larger than theS toM flux. BothM toS andS toM fluxes increased linearly with concentration, and the transport of one acid was not influenced by the presence of a tenfold greater concentration of a second heterocyclic acid. The fluxes decreased as the pH of the incubation saline was increased, but neither theM toS, nor theS toM fluxes could be described in terms of simple nonionic diffusion. It was found that the relation between the flux ratios of the transported acids and their pK _a values could be described by an equation derived from consideration of the transport of a weak acid in a series three compartment system, and it has been concluded that the three compartment system provides a good working hypothesis for the mechanism of heterocyclic acid transport across rat jejunum. It was found that the best fit of the theoretical curve to the experimental data was obtained when the ratio of permeabilities to the ionized and nonionized forms of a weak acid at one of the barriers was assigned the value 5×10^–1. It is suggested that this value may be characteristic of a noncellular restriction to diffusion, such as a layer of connective tissue, and substantiates previous suggestion that the intermediate compartment of the intestinal three compartment system is a component of the sub-epithelial extracellular space.     

Berberine bridge enzyme catalyzes the six electron oxidation of (S)-reticuline to dehydroscoulerine

Berberine bridge enzyme catalyzes the stereospecific oxidation and carbon–carbon bond formation of (S)-reticuline to (S)-scoulerine. In addition to this type of reactivity the enzyme can further oxidize (S)-scoulerine to the deeply red protoberberine alkaloid dehydroscoulerine albeit with a much lower rate of conversion. In the course of the four electron oxidation, no dihydroprotoberberine species intermediate was detectable suggesting that the second oxidation step leading to aromatization proceeds at a much faster rate. Performing the reaction in the presence of oxygen and under anoxic conditions did not affect the kinetics of the overall reaction suggesting no strict requirement for oxygen in the oxidation of the unstable dihydroprotoberberine intermediate. In addition to the kinetic characterization of this reaction we also present a structure of the enzyme in complex with the fully oxidized product. Combined with information available for the binding modes of (S)-reticuline and (S)-scoulerine a possible mechanism for the additional oxidation is presented. This is compared to previous reports of enzymes ((S)-tetrahydroprotoberberine oxidase and canadine oxidase) showing a similar type of reactivity in different plant species.     

Simulation of protein diffusion: a sensitive probe of protein–solvent interactions

Aqueous solutions of Candida antarctica lipase B (CALB) were simulated considering three different water models (SPC/E, TIP3P, TIP4P) by a series of molecular dynamics (MD) simulations of three different box sizes (L = 9, 14, and 19 nm) to determine the diffusion coefficient, the water viscosity and the protein density. The protein–water systems were equilibrated for 500 ns, followed by 100 ns production runs which were analysed. The diffusional properties of CALB were characterized by the Stokes radius (R_S), which was derived from the diffusion coefficient and the viscosity. R_S was compared to the geometric radius (R_G) of CALB, which was derived from the protein density. R_S and R_G differed by 0.27 nm for SPC/E and by 0.40 and 0.39 nm for TIP3P and TIP4P, respectively, which characterizes the thickness of the diffusive hydration layer on the protein surface. The simulated hydration layer of CALB resulted in agreement with those experimentally determined for other seven different proteins of comparable size. By avoiding the most common pitfalls, protein diffusion can be reliably simulated: simulating different box sizes to account for the finite size effect, equilibrating the protein–water system sufficiently, and using the complete production run for the determination of the diffusion coefficient.     

Organismic sets: II. Some general considerations

The theory of organismic sets, developed in previous papers (Bull. Math. Biophysics,29, 139–152; 389–393; 643–647) is further generalized. To conform better with some biological and sociological facts the basic definitions are made more general. The conclusion is reached that every organismic setS _o is in general the union of three disjoined subsetsS _o1 ,S _o2 andS _o3 . Of these the subsetS _o1 , called the “core” is equivalent to an organismic set defined in previous publications. Its functioning is essential for the functioning ofS _o . The subsetsS _o2 andS _o3 , taken alone, are not organismic sets. The first of them is responsible for such biological or sociological functions which are not necessary for the “immediate” survival ofS _o but which are important for adaptation to changing environment and are therefore essential for a “long range survival.” The second one,S _o3 , is responsible for biological or social functions which are irrelevant for the survival ofS _o . Biological and sociological examples ofS _o2 andS _o3 are given. In addition to the fundamental theorem established in the first of the above mentioned papers, three new conclusions are derived. One is that in organismic sets of order higher than zero not all elements are specialized. The second is that every organismic set of order higher than zero is mortal. The third is that with increasing specialization the intensities of some activities in some elements ofS _o are reduced. Again the biological and sociological examples are given. At the end some very general speculations are made on the possible relation between biology and physics and on the possibility of “relationalizing” physics.     

Absolute Configuration of Hydroxycitric Acid Produced by Microorganisms

Optical resolution for (2S,3R) and (2R,3S)-hydroxycitric acid (HCA) enantiomers was developed using chiral column chromatography. HCA from Bacillus megaterium G45C and Streptomyces sp. U121, newly isolated in our previous study, was analyzed to determine the absolute configuration. These results indicate that both strains generate optically pure (2S,3R)-hibiscus type HCA enantiomer.     

Adsorption of ethidium bromide from aqueous solution onto nutraceutical industrial fennel seed spent: Kinetics and thermodynamics modeling studies

Dye pollutants from research laboratories are one of the major sources for environmental contamination. In the present study, a nutraceutical industrial fennel seed spent (NIFSS) was explored as potential adsorbent for removal of ethidium bromide (EtBr) from aqueous solution. The adsorbent was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Through batch experiments, the operating variables like initial dye concentration, adsorbent dosage, temperature, contact time, and pH were optimized. Equilibrium data were analyzed using three number of two-parameter and six number of three-parameter isotherm models. The adsorption kinetics was studied using pseudo-first order and pseudo-second order. The diffusion effects were studied by film diffusion, Webber–Morris, and Dumwald–Wagner diffusion models. The thermodynamic parameters; change in enthalpy (ΔHº), entropy (ΔSº), and Gibbs free energy (ΔGº) of adsorption system were also determined and evaluated.     

Stereoselective uptake of the GABA-transaminase inhibitors gamma-vinyl gaba and gamma-acetylenic GABA into neurons and astrocytes

The cellular uptake of the GABA-transaminase inhibitors gamma-vinyl GABA (GVG) and gamma-acetylenic GABA (GAG) was studied in cultured neurons and astrocytes. By the use of the individual enantiomersR- andS-GVG andR- andS-GAG it could be shown that in both cell types only theS-enantiomers could be actively transported. Comparing neurons and astrocytes only neurons exhibited a high affinity uptake system forS-GVG (K _m 78.2±20.3 M;V _max 0.71±0.06 nmol · min^–1 · mg^–1 cell protein). In case ofS-GAG it could not be established with certainty whether the neuronal uptake was of the high affinity type. Both GVG and GAG were studied as inhibitors of GABA uptake into neurons and astrocytes.S-GVG andS-GAG were found to be weak inhibitors of GABA uptake suggesting thatS-GVG is not transported by the GABA carrier in neurons. The finding of a much more efficient uptake ofS-GVG into neurons than into astrocytes is in line with the previous observation that neuronal GABA-T is more sensitive than astrocytic GABA-T toS-GVG.     

Development of an in vitro colonization model to investigate Staphylococcus aureus interactions with airway epithelia

Staphylococcus aureus is a bacterial pathogen responsible for a wide range of diseases and is also a human commensal colonizing the upper respiratory tract. Strains belonging to the clonal complex group CC30 are associated with colonization, although the colonization state itself is not clearly defined. In this work, we developed a co‐culture model with S. aureus colonizing the apical surface of polarized human airway epithelial cells. The S. aureus are grown at the air–liquid interface to allow an in‐depth evaluation of a simulated colonization state. Exposure to wild‐type, S. aureus bacteria or conditioned media killed airway epithelial cells within 1 day, while mutant S. aureus strains lacking alpha‐toxin (hla) persisted on viable cells for at least 2 days. Recent S. aureus CC30 isolates are natural hla mutants, and we observed that these strains displayed reduced toxicity toward airway epithelial cells. Quantitative real‐time polymerase chain reaction of known virulence factors showed the expression profile of S. aureus grown in co‐culture correlates with results from previous human colonization studies. Microarray analysis indicated significant shifts in S. aureus physiology in the co‐culture model toward lipid and amino acid metabolism. The development of the in vitro colonization model will enable further study of specific S. aureus interactions with the host epithelia.     

Groundfish assemblages diversity in upwelling ecosystems: insights from the Mauritanian Exclusive Economic Zone

Upwelling ecosystems exhibit strong spatio-temporal variations of environmental conditions that drive the dynamics of marine diversity and ressources. Yet little is known in these ecosystems concerning the diversity of groundfishes. We studied the effects of environment (sea surface temperature, chlorophyll a concentration and bathymetric strata) and fishing pressure on this variability in the Mauritanian Exclusive Economic Zone (MEEZ), based on abundance data collected from 2158 hauls from scientific surveys performed on the continental shelf (15–200 m) between 1997 and 2010. First, for each haul (i.e. alpha-diversity), Species richness S and Berger Parker dominance D_bp were used as proxies of two complementary groups of nine indices, belonging to three main components of diversity (species number, evenness and taxonomic diversity), identified by a principal component analysis based on Spearman correlation coefficient. Thus the set of diversity indices used in this work suggests that a single component of diversity cannot represent the biodiversity of MEEZ groundfish. Second, generalized linear models (GLM) highlighted the stability of both indices for environmental variables, fishing effort and time, while, as shown by a previous study in the MEEZ, these variables influence species composition (i.e. beta-diversity). A longitudinal gradient of S and D_bp was highlighted, with coastal strata being richer in species and abundances more evenly distributed among species than offshore strata. Overall, this study provides a baseline of groundfish diversity in the MEEZ, that is also useful for comparison to other upwelling ecosystems, and essential for monitoring its potential shifts faced to climate change.

     

Gas exchange morphometry of the lungs of the tokay,Gekko gecko L. (Reptilia: Squamata: Gekkonidae)

The tokay lizard (Gekko gecko) possesses singlechambered lungs, eacch of which is a mirror image of the other reflected in the midsagittal body plane. When standard techniques are employed for instilling 2% phosphate-buffered glutaraldehyde to three-quarters of the total lung capacity, neither the left nor the right lung is consistently larger. Internally, the lungs are characterized by a row of 11 dorsomedial niches and by honeycomb-like (faveolar) gas exchange tissue, which is deeper cranially than caudally. Based upon mean values for all experimental animals, a 100-g tokay would have an overall anatomical diffusion factor (respiratory surface area divided by the appropriate _ht) of 203 cm²·m^-1·100 g^-1, 61% of which is located on the interfaveolar septa. Of the total septal anatomical diffusion factor, 94% is evenly divided between the anterior and middle thirds of the lung, with 6% in the posterior third. The 39% of the anatomical diffusion factor located on the inner lung wall is predominantly (76%) in the middle and posterior lung thirds, with only 24% in the anterior region. These tendencies toward heterogeneous distribution of anatomical diffusion factor were most pronounced in a 55 g juvenile animal. In this animal the total anatomical diffusion faxtor/body mass was 3.6 times that of a 197 g adult. This difference was attributable to a greater body massspecific lung volume and respiratory surface area as well as to a greater surface-to-volume ratio in the parenchyma and to a thinner air-blood diffusion barrier in the juvenile animal.Abbreviations ADF anatomical diffusion factor - %AR percentage of potential respiratory surface area which makes up S_AR - DtO₂ diffusing capacity for air-blood tissue barrier - IUR isotropic uniform randomly distributed - bm body mass - %P percentage of lung volume devoted to parenchyma - S _A potential respiratory surface area (S _L minus the surface area of the trabeculae) - S _ANR non-respiratory surface area - S _AR respiratory surface area - S _L total internal surface area of the lung - S _v surface area-to-volume ratio in parenchyma - _ht harmonic mean thickness of the air-blood tissue barrier - V _L morphometrically determined volume of both lungs, fixed at 0.75· V _Lm - V _Lm maximal lung volume, similar to total lung capacity in mammals - V _Lr resting lung volume, similar to functional residual capacity in mammals - VP morphometrically determined volume of parenchyma of both lungs, fixed at three-quarters of V_Lm     

Which function describes the species–area relationship best? A review and empirical evaluation

Aim The aims of this study are to resolve terminological confusion around different types of species–area relationships (SARs) and their delimitation from species sampling relationships (SSRs), to provide a comprehensive overview of models and analytical methods for SARs, to evaluate these theoretically and empirically, and to suggest a more consistent approach for the treatment of species–area data. Location Curonian Spit in north‐west Russia and archipelagos world‐wide. Methods First, I review various typologies for SARs and SSRs as well as mathematical models, fitting procedures and goodness‐of‐fit measures applied to SARs. This results in a list of 23 function types, which are applicable both for untransformed (S) and for log‐transformed (log S) species richness. Then, example data sets for nested plots in continuous vegetation (n = 14) and islands (n = 6) are fitted to a selection of 12 function types (linear, power, logarithmic, saturation, sigmoid) both for S and for log S. The suitability of these models is assessed with Akaike’s information criterion for S and log S, and with a newly proposed metric that addresses extrapolation capability. Results SARs, which provide species numbers for different areas and have no upper asymptote, must be distinguished from SSRs, which approach the species richness of one single area asymptotically. Among SARs, nested plots in continuous ecosystems, non‐nested plots in continuous ecosystems, and isolates can be distinguished. For the SARs of the empirical data sets, the normal and quadratic power functions as well as two of the sigmoid functions (Lomolino, cumulative beta‐P) generally performed well. The normal power function (fitted for S) was particularly suitable for predicting richness values over ten‐fold increases in area. Linear, logarithmic, convex saturation and logistic functions generally were inappropriate. However, the two sigmoid models produced unstable results with arbitrary parameter estimates, and the quadratic power function resulted in decreasing richness values for large areas. Main conclusions Based on theoretical considerations and empirical results, I suggest that the power law should be used to describe and compare any type of SAR while at the same time testing whether the exponent z changes with spatial scale. In addition, one should be aware that power‐law parameters are significantly influenced by methodology.     

Reproductive characteristics in an understory bamboo and gradual environmental changes after its dieback provide an extended opportunity for overstory tree regeneration in a mixed cool-temperate forest in central Japan

• The reproductive characteristics of understory bamboo and the effects of dieback on overstory tree seedlings through temporal changes in the environment at the forest floor have only been examined in a few bamboo species, due to the unpredictable occurrence of flowering events and long intervals between them but provide valuable information on tree regeneration and succession in a forest with dense dwarf bamboo cover.
• We investigated environmental conditions and assessed seedlings (< 30-cm tall) of the dwarf bamboo Sasa borealis and overstory tree species at 44–50 measurement points during 2016–2021, which included a S. borealis mass flowering event in 2017. We also conducted seed germination tests to determine germination rates and patterns in S. borealis. Environmental factors affecting seedling recruitment of S. borealis and of overstory trees were analysed using spatiotemporal generalized linear mixed models in the Bayesian framework.
• We observed gradual temporal changes in the environment, including increasing canopy openness and decreasing maximum height of dead S. borealis culms. The seeds germinated slowly and the emergence of current-year S. borealis seedlings peaked in spring–summer in 2019. The tree seedling density after 2019 increased significantly compared to that before the dieback. The model results suggest that tree seedling establishment was enhanced by increased light availability.
• Continuous field observation beginning before S. borealis dieback revealed gradually enhanced tree recruitment in response to slow decay of the remaining dead culms and slow recovery of S. borealis. The seedling regeneration pattern of understory bamboo partly contributes to a prolonged opportunity for overstory tree regeneration.

     

A Single Compartment Quantal Response Model with a Renewal Type Input Process and IID Releases

We deal with a single compartment quantal response model, where unlike the previous models, which do not have any input after the administration of a single dose Z(0)=z at time t=0, we allow inputs of doses after time t=0. More precisely, the system uses the (s, S) input policy as in inventory models, and has IID releases. Also when the amount of dose in the subject reaches 0, there is a probability p to stop having input thereafter. Among other results, the probability that the subject never responds and the expressions for some quantities of interest are obtained.     

Take the tube: remodelling of the endosomal system by intracellular Salmonella enterica

Salmonella enterica is a facultative intracellular pathogen residing in a unique host cell‐derived membrane compartment, termed Salmonella‐containing vacuole or SCV. By the activity of effector proteins translocated by the SPI2‐endoced type III secretion system (T3SS), the biogenesis of the SCV is manipulated to generate a habitat permissive for intracellular proliferation. By taking control of the host cell vesicle fusion machinery, intracellular Salmonella creates an extensive interconnected system of tubular membranes arising from vesicles of various origins, collectively termed Salmonella‐induced tubules (SIT). Recent work investigated the dynamic properties of these manipulations. New host cell targets of SPI2‐T3SS effector proteins were identified. By applying combinations of live cell imaging and ultrastructural analyses, the detailed organization of membrane compartments inhabited and modified by intracellular Salmonella is now available. These studies provided unexpected new details on the intracellular environments of Salmonella. For example, one kind of SIT, the LAMP1‐positive Salmonella‐induced filaments (SIF), are composed of double‐membrane tubules, with an inner lumen containing host cell cytosol and cytoskeletal filaments, and an outer lumen containing endocytosed cargo. The novel findings call for new models for the biogenesis of SCV and SIT and give raise to many open questions we discuss in this review.     

New species of alderfly genus Sialis (Megaloptera: Sialidae) from China and Vietnam,with a key to species of Sialis from Asia

The alderfly genus Sialis is the most species‐rich group of the family Sialidae. However, discovery of new Sialis species is becoming difficult because of previous good faunal exploration. In this paper, we describe two new Sialis species from the southern part of East Asia, S. australis and S. jiyuni, based on materials from historical and recent collections. These two species are closely related to the insular species S. kumejimae and are among the early diverged species within Sialis. Presently, 32 species of Sialis are recorded from Asia. A key to all the Sialis species from Asia is provided.     

The Multivalent Adhesion Molecule SSO1327 plays a key role in Shigella sonnei pathogenesis

Shigella sonnei is a bacterial pathogen and causative agent of bacillary dysentery. It deploys a type III secretion system to inject effector proteins into host epithelial cells and macrophages, an essential step for tissue invasion and immune evasion. Although the arsenal of bacterial effectors and their cellular targets have been studied extensively, little is known about the prerequisites for deployment of type III secreted proteins during infection. Here, we describe a novel S. sonnei adhesin, SSO1327 which is a multivalent adhesion molecule (MAM) required for invasion of epithelial cells and macrophages and for infection in vivo. The S. sonnei MAM mediates intimate attachment to host cells, which is required for efficient translocation of type III effectors into host cells. SSO1327 is non‐redundant to IcsA; its activity is independent of type III secretion. In contrast to the up‐regulation of IcsA‐dependent and independent attachment and invasion by deoxycholate in Shigella flexneri, deoxycholate negatively regulates IcsA and MAM in S. sonnei resulting in reduction in attachment and invasion and virulence attenuation in vivo. A strain deficient for SSO1327 is avirulent in vivo, but still elicits a host immune response.     

Comparison of potential fecundity models for walleye pollock Gadus chalcogrammus in the Pacific waters off Hokkaido,Japan

Potential fecundity models of walleye or Alaska pollock Gadus chalcogrammus in the Pacific waters off Hokkaido, Japan, were developed. They were compared using a generalized linear model with using either standard body length (L_S) or total body mass (M_T) as a main covariate along with Fulton's condition factor (K) and mean diameter of oocytes (D_O) as additional potential covariates to account for maternal conditions and maturity stage. The results of model selection showed that M_T was a better single predictor of potential fecundity (F_P) than L_S. The biological importance of K on F_P was obscure, because it was statistically significant when used in the predictor with L_S (i.e. length‐based model), but not significant when used with M_T (i.e. mass‐based model). Meanwhile, D_O was statistically significant in both length and mass‐based models, suggesting the importance of downregulation on the number of oocytes with advancing maturation. Among all candidate models, the model with M_T and D_O in the predictor had the lowest Akaike's information criterion value, suggesting its better predictive power. These newly developed models will improve future comparisons of the potential fecundity within and among stocks by excluding potential biases other than body size.     

Generalized population models and the nature of genetic drift

The Wright–Fisher model of allele dynamics forms the basis for most theoretical and applied research in population genetics. Our understanding of genetic drift, and its role in suppressing the deterministic forces of Darwinian selection has relied on the specific form of sampling inherent to the Wright–Fisher model and its diffusion limit. Here we introduce and analyze a broad class of forward-time population models that share the same mean and variance as the Wright–Fisher model, but may otherwise differ. The proposed class unifies and further generalizes a number of population-genetic processes of recent interest, including the Λ and Cannings processes. Even though these models all have the same variance effective population size, they encode a rich diversity of alternative forms of genetic drift, with significant consequences for allele dynamics. We characterize in detail the behavior of standard population-genetic quantities across this family of generalized models. Some quantities, such as heterozygosity, remain unchanged; but others, such as neutral absorption times and fixation probabilities under selection, deviate by orders of magnitude from the Wright–Fisher model. We show that generalized population models can produce startling phenomena that differ qualitatively from classical behavior — such as assured fixation of a new mutant despite the presence of genetic drift. We derive the forward-time continuum limits of the generalized processes, analogous to Kimura’s diffusion limit of the Wright–Fisher process, and we discuss their relationships to the Kingman and non-Kingman coalescents. Finally, we demonstrate that some non-diffusive, generalized models are more likely, in certain respects, than the Wright–Fisher model itself, given empirical data from Drosophila populations.