Development of secondary sexual characters in the seabob shrimp Xiphopenaeus kroyeri (Heller 1862) (Crustacea,Decapoda, Penaeidae): a scanning electron microscope study

The development of secondary sexual characters, the petasma, and thelycum growth were studied in Xiphopenaeus kroyeri. In adult females, the thelycum is a single plate and its anterolateral portion is characterized by a reduced hood. The aperture resembles a transverse ridge. In immature stages, the ridge has a space between the plates, which becomes narrower as it reaches the end of development. The female gonopore is ‘comma’ shaped. In adult males, the endopods of the petasma are linked at the dorsomedial margin by a large quantity of cincinnuli. In juveniles, cincinnuli gradually increase in number until they join both endopods. At the end of development the petasma is T-shaped. The male gonopore is C-shaped. The relative growth of the petasma total length versus juvenile body length showed a highly positive allometry, whereas in adults the growth was isometric. For the relationship carapace length versus thelycum width, the juvenile phase of females is characterized by an isometry and the adult phase by a negative allometry.     

Preclinical pharmacokinetics,pharmacodynamics, tissue distribution,and tumor penetration of anti-PD-L1 monoclonal antibody,an immune checkpoint inhibitor

MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.

The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg·kg^?1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg·kg^?1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.

The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ～0.5 µg·mL^?1. Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ～0.3; saturation of target-mediated uptake in non–tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.

The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.     

Structural and biochemical insights into 7β‐hydroxysteroid dehydrogenase stereoselectivity

Hydroxysteroid dehydrogenases are of great interest as biocatalysts for transformations involving steroid substrates. They feature a high degree of stereo‐ and regio‐selectivity, acting on a defined atom with a specific configuration of the steroid nucleus. The crystal structure of 7β‐hydroxysteroid dehydrogenase from Collinsella aerofaciens reveals a loop gating active‐site accessibility, the bases of the specificity for NADP⁺, and the general architecture of the steroid binding site. Comparison with 7α‐hydroxysteroid dehydrogenase provides a rationale for the opposite stereoselectivity. The presence of a C‐terminal extension reshapes the substrate site of the β‐selective enzyme, possibly leading to an inverted orientation of the bound substrate. Proteins 2016; 84:859–865. © 2016 Wiley Periodicals, Inc.     

Smoking Is Associated with More Abdominal Fat in Morbidly Obese Patients

IntroductionWhile the association between cigarette smoking and abdominal fat has been well studied in normal and overweight patients, data regarding the influence of tobacco use in patients with morbid obesity remain scarce. The aim of this study is to evaluate body fat distribution in morbidly obese smokers.MethodsWe employed a cross-sectional study and grouped severely obese patients (body mass index [BMI] >40 kg/m² or >35 kg/m² with comorbidities) according to their smoking habits (smokers or non-smokers). We next compared the anthropometrical measurements and body composition data (measured by electric bioimpedance) of both groups. We analyzed the effect of smoking on body composition variables using univariate and multiple linear regression (MLR); differences are presented as regression coefficients (b) and their respective 95% confidence intervals.ResultsWe included 536 morbidly obese individuals, 453 (84.5%) non-smokers and 83 (15.5%) smokers. Male smokers had a higher BMI (b=3.28 kg/m², p=0.036), larger waist circumference (b=6.07 cm, p=0.041) and higher percentage of body fat (b=2.33%, p=0.050) than non-smokers. These differences remained significant even after controlling for confounding factors. For females, the only significant finding in MLR was a greater muscle mass among smokers (b=1.34kg, p=0.028). No associations were found between tobacco load measured in pack-years and anthropometric measures or body composition.DiscussionPositive associations between smoking and BMI, and waist circumference and percentage of body fat, were found among male morbidly obese patients, but not among females. To the best of our knowledge, this study is the first investigation of these aspects in morbidly obese subjects. We speculate that our findings may indicate that the coexistence of morbid obesity and smoking helps to explain the more serious medical conditions, particularly cardiovascular diseases and neoplasms, seen in these patients.     

Age-Related Differences in the Accuracy of Web Query-Based Predictions of Influenza-Like Illness

BackgroundWeb queries are now widely used for modeling, nowcasting and forecasting influenza-like illness (ILI). However, given that ILI attack rates vary significantly across ages, in terms of both magnitude and timing, little is known about whether the association between ILI morbidity and ILI-related queries is comparable across different age-groups. The present study aimed to investigate features of the association between ILI morbidity and ILI-related query volume from the perspective of age.MethodsSince Google Flu Trends is unavailable in Italy, Google Trends was used to identify entry terms that correlated highly with official ILI surveillance data. All-age and age-class-specific modeling was performed by means of linear models with generalized least-square estimation. Hold-out validation was used to quantify prediction accuracy. For purposes of comparison, predictions generated by exponential smoothing were computed.ResultsFive search terms showed high correlation coefficients of > .6. In comparison with exponential smoothing, the all-age query-based model correctly predicted the peak time and yielded a higher correlation coefficient with observed ILI morbidity (.978 vs. .929). However, query-based prediction of ILI morbidity was associated with a greater error. Age-class-specific query-based models varied significantly in terms of prediction accuracy. In the 0–4 and 25–44-year age-groups, these did well and outperformed exponential smoothing predictions; in the 15–24 and ≥ 65-year age-classes, however, the query-based models were inaccurate and highly overestimated peak height. In all but one age-class, peak timing predicted by the query-based models coincided with observed timing.ConclusionsThe accuracy of web query-based models in predicting ILI morbidity rates could differ among ages. Greater age-specific detail may be useful in flu query-based studies in order to account for age-specific features of the epidemiology of ILI.     

Duplications of the X chromosome in males: evidence that most parts of the X chromosome can be active in two copies

Summary We have analysed two duplications of the X chromosome in male patients using chromosome replication and DNA methylation patterns as determinants of the functional status of the duplicated segments. In both cases, the large duplicated regions, Xq12-q22 and Xq26.3-qter, were not inactivated. A review of previously reported male cases revealed that these duplications were also not subject to inactivation. Taken together, the examined duplications cover almost the entire X chromosome except the pericentromeric region and Xq25–26. Thus, most regions of the X chromosome can be present in two functional copies without lethal consequences.     

E-NTPDase and E-ADA activities are altered in lymphocytes of patients with indeterminate form of Chagas' disease

Trypanosoma cruzi infection triggers a chronic inflammatory process in human host and purinergic system ecto-enzymes play an important role in modulating the inflammatory and immune responses. In this study, it was investigated ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase; EC 3.6.1.5; CD39) and ecto-adenosine deaminase (E-ADA; EC 3.5.4.4) activities in lymphocytes from patients with indeterminate form of Chagas' disease (IFCD). Twenty-five IFCD patients and 25 healthy subjects (control group) were selected. The peripheral lymphocytes were isolated and E-NTPDase and E-ADA activities were determined. Adenine nucleotides and adenosine levels were determined in serum by HPLC and the E-NTPDase1 expression in lymphocytes by Western blot analysis. E-NTPDase (ATP and ADP as substrates) and E-ADA (adenosine as substrate) activities were decreased in lymphocytes from IFCD patients (P<0.05 and P<0.01, respectively), while the E-NTPDase1 expression presented no changes in these patients. Serum ATP levels showed to be decreased (P<0.05) and both AMP (P<0.01) and adenosine (P<0.001) levels were increased in the IFCD group. The enzymatic alterations observed are in agreement with the immune response against T. cruzi infection in IFCD patients, since the decreased extracellular ATP and the increased adenosine levels trigger a Th2 anti-inflammatory response, which it is associated to adaptation of host to parasite, preventing clinical progress of disease.     

Cardiac sodium channel Na(v)1.5 interacts with and is regulated by the protein tyrosine phosphatase PTPH1

In order to identify proteins interacting with the cardiac voltage-gated sodium channel Na(v)1.5, we used the last 66 amino acids of the C-terminus of the channel as bait to screen a human cardiac cDNA library. We identified the protein tyrosine phosphatase PTPH1 as an interacting protein. Pull-down experiments confirmed the interaction, and indicated that it depends on the PDZ-domain binding motif of Na(v)1.5. Co-expression experiments in HEK293 cells showed that PTPH1 shifts the Na(v)1.5 availability relationship toward hyperpolarized potentials, whereas an inactive PTPH1 or the tyrosine kinase Fyn does the opposite. The results of this study suggest that tyrosine phosphorylation destabilizes the inactivated state of Na(v)1.5.     

Temperature-related divergence in experimental populations of Drosophila melanogaster. II. Correlation between fitness and body dimensions

From a laboratory stock of Drosophila melanogaster (Oregon), reared for more than 20 years at 18° C, a new population was derived and maintained at 28° C for 8 years. The chromosomal and cytoplasmic contribution to genetic divergence between the two populations was estimated. Six body traits and reproductive fitness were taken into account. The third chromosome is responsible for the adaptive difference for temperature between the two lines. Temperature-selected genes which control body size are located on the second and third chromosomes, although the contribution of each chromosome depends on the environment in which the flies develop. The correlation between the chromosomal and cytoplasmic contributions to different traits and fitness, changes with temperature. At 28° C the correlation between fitness and each body trait is proportional to the response to selection exhibited by each of them, but this is not true at 18° C. Body size has, therefore, an adaptive significance in relation to temperature, which is expressed only in the environment where selection occurs. Cytoplasmic genes affect almost all characters to an extent similar to that of chromosomal genes. Inter-chromosomal and nucleo-cytoplasmic interactions are present and also change with temperature. In general, genes selected in a given environment produce greater phenotypic changes in that environment than in another. The population that experienced both temperatures is fitter in both environments, suggesting that the capacity to adapt to warm temperatures depends on genes other than those which are involved in the adaptation to cold.