Effects of regular physical activity on skeletal muscle structural, energetic, and microvascular properties in carriers of sickle cell trait

To assess the effects of regular physical activity on muscle functional characteristics of carriers of sickle cell trait (SCT), 39 untrained (U) and trained (T) hemoglobin (Hb)AA (CON) and SCT subjects (U-CON, n = 12; U-SCT, n = 8; T-CON, n = 10; and T-SCT, n = 9) performed a graded exercise and a time to exhaustion (T(ex)) test, and were subjected to a muscle biopsy. Maximal power, total work performed during T(ex), citrate synthase and cytochrome c oxidase (COX) activities, respiratory chain complexes I and IV content, and capillary density (CD), diameter (COD), and surface area (CSA) were upregulated by the same proportion in T-CON and T-SCT compared with their untrained counterparts. These proportionally similar differences imply that the observed discrepancies between U-SCT and U-CON remained in the trained subjects. Specifically, both CD and COX remained and tended to remain lower, and both COD and CSA remained and tended to remain higher in T-SCT than in T-CON. Besides, carriers of SCT displayed specific adaptations with regular physical activity: creatine kinase activity; complexes II, III, and V content; and type I fiber surface area and capillary tortuosity were lower or unchanged in T-SCT than in U-SCT. In summary, our results show that 1) carriers of SCT adapted almost similarly to CON to regular physical activity for most of the studied muscle characteristics, 2) oxidative potential remains altered in physically active carriers of SCT compared with HbAA counterparts, and 3) the specific remodeling of muscle microvascular network persists in the trained state.     

What do we need to know about speciation?

Speciation has been a major focus of evolutionary biology research in recent years, with many important advances. However, some of the traditional organising principles of the subject area no longer provide a satisfactory framework, such as the classification of speciation mechanisms by geographical context into allopatric, parapatric and sympatry classes. Therefore, we have asked where speciation research should be directed in the coming years. Here, we present a distillation of questions about the mechanisms of speciation, the genetic basis of speciation and the relationship between speciation and diversity. Our list of topics is not exhaustive; rather we aim to promote discussion on research priorities and on the common themes that underlie disparate speciation processes.     

Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways

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Highlights? HECT ubiquitin ligases and YAP use single or multiple WW domains to select Smad protein targets ? The targets can require multiple binding sites (R-Smads) or unique sites (ISmads) ? Binding sites are phosphorylation dependent (R-Smads) or independent (ISmad) ? Smurf1 WW1-homodimers can stabilize the close and inactive conformation of the ligase     

Insights into the Mechanisms of Protective Immunity against Cryptococcus neoformans Infection Using a Mouse Model of Pulmonary Cryptococcosis

Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening pneumonia and meningoencephalitis in immune compromised individuals. Previous studies have shown that immunization of BALB/c mice with an IFN-γ-producing C. neoformans strain, H99γ, results in complete protection against a second pulmonary challenge with an otherwise lethal cryptococcal strain. The current study evaluated local anamnestic cell-mediated immune responses against pulmonary cryptococcosis in mice immunized with C. neoformans strain H99γ compared to mice immunized with heat-killed C. neoformans (HKC.n.). Mice immunized with C. neoformans strain H99γ had significantly reduced pulmonary fungal burden post-secondary challenge compared to mice immunized with HKC.n. Protection against pulmonary cryptococcosis was associated with increased pulmonary granulomatous formation and leukocyte infiltration followed by a rapid resolution of pulmonary inflammation, which protected the lungs from severe allergic bronchopulmonary mycosis (ABPM)-pathology that developed in the lungs of mice immunized with HKC.n. Pulmonary challenge of interleukin (IL)-4 receptor, IL-12p40, IL-12p35, IFN-γ, T cell and B cell deficient mice with C. neoformans strain H99γ demonstrated a requirement for Th1-type T cell-mediated immunity, but not B cell-mediated immunity, for the induction of H99γ-mediated protective immune responses against pulmonary C. neoformans infection. CD4⁺ T cells, CD11c⁺ cells, and Gr-1⁺ cells were increased in both proportion and absolute number in protected mice. In addition, significantly increased production of Th1-type/pro-inflammatory cytokines and chemokines, and conversely, reduced Th2-type cytokine production was observed in the lungs of protected mice. Interestingly, protection was not associated with increased production of cytokines IFN-γ or TNF-α in lungs of protected mice. In conclusion, immunization with C. neoformans strain H99γ results in the development of protective anti-cryptococcal immune responses that may be measured and subsequently used in the development of immune-based therapies to combat pulmonary cryptococcosis.     

Triphalangeal thumb and psychomotor retardation: a new association?

The triphalangeal thumb (TPT) is a rare malformation in which the thumb is presented as a long digit of three phalanges. We describe two brothers showing TPT and psychomotor retardation, especially in language. Difficulties in language development were also observed in children with TPT in another study. The coexistence of TPT and psychomotor retardation in those patients and in the two patients described here suggests that TPT and psychomotor retardation could be part of a syndromic association not described previously.     

Corepressor excess shifts the two-side chain vitamin D analog Gemini from an agonist to an inverse agonist of the vitamin D receptor

The vitamin D receptor (VDR) is an endocrine nuclear receptor that binds with high affinity its natural ligand 1alpha,25-dihydroxyvitamin D3. Gemini is a 1alpha,25-dihydroxyvitamin D3 analog with two identical side chains that, despite its significantly increased volume, binds to the VDR and can function as a potent agonist. This study demonstrates that, at excess corepressor (CoR) levels, Gemini shifts from an agonist to an inverse agonist that actively recruits CoR proteins to the VDR and mediates superrepression. Under these conditions Gemini stabilizes the VDR into a silent conformation, in which helix 12 of the ligand-binding domain is repositioned and thus unable to contribute to coactivator interaction. Amino acid F422 has been described as the lock of helix 12 and seems to be the most critical VDR residue in the inverse agonistic action of Gemini. Molecular dynamics simulations of the Gemini-VDR complex support these observation by indicating that the second side chain of Gemini induces tension to the receptor structure that can be released by a shift of helix 12. Taken together, Gemini is the first described (conditional) inverse agonist to an endocrine nuclear receptor and may function as a sensor for the cell-specific coactivator/CoR ratio.     

Role of FGFs in the control of programmed cell death during limb development

We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the autopodial mesoderm during the regression of the interdigital tissue, and the expression of FGFR3 in the interdigital regions is regulated by FGFs and BMPs in the same fashion as apopotosis. Together our findings indicate that, in the absence of FGF signaling BMPs are not sufficient to trigger apoptosis in the developing limb. Although we provide evidence for a positive influence of FGFs on BMP gene expression, the physiological implication of FGFs in apoptosis appears to result from their requirement for the expression of genes of the apoptotic cascade. We have identified MSX2 and Snail as candidate genes associated with apoptosis the expression of which requires the combined action of FGFs and BMPs.     

Leishmania infantum (Protozoa, kinetoplastida): transmission from infected patients to experimental animal under conditions that simulate needle-sharing

Morillas-Marquez, F., Martin-Sanchez, J., Acedo-Sanchez, C., Pineda, J. A., Macias, J., and Sanjuan-Garcia, J. Leishmania infantum (Protozoa, kinetoplastida): Transmission from infected patients to experimental animal under conditions that simulate needle-sharing. Experimental Parasitologym100, 71-74.     

Enzyme activation in organic solvents: co-lyophilization of subtilisin Carlsberg with methyl-beta-cyclodextrin renders an enzyme catalyst more active than the cross-linked enzyme crystals

In this study we explored the efficiency of the additive methyl-beta-cyclodextrin (M beta CD) to enhance the activity and enantioselectivity of the serine protease subtilisin Carlsberg in organic solvents. These two parameters, measured for different transesterification reactions and in several solvents, are compared with results obtained by using two additional preparations of the same enzyme: lyophilized powder and cross-linked enzyme crystals (CLEC). The results suggest that co-lyophilization of subtilisin with M beta CD preserves the enzyme's active site tertiary structure rendering a highly active and enantioselective catalyst.