Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.     

Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?

LFA-1 (Lymphocyte function-associated antigen-1) is a heterodimeric integrin (CD11a/CD18) present on the surface of all leukocytes; it is essential for leukocyte recruitment to the site of tissue inflammation, but also for other immunological processes such as T cell activation and formation of the immunological synapse. Absent or dysfunctional expression of LFA-1, caused by mutations in the ITGB2 (integrin subunit beta 2) gene, results in a rare immunodeficiency syndrome known as Leukocyte adhesion deficiency type I (LAD I). Patients suffering from severe LAD I present with recurrent infections of the skin and mucosa, as well as inflammatory symptoms complicating the clinical course of the disease before and after allogeneic hematopoietic stem cell transplantation (alloHSCT); alloHSCT is currently the only established curative treatment option. With this review, we aim to provide an overview of the intrinsic role of inflammation in LAD I.     

Enhanced Inhibition of Prostate Tumor Growth by Dual Targeting the Androgen Receptor and the Regulatory Subunit Type Iα of Protein Kinase A in Vivo

Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type Iα (RIα) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARIα is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers.     

Kinetic studies in the CaOSiO2 — System Part I Mechanism and kinetic data of the reactions between CaO- and SiO2- powder compacts

The phase composition of the reaction zones in the CaOSiO₂ system was determined by electron probe microanalysis in the temperature range between 1000 – 1450 °C depending on the time of annealing. The diffusion couple technique in combination with a new designed screw loaded sample holder was applied. The growth of all product layers is shown to obey the parabolic rate law for diffusion-controlled solid state reactions. Reaction rate constants and activation energies are presented and discussed.     

Intensification of G/L absorption in microstructured falling film. Application to the treatment of chlorinated VOC’s – part I: Comparison between structured and microstructured packings in absorption devices

The absorption of tetrachloroethylene – the VOC – in di-ethyl-hexyl-adipate – the solvent – was carried out as an example of gaseous waste treatment. Two gas–liquid contactors were used: a column provided with as structured Sulzer EX^® packing and a microstructured falling-film absorber provided with thin vertical channels, manufactured by the Institut für Mikrotechnik Mainz (IMM). The overall transfer coefficient of VOC, K_Ga, was calculated from the absorption efficiency of the various runs carried out, allowing comparison of the two gas–liquid contactors. Due to the high solubility of the considered VOC, mass transfer was shown to be mainly controlled by gas-side transfer rates. Transfer coefficient K_Ga of the two absorbers were found to be comparable, but with gas and liquid velocity in the microstructured absorber from one to two orders of magnitude below those in the column, expressing the high transfer performance offered by the microsystem. Moreover, the thickness of the liquid film in the channels was below 100 μm, much lower than that in a structured packing near 500 μm. This shows that lower liquid flow rates can be used for efficient absorption in the microsystem. It is shown that contrary to conventional structured packing, the designed contact specific area in the microabsorber strictly corresponds to the interfacial G/L surface. This enables more compact and to miniaturize G/L contactors to be designed.     

Larval Diet Affects Male Pheromone Blend in a Laboratory Strain of the Medfly, <Emphasis Type="Italic">Ceratitis capitata</Emphasis> (Diptera: Tephritidae)

The Mediterranean fruit fly (medfly) Ceratitis capitata is a polyphagous pest of fruits and crops with a worldwide distribution. Its ability to use different larval hosts may have multiple effects, including impacts on adult reproductive biology. The male sex pheromone, which plays a key role in attracting both other males to lekking arenas and females for mating, is a mixture of chemical compounds including esters, acids, alkanes and terpenes known to differ between laboratory strains and wild-type populations. The relationship between larval diet and adult pheromone composition remains unexplored. Here, we investigated the effect of larval diet, including laboratory media and fresh fruits, on the composition of the male pheromone mixture. Using Headspace Solid Phase Microextraction we collected the pheromone emitted by males reared as larvae on different substrates and found both qualitative and quantitative differences. A number of alkanes appeared to be typical of the pheromone of males reared on wheat bran-based larval medium, and these may be cuticular hydrocarbons involved in chemical communication. We also detected differences in pheromone composition related to adult male age, suggesting that variations in hormonal levels and/or adult diet could also play a role in determining the chemical profile emitted. Our findings highlight the plasticity of dietary responses of C. capitata, which may be important in determining the interactions of this pest with the environment and with conspecifics. These results also have applied relevance to increase the mating competitiveness of mass-reared C. capitata used in Sterile Insect Technique programs.     

Two intra-molecular inter-ligand C(aromatic)–H⋯O(carboxyl) interactions reinforce the formation of a single Cu(II)–N4(pza) bond in the molecular recognition between pyrazine-2-carboxamide (pza) and the (iminodiacetato)copper(II) chelate. Synthesis,molecular and crystal structure and properties of [Cu(IDA)(pza)(H2O)]·H2O

Aqua(pyrazine-2-carboxamide)(iminodiacetato)copper(II) monohydrate, [Cu(IDA)(pza)(H₂O)]·H₂O, was synthesised and characterised by thermal, spectral, magnetic and X-ray diffraction methods. Its crystal structure was solved to a final R1=0.058. The Cu(II) atom exhibits a square base pyramidal coordination (type 4+1) with IDA ligand in mer-tridentate configuration [Cu–N(aliphatic) 1.986(7), Cu–O(carboxyl) 1.933(6) and 1.938(5) Å], the Cu–N4(pza) bond [1.984(7) Å] and Cu–O(apical aqua) bond [2.347(8) Å]. The N4-monodentate ligand role of pza is in contrast with that of the N,O-bidentate pza-Cu(II) chelation in [Cu(pza)₂(ClO₄)₂] or [Cu(acac)(pza)(ClO₄)]·H₂O. In the molecular recognition between Cu(IDA) chelate and pza the Cu–N4(pyridine-like) coordination mode is preferred because it enables the additional contribution of two weak intra-molecular inter-ligand C(aromatic)–H⋯O (IDA) interactions.