Identification of the proteins, including MAGEG1, that make up the human SMC5-6 protein complex

The SMC protein complexes play important roles in chromosome dynamics. The function of the SMC5-6 complex remains unclear, though it is involved in resolution of different DNA structures by recombination. We have now identified and characterized the four non-SMC components of the human complex and in particular demonstrated that the MAGEG1 protein is part of this complex. MAGE proteins play important but as yet undefined roles in carcinogenesis, apoptosis, and brain development. We show that, with the exception of the SUMO ligase hMMS21/hNSE2, depletion of any of the components results in degradation of all the other components. Depletion also confers sensitivity to methyl methanesulfonate. Several of the components are modified by sumoylation and ubiquitination

Working with Chronic Musculoskeletal Disorders : Good Practice Advice Report

This report takes an in-depth look at working with chronic musculoskeletal disorders (MSDs) and makes a clear case for the benefits of enabling those with chronic conditions to remain in work. It highlights the importance of designing inclusive workplaces and sets out principles for managing chronic MSDs, with prevention, early intervention, and effective, participative rehabilitation and return-to-work planning being identified as key. Good practice examples detail a wide range of workplace adjustments made to accommodate individuals with MSDs, from offering flexitime to providing the right tools and ergonomic equipment. This comprehensive practical advice is complemented by broader recommendations for policy-makers

Comparison of the kinetic parameters of alternative oxidases from Trypanosoma brucei and Arabidopsis thaliana-a tale of two cavities

The alternative oxidase (AOX) is widespread in plants, fungi, and some protozoa. While the general structure of the AOX remains consistent, its overall activity, sources of kinetic activation and their sensitivity to inhibitors varies between species. In this study, the recombinant Trypanosoma brucei AOX (rTAO) and Arabidopsis thaliana AOX1A (rAtAOX1A) were expressed in the Escherichia coli ΔhemA mutant FN102, and the kinetic parameters of purified AOXs were compared. Results showed that rTAO possessed the highest V max and K m for quinol-1, while much lower V max and K m were observed in the rAtAOX1A. The catalytic efficiency (k cat/K m) of rTAO was higher than that of rAtAOX1A. The rTAO also displayed a higher oxygen affinity compared to rAtAOX1A. It should be noted that rAtAOX1a was sensitive to α-keto acids while rTAO was not. Nevertheless, only pyruvate and glyoxylate can fully activate Arabidopsis AOX. In addition, rTAO and rAtAOX1A showed different sensitivity to AOX inhibitors, with ascofuranone (AF) being the best inhibitor against rTAO, while colletochlorin B (CB) appeared to be the most effective inhibitor against rAtAOX1A. Octylgallate (OG) and salicylhydroxamic acid (SHAM) are less effective than the other inhibitors against protist and plant AOX. A Caver analysis indicated that the rTAO and rAtAOX1A differ with respect to the mixture of polar residues lining the hydrophobic cavity, which may account for the observed difference in kinetic and inhibitor sensitivities. The data obtained in this study are not only beneficial for our understanding of the variation in the kinetics of AOX within protozoa and plants but also contribute to the guidance for the future development of phytopathogenic fungicides

Black strings in AdS_5

We present non-extremal magnetic black string solutions in five-dimensional gauged supergravity. The conformal infinity is the product of time and S^1xS_h, where S_h denotes a compact Riemann surface of genus h. The construction is based on both analytical and numerical techniques. We compute the holographic stress tensor, the Euclidean action and the conserved charges of the solutions and show that the latter satisfy a Smarr-type formula. The phase structure is determined in the canonical ensemble, and it is shown that there is a first order phase transition from small to large black strings, which disappears above a certain critical magnetic charge that is obtained numerically. For another particular value of the magnetic charge, that corresponds to a twisting of the dual super Yang-Mills theory, the conformal anomalies coming from the background curvature and those arising from the coupling to external gauge fields exactly cancel. We also obtain supersymmetric solutions describing waves propagating on extremal BPS magnetic black strings, and show that they possess a Siklos-Virasoro reparametrization invariance.Comment: 40 pages, 7 figures, JHEP3. v2: minor corrections, 2 references added. v3: typos in holographic stress tensor corrected, 3 references adde

Kinetic characterisation and inhibitor sensitivity of Candida albicans and Candida auris recombinant AOX expressed in a self-assembled proteoliposome system

Candidemia caused by Candida spp. is a serious threat in hospital settings being a major cause of acquired infection and death and a possible contributor to Covid-19 mortality. Candidemia incidence has been rising worldwide following increases in fungicide-resistant pathogens highlighting the need for more effective antifungal agents with novel modes of action. The membrane-bound enzyme alternative oxidase (AOX) promotes fungicide resistance and is absent in humans making it a desirable therapeutic target. However, the lipophilic nature of the AOX substrate (ubiquinol-10) has hindered its kinetic characterisation in physiologically-relevant conditions. Here, we present the purification and expression of recombinant AOXs from C. albicans and C. auris in a self-assembled proteoliposome (PL) system. Kinetic parameters (Km and Vmax) with respect to ubiquinol-10 have been determined. The PL system has also been employed in dose–response assays with novel AOX inhibitors. Such information is critical for the future development of novel treatments for Candidemia

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Over-expression and purification of a pea mitochondrial heat-shock protein

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Musculoskeletal health in the workplace

Musculoskeletal (MSK) problems remain the most frequent reason why individuals are absent from work, including those with workrelated musculoskeletal disorders (WRMSDs or MSDs) and those with chronic MSK problems. This paper aims to examine changes in work and the workforce since 2000; how work impacts on chronic MSK conditions and how we can help people with these conditions to stay at work. While our knowledge of the causes of WRMSDs has increased since 2000, there has been limited workplace action in reducing exposure to hazards. A life course approach is needed as individuals of all ages are reporting MSK problems. How people work has also changed and informalisation of work contracts has increased with a perceived concurrent reduction in occupational safety and health (OSH) protection. Retaining people at work with MSK problems requires compliance with relevant safety, health and diversity legislation and a risk management approach. Good and open communication within the workplace and identification of other sources of support is also necessary. Considerations must be made at the individual level (internal motivation), organisational level (a supportive manager) and self-management of symptoms. Simple case examples are provided in the paper of what works in practice as well as a proposed research agenda. Increased awareness at all levels of society of MSK health is essential