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My brave year of firsts : tries, sighs, and high fives
\"Celebrates the extraordinary, everyday bravery of trying new things for the very first time\"--Dust jacket flap.
Book
Exceptionally widespread nanomachines composed of type IV pilins: the prokaryotic Swiss Army knives
Prokaryotes have engineered sophisticated surface nanomachines that have allowed them to colonize Earth and thrive even in extreme environments. Filamentous machineries composed of type IV pilins, which are associated with an amazing array of properties ranging from motility to electric conductance, are arguably the most widespread since distinctive proteins dedicated to their biogenesis are found in most known species of prokaryotes. Several decades of investigations, starting with type IV pili and then a variety of related systems both in bacteria and archaea, have outlined common molecular and structural bases for these nanomachines. Using type IV pili as a paradigm, we will highlight in this review common aspects and key biological differences of this group of filamentous structures.
Using type IV pili as a paradigm, we review common genetic, structural and mechanistic features (many) as well as differences (few) of the exceptionally widespread and functionally versatile prokaryotic nano-machines composed of type IV pilins.
Journal Article
Just one more sleep : all good things come to those who wait ... and wait ... and wait
Helping kids celebrate milestones and holidays throughout the year, this hilarious book channels childhood exuberance and explains why waiting can be wonderful - and why it can be worth it!
CHILDBOOK
An epigenetic clock for human skeletal muscle
Background Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan‐tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. Methods To address this, we developed a more accurate, muscle‐specific epigenetic clock based on the genome‐wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18–89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome‐wide association study of age‐associated DNA methylation patterns in skeletal muscle. Results The newly developed clock uses 200 cytosine‐phosphate–guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine‐phosphate–guanine dinucleotides of the pan‐tissue clock. The muscle clock outperformed the pan‐tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan‐tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan‐tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. Conclusions We have developed a muscle‐specific epigenetic clock that predicts age with better accuracy than the pan‐tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle‐specific biological ageing processes.
Journal Article
Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle
Exercise training prevents age‐related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late‐life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta‐analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age‐related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity. Higher fitness levels were associated with attenuated differential methylation and transcription during aging in human muscle. Furthermore, exercise training targets many of the age‐related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best exercise regimes to optimize longevity.
Journal Article
The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men
Skeletal muscle unloading due to joint immobilization induces muscle atrophy, which has primarily been attributed to reductions in protein synthesis in humans. However, no study has evaluated the skeletal muscle proteome response to limb immobilization using SWATH proteomic methods. This study characterized the shifts in individual muscle protein abundance and corresponding gene sets after 3 and 14 d of unilateral lower limb immobilization in otherwise healthy young men. Eighteen male participants (25.4 ±5.5 y, 81.2 ±11.6 kg) underwent 14 d of unilateral knee-brace immobilization with dietary provision and following four-weeks of training to standardise acute training history. Participant phenotype was characterized before and after 14 days of immobilization, and muscle biopsies were obtained from the vastus lateralis at baseline (pre-immobilization) and at 3 and 14 d of immobilization for analysis by SWATH-MS and subsequent gene-set enrichment analysis (GSEA). Immobilization reduced vastus group cross sectional area (-9.6 ±4.6%, P <0.0001), immobilized leg lean mass (-3.3 ±3.9%, P = 0.002), unilateral 3-repetition maximum leg press (-15.6 ±9.2%, P <0.0001), and maximal oxygen uptake (-2.9 ±5.2%, P = 0.044). SWATH analyses consistently identified 2281 proteins. Compared to baseline, two and 99 proteins were differentially expressed (FDR <0.05) after 3 and 14 d of immobilization, respectively. After 14 d of immobilization, 322 biological processes were different to baseline (FDR <0.05, P < 0.001). Most (77%) biological processes were positively enriched and characterized by cellular stress, targeted proteolysis, and protein-DNA complex modifications. In contrast, mitochondrial organization and energy metabolism were negatively enriched processes. This study is the first to use data independent proteomics and GSEA to show that unilateral lower limb immobilization evokes mitochondrial dysfunction, cellular stress, and proteolysis. Through GSEA and network mapping, we identify 27 hub proteins as potential protein/gene candidates for further exploration.
Journal Article
Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins
Conserved lipid transfer proteins of the Ups/PRELI family regulate lipid accumulation in mitochondria by shuttling phospholipids in a lipid-specific manner across the intermembrane space. Here, we combine structural analysis, unbiased genetic approaches in yeast and molecular dynamics simulations to unravel determinants of lipid specificity within the conserved Ups/PRELI family. We present structures of human PRELID1–TRIAP1 and PRELID3b–TRIAP1 complexes, which exert lipid transfer activity for phosphatidic acid and phosphatidylserine, respectively. Reverse yeast genetic screens identify critical amino acid exchanges that broaden and swap their lipid specificities. We find that amino acids involved in head group recognition and the hydrophobicity of flexible loops regulate lipid entry into the binding cavity. Molecular dynamics simulations reveal different membrane orientations of PRELID1 and PRELID3b during the stepwise release of lipids. Our experiments thus define the structural determinants of lipid specificity and the dynamics of lipid interactions by Ups/PRELI proteins.
The Ups/PRELI family mediates intramitochondrial lipid distribution and synthesis by shuttling phospholipids between both mitochondrial membranes. Here the authors combine X-ray crystallography, MD simulations and yeast genetic screens and identify residues that are important for Ups/PRELI lipid specificity and reveal a dual lipid recognition mechanism in Ups/PRELI family members.
Journal Article
Multi-clonal SARS-CoV-2 neutralization by antibodies isolated from severe COVID-19 convalescent donors
The interactions between antibodies, SARS-CoV-2 and immune cells contribute to the pathogenesis of COVID-19 and protective immunity. To understand the differences between antibody responses in mild versus severe cases of COVID-19, we analyzed the B cell responses in patients 1.5 months post SARS-CoV-2 infection. Severe, and not mild, infection correlated with high titers of IgG against Spike receptor binding domain (RBD) that were capable of ACE2:RBD inhibition. B cell receptor (BCR) sequencing revealed that VH3-53 was enriched during severe infection. Of the 22 antibodies cloned from two severe donors, six exhibited potent neutralization against authentic SARS-CoV-2, and inhibited syncytia formation. Using peptide libraries, competition ELISA and mutagenesis of RBD, we mapped the epitopes of the neutralizing antibodies (nAbs) to three different sites on the Spike. Finally, we used combinations of nAbs targeting different immune-sites to efficiently block SARS-CoV-2 infection. Analysis of 49 healthy BCR repertoires revealed that the nAbs germline VHJH precursors comprise up to 2.7% of all VHJHs. We demonstrate that severe COVID-19 is associated with unique BCR signatures and multi-clonal neutralizing responses that are relatively frequent in the population. Moreover, our data support the use of combination antibody therapy to prevent and treat COVID-19.
Journal Article
Culture Corrupts! A Qualitative Study of Organizational Culture in Corrupt Organizations
Although theory refers to organizational culture as an important variable in corrupt organizations, only little empirical research has addressed the characteristics of a corrupt organizational culture. Besides some characteristics that go hand in hand with unethical behavior and other features of corrupt organizations, we are still not able to describe a corrupt organizational culture in terms of its underlying assumptions, values, and norms. With a qualitative approach, we studied similarities of organizational culture across different corrupt organizations. In this study, we performed content analysis on interviews of 14 independent experts about their experience with corrupt organizations. With this approach, we gained insights about different corrupt organizations spanning different branches (e.g., government, foreign trade, pharmacy, sports, building industry). We found that corrupt organizations perceive themselves to fight in a war, which leads to their taken-for-granted assumption that \"the end justifies the means\". This assumption inspires many values and norms of the organizational culture. An important value in a corrupt organization is \"security\", and an important norm is punishment of deviant (i.e., non-corrupt) behavior. Furthermore, managers and employees differ in their perception of organizational culture. While the management endorses values, such as success, results, and performance, and implements these values in their norms of goal setting, employees make use of rationalization strategies and endorse values of security and team spirit.
Journal Article
Patient Experiences of the Emergency Laparotomy Pathway: A Qualitative Study
Introduction
Emergency laparotomy (EL) is a commonly performed operation with high rates of morbidity and mortality. Despite a growing body of literature on outcomes from EL, there is sparse literature on the patient experience. The aim of this study is to capture the perspective of patients on their EL experience. Qualitative methodology is used as a platform to allow patients to express their personal experiences and ideas around the EL process.
Materials and method
Participants were consented as a part of a large observational study, established across the three public teaching hospitals in Auckland, New Zealand. Patients who had an EL within the past 4 months were recruited. A recorded interview was conducted either face-to-face or over the telephone, using questions formulated from a previous systematic review on EL outcomes. Transcripts were transported to NVivo and thematically analysed by two reviewers.
Results
Fifteen participants were interviewed. The majority of participants were female, New Zealand European and 65 or older. Five important themes were identified. Overall, participants expressed satisfaction with their interactions with hospital staff. However, they wanted more information about their condition, operation and what outcomes might occur. Participants also described post-operative priorities in the acute setting, as well as long-standing physical and emotional impacts.
Conclusion
This study provides a better understanding of what is important to patients during the EL process. This information is important when considering ways to improve care and communication with patients undergoing EL.
Journal Article