Discrete arginine topologies guide escape of miniature proteins from early endosomes to the cytoplasm

Polypeptides and peptide mimetics sample a wide chemical space with broad potential to modulate cellular function, but their application to cytoplasmic targets is limited because when added to cells their cytosolic concentration remains low. This limitation is due to a diffusion barrier (the plasma membrane) and absence of dedicated import machinery. Highly cationic peptides and proteins sometimes gain cytosolic access, but how they do so is not well understood. Using a small library of cationic miniature proteins, I probe the influence of positive charge number and orientation on the ability the miniature protein to access the cytoplasm. Using a novel assay, I identify a cationic miniature protein, which we called 5·3, that carries a discrete arginine motif and efficiently reaches the cytoplasm. Database searches find that the precise motif identified (an arginine present in positions i, i + 4, i + 7, i + 10, and i + 11 of an alpha-helix) is not present in nature, but that similar motifs are present in natural proteins that interact with cellular membranes. Finally, I examine the cellular pathway by which 5·3 reaches the cytoplasm. I find that this miniature protein enters the cell via a dynamin and cholesterol dependent endocytic mechanism and is delivered to Rab5+ early endosomes. In contrast to the shiga-like toxins, and many non-enveloped viruses (which escape to the cytoplasm from the endoplasmic reticulum) as well as other peptides previously identified as \u27cell penetrating\u27, only 5·3 escapes from early endosomes. These findings should enable the future dissection of the precise molecular events underlying cytoplasmic access of peptides and proteins, and may illuminate principles for the engineering of peptides and peptidomimetics that access cytoplasmic targets

Le programme MORECOWBELL de la NSA sonne le glas du DNS

Traduit de l'anglais. Titre original : « NSA's MORECOWBELL: Knell for DNS ».Cet article décrit le programme « MORECOWBELL » de l'agence d'espionnage étasunienne NSA et montre les défauts du protocole DNS qu'il exploite. Un état de l'art des alternatives à DNS est ensuite donné, en évaluant l'efficiacité contre les attaques telles que celles perpétrées par la NSASur le net, presque tout commence par une requête au Domain Name System (DNS, pour « système de noms de domaine »), un protocole au cœur d'Internet qui permet aux usagers d'accéder à des services par un nom tel que www.example.com, plutôt que par une adresse IP numérique comme 2001:DB8:4145::4242. Développé au « bon vieux temps », le DNS contemporain ressemble à un tableau de bord de l'activité du réseau pour malvoyants. Par conséquent, il attire non seulement toutes sortes de surveillances à des fins commerciales, mais aussi la National Security Agency (NSA), comme le montrent de nouveaux documents sur son programme MORECOWBELL. Étant données les faiblesses de conception du DNS, on peut se demander si le DNS peut être sécurisé et sauvé ou bien si il doit être remplacé---tout du moins pour certains cas d'utilisation

Relative impact of residual cytogenetic abnormalities and flow cytometric measurable residual disease on outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia

Measurable residual disease (MRD) before hematopoietic cell transplantation (HCT) is an independent established prognostic factor in patients with acute myeloid leukemia (AML). Several methods exist to evaluate the presence of residual leukemia cells, but how these are used best in combination is unclear. In order to examine how residual cytogenetic abnormalities and MRD testing by multiparameter flow cytometry (MFC) may refine risk assessment before HCT, we analyzed 506 adults with cytogenetically abnormal AML who underwent both routine karyotyping and MFC MRD testing before receiving a first allograft while in morphologic remission. Testing for residual cytogenetic abnormalities and MFC MRD identified four groups of patients with differential relapse-free survival (RFS) (hazard ratio [HR]=1.63 for Cytoabnormal/MFCnegative [P=0.01, n=63], HR=3.24 for Cytonormal/MFCpositive [P<0.001, n=60], and HR=5.50 for Cytoabnormal/MFCpositive [P<0.001, n=56] with Cytonormal/MFCnegative as reference [n=327]) and overall survival (OS) (HR=1.55 for Cytoabnormal/MFCnegative [P=0.03], HR=2.69 for Cytonormal/MFCpositive [P<0.001], and HR=4.15 for Cytoabnormal/MFCpositive [P<0.001] with Cytonormal/MFCnegative as reference). Results were similar for patients who received myeloablative or non-myeloablative conditioning. C-statistic values were higher, indicating higher accuracy, when using pre-HCT cytogenetic and MFC MRD information together for prediction of relapse, RFS, and OS, rather than using either test result alone. This study indicates that residual cytogenetic abnormalities and MFC MRD testing provide complementary prognostic information for post- HCT outcomes in patients with cytogenetically abnormal AML undergoing allogeneic HCT

A meta-review of literature reviews assessing the capacity of patients with severe mental disorders to make decisions about their healthcare.

Background: Determining the mental capacity of psychiatric patients for making healthcare related decisions is crucial in clinical practice. This meta-review of review articles comprehensively examines the current evidence on the capacity of patients with a mental illness to make medical care decisions. Methods: Systematic review of review articles following PRISMA recommendations. PubMed, Scopus, CINAHL and PsycInfo were electronically searched up to 31 January 2020. Free text searches and medical subject headings were combined to identify literature reviews and meta-analyses published in English, and summarising studies on the capacity of patients with serious mental illnesses to make healthcare and treatment related decisions, conducted in any clinical setting and with a quantitative synthesis of results. Publications were selected as per inclusion and exclusion criteria. The AMSTAR II tool was used to assess the quality of reviews. Results: Eleven publications were reviewed. Variability on methods across studies makes it difficult to precisely estimate the prevalence of decision-making capacity in patients with mental disorders. Nonetheless, up to three-quarters of psychiatric patients, including individuals with serious illnesses such as schizophrenia or bipolar disorder may have capacity to make medical decisions in the context of their illness. Most evidence comes from studies conducted in the hospital setting; much less information exists on the healthcare decision making capacity of mental disorder patients while in the community. Stable psychiatric and non-psychiatric patients may have a similar capacity to make healthcare related decisions. Patients with a mental illness have capacity to judge risk-reward situations and to adequately decide about the important treatment outcomes. Different symptoms may impair different domains of the decisional capacity of psychotic patients. Decisional capacity impairments in psychotic patients are temporal, identifiable, and responsive to interventions directed towards simplifying information, encouraging training and shared decision making. The publications complied satisfactorily with the AMSTAR II critical domains. Conclusions: Whilst impairments in decision-making capacity may exist, most patients with a severe mental disorder, such as schizophrenia or bipolar disorder are able to make rational decisions about their healthcare. Best practice strategies should incorporate interventions to help mentally ill patients grow into the voluntary and safe use of medications

Genomic research, publics and experts in Latin America: Nation, race and body

The articles in this issue highlight contributions that studies of Latin America can make to wider debates about the effects of genomic science on public ideas about race and nation. We argue that current ideas about the power of genomics to transfigure and transform existing ways of thinking about human diversity are often overstated. If a range of social contexts are examined, the effects are uneven. Our data show that genomic knowledge can unsettle and reinforce ideas of nation and race; it can be both banal and highly politicized. In this introduction, we outline concepts of genetic knowledge in society; theories of genetics, nation and race; approaches to public understandings of science; and the Latin American contexts of transnational ideas of nation and race

Knowledge transfer and management in tourism organisations: an emerging research agenda

Authors' final draft version. Final version published in Tourism Management; available online at http://www.sciencedirect.com/This paper reviews current research on knowledge management and knowledge transfer in the context of innovations. Specific attention is focussed on the integration of management perspectives into tourism research. The paper explores some of the key mechanisms and conduits of knowledge transfer within tourism. In doing so it explores such concepts as interlocking directorships, communities of practice, learning regions and labour mobility. There is also an emerging research agenda on knowledge management within tourism but progress is variable with most research being within the hotel sector, where a range of recent studies have examined aspects of knowledge transfer. The paper also draws attention to the need to give closer attention to the nature of innovations within tourism and to consider these in a knowledge management framework

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony–stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease–negative complete remission (MRD– CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD– CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.The CLAG-M/sorafenib trial was supported by Bayer Pharmaceuticals Inc. A.B.H. was supported by an ASCO Young Investigator award.Peer reviewe