Biodistribution and dosimetry of the PET radioligand [F]CHDI-650 in mice for detection of mutant huntingtin aggregates.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene which encodes the mutant huntingtin protein (mHTT) that is associated with HD-related neuropathophysiology. Noninvasive visualization of mHTT aggregates in the brain, with positron emission tomography (PET), will allow to reliably evaluate the efficacy of therapeutic interventions in HD. This study aimed to assess the radiation burden of [F]CHDI-650, a novel fluorinated mHTT radioligand, in humans based on both in vivo and ex vivo biodistribution in mice and subsequent determination of dosimetry for dosing in humans.

Multi-omics analyses of cancer-linked clinical salmonellae reveal bacterial-induced host metabolic shift and mTOR-dependent cell transformation.

Salmonellae are associated epidemiologically and experimentally with colon cancer. To understand how Salmonella induces cell transformation, we performed multi-omics and phenotypic analyses of Salmonella clinical strains isolated from patients later diagnosed with colon cancer (case strains) and control strains from patients without cancer. We show that high transformation efficiency is a frequent intrinsic feature of clinical (case and control) salmonellae, yet case strains showed higher transformation efficiency than control strains.

Systems mapping of bidirectional endosomal transport through the crowded cell.

Kinesin and dynein-dynactin motors move endosomes and other vesicles bidirectionally along microtubules, a process mainly studied under in vitro conditions. Here, we provide a physiological bidirectional transport model following color-coded, endogenously tagged transport-related proteins as they move through a crowded cellular environment. Late endosomes (LEs) surf bidirectionally on Protrudin-enriched endoplasmic reticulum (ER) membrane contact sites, while hopping and gliding along microtubules and bypassing cellular obstacles, such as mitochondria.

The ORP9-ORP11 dimer promotes sphingomyelin synthesis.

Numerous lipids are heterogeneously distributed among organelles. Most lipid trafficking between organelles is achieved by a group of lipid transfer proteins (LTPs) that carry lipids using their hydrophobic cavities. The human genome encodes many intracellular LTPs responsible for lipid trafficking and the function of many LTPs in defining cellular lipid levels and distributions is unclear.

USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism.

Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified.

The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent.

The immune checkpoint NKG2A/CD94 is a promising target for cancer immunotherapy, and its ligand major histocompatibility complex E (MHC-E) is frequently upregulated in cancer. NKG2A/CD94-mediated inhibition of lymphocytes depends on the presence of specific leader peptides in MHC-E, but when and where they are presented in situ is unknown. We apply a nanobody specific for the Qdm/Qa-1 complex, the NKG2A/CD94 ligand in mouse, and find that presentation of Qdm peptide depends on every member of the endoplasmic reticulum-resident peptide loading complex.

Cellular Validation of a Chemically Improved Inhibitor Identifies Monoubiquitination on OTUB2.

Ubiquitin thioesterase OTUB2, a cysteine protease from the ovarian tumor (OTU) deubiquitinase superfamily, is often overexpressed during tumor progression and metastasis. Development of OTUB2 inhibitors is therefore believed to be therapeutically important, yet potent and selective small-molecule inhibitors targeting OTUB2 are scarce. Here, we describe the development of an improved OTUB2 inhibitor, , comprising a chloroacethydrazide moiety that covalently reacts to the active-site cysteine residue.

RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear.

Identification of pre-synaptic density networks using [C]UCB-J PET imaging and ICA in mice.

Background: Synaptic vesicle glycoprotein 2A (SV2A) is a vesicle glycoprotein involved in neurotransmitter release. SV2A is located on the pre-synaptic terminals of neurons and visualized using the radioligand [C]UCB-J and positron emission tomography (PET) imaging. Thus, SV2A PET imaging can provide a proxy for pre-synaptic density in health and disease.

Examining user perspective of an online learning resource for physiotherapists: A mixed methods study of the TRAIN program.

Background: Implementing task specific training is a commonly reported challenge for less experienced therapists. A potential method to improve the ability of recent graduate and student therapists is to upskill regarding task specific training via an online education resource.

Purpose: To evaluate the use and acceptability of the TRAIN program as an online learning resource for physiotherapists.

Mobile late endosomes modulate peripheral endoplasmic reticulum network architecture.

The endoplasmic reticulum (ER) is the largest organelle contacting virtually every other organelle for information exchange and control of processes such as transport, fusion, and fission. Here, we studied the role of the other organelles on ER network architecture in the cell periphery. We show that the co-migration of the ER with other organelles, called ER hitchhiking facilitated by late endosomes and lysosomes is a major mechanism controlling ER network architecture.

Human VAPome Analysis Reveals MOSPD1 and MOSPD3 as Membrane Contact Site Proteins Interacting with FFAT-Related FFNT Motifs.

Membrane contact sites (MCS) are intracellular regions where two organelles come closer to exchange information and material. The majority of the endoplasmic reticulum (ER) MCS are attributed to the ER-localized tether proteins VAPA, VAPB, and MOSPD2. These recruit other proteins to the ER by interacting with their FFAT motifs.

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility.

Post-Laser Twin Anemia Polycythemia Sequence: Diagnosis, Management, and Outcome in an International Cohort of 164 Cases.

The aim of this study was to investigate the management and outcome in the post-laser twin anemia polycythemia sequence (TAPS). Data of the international TAPS Registry, collected between 2014 and 2019, were used for this study. The primary outcomes were perinatal mortality and severe neonatal morbidity.

The Covid-19 crisis as a career shock: Implications for careers and vocational behavior.

The covid-19 pandemic is a for many people across the globe. In this article, we reflect on how insights from the literature on career shocks can help us understand the career consequences of the pandemic and offer suggestions for future research in this area. In particular, we offer three "key lessons".

SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport.

The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by small membrane-bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to regain functional autonomy is unknown.

A Sustainable Career Perspective of Work Ability: The Importance of Resources across the Lifespan.

In this study, we examine employees' perceptions of their work ability from a sustainable career perspective. Specifically, we investigate the role of a person's perceived current fit (i.e.

Should Employers Invest in Employability? Examining Employability as a Mediator in the HRM - Commitment Relationship.

This study investigates the relationship between perceived investments in Human Resource (HR) practices and workplace commitment, from the perspective of social exchange theory. An innovative feature is that we introduce perceived employability as a potential mediator, thus bringing in a career perspective: our argument is that perceived investments in HR practices promote feelings of employability, which then create workplace commitment. Based on a 6-week follow-up sample ( = 437) and a 1-year follow-up sample ( = 127), the results of structural equation modeling analyses mostly provided support for our hypotheses.

Buffering the Breach: Examining the Three-Way Interaction Between Unit Climate Level, Strength, and Psychological Contract Breach.

Despite the wealth of research showing that psychological contract breach (PCB) has negative outcomes for individuals, knowledge about the influence of the social context in which breaches are experienced is still scarce. This is surprising, as scholars have argued that work climates, such as when unit members are generally highly committed, could buffer an individual's negative experiences at work. Yet, to date, the unit climate and PCB literatures have largely remained separated and our main goal is to integrate these fields.

Decoding emotions in expressive music performances: A multi-lab replication and extension study.

With over 560 citations reported on Google Scholar by April 2018, a publication by Juslin and Gabrielsson (1996) presented evidence supporting performers' abilities to communicate, with high accuracy, their intended emotional expressions in music to listeners. Though there have been related studies published on this topic, there has yet to be a direct replication of this paper. A replication is warranted given the paper's influence in the field and the implications of its results.

The Best of Both Worlds: The Role of Career Adaptability and Career Competencies in Students' Well-Being and Performance.

In addition to acquiring occupation-specific knowledge and skills, students need to develop a set of career self-management skills - or resources - that helps them to successfully maneuver the various career-related challenges they face and that stimulate their well-being, engagement, and performance in studying tasks. In the current study, we apply the Job Demands-Resources (JD-R) theory in an educational setting and suggest that career adaptability and career competencies are important career resources that predict both life satisfaction and academic performance via students' satisfaction with the choice of their major and study engagement. Undergraduate students ( = 672) from nine different colleges and universities in Lithuania participated in the study.

Chemical and genetic control of IFNγ-induced MHCII expression.

The cytokine interferon-γ (IFNγ) can induce expression of MHC class II (MHCII) on many different cell types, leading to antigen presentation to CD4 T cells and immune activation. This has also been linked to anti-tumour immunity and graft-versus-host disease. The extent of MHCII upregulation by IFNγ is cell type-dependent and under extensive control of epigenetic regulators and signalling pathways.