Cargo adaptor identity controls the mechanism and kinetics of dynein activation.

Cytoplasmic dynein-1 (dynein), the primary retrograde motor in most eukaryotes, supports the movement of hundreds of distinct cargos, each with specific trafficking requirements. To achieve this functional diversity, dynein must bind to the multi-subunit complex dynactin and one of a family of cargo adaptors to be converted into an active, processive motor complex. Very little is known about the dynamic processes that promote the formation of this complex.

A phase I randomized study to evaluate safety, pharmacokinetics, and pharmacodynamics of SIR2446M, a selective RIPK1 inhibitor, in healthy participants.

Activation of receptor-interacting protein kinase 1 (RIPK1), a broadly expressed serine/threonine protein kinase, by pro-inflammatory cytokines and pathogens can result in apoptosis, necroptosis, or inflammation. RIPK1 inhibition has been shown to reduce inflammation and cell damage in preclinical studies and may have therapeutic potential for degenerative and inflammatory diseases. SIR2446 is a potent and selective novel small molecule RIPK1 kinase inhibitor.

CCSer2 gates dynein activity at the cell periphery.

Cytoplasmic dynein-1 (dynein) is a microtubule-associated, minus end-directed motor that traffics hundreds of different cargos. Dynein must discriminate between cargos and traffic them at the appropriate time from the correct cellular region. How dynein's trafficking activity is regulated in time or cellular space remains poorly understood.

Short Report: CAR Tregs mediate linked suppression and infectious tolerance in islet transplantation.

Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR Tregs limited anti-HLA-A2 alloimmunity. However, it was unknown if A2-CAR Tregs could also limit immunity to autoantigens.

Storylines of family medicine V: ways of thinking-honing the therapeutic self.

is a 12-part series of thematically linked essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'V: ways of thinking-honing the therapeutic self', authors present the following sections: 'Reflective practice in action', 'The doctor as drug-Balint groups', 'Cultivating compassion', 'Towards a humanistic approach to doctoring', 'Intimacy in family medicine', 'The many faces of suffering', 'Transcending suffering' and 'The power of listening to stories.' May readers feel a deeper sense of their own therapeutic agency by reflecting on these essays.

Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules.

Lis1 is a key cofactor for the assembly of active cytoplasmic dynein complexes that transport cargo along microtubules. Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping assays, we investigated how Lis1 binding affects the motility and force generation of yeast dynein in vitro.

Auditory Test of Processing Speed: Preliminary validation of a smartphone-based test of mental speed.

Background: The Symbol Digit Modalities Test (SDMT) is a gold-standard measure of cognitive efficiency and processing speed for people with multiple sclerosis (PwMS) but relies on vision and oculomotor function.

Objectives: To develop and validate a new processing speed test with minimal memory involvement and no eye function requirements.

Methods: We created an Auditory Test of Processing Speed (ATOPS).

"Smoking during pregnancy - Perinatal outcomes, financial implications, and tobacco treatment services".

Objective: Smoking in pregnancy is the leading modifiable risk factor for poor pregnancy outcomes. A sample population from United Lincolnshire Hospital NHS Trust (ULHT), with the highest prevalence of smoking at the time of delivery (SATOD) in England from April 2020 to March 2021 was studied. The project mapped the journey of women who smoked during pregnancy until birth and compared with a non-smoking cohort.

HIV-1 binds dynein directly to hijack microtubule transport machinery.

Viruses exploit host cytoskeletal elements and motor proteins for trafficking through the dense cytoplasm. Yet the molecular mechanism that describes how viruses connect to the motor machinery is unknown. Here, we demonstrate the first example of viral microtubule trafficking from purified components: HIV-1 hijacking microtubule transport machinery.

Predicting employment deterioration with the Processing Speed Test (PST) and SDMT in multiple sclerosis.

Background: Employment deterioration is common in people with multiple sclerosis (PwMS). Clinicians often learn of job loss after its occurrence, leaving no opportunity for preventive measures.

Objectives: Identify which neuropsychological measures discriminate between healthy volunteers (HVs) and employed/disabled PwMS at baseline and predict work deterioration over 2 years.

Erratum: 210 Preliminary Validation of the Arabic Global Neuropsychological Assessment (GNA) - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2023.

Ndel1 disfavors dynein-dynactin-adaptor complex formation in two distinct ways.

Dynein is the primary minus-end-directed microtubule motor protein. To achieve activation, dynein binds to the dynactin complex and an adaptor to form the "activated dynein complex." The protein Lis1 aids activation by binding to dynein and promoting its association with dynactin and the adaptor.

Distinct dynein complexes defined by DYNLRB1 and DYNLRB2 regulate mitotic and male meiotic spindle bipolarity.

Spindle formation in male meiosis relies on the canonical centrosome system, which is distinct from acentrosomal oocyte meiosis, but its specific regulatory mechanisms remain unknown. Herein, we report that DYNLRB2 (Dynein light chain roadblock-type-2) is a male meiosis-upregulated dynein light chain that is indispensable for spindle formation in meiosis I. In Dynlrb2 KO mouse testes, meiosis progression is arrested in metaphase I due to the formation of multipolar spindles with fragmented pericentriolar material (PCM).

Challenges in implementing GP clusters in Scotland: a qualitative study comparing the views of senior primary care stakeholders in 2016 with those in 2021.

Background: Formation of GP clusters began in Scotland in April 2016 as part of a new Scottish GP contract. They aim to improve the care quality for local populations (intrinsic role) and the integration of health and social care (extrinsic role).

Aim: To compare predicted challenges of cluster implementation in 2016 with reported challenges in 2021.

Evaluating primary care transformation: synthesis of findings from UK pilot project reviews.

Background: Pilot 'new models' of primary care have been funded across the UK since 2015, through various national transformation funds. Reflections and syntheses of evaluation findings provide an additional layer of insight into 'what works' in transforming primary care.

Aim: To identify good practice in policy design, implementation, and evaluation for primary care transformation.

How do the working lives of general practitioners in rural areas compare with elsewhere in Scotland? Cross-sectional analysis of the Scottish School of Primary Care Survey.

Introduction: The shortage of GPs in Scotland is concerning, particularly in rural areas. There are many reasons why GPs are leaving general practice; however, satisfaction with working life is an important predictor of GP retention. The aim of this study was to compare the working lives and intentions to reduce work participation of rural GPs and GPs working elsewhere in Scotland.

Ndel1 modulates dynein activation in two distinct ways.

Dynein is the primary minus-end-directed microtubule motor [1]. To achieve activation, dynein binds to the dynactin complex and an adaptor to form the "activated dynein complex" [2, 3]. The protein Lis1 aids activation by binding to dynein and promoting its association with dynactin and adaptor [4, 5].

Repeated forms, testing intervals, and SDMT performance in a large multiple sclerosis dataset.

Background: The Symbol Digit Modalities Test (SDMT), the most reliable and sensitive measure of cognition in people with multiple sclerosis (PwMS), is increasingly used in clinical trials and care.

Objectives: We aimed to establish how SDMT performance is influenced by repeating forms and frequency of use in PwMS.

Methods: A retrospective analysis was completed on a large database of PwMS (n = 740) with multiple SDMT administrations.

How do the working lives of general practitioners in rural areas compare with elsewhere in Scotland? Cross-sectional analysis of the Scottish School of Primary Care National GP Survey.

Introduction: Like many countries around the world, Scotland faces a shortage of general practitioners (GPs) due to both recruitment and retention issues. Such workforce shortages are of particular concern in rural areas. There are many reasons why GPs are leaving general practice; however, satisfaction with working life is an important predictor of GP retention.

PTEN is required for human Treg suppression of costimulation in vitro.

Regulatory T-cell (Treg) therapy is under clinical investigation for the treatment of transplant rejection, autoimmune disease, and graft-versus-host disease. With the advent of genome editing, attention has turned to reinforcing Treg function for therapeutic benefit. A hallmark of Tregs is dampened activation of PI3K-AKT signaling, of which PTEN is a major negative regulator.

The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor.

Dynein harnesses ATP hydrolysis to move cargo on microtubules in multiple biological contexts. Dynein meets a unique challenge in meiosis by moving chromosomes tethered to the nuclear envelope to facilitate homolog pairing essential for gametogenesis. Though processive dynein motility requires binding to an activating adaptor, the identity of the activating adaptor required for dynein to move meiotic chromosomes is unknown.

Crowd-sourcing observations of volcanic eruptions during the 2021 Fagradalsfjall and Cumbre Vieja events.

Two remarkable 2021 eruptions – Fagradalsfjall (Reykjanes, Iceland) and Cumbre Vieja (La Palma, Spain) – have been captured in imagery and videography at unprecedented spatial and temporal resolution by tourists, volcano-enthusiasts, and media organizations. We propose this represents the start of a new era for observational volcanology, with the abundance of eruption imagery leveraged for scientific use.

Nde1 and Ndel1: Outstanding Mysteries in Dynein-Mediated Transport.

Cytoplasmic dynein-1 (dynein) is the primary microtubule minus-end directed molecular motor in most eukaryotes. As such, dynein has a broad array of functions that range from driving retrograde-directed cargo trafficking to forming and focusing the mitotic spindle. Dynein does not function in isolation.