Tissue Resident CD8+T-cells as mediators of protective immunity in breastmilk transmission of HCMV.

While the role of breastmilk antibodies to protect infants from CMV has been investigated, the role of T-cells, have received little attention. We compared the frequency of memory T-cell populations in breastmilk between mothers of infants who acquired breastmilk HCMV (transmitters) and those with uninfected infants (non-transmitters). Non-transmitter moms had an increased frequency of CD8+ effector memory T-cells (Tem) in their breastmilk.

Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes.

Proteins can be targeted for degradation by engineering biomolecules that direct them to the eukaryotic ubiquitination machinery. For instance, the fusion of an E3 ubiquitin ligase to a suitable target binding domain creates a 'biological Proteolysis-Targeting Chimera' (bioPROTAC). Here we employ an analogous approach where the target protein is recruited directly to a human E2 ubiquitin-conjugating enzyme via an attached target binding domain.

Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation.

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs.

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded.

TIM-3 CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with expression and motif accessibility.

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss.

Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation.

Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs).

A simeprevir-inducible molecular switch for the control of cell and gene therapies.

Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components.

Huntingtin loss in hepatocytes is associated with altered metabolism, adhesion, and liver zonation.

Huntington's disease arises from a toxic gain of function in the ( ) gene. As a result, many HTT-lowering therapies are being pursued in clinical studies, including those that reduce HTT RNA and protein expression in the liver. To investigate potential impacts, we characterized molecular, cellular, and metabolic impacts of chronic HTT lowering in mouse hepatocytes.

TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice.

Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target.

Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity.

Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects.

Gender Equity in Oceanography.

Gender equity, providing for full participation of people of all genders in the oceanographic workforce, is an important goal for the continued success of the oceanographic enterprise. Here, we describe historical obstructions to gender equity; assess recent progress and the current status of gender equity in oceanography by examining quantitative measures of participation, achievement, and recognition; and review activities to improve gender equity. We find that women receive approximately half the oceanography PhDs in many parts of the world and are increasing in parity in earlier levels of academic employment.

Single-Nucleus RNA-Seq Reveals Dysregulation of Striatal Cell Identity Due to Huntington's Disease Mutations.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin () gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, , and from wild-type controls.

Respiratory alkalinization and posterior cerebral artery dilatation predict acute mountain sickness severity during 10 h normobaric hypoxia.

New Findings: What is the central question of this study? The pathophysiology of acute mountain sickness (AMS), involving the respiratory, renal and cerebrovascular systems, remains poorly understood. How do the early adaptations in these systems during a simulated altitude of 5000 m relate to AMS risk? What is the main finding and its importance? The rate of blood alkalosis and cerebral artery dilatation predict AMS severity during the first 10 h of exposure to a simulated altitude of 5000 m. Slow metabolic compensation by the kidneys of respiratory alkalosis attributable to a brisk breathing response together with excessive brain blood vessel dilatation might be involved in early development of AMS.

Age-Related Differences in Perceived Exertion While Walking and Running Near the Preferred Transition Speed.

Purpose: To investigate whether youth and adults can perceive differences in exertion between walking and running at speeds near the preferred transition speed (PTS) and if there are age-related differences in these perceptions.

Methods: A total of 49 youth (10-12 y, n = 21; 13-14 y, n = 10; 15-17 y, n = 18) and 13 adults (19-29 y) completed a walk-to-run transition protocol to determine PTS and peak oxygen uptake. The participants walked and ran on a treadmill at 5 speeds (PTS-0.

Tertiary education in ergonomics and human factors: quo vadis?

In 2019, the Human Factors and Ergonomics (HFE) discipline turned 70; to celebrate, an international group of academics and educators have reflected on the status of HFE tertiary education across the globe. This paper draws on presentations and discussions from the 20th Triennial International Ergonomics Association (IEA) conference and considers the implications for HFE education programmes. Past, current, and future challenges are outlined and discussed with examples from different countries and programmes.

Early-onset twin-twin transfusion syndrome: Case series and systematic review.

Introduction: Data on the outcomes of early-onset twin-twin transfusion syndrome (TTTS), diagnosed before 18 weeks gestational age (GA), are sparse. We aimed to review the diagnosis, management and outcomes of early-onset TTTS.

Material And Methods: Pregnancy records at a single referral unit 2010-6 were reviewed.

Age-dependent variability in spatiotemporal gait parameters and the walk-to-run transition.

Adolescents tend to exhibit more variability in their gait patterns than adults, suggesting a lack of gait maturity during this period of ongoing musculoskeletal growth and development. However, there is a lack of consensus over the age at which mature gait patterns are achieved and the factors contributing to gait maturation. Therefore, the purpose of this study was to investigate gait control and maturity in adolescents by determining if differences existed between adolescents and adults in a) the amount of spatiotemporal variability of walking and running patterns across a range of speeds, and b) how swiftly gait patterns are adapted to increasing gait speed during the walk-to-run transition.

Measuring Sperm Guidance and Motility within the Caenorhabditis elegans Hermaphrodite Reproductive Tract.

Successful fertilization is fundamental to sexual reproduction, yet little is known about the mechanisms that guide sperm to oocytes within the female reproductive tract. While in vitro studies suggest that sperm of internally fertilizing animals can respond to various cues from their surroundings, the inability to visualize their behavior inside the female reproductive tract creates a challenge for understanding sperm migration and mobility in its native environment. Here, we describe a method using C.

KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe.

Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells.

The impact of national guidelines covering moving and handling of people on injury rates and related costs.

Objective National guidelines for moving and handling of people (MHP) were introduced in New Zealand in 2012 to reduce MHP-related injuries in the healthcare sector. This study assessed the effectiveness of this on MHP-related injury claims. Methods MHP-related injury claims were identified from the national injury claims database, which included 118 755 accepted claims for 2005-2016 across 14 industries.

The effects of introducing electric adjustable height desks in an office setting on workplace physical activity levels: A randomised control field trial.

Background: Electric adjustable height desks (EAHD) have been promoted as an opportunity for desk based workers to stand at work but there is limited evidence that they have an effect on light physical activity.

Objective: The main objective was to determine if there would be a change in light physical activity with the introduction of EAHD. The secondary objective was to assess if there was an associated change in leisure time activity.