The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes ...primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138
Blimp1
splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.
The uptake of breast and cervical cancer screening services among women in Singapore remains inadequate. Little is known about how gender norms influence women's decision to undergo these screening ...services in a multi-ethnic Asian context. This research aimed to explore how gender-based qualitative factors influence women's decision to screen.
Qualitative data were collected using semi-structured interviews from 40 racially diverse women aged 25 and above who had visited polyclinics for their chronic disease management. Women were recruited using a purposive maximum variation sampling strategy to ensure representation of their views from the three major ethnic groups and based on inclusion criteria. Interviews were conducted either face-to-face or via telephone call. Interviews were audiotaped and lasted 30 minutes on average. Interviews were conducted until data saturation was reached. The data was transcribed and analysed thematically.
Gender norms and gender non-concordance with the healthcare professionals did not inhibit women from undergoing breast and cervical cancer screening services to a large extent. Women were empowered and had a central role in decision-making for screening services. Healthcare initiatives such as subsidies and mobile health applications facilitated the uptake of breast and cervical cancer screening services but can be improved further. Some of the barriers reported by Malay Muslims were not dissimilar to previous qualitative studies with women in this ethnic and religious group.
Gender socialisation, empowerment, and healthcare initiatives did not inhibit our study participants' decision to undergo breast and cervical cancer screening services. However, new initiatives and strengthening of the existing healthcare initiatives are needed to overcome any remnants of gender-related nuances and convert non-doers into doers.
Hippo signaling pathways are evolutionarily conserved signal transduction mechanisms mainly involved in organ size control, tissue regeneration, and tumor suppression. However, in mammals, the ...primary role of Hippo signaling seems to be regulation of immunity. As such, humans with null mutations in STK4 (mammalian homologue of Drosophila Hippo; also known as MST1) suffer from recurrent infections and autoimmune symptoms. Although dysregulated T cell homeostasis and functions have been identified in MST1-deficient human patients and mouse models, detailed cellular and molecular bases of the immune dysfunction remain to be elucidated. Although the canonical Hippo signaling pathway involves transcriptional co-activator Yes-associated protein (YAP) or transcriptional coactivator with PDZ motif (TAZ), the major Hippo downstream signaling pathways in T cells are YAP/TAZ-independent and they widely differ between T cell subsets. Here we will review Hippo signaling mechanisms in T cell immunity and describe their implications for immune defects found in MST1-deficient patients and animals. Further, we propose that mutual inhibition of Mst and Akt kinases and their opposing roles on the stability and function of forkhead box O and β-catenin may explain various immune defects discovered in mutant mice lacking Hippo signaling components. Understanding these diverse Hippo signaling pathways and their interplay with other evolutionarily-conserved signaling components in T cells may uncover molecular targets relevant to vaccination, autoimmune diseases, and cancer immunotherapies.
This research engaged Destination Imagination’s (DI) British Columbia Division in dialogue with an appreciative stance to explore what it means for this nonprofit, volunteer-driven organization to ...stay relevant in a changing marketplace and how collaboratively, they can prepare for change. Participant groups built on what DI is doing well, reinforcing the organizational roof to help DI better weather future storms, whether expected or unexpected, gradual or significant. A total of 19 in-depth interviews were conducted. Five major findings emerged from the analysis of the data and led to the identification of DI’s core elements – creating a passion for learning, embracing obstacles and failure, and facilitating a community of care. Upheld by like-minded champions with diverse skills and a shared vision to support children, the participants – the human side of DI – and its core dimensions have contributed to the organization’s success over the years. Keywords: marketplace relevance, organizational change, action research engagement, participant engagement
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion ...of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell–B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage–defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule–associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.
•AITL-like tumors in mice continuously require key Tfh factors, such as Bcl6 and SAP.•Molecular pathways crucial for Tfh identity and T-B collaboration could be promising therapeutic targets for AITL.
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ICOS is a T-cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout ...(ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3
cells at an early stage of the GC reaction suggests that ICOS normally inhibits
expression to promote follicular features including
up-regulation. Furthermore, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B-cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.
We investigate phonon thermal transport of fullerene-based single-molecule junctions by employing classical molecular dynamics simulations. The thermal conductances of fullerene monomers, dimers, and ...trimers are computed through three distinct molecular dynamics methods, by following the equilibration dynamics in one method, and using two other nonequilibrium simulation methods. We discuss technical aspects of the simulation techniques, and show that their predictions for the thermal conductance agree. Our simulations reveal that the thermal conductance of fullerene monomer and dimer junctions are similar, yet the thermal conductance of trimer junctions is significantly reduced. This study could assist in the design of high-performing thermoelectric junctions, where low thermal conductance is desired.
A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were ...synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound,
, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC
values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of
was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following
treatment. We further show that the cytotoxicity of
is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the
efficacy of
against aggressive models of acute leukemias in mice.
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