Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing ...loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard of hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health-care services are provided in a linguistically and culturally sensitive manner. This guideline offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Physical characterization of nanoparticles is required for a wide range of applications. Nanomechanical resonators can quantify the mass of individual particles with detection limits down to a single ...atom in vacuum. However, applications are limited because performance is severely degraded in solution. Suspended micro- and nanochannel resonators have opened up the possibility of achieving vacuum-level precision for samples in the aqueous environment and a noise equivalent mass resolution of 27 attograms in 1-kHz bandwidth was previously achieved by Lee et al. (2010) Nano Lett 10(7):2537–2542. Here, we report on a series of advancements that have improved the resolution by more than 30-fold, to 0.85 attograms in the same bandwidth, approaching the thermomechanical noise limit and enabling precise quantification of particles down to 10 nm with a throughput of more than 18,000 particles per hour. We demonstrate the potential of this capability by comparing the mass distributions of exosomes produced by different cell types and by characterizing the yield of self-assembled DNA nanoparticle structures.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The formation of the vascular system is essential for embryonic development and homeostasis. However, transcriptional control of this process is not fully understood. Here we report an evolutionarily ...conserved role for the transcription factor CASZ1 (CASTOR) in blood vessel assembly and morphogenesis. In the absence of CASZ1, Xenopus embryos fail to develop a branched and lumenized vascular system, and CASZ1-depleted human endothelial cells display dramatic alterations in adhesion, morphology, and sprouting. Mechanistically, we show that CASZ1 directly regulates Epidermal Growth Factor-Like Domain 7 (Egfl7). We further demonstrate that defects of CASZ1- or EGFL7-depleted cells are in part due to diminished RhoA expression and impaired focal adhesion localization. Moreover, these abnormal endothelial cell behaviors in CASZ1-depleted cells can be rescued by restoration of Egfl7. Collectively, these studies show that CASZ1 is required to directly regulate an EGFL7/RhoA-mediated pathway to promote vertebrate vascular development.
► CASZ1 is a conserved transcription factor required for vascular patterning ► CASZ1 controls endothelial cell adhesion, contractility, and proliferation ► This control is exerted through the regulation of target genes Egfl7 and miR-126 ► RhoA functions downstream of CASZ1/EGFL7 to mediate endothelial cell behavior
Mutations in CASZ1 are associated with hypertension; however, the vascular function of this transcription factor has been unclear. Charpentier et al. identify Egfl7 as a direct target of CASZ1 in endothelial cells. These factors promote RhoA GTPase signaling to modulate cell behaviors that control vascular patterning and lumen formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.
•T cells from bone marrow egress to blood during SCM and preferentially home back to marrow after adoptive transfer.•Treg depletion during SCM expands polyfunctional effector T cells in mobilized ...grafts and enhances antimyeloma immunity after ASCT.
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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). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT.
Autograft remains a key component of management of fit patients diagnosed with multiple myeloma, in part because it establishes an antimyeloma immune response. Takahashi et al explored how this emerges, showing that during stem cell mobilization, both effector CD8 T cells necessary for the antimyeloma response and immunosuppressive regulatory T cells (Tregs), which dampen the response, are collected in high numbers. In murine models, manipulation of the graft to reduce Tregs and expand effector CD8 T cells improved the antitumor effect of autografts, setting the scene for an ongoing phase 1 study in patients.
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. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.
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•The recipient microbiota dictates clonal selection of donor T cells post HSCT•Microbiota-specific donor T cells augment GVHD in the presence of cognate antigen•Allogeneic T cells promote activation and TNF response in microbiota-specific T cells•Allogeneic T cells facilitate microbial antigen presentation by recipient GI epithelium
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. Yeh et al. found that a subset of donor CD4+ T cell clonal expansion was microbiota dependent and that microbiota-specific T cells augmented GVHD lethality independent of donor-recipient genetics.
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. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal ...microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4+ T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.
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•MHC-II inducer taxa preferentially control MHC-II expression by intestinal epithelia•Pre-transplant vancomycin depletes MHC-II inducers and attenuates GVHD•Pre-transplant commensal bacterial taxa control CD4+ T-mediated GVHD•Pre-transplant taxa in the GI tract correlate with clinical transplant outcomes
Genetically identical recipient and donor pairs are associated with differential MHC-II expression on intestinal epithelial cells (IECs) and subsequent graft-versus-host disease, which is controlled by the composition of commensal bacteria. Koyama et al. identify taxa that positively (inducers) and negatively (suppressors) correlate with MHC-II expression on IECs and show that this is regulated by IFNγ-secreting intestinal T cells.
Drying regime map demonstrating role of soluble polymer on particle distribution in a drying coating: E – evaporation, D – diffusion, and S – sedimentation. Display omitted
► A model predicts ...particle and polymer distribution in a drying coating. ► Results are summarized in maps showing regions of particle accumulation. ► Addition of binder slows particles, favors particle accumulation at the surface. ► Experimental results corroborate model predictions.
Soluble polymer is frequently added to inorganic particle suspensions to provide mechanical strength and adhesiveness to particulate coatings. To engineer coating microstructure, it is essential to understand how drying conditions and dispersion composition influence particle and polymer distribution in a drying coating. Here, a 1D model revealing the transient concentration profiles of particles and soluble polymer in a drying suspension is proposed. Sedimentation, evaporation and diffusion govern particle movement with the presence of soluble polymer influencing the evaporation rate and solution viscosity. Results are summarized in drying regime maps that predict particle accumulation at the free surface or near the substrate as conditions vary. Calculations and experiments based on a model system of poly(vinyl alcohol) (PVA), silica particles and water reveal that the addition of PVA slows the sedimentation and diffusion of the particles during drying such that accumulation of particles at the free surface is more likely.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The CASTOR (CST) transcription factor was initially identified for its role in maintaining stem cell competence in the Drosophila dorsal midline. Here we report that Xenopus CST affects ...cardiogenesis. In CST-depleted embryos, cardiomyocytes at the ventral midline arrest and are maintained as cardiac progenitors, while cells in more dorsal regions of the heart undergo their normal program of differentiation. Cardia bifida results from failed midline differentiation, even though cardiac cell migration and initial cell fate specification occur normally. Our fate mapping studies reveal that this ventral midline population of cardiomyocytes ultimately gives rise to the outer curvature of the heart; however, CST-depleted midline cells overproliferate and remain a coherent population of nonintegrated cells positioned on the outer wall of the ventricle. These midline-specific requirements for CST suggest the regulation of cardiomyocyte differentiation is regionalized along a dorsal-ventral axis and that this patterning occurs prior to heart tube formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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