Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort.

Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.

Promoted NIR-II Fluorescence by Heteroatom-Inserted Rigid-Planar Cores for Monitoring Cell Therapy of Acute Lung Injury.

Fluorophores with emission in the second near-infrared (NIR-II) window have displayed salient advantages for biomedical applications. However, exploration of new luminogens with high NIR-II fluorescent brightness is still challenging. Herein, based on the "ring-fusion" strategy, a series of heteroatom-inserted rigid-planar cores is proposed to achieve the bathochromic NIR-II fluorophores with aggregation-induced emission (AIE) performance. Interestingly, one of the representative fluorophores, 4,4'-(5,5'-([1,2,5]thiadiazolo[3,4-i]dithieno[2,3-a:3',2'-c]phenazine-8,12-diyl)bis(4-octylthiophene-5,2-diyl))bis(N,N-diphenylaniline) (TTQiT), enjoys a maximum emission beyond 1100 nm because of the efficiently narrowed energy bandgap by electron-rich sulfur-atom-inserted core, which is verified by theoretical calculation. Taking advantage of the bright NIR-II emission of TTQiT nanoparticles, the desirable in vivo NIR-II imaging with high signal-to-background ratios is successfully performed and a long-term stem cell tracking in the detection of acute lung injury is further realized. Therefore, it is anticipated that this work will provide a promising molecular engineering strategy to enrich the scope of NIR-II fluorophores for catering to diverse demands in biomedical applications.

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.

PURPOSE: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families. METHODS: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants. RESULTS: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression. CONCLUSION: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.

Generation and pathological characterization of a transgenic mouse model carrying a missense PJVK mutation.

Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59.

Room-Temperature Macroscopic Coherence of Two Electron-Hole Plasmas in a Microcavity.

Macroscopic coherence of Bose condensates is a fundamental and practical phenomenon in many-body systems, such as the long-range correlation of exciton-polariton condensates with a dipole density typically below the exciton Mott-transition limit. Here we extend the macroscopic coherence of electron-hole-photon interacting systems to a new region in the phase diagram-the high-density plasma region, where long-range correlation is generally assumed to be broken due to the rapid dephasing. Nonetheless, a cooperative state of electron-hole plasma does emerge through the sharing of the superfluorescence field in an optical microcavity. In addition to the in situ coherence of e-h plasma, a long-range correlation is formed between two 8-µm-spaced plasma ensembles even at room temperature. Quantized and self-modulated correlation modes are generated for e-h ensembles in the plasma region. By controlling the distance between the two ensembles, multiple coupling regimes are revealed, from strong correlation to perturbative phase correlation and finally to an incoherent classical case, which has potential implications for tunable and high-temperature-compatible quantum devices.

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

BACKGROUND: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Folate Receptor α-Targeted 89Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer.

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (89Zr)-radiolabeled M9346A (89Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of 89Zr-M9346A by in vitro studies in FRαhigh cells (HeLa) and FRαlow cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRαhigh and FRαlow TNBC PDX models. The correlation between 89Zr-M9346A tumor uptake and treatment response using IMGN853 in FRαhigh TNBC PDX model suggested the potential of 89Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.

Lack of a Prognostic Impact of the MyD88 L265P Mutation for Diffuse Large B Cell Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS.

Polarization properties of strongly coupled exchange-split excitons and pillar microcavities.

We demonstrate a combined experimental and theoretical investigation of the polarization properties of the strong coupling between fine structure-split excitons and anisotropy-split cavity modes. While the temperature is varied to control the light-matter coupling, we observe a notable change in the emission polarization for the branch of the exciton-like polariton. The exciton dephasing is introduced in order to explain the temperature-sensitive effect on the emission polarization. We apply the medium-dependent Green function approach involving the polarization-dependent exciton dephasing to model the emission spectra, which shows qualitative agreement with our experimental results.

Method to evaluate afterpulsing probability in single-photon avalanche diodes.

We propose and demonstrate a new method for evaluating the afterpulsing effect in single-photon avalanche photodiodes (SPADs). By analyzing the statistical property of dark count rate, we can quantitatively characterize afterpulsing probability (APP) of a SPAD. In experiment, the temperature-dependent low dark count rate (DCR) distribution becomes non-Poissonian at lower temperature and has higher excess bias as the afterpulsing effect becomes significant. Our work provides a flexible way to examine APP in either single-device or circuit level.

Polarized emission of quantum dots in microcavity and anisotropic Purcell factors.

We study the polarization properties of quantum dot (QD) emission coupled with the fundamental cavity modes. A rotation of polarization axis and a change of polarization degree are observed as the coupling is varied. To explain this observation, we derive an analytical model considering the polarization misalignment between QD dipole and cavity mode field. Our model also provides a new approach to extract the anisotropic Purcell factors by analyzing the polarization of detected quantum dot emission coupled to the cavity mode, which paves the way to develop high-efficiency polarized single photon sources.

High-quality planar light emitting diode formed by induced two-dimensional electron and hole gases.

A high-quality planar two-dimensional p-i-n light emitting diode in an entirely undoped GaAs/AlGaAs quantum well has been fabricated by using conventional lithography process. With twin gate design, two-dimensional electron and hold gases can be placed closely on demand. The electroluminescence of the device exhibit high stability and clear transition peaks so it is promising for applications on electrically-driven single photon sources.

Role of incoherent pumping in a strongly coupled system of exchange-split excitons and pillar-microcavities.

We present an experimental study of the influence of incoherent pumping upon the strong coupling between quantum dot excitons and a micropillar-cavity. For two exchange-split excitons, the inherent difference in the detuning with respect to the cavity modes leads to an unequal reduction of Rabi splitting for two orthogonal polarizations as excitation power is increased, which could destroy the indistinguishable decay paths built by the coupled states. This work prompts a careful implementation of optical pumping for the pursuit of polarization-entangled photon pairs in the strong coupling regime.

Evaluation of a 3D-Printed Writing Assistive Device for People With Brain Injury.

Three-dimensional-printed assistive devices hold promise for improving writing abilities, yet factors influencing device selection and their impact on satisfaction and effectiveness remain unclear, especially in adults, as they are typically tested on children. The aim of this article is to assess the efficacy and satisfaction with a writing assistive device at different angles among individuals with brain injury and explore device selection factors. Twenty-six participants with brain injuries selected their preferred device angle. Writing speed, quality, and satisfaction were recorded. Immediate speed improvements were significant at 5° and 30° (p = .006, .013, respectively). Satisfaction scores did not significantly differ among angles. Normotonia in elbow (p < .001; odds ratio: 3.403) and wrist (p ≤ .001; odds ratio: 2.695) muscles increased the likelihood of selecting the 5° device. Immediate speed improvements at specific angles highlight the influence of muscle normotonia on device selection, vital for tailored brain injury rehabilitation.

Evaluation of a 3D-Printed Writing Assistive Device for People With Brain InjuryThis study, titled "Evaluation of a 3D-Printed Writing Assistive Device for People with Brain Injury," aimed to understand how 3D-printed devices could improve writing for individuals with brain injuries. The researchers explored the effectiveness and satisfaction of using these devices at different angles (5°, 20°, and 30°) among 26 participants with brain injuries. Participants chose the device angle that felt most comfortable to them, and the study measured their writing speed, quality, and satisfaction. The findings revealed that using 3D-printed writing devices significantly improved writing speed immediately, regardless of the chosen angle (5° or 30°). Satisfaction scores were similar across all angles. Interestingly, individuals with normal elbow and wrist muscle tone were more likely to prefer the 5° device. In summary, this study concludes that 3D-printed writing devices can promptly enhance writing for people with brain injuries. The specific angle of the device significantly affect outcomes, and participants generally find satisfaction with their choice. If you have normal elbow and wrist muscle tone, the 5° angle may be the optimal choice for you.

Design and demonstration of high quality-factor H1-cavity in two-dimensional photonic crystal.

We introduce a method for designing an H1 photonic crystal cavity to enhance its quality factor (Q factor). The highest theoretical Q factor of 120,000 is obtained. The Fourier transformation of field distribution shows that the enhancement arises from the component reduction of a leaky mode. The Q-factor improvement has also been demonstrated experimentally with the highest value of 11,700. Our design could be useful for studying light-matter interaction in an H1 cavity as the mode volume only increases slightly.

Effects of a wearable sensor-based virtual reality game on upper-extremity function in patients with stroke.

BACKGROUND: PABLO is a virtual reality game where a motion sensor system is used. Few studies have investigated the effects of the PABLO system in stroke rehabilitation. We investigated the effects of upper-extremity virtual reality training with the PABLO system in patients with stroke. METHODS: Stroke patients were randomly assigned to the virtual reality (n = 19) or standard rehabilitation groups (n = 18). Total of 18 sessions were conducted twice per week. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity subscale. Secondary outcome measures included the active ranges of motion of the shoulder and elbow, the box and block test, hand grip strength, and the Stroke Impact Scale. Enjoyment of activities and side effects were also recorded. FINDINGS: No difference was observed between two groups in primary outcome. Virtual reality group exhibited greater improvements in the hand dexterity between groups (p = .05). In active motion, virtual reality group showed greater improvement in shoulder flexion between groups (p = .03). Virtual reality group also showed greater improvements in elbow pronation between groups (p = .03). The groups differed in their assessments of how enjoyment the rehabilitation activities were found (p = .01). No significant differences between groups were observed in any other tests. INTERPRETATION: Interventions based on the PABLO virtual reality system improved upper extremity hand function, shoulder and elbow movements, and elicited a higher degree of enjoyment from study participants, than did traditional treatment. TRIALS REGISTRATION: The study protocol was registered at ClinicalTrials.gov PRS (No.NCT04296032).