Faculty Bibliography
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person:yz21
Total Results:
165
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
PMCID:8532080
PMID: 34413140
ISSN: 2470-9468
CID: 5065122
A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy
Specific mechanisms by which tumor infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 resectable and 35 advanced non-small cell lung cancer (NSCLC) patients. We identified a burned-out CD8+ TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME), but not in adjacent non-tumoral tissues. Ebo showed the highest expression of proliferation and activation markers, but produced the lowest amount of IFNy and were the most apoptotic CD8+ TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in NSCLC patients. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance.
PMID: 33658301
ISSN: 2159-8290
CID: 4819592
Brainstem damage is associated with poorer sleep quality and increased pain in gulf war illness veterans
AIMS/OBJECTIVE:Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. MATERIALS AND METHODS/METHODS:We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. KEY FINDINGS/RESULTS:Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. SIGNIFICANCE/CONCLUSIONS:These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.
PMID: 34144059
ISSN: 1879-0631
CID: 4917832
Novel speed sintered zirconia by microwave technology
OBJECTIVE:Continuous efforts have been made to hasten the zirconia densification process without compromising properties. This study evaluated the long-term structural durability of microwave speed-sintered zirconia (MWZ) relative to a conventionally sintered zirconia (CZ). METHODS:As-machined dental 3Y-TZP discs (Ø12 × 1.2 mm) were speed sintered at 1450 °C for 15 min using an industrial microwave oven, while conventional sintering was conducted in a standard dental furnace at 1530 °C for 2 h. Both were followed by natural cooling. The total sintering time was 105 min for MWZ and 600 min for CZ. Groups were compared regarding density, grain size, phase composition, and fracture resistance. Structural durability was investigated employing two fatigue protocols, step-stress and dynamic fatigue. RESULTS:), but significantly smaller grain sizes (MWZ = 0.53 ± 0.09 μm, CZ = 0.89 ± 0.10 μm), lower cubic-zirconia contents (MWZ = 15.3%, CZ = 22.7%), and poorer translucency properties (TP) (MWZ = 13 ± 1, CZ = 29 ± 0.8). However, the two materials showed similar flexural strength (MWZ = 978 ± 112 MPa, CZ = 1044 ± 161 MPa). Additionally, step-stress testing failed to capture the fatigue effect in 3Y-TZP, whereas dynamic fatigue revealed structural degradation due to moisture-assisted slow-crack-growth (SCG). Finally, MWZ possessed a slightly higher Weibull modulus (MWZ = 7.9, CZ = 6.7) but similar resistance to SCG (MWZ = 27.5, CZ = 24.1) relative to CZ. SIGNIFICANCE/CONCLUSIONS:Dental 3Y-TZP with similar structural durability can be fabricated six-times faster by microwave than conventional sintering.
PMID: 33715863
ISSN: 1879-0097
CID: 4836552
Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography
The understanding and treatment of psychiatric disorders, which are known to be neurobiologically and clinically heterogeneous, could benefit from the data-driven identification of disease subtypes. Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional connectivity patterns, prominently within the frontoparietal control network and the default mode network. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets of patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis.
PMID: 33077939
ISSN: 2157-846x
CID: 4642092
Damage sensitivity of dental zirconias to simulated occlusal contact
OBJECTIVE:Mechanical damages can occur from dental restoration processing and fitting, or while it is in-service. This study evaluates the damage sensitivity of translucent zirconia (5Y-PSZ) relative to conventional 3Y-PSZ following mouth-motion simulations at various loads. METHODS:) used in the chewing simulation. Specimens were mounted with 30° inclination in an electrodynamic mouth-motion simulator, and subjected to contact-slide-liftoff cyclic loading in water. Surface and sub-surface damages were analyzed using a sectioning technique. After the simulation, specimens were removed from the substrate and loaded with the damaged surface in tension for biaxial strength testing to assess their damage tolerance. RESULTS:The strength of both ceramics underwent significant degradation after mouth-motion simulations. For 5Y-PSZ, the strength degradation was greater (∼60%) and occurred at a lower number of cycles than 3Y-PSZ. Herringbone cracks emerged on 3Y-PSZ and 5Y-PSZ surfaces under a 200-N load after 50 and 10 cycles, respectively. Meanwhile at a 50-N load, cracks formed at ∼1000 cycles in both ceramics. Further increasing the number of cycles only had moderate effects on the strength of both ceramics, despite an increase in surface and sub-surface damage. More significantly, a 50-N occlusal load can debase the zirconia strengths as much as a 200-N load. SIGNIFICANCE/CONCLUSIONS:Surface flaws produced during the chewing simulation are capable of significant strength degradation in zirconia, even after a small number of low-load cycles.
PMCID:7775910
PMID: 33234315
ISSN: 1879-0097
CID: 4735122
Coating Dental Implants with Synthetic Bone Mineral for Early New Bone Formation in Vivo
ISI:000727220000001
ISSN: 1341-7649
CID: 5141892
Wear behavior and microstructural characterization of translucent multilayer zirconia
OBJECTIVE:To characterize the composition, microstructure and wear properties of a multilayer translucent zirconia relative to the conventional 3Y-TZP. METHODS:Two types of ceramics were evaluated: a multilayer zirconia (MULTI, IPS e.max ZirCAD Multi, Ivoclar Vivadent) and a control 3Y-TZP (IPS e.max ZirCAD LT, Ivoclar Vivadent). Pre-sintered CAD-CAM blocks were cut, ground, sintered and polished to 1 μm finish. The phase fraction and grain size were measured using XRD and FE-SEM. For wear testing (n = 12), square-shaped specimens (16 × 16 × 1 mm) were adhesively bonded to a dentin analog. Sliding wear tests were performed using a spherical zirconia antagonist (r = 3.15 mm), with 30 N load at 1.5 Hz for 500,000 cycles in water. Optical and scanning electron microscopes and 3D laser scanner were used for quantitative wear analyses. Data were analyzed using Student's t-test (α = 0.05). RESULTS:For MULTI, the enamel layer had the highest cubic content and the largest grain size, followed by the two transition layers, and the dentin layer. 3Y-TZP showed the smallest grain size and cubic content. A significant amount of wear was observed in both materials up to 50,000 cycles until it reached a plateau. MULTI showed higher volume loss and greater wear depth than 3Y-TZP (p < 0.01). The higher volume loss was associated with extensive lateral fracture, leading to material spalling from the surface of cubic-containing zirconias. SIGNIFICANCE/CONCLUSIONS:The wear pattern in multi-layered zirconia was more severe than 3Y-TZP. Additionally, the different layers of the multi-layered zirconia had similar wear behavior.
PMID: 32958309
ISSN: 1879-0097
CID: 4615682
Flexural strength and crystalline stability of a monolithic translucent zirconia subjected to grinding, polishing and thermal challenges
The objective of this study is to investigate the magnitude of structural degradation of a monolithic translucent zirconia caused by clinically relevant grinding and polishing procedures, when associated or not with low temperature degradation (LTD), induced by accelerated hydrothermal aging using autoclave or thermocycling Ninety disks (Ø12 × 1 mm) were prepared from dental zirconia for monolithic restorations (Vipi Block Zirconn Translucent, Vipi). The specimens were divided into 3 groups (n = 30) according to surface treatment: As Sintered (untreated), Grind (diamond bur), Grind + Polish (diamond bur + polish); and then subdivided according to aging method (n = 10): Baseline (no aging), Autoclave (134°C, 2.2 kgf/cm2 pressure for 5 h), and Thermocycling (200,000 cycles, 5°C and 55°C, for 15 s each). Roughness, biaxial flexural strength and percentage of monoclinic phase were evaluated. Regarding surface treatment, the Grind group presented higher roughness and greater flexural strength compared to As Sintered group, while Grind + Polish showed intermediate roughness and flexural strength similar to Grind group. Aging had little effect on roughness, but yielded a significant reduction in flexural strength. Tetragonal to monoclinic phase transformation was observed in all groups, caused by both mechanical stresses (grinding and polishing) and LTD, which was similarly induced by the traditional autoclave method, as well as the thermocycling method The use of diamond burs to grind zirconia surface may result in deleterious effects on the surface quality of monolithic zirconia restorations, yet has a potential toughening effect by phase transformation. However, when zirconia is exposed to LTD, regardless of the surface treatment, degradation of the surface quality and strength are observed.
PMCID:7946154
PMID: 33716378
ISSN: 0272-8842
CID: 4875012
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
PMID: 32972996
ISSN: 1095-9203
CID: 5065072
