Exhaustion of cytotoxic effector natural killer (NK) and CD8
T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic ...hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/O
mice permissive for persistent HCV infection, that NK and CD8
T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8
T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8
T cell functions to prevent persistent HCV infection.
Efficacy evaluation through human trials is crucial for advancing a vaccine candidate to clinics. Next-generation sequencing (NGS) can be used to quantify B cell repertoire response and trace ...antibody lineages during vaccination. Here, we demonstrate this application with a case study of Hecolin®, the licensed vaccine for hepatitis E virus (HEV). Four subjects are administered the vaccine following a standard three-dose schedule. Vaccine-induced antibodies exhibit a high degree of clonal diversity, recognize five conformational antigenic sites of the genotype 1 HEV p239 antigen, and cross-react with other genotypes. Unbiased repertoire sequencing is performed for seven time points over six months of vaccination, with maturation pathways characterize for a set of vaccine-induced antibodies. In addition to dynamic repertoire profiles, NGS analysis reveals differential patterns of HEV-specific antibody lineages and highlights the necessity of the long vaccine boost. Together, our study presents a quantitative strategy for vaccine evaluation in small-scale human studies.
This paper investigates the theoretical underpinnings of two fundamental statistical inference problems, the construction of confidence sets and large-scale simultaneous hypothesis testing, in the ...presence of heavy-tailed data. With heavy-tailed observation noise, finite sample properties of the least squares-based methods, typified by the sample mean, are suboptimal both theoretically and empirically. In this paper, we demonstrate that the adaptive Huber regression, integrated with the multiplier bootstrap procedure, provides a useful robust alternative to the method of least squares. Our theoretical and empirical results reveal the effectiveness of the proposed method, and highlight the importance of having inference methods that are robust to heavy tailedness.
Lignin depolymerization into aromatic monomers with high yields and selectivity is essential for the economic feasibility of biorefinery. However, the relationship between lignin structure and its ...reactivity for upgradeability is still poorly understood, in large part owing to the difficulty in quantitative characterization of lignin structural properties. To overcome these shortcomings, advanced NMR technologies 2D HSQC (heteronuclear single quantum coherence) and 31P were used to accurately quantify lignin functionalities. Diverse lignin samples prepared from Eucalyptus grandis with varying β‐O‐4 linkages were subjected to Pd/C‐catalyzed hydrogenolysis for efficient C−O bond cleavage to achieve theoretical monomer yields. Strong correlations were observed between the yield of monomeric aromatic compounds and the structural features of lignin, including the contents of β‐O‐4 linkages and phenolic hydroxyl groups. Notably, a combined yield of up to 44.1 wt % was obtained from β‐aryl ether rich in native lignin, whereas much lower yields were obtained from technical lignins low in β‐aryl ether content. This work quantitatively demonstrates that the lignin reactivity for acquiring aromatic monomer yields varies depending on the lignin fractionation processes.
Forecasting lignin reactivity: Diverse lignin samples with varying β‐O‐4 linkages are subjected to Pd/C‐catalyzed hydrogenolysis for efficient C−O bond cleavage to achieve theoretical monomer yields. Strong correlations are observed between the yield of phenolic monomers and the contents of β‐O‐4 linkages as well as phenolic hydroxyl groups. This provides a new vision to forecast lignin reactivity towards predicting catalytic depolymerization monomer yields.
We calculate the structure of accretion disks around Kerr black holes for accretion rates = 0.001-10 M sub( )s super(-1). Such high- disks are plausible candidates for the central engine of gamma-ray ...bursts. Our disk model is fully relativistic and accurately treats the microphysics of the accreting matter: neutrino emissivity, opacity, electron degeneracy, and nuclear composition. The neutrino-cooled disk forms above a critical accretion rate sub(ign) that depends on the black hole spin. The disk has an "ignition" radius r sub(ign) where neutrino flux rises dramatically, cooling becomes efficient, and the proton-to-nucleon ratio Y sub(e) drops. Other characteristic radii are r sub(a), where most of a-particles are disintegrated, r sub(u) where the disk becomes u-opaque, and r sub(tr) where neutrinos get trapped and advected into the black hole. We find r sub(a) r sub(ign), r sub(u), and r sub(tr) and show their dependence on . We discuss the qualitative picture of accretion and present sample numerical models of the disk structure. All neutrino-cooled disks regulate themselves to a characteristic state such that: (1) electrons are mildly degenerate, (2) Y sub(e) 6 0.1, and (3) neutrons dominate the pressure in the disk.
Cerium (IV)‐based metal‐organic frameworks (MOFs) are highly desirable due to their unique potential in fields such as redox catalysis and photocatalysis. However, due to the high reduction potential ...of CeIV species in solution, it is still a great challenge to synthesize CeIV‐MOFs with novel structures, which are extremely dominated by the hexanuclear Ce−O cluster inorganic building units (IBUs). Herein, a Ce−O IBU chain containing CeIV‐MOF, CSUST‐3 (CSUST: Changsha University of Science and Technology), was successfully prepared using the kinetic stabilization study of UiO‐66(Ce)‐NDC (H2NDC=2,6‐naphthalenedicarboxylic acid). Furthermore, owing to the superior redox activity, Lewis acidity and semiconductor‐like behavior owing to Ce4+, activated CSUST‐3 was demonstrated to be an excellent catalyst for CO2 chemical fixation. One‐pot synthesis of styrene carbonate from styrene and CO2 was achieved under mild conditions (1 atm CO2, 80 °C, and solvent free). Moreover, activated CSUST‐3 was shown to be a remarkable co‐catalyst‐free photocatalyst for overall water splitting (OWS), rendering 59 μmol g−1 h−1 of H2 and 22 μmol g−1 h−1 of O2 under simulated sunlight irradiation (Na2S‐Na2SO3 as sacrificial agent).
I Ce Now: A CeIV‐MOF with Ce−O chains as inorganic building units was successfully synthesized guided by the kinetic stabilization study of UiO‐66(Ce)‐NDC (H2NDC=2,6‐naphthalenedicarboxylic acid). Due to the superior redox activity, Lewis acidity and semiconductor‐like behavior owing to Ce4+, activated CSUST‐3 (3 (CSUST: Changsha University of Science and Technology) was shown as an excellent catalyst for CO2 chemical fixation as well as a remarkable co‐catalyst‐free photocatalyst for overall water splitting.
Single molecular nanoparticles (SMNPs) integrating imaging and therapeutic capabilities exhibit unparalleled advantages in cancer theranostics, ranging from excellent biocompatibility, high ...stability, prolonged blood lifetime to abundant tumor accumulation. Herein, we synthesize a sophisticated porphyrin nanocage that is further functionalized with twelve polyethylene glycol arms to prepare SMNPs (porSMNPs). The porphyrin nanocage embedded in porSMNPs can be utilized as a theranostic platform. PET imaging allows dynamic observation of the bio‐distribution of porSMNPs, confirming their excellent circulation time and preferential accumulation at the tumor site, which is attributed to the enhanced permeability and retention effect. Moreover, the cage structure significantly promotes the photosensitizing effect of porSMNs by inhibiting the π–π stacking interactions of the photosensitizers, ablating of the tumors without relapse by taking advantage of photodynamic therapy.
Sophisticated porphyrin nanocages, which can be utilized as a functional platform to develop single molecular nanoparticles, were synthesized. The unique topological structure of the nanocages results in their excellent performance as cancer nanotheranostics, as demonstrated through applications in PET imaging and photodynamic therapy.
Few studies have investigated the relationship between sarcopenia and mild to moderate renal decline. This study aimed to investigate the relationship between chronic kidney disease (CKD) and ...sarcopenia. In total, 123 patients hospitalized with CKD and 57 healthy volunteers who underwent physical examination during the same period (control group) were analyzed. Body compositions were measured by dual-energy X-ray absorptiometry, and the relative appendicular skeletal muscle index (RASMI) was calculated. Muscular strength was evaluated using hydraulic hand dynamometer. Walking speed within 6 m was measured for muscular function assessment. Single-photon emission computed tomography was performed to measure the glomerular filtration rate of CKD patients, who were then divided into CKD1 (55 patients in CKD stages 1 and 2) and CKD2 (68 patients in CKD stages 3-5). RASMI showed a downward trend with CKD progression (P = 0.001). Multivariate logistic regression analysis showed that age and CKD progression were independent risk factors for sarcopenia. The morbidity of sarcopenia was significantly greater in CKD patients than in healthy volunteers, and the degree of muscle loss was closely related to CKD progression.
Sodium‐ and potassium‐ion batteries have attracted intensive attention recently as low‐cost alternatives to lithium‐ion batteries with naturally abundant resources. However, the large ionic radii of ...Na+ and K+ render their slow mobility, leading to sluggish diffusion in host materials. Herein, hierarchical FeSe2 microspheres assembled by closely packed nano/microrods are rationally designed and synthesized through a facile solvothermal method. Without carbonaceous material incorporation, the electrode delivers a reversible Na+ storage capacity of 559 mA h g−1 at a current rate of 0.1 A g−1 and a remarkable rate performance with a capacity of 525 mA h g−1 at 20 A g−1. As for K+ storage, the FeSe2 anode delivers a high reversible capacity of 393 mA h g−1 at 0.4 A g−1. Even at a high current rate of 5 A g−1, a discharge capacity of 322 mA h g−1 can be achieved, which is among the best high‐rate anodes for K+ storage. The excellent electrochemical performance can be attributed to the favorable morphological structure and the use of an ether‐based electrolyte during cycling. Moreover, quantitative study suggests a strong pseudocapacitive contribution, which boosts fast kinetics and interfacial storage.
Microsphere anode materials: Self‐assembled FeSe2 microspheres are synthesized through a facile solvothermal method. The FeSe2 microspheres exhibit superior rate performance and long cycle stability in both sodium‐ and potassium‐ion batteries.
A Lewis acid‐catalyzed (3+2) cycloaddition of 2‐indolylmethanols with β,γ‐unsaturated α‐ketoesters was established, which afforded a series of cyclopentabindoles in overall high yields (up to 98 %) ...with excellent diastereoselectivities (up to >95 : 5 dr). This reaction not only represents the first C3‐nucleophilic (3+2) cycloaddition of 2‐indolylmethanols, but also provides a good example for (2+n) cycloaddition of β,γ‐unsaturated α‐ketoesters, which will add new contents to the chemistry of 2‐indolylmethanols. In addition, this approach provides an atom‐economic and useful method for the construction of biologically important cyclopentabindole scaffold.
A Lewis acid‐catalyzed (3+2) cycloaddition of 2‐indolylmethanols with β,γ‐unsaturated α‐ketoesters was established. Various cyclopentabindoles were obtained in overall high yields with excellent diastereoselectivities. This reaction not only represents the first C3‐nucleophilic (3+2) cycloaddition of 2‐indolylmethanols, but also provides a good example for (2+n) cycloaddition of β,γ‐unsaturated α‐ketoesters.
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