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Background: Impaired ventilatory efficiency during exercise is a predictor of mortality in chronic obstructive pulmonary disease. However, little is known about the clinical features and associated factors of impaired ventilatory efficiency in China., Methods: We conducted a cross-sectional community-based study in China and collected demographic and clinical information, cardiopulmonary exercise testing, spirometry, and CT data. Impaired ventilatory efficiency was defined by a nadir ventilatory equivalent for CO 2 production above the upper limit of normal. Multivariable linear and logistic regression models were used to explore the clinical features and associated factors of impaired ventilatory efficiency., Results: The final analyses included 941 subjects, 702 (74.6%) of whom had normal ventilatory efficiency and 239 (25.4%) had impaired ventilatory efficiency. Participants with impaired ventilatory efficiency had more chronic respiratory symptoms, poorer lung function and exercise capacity, and more severe emphysema (natural logarithm transformation of the low-attenuation area of the lung with attenuation values below -950 Hounsfield units, logLAA -950 : 0.19±0.65 vs -0.28±0.63, p<0.001) and air trapping (logLAA -856 : 1.03±0.65 vs 0.68±0.70, p<0.001) than those with normal ventilatory efficiency. Older age (60-69 years, OR 3.10 (95% CI 1.33 to 7.21), p=0.009 and 70-80 years, OR 6.48 (95% CI 2.56 to 16.43), p<0.001 vs 40-49 years) and smoking (former, OR 3.19 (95% CI 1.29 to 7.86), p=0.012; current, OR 4.27 (95% CI 1.78 to 10.24), p=0.001 vs never) were identified as high risk factors of impaired ventilatory efficiency., Conclusions: Impaired ventilatory efficiency was associated with poorer respiratory characteristics. Longitudinal studies are warranted to explore the progression of individuals with impaired ventilatory efficiency., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High blood eosinophil count (BEC) is a useful biomarker for guiding inhaled corticosteroid therapy in patients with chronic obstructive pulmonary disease (COPD), yet its implications in a community setting remain underexplored. This study aimed to elucidate the clinical characteristics and outcomes of COPD patients with high BEC within the Chinese community., Methods: We obtained baseline and 2-year follow-up data from COPD patients (post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.70) in the early COPD study. Patients with a BEC ≥300cells/μL were classified as the high BEC group. We assessed differences in the clinical characteristics and outcomes between high and low BEC patients. Subgroup analyses were conducted on COPD patients without a history of corticosteroid use or asthma., Results: Of the 897 COPD patients, 205 (22.9%) had high BEC. At baseline, high BEC patients exhibited a higher proportion of chronic respiratory symptoms, lower lung function, and more severe small airway dysfunction than low BEC patients. Over the 2-year period, high BEC patients experienced a significantly higher risk of acute exacerbations (relative risk: 1.28, 95% confidence interval: 1.09-1.49; P=0.002), even after adjusting for confounders. No significant difference was observed in lung function decline rates. The subgroup analysis yielded consistent results., Conclusions: COPD patients with high BEC in a Chinese community exhibited poorer health status, more severe small airway dysfunction, and a higher risk of exacerbations. Future research should explore the pathological mechanisms underlying the poorer prognosis in patients with high BEC., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

3D assembly technology is a cutting-edge methodology for constructing high-performance and multifunctional photodetectors since some attractive photodetection features such as light trapping effect, omnidirectional ability, and high spatial resolution can be introduced. However, there has not been any report of 3D-assembled multimode photodetectors owing to the lack of design and fabrication guideline of electrodes serving for 3D heterostructures. In this study, a 3D-assembled dual-mode photodetector (3DdmPD) was realized successfully via the clever electrical contact between the rolled-up tubular graphene/GaAs/InGaAs heterostructure and planar metal electrode. Arbitrary switching of three coplanar electrodes makes the as-fabricated tubular 3D photodetector work at the unbiased photodiode mode, which is suitable for energy conservation high-speed photodetection, or the biased photoconductive mode, which favors extremely weak light photodetection, fully showing the advantages of multifunctional detection. In more detail, the I light / I dark ratio reached as high as 2 × 10 4 , and a responsivity of 42.3 mA/W, a detectivity of 1.5 × 10 10 Jones, as well as a rising/falling time (τ r /τ f ) of 360/370 μs were achieved under the self-driven photodiode mode. Excitingly, 3DdmPD shows omnidirectional photodetection ability at the same time. When 3DdmPD works at the photoconductive mode with 5 V bias, its responsivity is extremely high as 7.9 × 10 4 A/W and corresponding detectivity is increased to 1.0 × 10 11 Jones. Benefiting from the totally independent coplanar electrodes, 3DdmPD is much more easily integrated as arrays that are expected to offer the function of high-speed omnidirectional image-sensing with ultralow power consumption than the planar counterparts which share communal bottom electrodes. We believe that our work can contribute to the progress of 3D-assembled optoelectronic devices.

The large amount of sampled data in coherent phase-sensitive optical time-domain reflectometry (Φ-OTDR) brings heavy data transmission, processing, and storage burdens. By using the comparator combined with undersampling, we achieve simultaneous reduction of sampling rate and sampling resolution in hardware, thus greatly decreasing the sampled data volume. But this way will inevitably cause the deterioration of detection signal-to-noise ratio (SNR) due to the quantization noise's dramatic increase. To address this problem, denoising the demodulated phase signals using compressed sensing, which exploits the sparsity of spectrally sparse vibration, is proposed, thereby effectively enhancing the detection SNR. In experiments, the comparator with a sampling parameter of 62.5 MS/s and 1 bit successfully captures the 80 MHz beat signal, where the sampled data volume per second is only 7.45 MB. Then, when the piezoelectric transducer's driving voltage is 1 Vpp, 300 mVpp, and 100 mVpp respectively, the SNRs of the reconstructed 200 Hz sinusoidal signals are respectively enhanced by 23.7 dB, 26.1 dB, and 28.7 dB by using compressed sensing. Moreover, multi-frequency vibrations can also be accurately reconstructed with a high SNR. Therefore, the proposed technique can effectively enhance the system's performance while greatly reducing its hardware burden.

This paper introduces an automatic intelligent design method for the modified uni-traveling carrier photodetector (MUTC-PD). The conventional photodetector design process often relies on the numerical solution of complex nonlinear partial differential equations to simulate and optimize device performance, which is not only computationally intensive but also inefficient. To overcome this challenge, we apply the charge control principle to calculate the photodetector bandwidth, which improves the computational speed by a factor of approximately 1800 compared to the numerical solution of nonlinear partial differential equations. To further optimize the structure of the photodetector, we incorporate the Velocity Varying Climbing Particle Swarm Optimization (VVCPSO) algorithm. This is an improved algorithm based on the traditional particle swarm algorithm, which is able to quickly find the optimal solution in a complex parameter space. By applying the VVCPSO algorithm, we successfully fine-tuned the photodetector structure and obtained structural parameters with optimal performance. Our thorough verification process confirms that the proposed method is consistent with the results of ATLAS simulation software. Automated design has resulted in a high-performance MUTC-PD with a responsivity of 0.52A/W and a bandwidth of 60 GHz (@-3 V) at a mesa diameter of 16µm. Compared to the pre-optimized device, the bandwidth is increased to three times the original. By reducing the mesa diameter to 4µm, the bandwidth can be further increased to 82 GHz (@-3 V). The proposed method's calculation speed is fast enough, enabling extensive parameter studies to optimize device performance.

Objectives: To establish a three-dimensional finite element model of the upper palate, pharyngeal cavity, and levator veli palatini muscle in patients with unilateral complete cleft palate, simulate two surgical procedures that the two-flap method and Furlow reverse double Z method, observe the stress distribution of the upper palate soft tissue and changes in pharyngeal cavity area after different surgical methods, and verify the accuracy of the model by reconstructing and measuring the levator veli palatini muscle., Materials and Methods: Mimics, Geomagic, Ansys, and Hypermesh were applied to establish three-dimensional finite element models of the pharyngeal cavity, upper palate, and levator veli palatini muscle in patients with unilateral complete cleft palate. The parameters including length, angle, and cross-sectional area of the levator veli palatini muscle etc. were measured in Mimics, and two surgical procedures that two-flap method and Furlow reverse double Z method were simulated in Ansys, and the area of pharyngeal cavity was measured by hypermesh., Results: A three-dimensional finite element model of the upper palate, pharyngeal cavity, and bilateral levator veli palatini muscle was established in patients with unilateral complete cleft palate ; The concept of horizontal projection characteristics of the palatal dome was applied to the finite element simulation of cleft palate surgery, vividly simulating the displacement and elastic stretching of the two flap method and Furlow reverse double Z method during the surgical process; The areas with the highest stress in the two-flap method and Furlow reverse double Z method both occur in the hard soft palate junction area; In resting state, as measured, the two flap method can narrow the pharyngeal cavity area by 50.9%, while the Furlow reverse double Z method can narrow the pharyngeal cavity area by 65.4%; The measurement results of the levator veli palatini muscle showed no significant difference compared to previous studies, confirming the accuracy of the model., Conclusions: The finite element method was used to establish a model to simulate the surgical procedure, which is effective and reliable. The area with the highest postoperative stress for both methods is the hard soft palate junction area, and the stress of the Furlow reverse double Z method is lower than that of the two-flap method. The anatomical conditions of pharyngeal cavity of Furlow reverse double Z method are better than that of two-flap method in the resting state., Clinical Relevance: This article uses three-dimensional finite element method to simulate the commonly used two-flap method and Furlow reverse double Z method in clinical cleft palate surgery, and analyzes the stress distribution characteristics and changes in pharyngeal cavity area of the two surgical methods, in order to provide a theoretical basis for the surgeon to choose the surgical method and reduce the occurrence of complications., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this paper, we propose a system for enhancing the RF output power of the photodetector, especially the power of fundamental tune and second-order harmonic, by feeding back part of the RF signal through an electrical feedback circuit. As a result of bias modulation and opto-electric mixing, the RF output power can be effectively enhanced. The structure of uni-traveling carrier photodetector (UTC-PD) is employed in this work. With the RF enhancement system, the power of fundamental tune and second-order harmonic improve by 6.4 dB and 9.9 dB respectively, under the condition of 26 dBm input optical power, 3 V bias voltage, and 14 GHz input optical signal. Further, it was observed that third-order harmonic appeared under the influence of this system.

H subunit of V-ATPase (ATP6V1H) is specifically expressed in osteoclasts and its deficiency lead to osteoporosis. Our group previously found four intronic SNPs of ATP6V1H related to reduced bone mineral density, but the mechanisms was not clear. In this study, we found that the above four SNPs were located at lncRNA lnc-TCEA1-3 by using bioinformatics analysis. We further detected the function of lnc-TCEA1-3 on regulating ATP6V1H and osteoclast function using Atp6v1h knockout mice, lentivirus transfection and qPCR analysis. Over expression of lnc-TCEA1-3 up regulated the expression of ATP6V1H in HEK293 cells, HOS cells and primarily cultured osteoclasts, and increased the number of primarily cultured osteoclasts. In addition, over expression of lnc-TCEA1-3 exerted distinct effect on two transcripts of ATP6V1H in HEK293, HOS and osteoclasts. This study will facilitate the in-depth analysis of the effects of ATP6V1H on bone diseases, and discover new therapeutic strategies.

We numerically investigate two Fano resonances with high Q-factors based on a permittivity-asymmetric metastructure composed of two pea-shaped cylinders. By employing different materials to break the permittivity-asymmetry, the quasi-bound state of the continuum spectrum (BIC) resonance at 982.87 nm is excited, showing the Q-factor as high as 8183.7. The electromagnetic fields and vectors are analyzed by using the finite-difference time-domain (FDTD) method, and the resonance modes are identified as magnetic dipole (MD) responses and MDs by multipole decomposition in Cartesian coordinates, displaying that the light is confined within a pea-shaped cylinder to achieve localized field enhancement. In addition, the sensing performances of the metastructure are evaluated, and an optical refractive index sensor can be obtained with the sensitivity of 152 nm/RIU and maximum figure of merit (FOM) of 832.6. This proposed structure offers a new, to the best of our knowledge, way to achieve Fano resonant excitation on all-dielectric metastructures and can be used in nonlinear optics, biosensing, optical switches, and lasers.

In the domain of optical fiber distributed acoustic sensing, the persistent challenge of extending sensing distances while concurrently improving spatial resolution and frequency response range has been a complex endeavor. The amalgamation of pulse compression and frequency division multiplexing methodologies has provided certain advantages. Nevertheless, this approach is accompanied by the drawback of significant bandwidth utilization and amplified hardware investments. This study introduces an innovative distributed optical fiber acoustic sensing system aimed at optimizing the efficient utilization of spectral resources by combining compressed pulses and frequency division multiplexing. The system continuously injects non-linear frequency modulation detection pulses spanning various frequency ranges. The incorporation of non-uniform frequency division multiplexing augments the vibration frequency response spectrum. Additionally, nonlinear frequency modulation adeptly reduces crosstalk and enhances sidelobe suppression, all while maintaining a favorable signal-to-noise ratio. Consequently, this methodology substantially advances the spatial resolution of the sensing system. Experimental validation encompassed the multiplexing of eight frequencies within a 120 MHz bandwidth. The results illustrate a spatial resolution of approximately 5 m and an expanded frequency response range extending from 1 to 20 kHz across a 16.3 km optical fiber. This achievement not only enhances spectral resource utilization but also reduces hardware costs, making the system even more suitable for practical engineering applications.

Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride-induced cellular stress and autophagy remain unclear. This study investigated ER stress-induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride-induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride-induced ER stress and autophagy, we assessed changes in fluoride-induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride-induced autophagy was reduced in GRP78-silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride-treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride-induced damage by inducing ameloblast autophagy., (© 2023 Wiley Periodicals LLC.)

Objectives: To investigate the association between PTCH1 single nucleotide polymorphism(SNP) and non-syndromic cleft lip with or without palate (NSCL/P) in the Ningxia Hui Autonomous region and predict the function of single nucleotide polymorphism through bioinformatics analysis., Design: A case-control analysis of 31 single nucleotide polymorphism locus alleles on PTCH1 gene (504 cases and 455 controls) was performed to explore the association between PTCH1 gene polymorphisms and non-syndromic cleft lip with or without palate in Ningxia region. Transcription factors, 3D single nucleotide polymorphism and other related information of single nucleotide polymorphism loci with statistical significance were screened by the case-control experiments, and then analyzed the corresponding transcription factors through the NCBI database., Results: The case-control study showed that 5 of the 31 single nucleotide polymorphism loci rs357564 (P = 0.0233), rs1805155 (P = 0.0371), rs28446116 (P = 0.0408), rs2282041 (P = 0.0439), rs56119276 (P = 0.0256) had statistically significant differences in allele frequencies between the case and control groups. Bioinformatics analysis revealed that EP300 and RUNX3, among the transcription factors associated with rs28446116, may be associated with the development of non-syndromic cleft lip with or without palate., Conclusion: PTCH1 gene may be associated with the occurrence of non-syndromic cleft lip with or without palate in the Ningxia region, which may be related to the role of EP300 and RUNX3 in the development of cleft lip and palate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

InGaAs/AlGaAs multiple quantum well lasers grown on silicon (001) by molecular beam epitaxy have been demonstrated. By inserting InAlAs trapping layers into AlGaAs cladding layers, misfit dislocations easily located in the active region can be effectively transferred out of the active region. For comparison, the same laser structure without the InAlAs trapping layers was also grown. All these as-grown materials were fabricated into Fabry-Perot lasers with the same cavity size of 20 × 1000 µm 2 . The laser with trapping layers achieved a 2.7-fold reduction in threshold current density under pulsed operation (5 µs-pulsed width, 1%-duty cycle) compared to the counterpart, and further realized a room-temperature continuous-wave lasing with a threshold current of 537 mA which corresponds to a threshold current density of 2.7 kA/cm 2 . When the injection current reached 1000 mA, the single-facet maximum output power and slope efficiency were 45.3 mW and 0.143 W/A, respectively. This work demonstrates significantly improved performances of InGaAs/AlGaAs quantum well lasers monolithically grown on silicon, providing a feasible solution to optimize the InGaAs quantum well structure.

A modified uni-traveling carrier photodiode with an electric field control layer is proposed to achieve high-speed and high-power performance at a lower bias voltage. By inserting the 10 nm p-type InGaAs electric field control layer between the intrinsic absorption layer and space layer, the electric field distribution in the depleted absorption layer and depleted non-absorption layer can be changed. It is beneficial for reducing power consumption and heat generation, meanwhile suppressing the space-charge effect. Compared with the original structure without the electric field control layer, the 3 dB bandwidth of the 20 µm diameter novel structure, to the best of our knowledge, is improved by 27.1% to 37.5 GHz with a reverse bias of 2 V, and the RF output power reaches 23.9 dBm at 30 GHz. In addition, under 8 V bias voltage, the bandwidth reaches 47.3 GHz.

Background: Acute kidney injury (AKI) is a common complication in critically ill patients. Some predictive models have been reported, but the conclusions are controversial. The aim of this study was the formation of nomograms to predict risk factors for AKI in critically ill patients within the first 7 days after admission to the intensive care unit (ICU)., Methods: Data were extracted from the Medical Information Mart for Intensive Care- (MIMIC-) III database. The random forest method was used to fill in the missing values, and least absolute shrinkage and selection operator (Lasso) regression analysis was performed to screen for possible risk factors., Results: A total of 561 patients were enrolled. Complication with AKI is significantly associated with a longer length of stay (LOS). For all patients, the predictors contained in the prediction nomogram included hypertension, coronary artery disease (CAD), cardiopulmonary bypass (CPB), coronary artery bypass grafting (CABG), Simplified Acute Physiology Score II (SAPS II), central venous pressure (CVP) measured for the first time after admission, and maximum and minimum mean artery pressure (MAP). The model showed good discrimination (C - index = 0.818, 95% CI: 0.779-0.857). In the subgroup of patients with well-controlled blood glucose levels, the significant predictors included hypertension, CABG, CPB, SAPS II, and maximum and minimum MAP. Good discrimination was also present before (C - index = 0.785, 95% CI: 0.736-0.834) and after adjustment (adjusted C - index = 0.770)., Conclusion: Hypertension, CAD, CPB, CABG, SAPS II, CVP measured for the first time after admission, and maximum and minimum MAP were independent risk factors for AKI in critically ill patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Kexin Wen et al.)

Topology optimization has been widely adopted in the inverse design of nanophotonic devices due to low computation cost, which unfortunately produces intermediate relative permittivity values that fail to meet fabrication constraints. Additionally, the postprocessing required inevitably increases the complexity of the inverse design. In this Letter, we propose an adaptive projection method for topology optimization, in which a two-level hierarchical hyperbolic tangent projection function with linear increment and differentiation is constructed and applied to eliminate inherent defects of conventional topology optimization. Two binarized nanophotonic devices have been designed by our adaptive projection method, among which one ultra-compact dual 90°-bend waveguide reduces the average insertion loss to 20.3% of its similar counterpart and shows an 8.1% reduction for the average crosstalk in the O band, the other ultralow-loss waveguide crossing features an average insertion loss as low as 0.09 dB. With the significant advantages of excellent performance guarantee and fabrication-friendly geometry control fully demonstrated, our inverse design solution shows potential to contribute to nanophotonic devices and integrated chips.

The brown bear (Ursus arctos) is the second largest and most widespread extant terrestrial carnivore on Earth and has recently emerged as a medical model for human metabolic diseases. Here, we report a fully phased chromosome-level assembly of a male North American brown bear built by combining Pacific Biosciences (PacBio) HiFi data and publicly available Hi-C data. The final genome size is 2.47 Gigabases (Gb) with a scaffold and contig N50 length of 70.08 and 43.94 Megabases (Mb), respectively. Benchmarking Universal Single-Copy Ortholog (BUSCO) analysis revealed that 94.5% of single copy orthologs from Mammalia were present in the genome (the highest of any ursid genome to date). Repetitive elements accounted for 44.48% of the genome and a total of 20,480 protein coding genes were identified. Based on whole genome alignment to the polar bear, the brown bear is highly syntenic with the polar bear, and our phylogenetic analysis of 7,246 single-copy orthologs supports the currently proposed species tree for Ursidae. This highly contiguous genome assembly will support future research on both the evolutionary history of the bear family and the physiological mechanisms behind hibernation, the latter of which has broad medical implications., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

An interesting phenomenon that the photocurrent (the difference between illumination and dark current) of a ZnO nanowire (NW) under a specified voltage increased as its length increased in a certain range was observed previously and it was supposed to be mainly due to a special mean free path effect (MFPE) which caused a special distribution of dark electron density along the length with two higher electron density regions near the two ends of the NW, respectively, and the lower one in the middle part. However, such an explanation would be unreasonable and the true reasons should be the growing-process caused variation of the oxygen adsorption capacity along the NW length and the length-dependent lifetime of photogenerated carriers. Based on this understanding, a theoretical model to properly explain this phenomenon is proposed and the calculation results are in good agreement with the experimental data. This work has introduced an improved insight into the theory of the length-dependent photoelectric property of ZnO NWs., (© 2022. The Author(s).)

Developing novel electrode materials with reasonable structures and ideal conductivity is of great significance for energy storage devices. In this work, Ni 3 Se 2 @C yolk-shell nanorods are grown on nickel foam (NF) via a one-step selenization and carbonization process. The carbon shell not only improves the conductivity and charge transfer of electrodes, but also inhibits the dissociation of Ni 3 Se 2 core during redox reactions, which is crucial to electrochemical performances of SCs. Owing to the yolk-shell nanorod structure, the Ni 3 Se 2 @C electrode exhibits an outstanding specific capacitance of 1669.7F g -1 at 1 A g -1 . Moreover, an asymmetric supercapacitor (ASC) is successfully assembled using Ni 3 Se 2 @C and active carbon (AC) electrodes as the anode and cathode respectively, which delivers remarkable energy-storage characteristics. Specifically, the Ni 3 Se 2 @C//AC ASC shows a high energy density (31.0 Wh kg -1 ) at a power density (723.7 W kg -1 ), and stable cycling performance (97% capacitance retention after 9000 cycles). These results make the Ni 3 Se 2 @C a promising electrode for SCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To explore the potential heterogeneity of acute kidney injury (AKI) and evaluate the prognostic differences among AKI subphenotypes in critically ill patients with cardiovascular diseases., Methods: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database. Latent class analysis (LCA) was used to explore the potential subphenotypes of AKI in critically ill patients with cardiovascular diseases. The number of classes was identified by the Bayesian information criterion and entropy. The differences in prognostic ability among the AKI subphenotypes were evaluated by logistic regression analysis., Result: A total of 7738 AKI patients were enrolled in this study. Using LCA, AKI patients were divided into 4 heterogeneous subphenotypes, which were obviously different from the Kidney Disease: Improving Global Outcomes (KDIGO) stages. Interestingly, class 3 classified by LCA was dominated by stage 2, while the mortality rate in class 3 was significantly different from that in class 1 (15.2% vs. 1.6%, p < 0.05). After further adjustment, the mortality rate in class 3 remained higher than that in class 1, with an odds ratio of 12.31 (95% confidence interval, 8.96-16.89)., Conclusions: LCA was feasible for AKI classification in critically ill patients with cardiovascular disease, and 4 distinct subphenotypes of AKI patients with different prognoses were identified. Our results highlighted the potential heterogeneity of AKI patients, which is worthy of further investigation., (© 2022. The Author(s).)

In this Letter, a novel "stepped particle swarm optimization" (SPSO) based on field intensity adjustment is proposed. After that, we used this algorithm to design a sub-wavelength converging grating that could be integrated with the detector on the back. Firstly, the advantages of reverse design in the process of two-dimensional or multi-element grating pattern design were summarized by comparing the theory of forward and reverse design. Then, the common "particle swarm optimization" (PSO) and our proposal were compared in the reverse design process; we found that the field strength at the focal point obtained by the improved algorithm was approximately twice of the conventional PSO, and the SPSO had higher computational efficiency and better global convergence. The value of the SPSO had been steadily enlarged, which significantly improved the performance of the sub-wavelength convergent grating. Finally, the property of the sub-wavelength converging grating was simulated, and we found that the grating could achieve good convergence in the focal length range of 100-150 µm, and had a strong ability to compensate for the position deviation of the incident light. In actual optical communications, this sub-wavelength converging grating will play an important role in alleviating the bandwidth and quantum efficiency, improving the performance of the detectors.

We report electrically pumped continuous-wave (CW) InAs/GaAs quantum dot lasers directly grown on planar exact silicon (001) with asymmetric waveguide structures. Surface hydrogen-annealing for the GaAs/ Si (001) templates and low-temperature growth for GaInP upper cladding layers were combined in the growth of the laser structure to achieve a high slope efficiency. For the broad-stripe edge-emitting lasers with 2-mm cavity length and 20-µm stripe width made from the above laser structure, a threshold current density of 203.5 A/cm 2 and a single-facet slope efficiency of 0.158 W/A are achieved at ∼1.31 µm band under CW conditions. The extrapolated mean-time-to-failure reaches up to 21000 hours at room temperature, which is deduced from the data measured from C-mount packaged devices. Importantly, these results can provide a practical strategy to realize 1.3 µm wavelength band distributed feedback lasers directly on planar exact Si (001) templates with thin buffer layers.

Advanced carbon-based electrode materials derived from wastes are essential to high-performance supercapacitors due to their abundance and sustainability. In this work, we fabricate novel cathodes and anodes based on discarded surgicalmask-derived carbon (DSM-C). Discarded surgicalmasks are good candidates for carbon-based electrode materials due to their unique fibrous structure and simple composition compared to conventional biomass sources. Benefiting from the excellent electrical conductivity of DSM-C and abundant redox reactions from nickel oxide (NiO), the electrochemical performances of NiO/DSM-C composites have been greatly improved. Specifically, the DSM-C and NiO/DSM-C electrodes show high specific capacitances of 240 F g -1 and 496 F g -1 at 1 A g -1 respectively, and excellent rate capability. Moreover,asymmetric supercapacitors (ASCs) are assembled using DSM-C and NiO/DSM-C as anodes and cathodes, respectively. They deliver a high energy density of 57 Wh kg -1 at a power density of 702 W kg -1 , accompanied by superior cycling stability (98.5% capacitance retention after 10,000 cycles). This work shows prospective applications of DSM-C as an electrode material for energy storage systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We propose a multilayer silicon nitride (SiN) -on-silicon photonic integrated circuit (PIC) platform with a monolithic laser at the C-band. A tapered edge coupler and a meta-structure-based interlayer directional coupler in the platform were designed to realize low-loss broadband laser-to-chip 3D coupling with small footprint. The coupling length of the interlayer directional coupler and the gap between different SiN layers were optimized as 12.7 µm and 1.4 µm. We measured the 1-dB-drop optical operation bandwidth of greater than 76 nm and the coupling loss of 6.1 ± 0.1 dB at 1550 nm for the interlayer directional coupler. The hybrid integration was demonstrated as a proof of concept for monolithic integration of light sources. The butt-coupling loss of 3.7 ± 0.1 dB between an on-chip DFB laser and a SiN edge coupler at 1549.48 nm was achieved. This approach opens the possibility of employing monolithic laser in the silicon photonics platform.

Virtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and medical genetic initiatives are reliant upon short-read whole-genome sequencing (srWGS), which presents challenges for the detection of structural variants (SVs) relative to emerging long-read WGS (lrWGS) technologies. Given this ubiquity of srWGS in large-scale genomics initiatives, we sought to establish expectations for routine SV detection from this data type by comparison with lrWGS assembly, as well as to quantify the genomic properties and added value of SVs uniquely accessible to each technology. Analyses from the Human Genome Structural Variation Consortium (HGSVC) of three families captured ~11,000 SVs per genome from srWGS and ~25,000 SVs per genome from lrWGS assembly. Detection power and precision for SV discovery varied dramatically by genomic context and variant class: 9.7% of the current GRCh38 reference is defined by segmental duplication (SD) and simple repeat (SR), yet 91.4% of deletions that were specifically discovered by lrWGS localized to these regions. Across the remaining 90.3% of reference sequence, we observed extremely high (93.8%) concordance between technologies for deletions in these datasets. In contrast, lrWGS was superior for detection of insertions across all genomic contexts. Given that non-SD/SR sequences encompass 95.9% of currently annotated disease-associated exons, improved sensitivity from lrWGS to discover novel pathogenic deletions in these currently interpretable genomic regions is likely to be incremental. However, these analyses highlight the considerable added value of assembly-based lrWGS to create new catalogs of insertions and transposable elements, as well as disease-associated repeat expansions in genomic sequences that were previously recalcitrant to routine assessment., (Copyright © 2021. Published by Elsevier Inc.)

Background: Patients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated., Objective: This work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases., Methods: Samples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis via the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents., Results: A total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were Candida (90.50%), Aspergillus (8.93%), and Cryptococcus neoformans (0.56%). The infective candida subgroups were Candida albicans (70.95%), Candida krusei (6.15%), Candida glabrata (5.59%), Candida parapsilosis (3.91%), and Candida tropicalis (3.91%). The susceptibility of non- Aspergillus fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for C. krusei , 98.43 and 100% for C. albicans , and 100% for both drugs for C. glabrata , C. parapsilosis , and C. tropicalis . The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for C. krusei , 20 and 20% for C. glabrata , and 57.14 and 57.14% for C. tropicalis . The resistance rate of C. tropicalis for both fluconazole and itraconazole was 41.43%., Conclusion: Patients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. Candida , especially C. albicans , was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non- Aspergillus fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zeng, Peng, Liu, Huang, Zhang, Wen, Lai and Zheng.)

We present an ultrasensitive enhanced fabrication-tolerance refractometer utilizing the polarimetric interference of a tapered PANDA-air-hole fiber (PAHF). To obtain high birefringence and unique group birefringence, the PAHF is specially designed by introducing double air holes into the cladding. Ultrahigh sensitivity can be achieved by reducing the group birefringence difference to zero, defined as birefringent dispersion turning point (BDTP). By modifying the diameter of PAHF, the birefringent dispersion can be effectively manipulated to reduce the group birefringence difference. In this way, the workable diameter range for realizing the ultrahigh sensitivity is twice as large as that of conventional microfibers. Additionally, the ultrasensitive wavelength band is dramatically expanded by at least 600 nm, enabling a compact structure and a flexible fiber-length design. Due to the tunable dispersion optimization, the distinctive properties of ultrahigh sensitivity, enhanced fabrication tolerance, and broadband operation can be achieved. We experimentally verified the ultrahigh refractive index sensitivity of 47223 nm/RIU around the BDTP, and the experimental results matched well with the simulations.

As an emerging ultrathin semiconductor material, Bi 2 O 2 Se exhibits prominent performances in electronics, optoelectronics, ultrafast optics, etc. However, until now, the in-plane growth of Bi 2 O 2 Se thin films is mostly fulfilled on atomically flat mica substrates with interfacial electrostatic forces setting obstacles for Bi 2 O 2 Se transfer to fabricate functional van der Waals heterostructures. In this work, controlled growth of inclined Bi 2 O 2 Se ultrathin films is realized with apparently reduced interfacial contact areas upon mica flakes. Consequently, the transfer of Bi 2 O 2 Se could be facile by overcoming weaker electrostatic interactions. From cross-sectional characterizations at the Bi 2 O 2 Se/mica interfaces, it is found that there are no oxide buffer layers in existence for both in-plane and inclined growths, while the un-neutralized charge density is apparently decreased for inclined films. By mechanical pressing, inclined Bi 2 O 2 Se could be transferred onto SiO 2 /Si substrates, and back-gated Bi 2 O 2 Se field effect transistors are fabricated, outperforming previously reported in-plane Bi 2 O 2 Se devices transferred with the assistance of corrosive acids and adhesive polymers. Furthermore, Bi 2 O 2 Se/graphene heterostructures are fulfilled by a probe tip to fabricate hybrid phototransistors with pristine interfaces, exhibiting highly efficient photoresponses. The results in this work demonstrate the potential of inclined Bi 2 O 2 Se to act as a building block for prospective van der Waals heterostructures.

The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair 1-4 . Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides 5 . Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers.

DNA methylation regulated gene expression is important for osteoblast proliferation and differentiation during bone remodeling and its deregulation leads to the development of osteoporosis. DNA methyltransferase 1 (DNMT1) is an important regulator of DNA methylation. To explore the effect and mechanism of differential expression of DNMT1 in osteoblast precursor cells, DNMT1 siRNAs were designed and synthesized to interfere with DNMT1 expression in the osteoblast precursor cells, MC3T3E1 (Clone 24; MC3T3E1-24). The expression of the target gene, DNMT1, and osteogenic differentiation indicators osteoprotegerin (OPG) and receptor activator of nuclear factor- κ B ligand (RANKL) were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). MTT assay was used to detect the effect on cell proliferation. Alkaline phosphatase (ALP) activity and alizarin red staining were used to detect the effect of DNMT1 on osteogenic differentiation. Hematoxylin and eosin (H&E) staining was used to detect the morphological changes in MC3T3E1-24 cells. Twenty-four hours following the transfection of MC3T3E1-24 cells with DNMT1 siRNA using cationic liposomes, DNMT1 mRNA and protein levels decreased significantly ( P <0.001 for both). The reduced expression of DNMT1 promoted the OPG mRNA and protein expression ( P <0.05), increased the ratio of OPG to RANKL ( P <0.05), inhibited the expression of RANKL ( P <0.01) without affecting the RANKL gene expression (not significant, P >0.05). The reduced expression of DNMT1 also promoted the proliferation of osteoblast precursor cells. In addition, ALP activity test and alizarin red staining showed that reduced expression of DNMT1 resulted in an increase in OPG/RANKL ratio and promoted the differentiation of the precursor cells. The cultured cells were found to have fibroblast-like appearance, and calcium nodules were observed after 7 days of conventional culture. In addition, to improve the efficiency of RNA extraction and save time, a type of silica nanomagnetic beads was used in the early stage of this study to extract RNA and assist qPCR detection of the target genes. The results showed that the magnetic beads could effectively extract RNA from the cells. In conclusion, low expression of DNMT1 affects proliferation and maturation of osteoblasts by upregulating OPG and OPG/RANKL ratio.

Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2,3 . As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) 4 have become integral in the interpretation of single-nucleotide variants (SNVs) 5 . However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage 6 . We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings 7 . This SV resource is freely distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Different from the traditional healthcare field, Medical Cyber Physical Systems (MCPS) rely more on wireless wearable devices and medical applications to provide better medical services. The secure storage and sharing of medical data are facing great challenges. Blockchain technology with decentralization, security, credibility and tamper-proof is an effective way to solve this problem. However, capacity limitation is one of the main reasons affecting the improvement of blockchain performance. Certificateless aggregation signature schemes can greatly tackle the difficulty of blockchain expansion. In this paper, we describe a two-layer system model in which medical records are stored off-blockchain and shared on-blockchain. Furthermore, a multi-trapdoor hash function is proposed. Based on the proposed multi-trapdoor hash function, we present a certificateless aggregate signature scheme for blockchain-based MCPS. The purpose is to realize the authentication of related medical staffs, medical equipment, and medical apps, ensure the integrity of medical records, and support the secure storage and sharing of medical information. The proposed scheme is highly computationally efficient because it does not use bilinear maps and exponential operations. Many certificateless aggregate signature schemes without bilinear maps in Internet of things (IoT) have been proposed in recent years, but they are not applied to the medical field, and they do not consider the security requirements of medical data. The proposed scheme in this paper has high computing and storage efficiency, while meeting the security requirements in MCPS.

As one of the bismuth-based oxychalcogenide materials, Bi 2 O 2 Se ultrathin films have received intense research interest due to their high carrier mobility, narrow bandgaps, ultrafast intrinsic photoresponse and long-term ambient stability; they exhibit great potential in electronic and optoelectronic applications. However, the device performance of photodetectors based on metal/Bi 2 O 2 Se/metal structures has degraded due to the undesirable defects or contaminants from the electrode deposition or the sample transfer processes. In this work, highly efficient photodetectors based on Au/Bi 2 O 2 Se junctions were achieved with Au electrodes transferred under the assistance of a probe tip to avoid contaminants from traditional lighography methods. Furthermore, to improve the charge transfer efficiency, specifically by increasing the intensity of the electrical field at the Au/Bi 2 O 2 Se interface and along the Bi 2 O 2 Se channels, the device annealing temperature was optimized to narrow the van der Waals gap at the Au/Bi 2 O 2 Se interface and the device channel length was shortened to improve the overall device performance. Among all the devices, the maximum device photoresponsivity was 9.1 A W -1 , and the device response time could approach 36 μs; moreover, the photodetectors featured broadband spectral responses from 360 nm to 1090 nm.

We have designed three mode order converters using the sub-wavelength grating on the silicon-on-insulator substrate. The proposed mode order converters can separately realize the mode order conversion from the fundamental transverse electric mode to the first-order transverse electric mode (TE 0 -to-TE 1 ), the second-order transverse electric mode (TE 0 -to-TE 2 ) and the third-order transverse electric mode (TE 0 -to-TE 3 ) with compact device sizes and good performances. The simulation results show that the mode order conversion efficiencies of TE 0 -to-TE 1 , TE 0 -to-TE 2 and TE 0 -to-TE 3 are larger than 94.4%, 95.7% and 83.7% in the wavelength ranging from 1.5 µm to 1.6 µm, the corresponding device length are 8.72 µm, 4.98 µm and 14.54 µm. In addition, the mode order converter can be fabricated with only once etching which will be advantage to the device fabrication.

With the rapid development of the Internet of Things (IoT), it becomes challenging to ensure its security. Identity authentication and integrity verification can be achieved by secure hash functions and digital signature algorithms for IoT applications. In order to solve the issues of bandwidth limitation and computational efficiency of secure communication in IoT applications, an aggregate signature scheme based on multi- trapdoor hash function is proposed in this paper. Firstly, to prevent key exposition, based on the elliptic curve discrete logarithm problem (ECDLP), we constructed a double trapdoor hash function (DTH) and proved its reliability. Secondly, the multi-trapdoor hash function (MTH) based on DTH is presented. Finally, an MTH-based aggregate signature scheme (MTH-AS) with constant signature length is proposed. Based on the assumption of ECDLP, the proposed scheme is proven unforgeable against adaptive chosen message attacks with the Forking Lemma. Different from the most signature schemes with bilinear mapping, the proposed scheme has higher computational efficiency and shorter aggregate signature length. Moreover, it is independent of the number of signers. Security analysis and performance evaluation has revealed that the proposed scheme is an ideal solution for secure IoT applications with limited computing power, storage capacity, or limited bandwidth, such as wireless sensor networks, vehicular ad hoc networks, or healthcare sensor networks., Competing Interests: The authors declare no conflict of interest.

Objectives: The treatment of condylar fractures has long been controversial. In this paper, we established a database for accurate measurement, storage, management and analysis of patients' data, in order to help determine the best treatment plan., Methods: First of all, the diagnosis and treatment database was established based on XNAT, including 339 cases of condylar fractures and their related information. Then image segmentation, registration and three-dimensional (3D) measurement were used to measure and analyze the condyle shapes. Statistical analysis was used to analyze the anatomical structure changes of condyle and the surrounding tissues at different stages before and after treatment. The processes of condylar fracture reestablishment at different stages were also dynamically monitored. Finally, based on all these information, the digital diagnosis and treatment plans for condylar fractures were developed., Results: For the patients less than 18 years old with no significant dislocation, surgical treatment and conservative treatment were equally effective for intracapsular fracture, and had no significant difference for neck and basal fractures. For patients above 18 years old, there was no significant difference between the two treatment methods for intracapsular fractures; but for condylar neck and basal fractures, surgical treatment was better than conservative treatment. When condylar fracture shift angle was greater than 11 degrees, and mandibular ramus height reduction was greater than 4mm, the patients felt the strongest pain, and their mouths opening was severely restricted. There were 170 surgical cases with condylar fracture shift angel greater than 11 degrees, and 118 of them (69.4%) had good prognosis, 52 of them (30.6%) had complications such as limited mouth opening. There were 173 surgical cases with mandibular ramus height reduction more than 4mm, and 112 of them (64.7%) had good prognosis, 61 of them (35.3%) had complications such as limited mouth opening., Conclusions: The establishment of XNAT condylar fracture database is helpful for establishing a digital diagnosis and treatment workflow for mandibular condylar fractures, providing new theoretical foundation and application basis for diagnosis and treatment of condylar fractures.

We present a two-element back-illuminated symmetric-connected uni-traveling-carrier photodiode array (SC-PDA) integrated with sub-wavelength-gratings based beam-splitter (SWGs-BS) for high power optoelectronic applications. The SC-PDA with SWGs-BS, a top-illuminated SC-PDA and a single PD were fabricated and tested. The proposed SC-PDA with SWGs-BS demonstrates a 3dB bandwidth of 23.8GHz@60mA, a saturation current of 87.9mA@12GHz and a maximum output RF power of ~16dBm@12GHz. Compared to the top-illuminated SC-PDA and the single PD, the proposed SC-PDA with SWGs-BS achieved high-power handling capability at low coupling complexity and requires no phase-matching techniques in the system.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect due to abnormal orofacial development. Previous studies report abnormal sonic hedgehog (SHH) signalling activity during NSCL/P pathogenesis and propose several genes in the SHH pathway as candidate risk genes. As such, we focussed on GLI3, a downstream modulator of the SHH pathway. In the present study,we genotyped 34 tag SNPs covering GLI3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified risk variants of GLI3 that are associated with NSCL/P susceptibility in a Chinese population. In particular, rs3801161 and its haplotypes rs3801161-rs7785287 displayed significant association with NSCL/P and survived Bonferroni correction for multiple comparisons. The robustness of the association between GLI3 and NSCL/P is worth further examination in the future across different populations.

Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA -null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome., (Copyright© Ferrata Storti Foundation.)

Orofacial clefts are among the most common birth defects in humans worldwide. A large-scale, genome-wide association study (GWAS) in the Chinese population recently identified several genetic risk variants for nonsyndromic cleft lip with or without cleft palate (NSCL/P). We selected 16 significant SNPs from the GWAS I stage (P < 1.00E-5) that had not been replicated to validate their association with NSCL/P in 1931 NSCL/P cases and 2258 controls. Ultimately, we identified a NSCL/P susceptibility loci (rs17095681 at 10q25.3, intron of SHTN1 and 27.2 kb downstream of VAX1, P meta  = 3.80E-9, OR = 0.64) in Chinese Han and Hui populations. This locus was not high LD with the reported loci in 10q25.3. It was a newly identified independent locus in 10q25.3 associated with NSCL/P. These results imply that SHTIN1 may involve in the pathogenesis of NSCL/P advance our understanding of the genetic susceptibility to NSCL/P.

Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects worldwide and is characterized by abnormalities of the orofacial structure. Syndromic CL/P is mainly caused by Mendelian disorders such as Van der Woude Syndrome (VWS). However, >70% of CL/P cases are nonsyndromic, characterized by isolated orofacial cleft without any known syndrome. The etiology of nonsyndromic CL/P (NSCL/P) remains elusive, but it has been suggested that causative genes of syndromic CL/P might also contribute to NSCL/P. As such, the VWS causative gene IRF6 has been extensively studied in NSCL/P. Recently, GRHL3 was identified as another VWS causative gene. Thus, it may be a novel candidate gene for NSCL/P. In the present study, we genotyped 10 tag SNPs covering GRHL3 and performed association analysis with NSCL/P in 504 cases and 455 healthy controls. Our preliminary results identified rs10903078, rs4638975, and a haplotype rs10903078-rs6659209 of GRHL3 that exceeded the significance threshold (p<0.05), though none survived Bonferroni correction for multiple comparisons. As the first study between GRHL3 and NSCL/P, the contribution of this gene to NSCL/P etiology should be interpreted with caution based on existing evidence. Further, the robustness of association between GRHL3 and NSCL/P should be further validated in expanded cohorts., (Copyright © 2016. Published by Elsevier B.V.)

Complex mixtures of molecular species, such as glycoproteins and glycosaminoglycans, have important biological and therapeutic functions. Characterization of these mixtures with analytical chemistry measurements is an important step when developing generic drugs such as biosimilars. Recent developments have focused on analytical methods and statistical approaches to test similarity between mixtures. The question of how much uncertainty on mixture composition is reduced by combining several measurements still remains mostly unexplored. Mathematical frameworks to combine measurements, estimate mixture properties, and quantify remaining uncertainty, i.e. a characterization extent, are introduced here. Constrained optimization and mathematical modeling are applied to a set of twenty-three experimental measurements on heparan sulfate, a mixture of linear chains of disaccharides having different levels of sulfation. While this mixture has potentially over two million molecular species, mathematical modeling and the small set of measurements establish the existence of nonhomogeneity of sulfate level along chains and the presence of abundant sulfate repeats. Constrained optimization yields not only estimations of sulfate repeats and sulfate level at each position in the chains but also bounds on these levels, thereby estimating the extent of characterization of the sulfation pattern which is achieved by the set of measurements.

Objectives: Accurate registration and feasible fusion of a three-dimensional (3D) photorealistic surface images (captured using the FaceSCAN3D® Scientific Photo Lab) from multislice spiral computed tomography (MSCT) images is important to achieve optimal craniomaxillofacial surgery outcomes; thus, the aim of this work was to optimize this process., Methods: MSCT and 3D facial scans were acquired from 37 randomly selected patients. Using the Invesalius software package, skin and bone tissue models were reconstructed. The 3D photorealistic surface images were then constructed. Four image registration processes were performed using Geomagic Studio software: manual Procrustes and semi-automatic registration (global modified ICP) using both 7 and 15 anthropometric landmarks. The statistical differences were assessed using one-way ANOVA and LSD tests. P values <0.05 were considered significant., Results: Average distances between these two surfaces measured 0.99 (SD 0.13 mm), 0.77 (SD 0.11 mm), 0.99 (SD 0.15 mm), and 0.77 mm (SD 0.10 mm) via the four image registration methods. Statistical differences were observed between the manual and semi-automatic registration groups (according to 7 and 15 anthropometric landmarks, respectively). Image registration errors for the entire virtual face were <0.8 mm in the semi-automatic registration groups., Conclusion: Employing the Procrustes registration system using seven anthropometric landmarks together with global registration allows accurate registration and feasible fusion of 3D facial scans with reconstructed 3D MSCT image data.

Adjuvanted vaccines afford invaluable protection against disease, and the molecular and cellular changes they induce offer direct insight into human immunobiology. Here we show that within 24 h of receiving adjuvanted swine flu vaccine, healthy individuals made expansive, complex molecular and cellular responses that included overt lymphoid as well as myeloid contributions. Unexpectedly, this early response was subtly but significantly different in people older than ∼35 years. Wide-ranging adverse clinical events can seriously confound vaccine adoption, but whether there are immunological correlates of these is unknown. Here we identify a molecular signature of adverse events that was commonly associated with an existing B cell phenotype. Thus immunophenotypic variation among healthy humans may be manifest in complex pathophysiological responses.

Nonsyndromic cleft lip with or without a cleft palate (NSCL/P) is among the most common human congenital birth defects and imposes a substantial physical and financial burden on affected individuals. Here, we conduct a case-control-based GWAS followed by two rounds of replication; we include six independent cohorts from China to elucidate the genetic architecture of NSCL/P in Chinese populations. Using this combined analysis, we identify a new locus at 16p13.3 associated with NSCL/P: rs8049367 between CREBBP and ADCY9 (odds ratio=0.74, P=8.98 × 10(-12)). We confirm that the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 are also involved in NSCL/P development in Chinese populations. Our results provide additional evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in Chinese populations. These findings provide information on the genetic basis and mechanisms of NSCL/P.

We propose a planar dielectric reflector with focusing ability using concentric circular subwavelength gratings (CC-SWGs). The two-dimensional focusing ability of CC-SWGs is investigated by the rigorous coupled-wave analysis (RCWA) and finite element method (FEM). By designing the concentric circular pattern of the grating surface, a focusing reflector with high numerical aperture (NA) and high reflectivity is constructed. A CC-SWG reflector with a diameter of 32.6μm and a focal length of 6μm is investigated, which exhibits high focusing ability at normal incidence with a radially polarized plane wave. At the reflection focal plane, the full-width-half-maximum (FWHM) of the electric field intensity is 0.89μm. Numerical aperture value as high as 0.93 is achieved for the reflector with very high reflectivity of 92%.

We present a concise approach to design focusing reflectors using concentric circular subwavelength high-contrast gratings (CCSW-HCGs). With this method, we design a high-numerical-aperture, high-reflectivity CCSW-HCG focusing reflector. By designing the CCSW-HCG structure, the grating can give the target phase front of reflected light while maintaining a high reflectivity. The properties of focusing and reflection are numerically studied with the finite element method. Simulation results show that, when the incident wavelength is 1550 nm, the reflectivity is 0.8538, and the numerical aperture is up to 0.9213. At the reflection focal plane, the full width at half-maximum of the field distribution is 0.9845 μm. Furthermore, the CCSW-HCG can simultaneously focus the reflected and transmitted light and has a strong robustness.

A reflection-enhanced dual-absorption InP-PIN/GaAs-DBR photodetector was fabricated and characterized. The photodetector is monolithically integrated using a heteroepitaxy growth of an InGaAs/InP dual-absorption "PINIP" structure on the GaAs/AlGaAs Bragg reflectors. These features lead to an increase in quantum efficiency over a wide wavelength range while maintaining a high speed. The measured quantum efficiency was increased by 48.8% in comparison with that without reflectors. A quantum efficiency of 64% at a wavelength of 1522 nm and a 3 dB bandwidth of 26 GHz at a reverse bias of 3 V were simultaneously obtained in the device.