Artificial intelligence assists identification and pathologic classification of glomerular lesions in patients with diabetic nephropathy.

BACKGROUND: Glomerular lesions are the main injuries of diabetic nephropathy (DN) and are used as a crucial index for pathologic classification. Manual quantification of these morphologic features currently used is semi-quantitative and time-consuming. Automatically quantifying glomerular morphologic features is urgently needed. METHODS: A series of convolutional neural networks (CNN) were designed to identify and classify glomerular morphologic features in DN patients. Associations of these digital features with pathologic classification and prognosis were further analyzed. RESULTS: Our CNN-based model achieved a 0.928 F1-score for global glomerulosclerosis and 0.953 F1-score for Kimmelstiel-Wilson lesion, further obtained a dice of 0.870 for the mesangial area and F1-score beyond 0.839 for three glomerular intrinsic cells. As the pathologic classes increased, mesangial cell numbers and mesangial area increased, and podocyte numbers decreased (p for all < 0.001), while endothelial cell numbers remained stable (p = 0.431). Glomeruli with Kimmelstiel-Wilson lesion showed more severe podocyte deletion compared to those without (p < 0.001). Furthermore, CNN-based classifications showed moderate agreement with pathologists-based classification, the kappa value between the CNN model 3 and pathologists reached 0.624 (ranging from 0.529 to 0.688, p < 0.001). Notably, CNN-based classifications obtained equivalent performance to pathologists-based classifications on predicting baseline and long-term renal function. CONCLUSION: Our CNN-based model is promising in assisting the identification and pathologic classification of glomerular lesions in DN patients.

Improving knowledge, attitude and practice on norovirus infection diarrhea among staff of kindergartens and schools: a before-after study.

BACKGROUND: Norovirus gastroenteritis outbreaks were common in schools and kindergartens and were more related to faculty knowledge, attitude, and practice level. Gastroenteritis outbreaks caused by norovirus in educational institutions were the prominent cause of Public Health Emergency Events in China. This study aimed to explore the transformation in the contribution of KAP items related to outbreak prevention before and after intervention and the impact of demography factors on the intervention. METHODS: This study sampled 1095 kindergarten and 1028 school staff in Shenzhen, China. We created a questionnaire consisting of 35 items in 4 parts, and each item was rated on a scale of 1-5 according to the accuracy. Univariate analysis of non-parametric tests and binary logistic regression were used to estimate the score difference on demographic characteristics, each item and KAP. The odds ratios (OR) with 95% confidence and intervals (CI) for the association between statistical indicators were mainly used to explain the effects before and after intervention. RESULTS: Overall, 98.72% and 74.9% of the kindergarten and school participants were female, and all respondents had the highest scores difference of practice. Following intervention, univariate analysis indicated that primary school and female respondents achieved higher knowledge scores. Staff age beyond 35 (OR = 0.56, CI:0.34-0.92; OR = 0.67, CI:0.50-0.90) and with more than ten years of service (OR = 0.58, CI:0.36-0.91; OR = 0.38, CI:0.17-0.84) demonstrated a significantly lower post-intervention score for attitude and practice in both kindergartens and schools. The staff members exhibited a general lack of familiarity with the transmission of aerosols and the seasonal patterns of NoVs diarrhea pandemics. Item analysis revealed that kindergarten staff aged 26 and above demonstrated superior performance in terms of the efficacy of medical alcohol for inactivation (OR = 1.93, CI:1.13-3.31) and management strategies for unexplained vomiting among students (OR = 1.97, CI:1.21-3.18). Private school personnel displayed more significant improvement in their practices following educational interventions. School administrators' negative attitudes were primarily evident in their perspectives on morning inspections (OR = 0.11, CI:0.05-0.84). CONCLUSIONS: The potential negative impact of faculty age on NoVs-related knowledge can be mitigated by the positive attitudes fostered through seniority. Furthermore, it is imperative to urgently address the lack of knowledge among administrators, and the identification and treatment of vomiting symptoms should be emphasized as crucial aspects of school prevention strategies. Therefore, education authorities should implement comprehensive public health interventions in the future.

Advancing the application of the analytical renal pathology system in allograft IgA nephropathy patients.

BACKGROUND: The analytical renal pathology system (ARPS) based on convolutional neural networks has been used successfully in native IgA nephropathy (IgAN) patients. Considering the similarity of pathologic features, we aim to evaluate the performance of the ARPS in allograft IgAN patients and broaden its implementation. METHODS: Biopsy-proven allograft IgAN patients from two different centers were enrolled for internal and external validation. We implemented the ARPS to identify glomerular lesions and intrinsic glomerular cells, and then evaluated its performance. Consistency between the ARPS and pathologists was assessed using intraclass correlation coefficients. The association of digital pathological features with clinical and pathological data was measured. Kaplan-Meier survival curve and cox proportional hazards model were applied to investigate prognosis prediction. RESULTS: A total of 56 biopsy-proven allograft IgAN patients from the internal center and 17 biopsy-proven allograft IgAN patients from the external center were enrolled in this study. The ARPS was successfully applied to identify the glomerular lesions (F1-score, 0.696-0.959) and quantify intrinsic glomerular cells (F1-score, 0.888-0.968) in allograft IgAN patients rapidly and precisely. Furthermore, the mesangial hypercellularity score was positively correlated with all mesangial metrics provided by ARPS [Spearman's correlation coefficient (r), 0.439-0.472, and all p values < 0.001]. Besides, a higher allograft survival was noticed among patients in the high-level groups of the maximum and ratio of endothelial cells, as well as the maximum and density of podocytes. CONCLUSION: We propose that the ARPS could be implemented in future clinical practice with outstanding capability.

Achievements and perspectives of synthetic biology in botanical insecticides.

Botanical insecticides are the origin of all insecticidal compounds. They have been widely used to control pests in crops for a long time. Currently, the commercial production of botanical insecticides extracted from plants is limited because of insufficient raw material supply. Synthetic biology is a promising and effective approach for addressing the current problems of the production of botanical insecticides. It is an emerging biological research hotspot in the field of botanical insecticides. However, the biosynthetic pathways of many botanical insecticides are not completely elucidated. On the other hand, the cytotoxicity of botanical pesticides and low efficiency of these biosynthetic enzymes in new hosts make it still challenging for their heterologous production. In the present review, we summarized the recent developments in the heterologous production of botanical insecticides, analyzed the current challenges, and discussed the feasible production strategies, focusing on elucidating biosynthetic pathways, enzyme engineering, host engineering, and cytotoxicity engineering. Looking to the future, synthetic biology promises to further advance heterologous production of more botanical pesticides.

Circulating Tfh cell and subsets distribution are associated with low-responsiveness to hepatitis B vaccination.

BACKGROUND: An estimated 5-10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date. METHODS: There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine. RESULTS: We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production. CONCLUSIONS: Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.

Comparative transcriptome analysis of sesquiterpene biosynthesis and functional characterization of sesquiterpene synthases in Leonurus sibiricus L.

MAIN CONCLUSION: Two sesquiterpene synthases were identified through comparative transcriptome analysis of Leonurus sibiricus. LsSqTPS2 could produce high titer of δ-cadinene in vivo which suggests the terpene specificity of L. sibiricus. Leonurus sibiricus L., a medicinal herb, is widely used in China due to its pharmacological activities. Cadinene type sesquiterpenes, one of major bioactive components mainly present in aerial parts of L. sibiricus, showed antibacterial, anti-inflammatory, antioxidant and antiproliferative properties. However, there is no report about the sesquiterpene biosynthesis in L. sibiricus. This study identified L. sibiricus sesquiterpene synthases (LsSqTPSs) through comparative transcriptome analysis of L. sibiricus leaf and root samples using the BGISEQ-500 sequencing technique. A total of 83,244 unigenes were obtained with an average length of 1025 bp. Among them, 50,356 unigenes (60.49%) acquired annotations according to the BLAST searching results. A total of 68 differentially expressed genes (DEGs) were potentially involved in the sesquiterpene biosynthesis. Furthermore, four candidate DEGs encoding LsSqTPSs were characterized. The enzymatic characterization in engineered yeast showed that LsSqTPS1 produced α-farnesene as the single product and LsSqTPS2 mainly produced 76.23 mg/L of δ-cadinene, which constituted the major component of L. sibiricus leaf essential oil. This work contributes to the investigation of sesquiterpene biosynthesis in L. sibiricus.

De novo assembly of the Mylia taylorii transcriptome and identification of sesquiterpene synthases.

Mylia taylorii is an ancient nonseed land plant that accumulates various sesquiterpenes with insecticidal and antibacterial activities. Recently, microbial-type sesquiterpene synthases (STSs) with atypical aspartate-rich metal ion binding motifs have been identified in some liverworts. Here, transcriptome analysis of M. taylorii was performed to identify M. taylorii sesquiterpene synthases (MtSTSs) that are potentially involved in sesquiterpene biosynthesis and diversity. A total of 255,669 unigenes were obtained with an average length of 963 bp in the transcriptome data of M. taylorii, among which 148,093 (57.92%) unigenes had BLAST results. Forty-eight unigenes were related to the sesquiterpene backbone biosynthesis according to KEGG annotation. In addition, MtSTS1, MtSTS2 and MtSTS3 identified from putative MtSTSs display sesquiterpene catalytic activities on the basis of functional characterizations in yeast. Interestingly, MtSTSs exhibit a noncanonical metal ion binding motif and the structural composition of a single α-domain, which are features of microbial STSs instead of archetypical plant STSs. This study revealed new microbial-type STS members of nonseed plants, and functionally identified that MtSTSs may contribute to the investigation of the biosynthesis and biological role of sesquiterpenes in M. taylorii.

Two-dimensional ScN with high carrier mobility and unexpected mechanical properties.

Two-dimensional (2D) semiconductors with desirable bandgaps and high carrier mobility have great potential in electronic and optoelectronic applications. In the present work, 2D M-ScN, H-ScN, and O-ScN are predicted by the swarm-intelligent global structure search method. The low formation energies and high dynamical and thermal stabilities indicate the high feasibility of experimental synthesis of these ScN monolayers. The electronic structure calculations reveal that M-ScN and O-ScN are both direct bandgap semiconductors with the bandgaps of 1.39 and 2.14 eV, respectively, while H-ScN has a large indirect bandgap of 3.21 eV. In addition, both M-ScN and H-ScN exhibit ultra-high electron mobilities (3.09 × 104 cm2 V-1 s-1 and 1.22 × 104 cm2 V-1 s-1, respectively). More notably, O-ScN is found to be a promising 2D auxetic and ferroelastic material. The values of negative Possion's ratios and reversible strain of this monolayer are predicted to be -0.27% and 15%, respectively.

Two-dimensional ZrC2 as a novel anode material with high capacity for sodium ion battery.

Rational design of high-performance anode materials is of paramount importance for developing rechargeable lithium ion batteries (LIBs) and sodium ion batteries (SIBs). In this work, a ZrC2 monolayer is predicted by performing the particle swarm optimization (PSO) algorithm. The high energetic, dynamic, and thermal stabilities of the ZrC2 monolayer are confirmed by cohesive energy, phonon dispersion, and molecular dynamics simulations, respectively. Unexpectedly, we find that the theoretical specific capacity for Na on the ZrC2 monolayer reaches as high as 932 mA h g-1, which is even higher than that of Li. Meanwhile, the diffusion energy barrier of Na on the ZrC2 monolayer is only 0.02 eV, ensuring the ultrafast charge/discharge rate. Additionally, the calculated open-circuit voltage (OCV) suggests that the change of Na intercalation voltage is steady. Therefore, our results consistently demonstrate that the ZrC2 monolayer can be an ideal anode material for SIBs.

ComX improves acid tolerance by regulating the expression of late competence proteins in Lactococcus lactis F44.

ComX can improve bacterial competence by modulating global gene expression. Although competence induction may also be a protective mechanism under stress, this has not been investigated in detail. Here, we demonstrated that ComX improved the acid tolerance and nisin yield of Lactococcus lactis, which is an important gram-positive bacterium increasingly used in modern biotechnological applications. We found that overexpression of comX could improve the survival rate up to 36.5% at pH 4.0, compared with only 5.4% and 1.1% with the wild-type and comX knockout strains, respectively. Moreover, quantitative real-time PCR results indicated that comX overexpression stimulated the expression of late competence genes synergistically with exposure to acid stress. Finally, electrophoretic mobility shift assay demonstrated the binding of purified ComX to the cin-box in the promoters of these genes. Taken together, our results reveal a regulation mechanism by which ComX and acid stress can synergistically modulate the expression of late competence genes to enhance cells' acid tolerance and nisin yield.

Noncontact Damage Topography Reconstruction by Wavenumber Domain Analysis Based on Air-Coupled Ultrasound and Full-Field Laser Vibrometer.

Noncontact ultrasonic detection technology is an effective method to detect damage in time. This paper proposes a noncontact damage detection system based on air-coupled ultrasound and full-field laser vibrometer, which realizes the excitation of relatively single-mode guided waves and the wavefield automatic detection. The system performance is verified through experiments, and the experimental wavenumber is consistent with the theoretical dispersion characteristics of the Lamb wave in the A0 mode. Based on this system, the topography reconstruction algorithms, including the Wavenumber Filtering Algorithm and Spatial Wavenumber Algorithm, were tested and compared with the aluminum alloy plate and the carbon fiber reinforced polymer plate. The results show that, based on the air-coupled ultrasound and full-field laser vibrometer detection system, the Spatial Wavenumber Algorithm has better imaging error and contrast, and the damage edge detection is smoother.

Molecular and Functional Evolution of the Spermatophyte Sesquiterpene Synthases.

Sesquiterpenes are important defense and signal molecules for plants to adapt to the environment, cope with stress, and communicate with the outside world, and their evolutionary history is closely related to physiological functions. In this study, the information of plant sesquiterpene synthases (STSs) with identified functions were collected and sorted to form a dataset containing about 500 members. The phylogeny of spermatophyte functional STSs was constructed based on the structural comparative analysis to reveal the sequence-structure-function relationships. We propose the evolutionary history of plant sesquiterpene skeletons, from chain structure to small rings, followed by large rings for the first time and put forward a more detailed function-driven hypothesis. Then, the evolutionary origins and history of spermatophyte STSs are also discussed. In addition, three newly identified STSs CaSTS2, CaSTS3, and CaSTS4 were analyzed in this functional evolutionary system, and their germacrene D products were consistent with the functional prediction. This demonstrates an application of the structure-based phylogeny in predicting STS function. This work will help us to understand evolutionary patterns and dynamics of plant sesquiterpenes and STSs and screen or design STSs with specific product profiles as functional elements for synthetic biology application.

Functional characterization and catalytic activity improvement of BAHD acyltransferase from Celastrus angulatus Maxim.

MAIN CONCLUSION: A BAHD terpene alcohol acyltransferase, CaAT20, was identified from Celastrus angulatus Maxim, expressed in E. coli and functionally characterized. S405A mutant of CaAT20 increased the enzyme activity. Acylation is a diversely physiological process in the biosynthesis of plant secondary metabolites. Plant BAHD acyltransferases play an important role in the modification of volatile esters with biological activities. In this research, a BAHD acyltransferase (CaAT20) was identified from Celastrus angulatus Maxim and the function of this enzyme was characterized. CaAT20 could convert geraniol to geranyl esters by using benzoyl-CoA and acetyl-CoA as the acyl donors respectively. Furthermore, the catalytic activity of CaAT20 for benzoyl-CoA was higher than that of acetyl-CoA. Site-directed mutation of CaAT20 was carried out based on the results of molecular simulation. In vitro site-directed mutant S405A of CaAT20 increased the volume of binding cavity so as to facilitate the entry of geraniol, indicating a more efficient acylation for geraniol and benzoyl-CoA. Our research provides new insight for the catalytic functions of CaAT20.

An Integrated Front-end Circuit Board for Air-Coupled CMUT Burst-Echo Imaging.

To conduct burst-echo imaging with air-coupled capacitive micromachined ultrasonic transducers (CMUTs) using the same elements in transmission and reception, this work proposes a dedicated and integrated front-end circuit board design to build an imaging system. To the best of the authors' knowledge, this is the first air-coupled CMUT burst-echo imaging using the same elements in transmission and reception. The reported front-end circuit board, controlled by field programmable gate array (FPGA), consisted of four parts: an on-board pulser, a bias-tee, a T/R switch and an amplifier. Working with our 217 kHz 16-element air-coupled CMUT array under 100 V DC bias, the front-end circuit board and imaging system could achieve 22.94 dB signal-to-noise ratio (SNR) in burst-echo imaging in air, which could represent the surface morphology and the three-dimensional form factor of the target. In addition, the burst-echo imaging range of our air-coupled CMUT imaging system, which could work between 52 and 273 mm, was discussed. This work suggests good potential for ultrasound imaging and gesture recognition applications.

Phosphoinositide 3-kinase/protein kinase B inhibition restores regulatory T cell's function in pulmonary sarcoidosis.

Sarcoidosis is a systemic granulomatous disease associated with Th1/ regulatory T cells (Treg) paradigm. PI3K/Akt signaling, critical for maintaining Treg's homeostasis, is aberrantly activated in sarcoidosis patients. Here we tested the role of the PI3K inhibitors, LY294002 and BKM120, in immune modulation in experimental pulmonary sarcoidosis, concerning Th1/Th17/Treg immune profile detected by fluorescence-activated cell sorting analysis or quantitative polymerase chain reaction, as well as the effect on Treg's suppressive functions. Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis, along with decreased frequency and damaged function of Treg. Blockage of PI3K suppressed this signaling in Treg, rebalanced Th1/Treg, inhibited the production of inflammatory cytokines, and enhanced Treg's function. These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add-on drugs to treat pulmonary sarcoidosis.

De novo leaf and root transcriptome analysis to explore biosynthetic pathway of Celangulin V in Celastrus angulatus maxim.

BACKGROUND: Celastrus angulatus Maxim is a kind of crucial and traditional insecticidal plant widely distributed in the mountains of southwest China. Celangulin V is the efficient insecticidal sesquiterpenoid of C. angulatus and widely used in pest control in China, but the low yield and discontinuous supply impeded its further popularization and application. Fortunately, the development of synthetic biology provided an opportunity for sustainable supply of Celangulin V, for which understanding its biosynthetic pathway is indispensable. RESULTS: In this study, six cDNA libraries were prepared from leaf and root of C. angulatus before global transcriptome analyses using the BGISEQ-500 platform. A total of 104,950 unigenes were finally obtained with an average length of 1200 bp in six transcriptome databases of C. angulatus, in which 51,817 unigenes classified into 25 KOG classifications, 39,866 unigenes categorized into 55 GO functional groups, and 48,810 unigenes assigned to 135 KEGG pathways, 145 of which were putative biosynthetic genes of sesquiterpenoid and triterpenoid. 16 unigenes were speculated to be related to Celangulin V biosynthesis. De novo assembled sequences were verified by Quantitative Real-Time PCR (qRT-PCR) analysis. CONCLUSIONS: This study is the first report on transcriptome analysis of C. angulatus, and 16 unigenes probably involved in the biosynthesis of Celangulin V were finally collected. The transcriptome data will make great contributions to research for this specific insecticidal plant and the further gene mining for biosynthesis of Celangulin V and other sesquiterpene polyol esters.

Interface Schottky barrier in Hf2NT2/MSSe (T = F, O, OH; M = Mo, W) heterostructures.

The Schottky barrier height (SBH) is a critical parameter that determines the carrier transfer at metal/semiconductor interfaces. In this work, the interfacial properties of Hf2NT2/MSSe (T = F, O, OH; M = Mo, W) heterostructures are systematically investigated using first-principles calculations. It is found that, for MoSSe and WSSe, the use of S or Se atomic layers in contact with Hf2NT2 can give significantly different SBHs. In addition, SB-free contact for electron injection can be realized for F-S interfaces in Hf2NF2/MoSSe and Hf2NF2/WSSe heterostructures. Furthermore, the SBHs of the heterostructures can be tuned by applying compressive strain and p-type ohmic contact can be obtained for O-Se interfaces in Hf2NO2/MoSSe and Hf2NO2/WSSe heterostructures. This work proposes a feasible strategy to regulate the SBHs of interfaces.

Single Pt atoms stabilized on Mo2TiC2O2 for hydrogen evolution: A first-principles investigation.

Single-atom catalysis offers an effective way to reduce the amount of used noble metals and maximizes their catalytic activity. We systematically explore electrocatalytic performances of Pt doped Mo2TiC2O2 monolayer by the first principles calculations. Our results show that the presence of donor defects in Mo2TiC2O2 can always increase the reaction free energy of hydrogen adsorption and further promotes the performance in hydrogen evolution reaction (HER). More interestingly, the substitution of Pt for O in the Mo2TiC2 can modify the free energy to an ideal value and is responsible for the significantly enhanced catalytic activity. Furthermore, the large value of diffusion barrier indicates that single Pt atoms can be stabilized onto the O vacancy sites, which can effectively prevent them to aggregate into nanoparticles. Our works are useful for understanding the recent experimental observations and pave the way for further experimental improvements of catalytic activity for the HER.

Global evolution of glycosylated polyene macrolide antibiotic biosynthesis.

Antibiotics are the most marvelous evolutionary products of microbes to obtain competitive advantage and maintain ecological balance. However, the origination and development of antibiotics has yet to be explicitly investigated. Due to diverse structures and similar biosynthesis, glycosylated polyene macrolides (gPEMs) were chosen to explore antibiotic evolution. A total of 130 candidate and 38 transitional gPEM clusters were collected from actinomycetes genomes, providing abundant references for phenotypic gaps in gPEM evolution. The most conserved parts of gPEM biosynthesis were found and used for phylogeny construction. On this basis, we proposed ancestral gPEM clusters at different evolutionary stages and interpreted the possible evolutionary histories in detail. The results revealed that gPEMs evolved from small rings to large rings and continuously increased structural diversity through acquiring, discarding and exchanging genes from different evolutionary origins, as well as co-evolution of functionally related proteins. The combination of horizontal gene transfers, environmental effects and host preference resulted in the diversity and worldwide distribution of gPEMs. This study is not only a useful exploration on antibiotic evolution but also an inspiration for diversity and biogeographic investigations on antibiotics in the era of Big Data.

The increase of O-acetylation and N-deacetylation in cell wall promotes acid resistance and nisin production through improving cell wall integrity in Lactococcus lactis.

Cell wall is closely related to bacterial robustness and adsorption capacity, playing crucial roles in nisin production in Lactococcus lactis. Peptidoglycan (PG), the essential component of cell wall, is usually modified with MurNAc O-acetylation and GlcNAc N-deacetylation, catalyzed by YvhB and XynD, respectively. In this study, increasing the two modifications in L. lactis F44 improved autolysis resistance by decreasing the susceptibility to PG hydrolases. Furthermore, both modifications were positively associated with overall cross-linkage, contributing to cell wall integrity. The robust cell wall rendered the yvhB/xynD-overexpression strains more acid resistant, leading to the increase of nisin production in fed-batch fermentations by 63.7 and 62.9%, respectively. Importantly, the structural alterations also reduced nisin adsorption capacity, resulting in reduction of nisin loss. More strikingly, the co-overexpression strain displayed the highest nisin production (76.3% higher than F44). Our work provides a novel approach for achieving nisin overproduction via extensive cell wall remodeling.