Versatile CYP98A enzymes catalyse meta-hydroxylation reveals diversity of salvianolic acids biosynthesis.

Salvianolic acids (SA), such as rosmarinic acid (RA), danshensu (DSS), and their derivative salvianolic acid B (SAB), etc. widely existed in Lamiaceae and Boraginaceae families, are of interest due to medicinal properties in the pharmaceutical industries. Hundreds of studies in past decades described that 4-coumaroyl-CoA and 4-hydroxyphenyllactic acid (4-HPL) are common substrates to biosynthesize SA with participation of rosmarinic acid synthase (RAS) and cytochrome P450 98A (CYP98A) subfamily enzymes in different plants. However, in our recent study, several acyl donors and acceptors included DSS as well as their ester-forming products all were determined in SA-rich plants, which indicated that previous recognition to SA biosynthesis is insufficient. Here, we used Salvia miltiorrhiza, a representative important medicinal plant rich in SA, to elucidate the diversity of SA biosynthesis. Various acyl donors as well as acceptors are catalysed by SmRAS to form precursors of RA and two SmCYP98A family members, SmCYP98A14 and SmCYP98A75, are responsible for different positions' meta-hydroxylation of these precursors. SmCYP98A75 preferentially catalyses C-3' hydroxylation, and SmCYP98A14 preferentially catalyses C-3 hydroxylation in RA generation. In addition, relative to C-3' hydroxylation of the acyl acceptor moiety in RA biosynthesis, SmCYP98A75 has been verified as the first enzyme that participates in DSS formation. Furthermore, SmCYP98A enzymes knockout resulted in the decrease and overexpression leaded to dramatic increase of SA accumlation. Our study provides new insights into SA biosynthesis diversity in SA-abundant species and versatility of CYP98A enzymes catalytic preference in meta-hydroxylation reactions. Moreover, CYP98A enzymes are ideal metabolic engineering targets to elevate SA content.

Pathogenomics for accurate diagnosis, treatment, prognosis of oncology: a cutting edge overview.

The capability to gather heterogeneous data, alongside the increasing power of artificial intelligence to examine it, leading a revolution in harnessing multimodal data in the life sciences. However, most approaches are limited to unimodal data, leaving integrated approaches across modalities relatively underdeveloped in computational pathology. Pathogenomics, as an invasive method to integrate advanced molecular diagnostics from genomic data, morphological information from histopathological imaging, and codified clinical data enable the discovery of new multimodal cancer biomarkers to propel the field of precision oncology in the coming decade. In this perspective, we offer our opinions on synthesizing complementary modalities of data with emerging multimodal artificial intelligence methods in pathogenomics. It includes correlation between the pathological and genomic profile of cancer, fusion of histology, and genomics profile of cancer. We also present challenges, opportunities, and avenues for future work.

MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

Associations of urinary 1,3-butadiene metabolite with glucose homeostasis, prediabetes, and diabetes in the US general population: Role of alkaline phosphatase.

The chemical - 1,3-butadiene (BD) is a volatile organic compound ubiquitous in the environment. However, the relationships and underlying mechanisms between BD exposure and glucose dyshomeostasis and diabetes in the general population remain unclear. We sought to explore the associations of BD exposure with glucose homeostasis, prediabetes, and diabetes, as well as the role of serum alkaline phosphatase (ALP) in these associations. This study included 5092 US general residents from the National Health and Nutrition Examination Survey with measurements of urinary BD metabolite (N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine, DHBMA) and serum ALP. Glucose homeostasis was evaluated by fasting plasma glucose (FPG), fasting serum insulin (FINS), glycohemoglobin (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR). HOMA-IR>2.6 was considered as insulin resistance (IR). Prediabetes and diabetes were determined according to the recommendations of the American Diabetes Association. The associations of DHBMA with glucose homeostasis, prediabetes, and diabetes were assessed by linear regression models and logistic regression models. The mediating role of ALP was evaluated by mediation analysis. We observed positive dose-response relationships of DHBMA level with glucose homeostasis indices and ALP levels, as well as with the risks of prediabetes and diabetes (all P < 0.05 and/or P for trend <0.05). Each 2-fold increase in DHBMA was associated with a 1.32%, 9.20%, 0.72%, and 10.64% increase in FPG, FINS, HbA1c, and HOMA-IR, respectively (all P < 0.05). And the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) for IR, prediabetes, and diabetes were 1.36 (1.14, 1.61), 1.51 (1.26, 1.83), and 1.20 (0.90, 1.61), respectively. Furthermore, increased ALP significantly mediated 15.29%-41.12% of the associations of DHBMA with glucose dyshomeostasis and increased risks of prediabetes and diabetes. Our findings indicated that BD exposure was associated with glucose dyshomeostasis and increased risks of prediabetes and diabetes. The upregulation of ALP might play a significant role in these associations.

The global burden of disease attributable to high fasting plasma glucose in 204 countries and territories, 1990-2019: An updated analysis for the Global Burden of Disease Study 2019.

AIMS: High fasting plasma glucose (HFPG) is an independent risk factor for several adverse health outcomes and has become a serious public health problem. We aimed to evaluate the spatial pattern and temporal trend of disease burden attributed to HFPG from 1990 to 2019 using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. MATERIALS AND METHODS: Using data from GBD 2019, we estimated the numbers and age-standardized rates of deaths and disability-adjusted life years (DALYs) attributed to HFPG by calendar year, age, gender, country, region, Socio-demographic Index (SDI), and specific causes. The joinpoint regression analysis was used to assess the temporal trends of deaths and DALYs from 1990 to 2019. RESULTS: In 2019, globally, the numbers of deaths and DALYs attributable to HFPG were approximately 6.50 million and 172.07 million, respectively, with age-standardized rates of 83.00 per 100,000 people and 2104.26 per 100,000 people, respectively. From 1990 to 2019, the global numbers of deaths and DALYs attributed to HFPG have over doubled. The age-standardized rate of DALYs showed an increasing trend, particularly in males and in regions with middle SDI or below. The leading causes of the global disease burden attributable to HFPG in 2019 were diabetes mellitus, ischaemic heart disease, stroke, and chronic kidney disease. CONCLUSIONS: HFPG is an important contributor to increasing the global and regional disease burden. Necessary measures should be taken to curb the growing burden attributed to HFPG, particularly in males and in regions with middle SDI or below.

Highly individual- and tissue-specific expression of glycoprotein group A and B blood antigens in the human kidney and liver.

BACKGROUND: Currently, research on the quantitative distribution of ABO antigens in different organs and tissues remains limited. We aimed to examine the individual characteristics of blood group glycoprotein A and B antigen expression in human kidneys and livers. METHODS: We obtained human samples, including the renal artery, renal vein, renal tissue, hepatic artery, hepatic vein, portal vein, and hepatic tissue, from 24 deceased organ transplant donors. The expression of the blood group antigens glycoprotein A and B was analysed and compared by Western blotting. RESULTS: There was no significant difference in the expression between blood group glycoprotein A and B antigens at any of the seven sites (p > 0.05). The expression of both A and B antigens was highest in renal tissue and the portal vein and was lowest in the renal artery. A large difference in glycoprotein antigen expression was observed among various donors or different regions of the same individual. Univariate analysis revealed that glycoprotein A/B antigens were affected by the age and sex of donors and were significantly higher in males and in young people. CONCLUSIONS: Our study found that blood group glycoprotein antigen expression showed certain trends and distinct distribution in the kidney, liver, and vessels among individuals and in different regions of the same individual, which may explain the different clinical outcomes of patients who received ABO-incompatible transplantation.

Peripheral white blood cell counts mediated the associations of sleep duration with atherosclerotic cardiovascular disease risk: a cross-sectional study of middle-aged and older Chinese.

PURPOSE: To investigate the associations between sleep duration and atherosclerotic cardiovascular disease (ASCVD) risk and the potential mechanism. METHODS: Overall, 24,471 subjects without ASCVD were included from Dongfeng-Tongji (DFTJ) cohort. Data collection included questionnaires and general medical examinations. We used logistic regression models and generalized linear models to examine the associations between sleep duration, peripheral white blood cell (WBC) counts, and 10-year ASCVD risk. Mediation analyses were further performed to assess the potential role of peripheral WBC counts in the associations between sleep duration and 10-year ASCVD risk. RESULTS: Increased risk of 10-year ASCVD was observed as sleep duration extended. After adjusting for potential confounders, the odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of 10-year ASCVD were 1.24 (1.11-1.38), 1.12 (1.03-1.22), and 1.21(1.08-1.36) for individuals with nighttime sleeping duration of ≥ 9 h, daytime napping duration of > 30 min, and daily sleep duration of ≥ 9 h, respectively. Peripheral WBC counts mediated 14.1%, 14.5%, and 12.6% in the associations of nighttime sleep duration of ≥ 9 h, daytime napping duration of > 30 min and daily sleep duration of ≥ 9 h with 10-year ASCVD risk, respectively. CONCLUSIONS: Extended sleep durations are associated with the increased 10-year ASCVD risk, and the associations are partially mediated by peripheral WBC counts.

[Identifying Molecular Subtypes of Whole-Slide Image in Colorectal Cancer via Deep Learning].

OBJECTIVE: To establish an artificial intelligence-assisted diagnosis system for molecular subtyping of colorectal cancer (CRC). METHODS: 812 whole-slide images (WSIs) of 422 patients were selected from the database of The Cancer Genome Atlas (TCGA) and were put into the training set (75%) and the test set (25%). The slides were stored in the www.paiwsit.com database. We preprocessed and segmented the slides based on the labelling results of experienced pathologists to generate a training set of more than 4 million labeled samples. Finally, deep learning models were adopted for training. RESULTS: After training with several convolutional neural network models, we tested the performance of the trained deep learning model on the test set of 203 WSIs from 110 patients, and our model achieved an accuracy of 53.04% at patch-level and 51.72% at slide-level, while the accuracy of CMS2 (one of a consensus of four subtypes for CRC) at slide-level was as high as 75.00%. CONCLUSION: This study is of great significance to the promotion of colorectal cancer screening and precision treatment.

Epidemiological characteristics and the entire evolution of coronavirus disease 2019 in Wuhan, China.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) spread rapidly around the world. We aimed to describe the epidemiological characteristics and the entire evolution of COVID-19 in Wuhan, and to evaluate the effect of non-pharmaceutical intervention by the government. METHODS: The information of COVID-19 cases until Mar 18, 2020 in Wuhan were collected from the national infectious disease surveillance system in Hubei province. RESULTS: A total of 49,973 confirmed cases were reported until Mar 18, 2020 in Wuhan. Among whom, 2496 cases died and the overall mortality was 5.0%. Most confirmed cases (25,619, 51.3%) occurred during Jan 23 to Feb 4, with a spike on Feb 1 (new cases, 3374). The number of daily new cases started to decrease steadily on Feb 19 (new cases, 301) and decreased greatly on Mar 1 (new cases, 57). However, the mortality and the proportion of severe and critical cases has been decreasing over time, with the lowest of 2.0 and 10.1% during Feb 16 to Mar 18, 2020, respectively. The percentage of severe and critical cases among all cases was 19.6%, and the percentage of critical and dead cases aged over 60 was 70.1 and 82.0%, respectively. CONCLUSION: The number of new cases has dropped significantly after the government taking the isolation of four types of personnel and the community containment for 14 days. Our results indicate that the mortality and proportion of severe and critical cases gradually decreased over time, and critical and dead cases are more incline to be older individuals.

Genomic, molecular evolution, and expression analysis of NOX genes in soybean (Glycine max).

Reactive oxygen species (ROS) are versatile signaling molecules in sensing stresses and play critical roles in signaling and development. Plasma membrane NADPH oxidases (NOXs) are key producers of ROS, and play important roles in the regulation of plant-pathogen interactions. Here, we performed a comprehensive analysis of the NOX gene family in the soybean genome (Glycine max) and 17 NOX (GmNOX) genes were identified. Structural analysis revealed that the GmNOX proteins in soybean were as conserved as those in other plants. 8 duplicated gene pairs were formed by a Glycine-specific whole-genome duplication (WGD) event approximately 13 million years ago (Mya). The Ka/Ks ratios of GmNOX genes ranged from 0.04 to 0.28, suggesting that the GmNOX family had undergone purifying selection in soybean. Gene expression patterns showed different expression of these duplicate genes, suggesting that the GmNOXs were retained by substantial subfunctionalization during the soybean evolutionary processes. Subsequently, the expression of GmNOXs in response to drought and phytohormones were characterized via qPCR. Importantly, four GmNOXs showed strong expression in nodules, pointing to their probable involvement in nodulation. Thus, our results shed light on the evolutionary history of this family in soybean and contribute to the functional characterization of GmNOX genes in soybean.

[Predictive Value of Obesity Indicators for Metabolic Syndrome in Adults of Han and Yi Nationalities in Sichuan].

OBJECTIVE: To compare the predictive value of different measures of obesity for metabolic syndrome (MetS) in adult Yi and Han nationality population. METHODS: A total of 3 492 urban and rural residents in Chengdu and Liangshan Yi Autonomous Prefecture participated in this study. Demographic and laboratory data were collected. Spearman correlation analysis was used to investigate the relationship between different obesity measurement indexes and MetS. Receiver operating characteristic (ROC) curve was used to compare the predictive value between different obesity measurement indexes. RESULTS: Spearman correlation analysis showed that MetS was related to body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), lipid accumulation index (LAP) and visceral adiposity index (VAI). The ROC curve showed that the LAP had the highest predictive value for MetS in both Yi and Han male adults, area under the curves (AUCs) >0.90; whereas WHR had the lowest predictive value. WHtR had high predictive value for MetS in both Yi and Han female adults (AUCs >0.88), VAI had the worst predictive value. CONCLUSION: Among different measures of obesity, LAP may have the optimal predictive value for MetS in male adults as do WHtR in female adults either in Yi or Han nationality. These findings should be confirmed through the measure of visceral fat volume and prospective study.

Fast and cost-effective in-process defect inspection for printed electronics based on coherent optical processing.

This paper presents an all-optical difference engine (AODE) sensor for detecting the defects in printed electronics produced with roll-to-roll processes. The sensor is based on the principle of coherent optical subtraction and is able to achieve high-speed inspection by minimising data post-processing. A self-comparison inspection strategy is introduced to allow defect detection by comparing the printed features and patterns that have the same nominal dimensions. In addition, potential applications of the AODE sensor in an on-the-fly pass-or-reject production control scenario are presented. A prototype AODE sensor using a digital camera is developed and demonstrated by detecting defects on several industrial printed electrical circuitry samples. The camera can be easily replaced by a low-cost photodiode to realise high-speed all-optical information processing and inspection. The developed sensor is capable of inspecting areas of 4 mm width with a resolution of the order of several micrometres, and can be duplicated in parallel to inspect larger areas without significant cost.

Proteomes and Phosphoproteomes of Anther and Pollen: Availability and Progress.

In flowering plants, anther development plays crucial role in sexual reproduction. Within the anther, microspore mother cells meiosis produces microspores, which further develop into pollen grains that play decisive role in plant reproduction. Previous studies on anther biology mainly focused on single gene functions relying on genetic and molecular methods. Recently, anther development has been expanded from multiple OMICS approaches like transcriptomics, proteomics/phosphoproteomics, and metabolomics. The development of proteomics techniques allowing increased proteome coverage and quantitative measurements of proteins which can characterize proteomes and their modulation during normal development, biotic and abiotic stresses in anther development. In this review, we summarize the achievements of proteomics and phosphoproteomics with anther and pollen organs from model plant and crop species (i.e. Arabidopsis, rice, tobacco). The increased proteomic information facilitated translation of information from the models to crops and thus aid in agricultural improvement.

Stroboscope Based Synchronization of Full Frame CCD Sensors.

The key obstacle to the use of consumer cameras in computer vision and computer graphics applications is the lack of synchronization hardware. We present a stroboscope based synchronization approach for the charge-coupled device (CCD) consumer cameras. The synchronization is realized by first aligning the frames from different video sequences based on the smear dots of the stroboscope, and then matching the sequences using a hidden Markov model. Compared with current synchronized capture equipment, the proposed approach greatly reduces the cost by using inexpensive CCD cameras and one stroboscope. The results show that our method could reach a high accuracy much better than the frame-level synchronization of traditional software methods.

[Clinical Characteristics of Patients with Type 2 Diabetes Mellitus and Obstructive Sleep Apnea Syndrome].

OBJECTIVES: To compare the clinical characteristics and prevalence of chronic complications in type 2 diabetes mellitus (T2DM) patients with various degrees of obstructive sleep apnea syndrome (OSAS). METHODS: A total of 170 patients with T2DM and OSAS were enrolled in this study. These participants were divided into three groups with low, medium and high apnea-hypopnea index (AHI), respectively. The demographic characteristics, biochemical indicators and chronic complications of the patients in the three groups were compared. Multivariate Logistic regression analysis was performed to determine the associations between chronic complications and OSAS. RESULTS: The patients with severe OSAS had higher waist circumference (P=0.045), higher BMI (P=0.069), higher prevalence of diabetic peripheral neuropathy (DPN), and higher prevalence of diabetic retinopathy (DR) than the patients with mild-moderate OSAS. Similar levels of macrovascular complications were found in the three groups (P>0.05). The logistic regression analyses showed that DPN (OR=1.024, 95%CI 1.002-1.046) and chronic kidney disease (OR=1.026, 95%CI 1.004-1.049) were independent predictors of AHI, adjusting for the lowest oxygen saturation, gender, age, diabetic duration, family history of diabetes, BMI, and HbA1c. Other microvascular and macrovascular complications were not predictors of AHI. CONCLUSIONS: Patients with T2DM and severe OSAS have a higher risk of DPN and DR. Particular attention should be paid to T2DM patients with severe OSAS to prevent complications.

Mathematical and numerical analysis for PDE systems modeling intravascular drug release from arterial stents and transport in arterial tissue.

This paper is concerned with the PDE (partial differential equation) and numerical analysis of a modified one-dimensional intravascular stent model. It is proved that the modified model has a unique weak solution by using the Galerkin method combined with a compactness argument. A semi-discrete finite-element method and a fully discrete scheme using the Euler time-stepping have been formulated for the PDE model. Optimal order error estimates in the energy norm are proved for both schemes. Numerical results are presented, along with comparisons between different decoupling strategies and time-stepping schemes. Lastly, extensions of the model and its PDE and numerical analysis results to the two-dimensional case are also briefly discussed.

Improved Liver Intravital Microscopic Imaging Using a Film-Assisted Stabilization Method.

Intravital microscopy (IVM) is a valuable method for biomedical characterization of dynamic processes, which has been applied to many fields such as neuroscience, oncology, and immunology. During IVM, vibration suppression is a major challenge due to the inevitable respiration and heartbeat from live animals. In this study, taking liver IVM as an example, we have unraveled the vibration inhibition effect of liquid bridges by studying the friction characteristics of a moist surface on the mouse liver. We confirmed the presence of liquid bridges on the liver through fluorescence imaging, which can provide microscale and nondestructive liquid connections between adjacent surfaces. Liquid bridges were constructed to sufficiently stabilize the liver after abdominal dissection by covering it with a polymer film, taking advantage of the high adhesion properties of liquid bridges. We further prototyped a microscope-integrated vibration-damping device with adjustable film tension to simplify the sample preparation procedure, which remarkably decreased the liver vibration. In practical application scenarios, we observed the process of liposome phagocytosis by liver Kupffer cells with significantly improved image and video quality. Collectively, our method not only provided a feasible solution to vibration suppression in the field of IVM, but also has the potential to be applied to vibration damping of precision instruments or other fields that require nondestructive ″soft″ vibration damping.

Associations of short-term ambient temperature exposure with lung function in middle-aged and elderly people: A longitudinal study in China.

The short-term associations of ambient temperature exposure with lung function in middle-aged and elderly Chinese remain obscure. The study included 19,128 participants from the Dongfeng-Tongji cohort's first (2013) and second (2018) follow-ups. The lung function for each subject was determined between April and December 2013 and re-assessed in 2018, with three parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) selected. The China Meteorological Data Sharing Service Center provided temperature data during the study period. In the two follow-ups, a total of 25,511 records (average age: first, 64.57; second, 65.80) were evaluated, including 10,604 males (41.57%). The inversely J-shaped associations between moving average temperatures (lag01-lag07) and FVC, FEV1, and PEF were observed, and the optimum temperatures at lag04 were 16.5 °C, 18.7 °C, and 16.2 °C, respectively. At lag04, every 1 °C increase in temperature was associated with 14.07 mL, 9.78 mL, and 62.72 mL/s increase in FVC, FEV1, and PEF in the low-temperature zone (