Supramolecular Assembly in Live Cells Mapped by Real-Time Phasor-Fluorescence Lifetime Imaging.

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters. Tracked by phasor-fluorescence lifetime imaging (phasor-FLIM) in epithelial cells (L929, A549, MDA-MB 231) and correlative light-electron microscopy and tomography (CLEM), spatiotemporal splicing of the assembly events shows time-correlated metabolic dysfunction. The biological impact begins with assembly-induced endosomal disruption that reduces glucose transport into the cells, which, in turn, stymies mitochondrial respiration.

A-D-A Type Nonfullerene Acceptors Synthesized by Core Segmentation and Isomerization for Realizing Organic Solar Cells with Low Nonradiative Energy Loss.

Reducing non-radiative recombination energy loss (ΔEnonrad ) in organic solar cells (OSCs) has been considered an effective method to improve device efficiency. In this study, the backbone of PTBTT-4F/4Cl is divided into D1-D2-D3 segments and reconstructed. The isomerized TPBTT-4F/4Cl obtains stronger intramolecular charge transfer (ICT), thus leading to elevated highest occupied molecular orbital (HOMO) energy level and reduced bandgap (Eg ). According to ELoss  = Eg- qVOC , the reduced Eg and enhanced open circuit voltage (VOC ) result in lower ELoss , indicating that ELoss has been effectively suppressed in the TPBTT-4F/4Cl based devices. Furthermore, compared to PTBTT derivatives, the isomeric TPBTT derivatives exhibit more planar molecular structure and closer intermolecular stacking, thus affording higher crystallinity of the neat films. Therefore, the reduced energy disorder and corresponding lower Urbach energy (Eu ) of the TPBTT-4F/4Cl blend films lead to low ELoss and high charge-carrier mobility of the devices. As a result, benefitting from synergetic control of molecular stacking and energetic offsets, a maximum power conversion efficiency (PCE) of 15.72% is realized from TPBTT-4F based devices, along with a reduced ΔEnonrad of 0.276 eV. This work demonstrates a rational method of suppressing VOC loss and improving the device performance through molecular design engineering by core segmentation and isomerization.

Genome-wide mapping of quantitative trait loci conferring resistance to stripe rust in spring wheat line PI 660072.

KEY MESSAGE: Two major QTL for resistance to stripe rust were mapped on chromosome 2BL and 4BL in spring wheat PI 660072, and their KASP markers were developed. Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat worldwide. Identifying resistance genes is crucial for developing resistant cultivars to control the disease. Spring wheat PI 660072 (Triticum aestivum) has been identified to possess both adult-plant resistance (APR) and all-stage resistance (ASR) to stripe rust. To elucidate the genetic basis of the resistance in PI 660072, a mapping population consisting of 211 F5-F7 recombinant-inbred lines (RILs) was developed from a cross of PI 660072 with susceptible spring wheat Avocet S. The mapping population was phenotyped for stripe rust responses across five field environments from 2020 to 2022 and genotyped using the 15 K SNP (single nucleotide polymorphism) array to map stripe rust resistance loci. The mapping population was also tested at the seedling stage with predominant Chinese Pst races CYR31, CYR32, CYR34 and PST-YX1-3-1 in the greenhouse. Stripe rust resistance genes were identified using the quantitative trait locus (QTL) mapping approach. Two QTL were identified with QYrPI660072.swust-2BL mapped on the long arm of chromosome 2B for ASR and QYrPI660072.swust-4BL on the long arm of chromosome 4B for APR. To facilitate marker-assisted selection breeding, Kompetitive allele specific PCR (KASP) markers, KASP-1269 for QYrPI660072.swust-2BL and KASP-3209 for QYrPI660072.swust-4BL, were developed. These markers could be used to introgress the effective resistance QTL into new wheat cultivars.

A co-located QTL for seven spike architecture-related traits shows promising breeding use potential in common wheat (Triticum aestivum L.).

KEY MESSAGE: A co-located novel QTL for TFS, FPs, FMs, FFS, FFPs, KWS, and KWPs with potential of improving wheat yield was identified and validated. Spike-related traits, including fertile florets per spike (FFS), kernel weight per spike (KWS), total florets per spike (TFS), florets per spikelet (FPs), florets in the middle spikelet (FMs), fertile florets per spikelet (FFPs), and kernel weight per spikelet (KWPs), are key traits in improving wheat yield. In the present study, quantitative trait loci (QTL) for these traits evaluated under various environments were detected in a recombinant inbred line population (msf/Chuannong 16) mainly genotyped using the 16 K SNP array. Ultimately, we identified 60 QTL, but only QFFS.sau-MC-1A for FFS was a major and stably expressed QTL. It was located on chromosome arm 1AS, where loci for TFS, FPs, FMs, FFS, FFPs, KWS, and KWPs were also simultaneously co-mapped. The effect of QFFS.sau-MC-1A was further validated in three independent segregating populations using a Kompetitive Allele-Specific PCR marker. For the co-located QTL, QFFS.sau-MC-1A, the presence of a positive allele from msf was associate with increases for all traits: + 12.29% TFS, + 10.15% FPs, + 13.97% FMs, + 17.12% FFS, + 14.75% FFPs, + 22.17% KWS, and + 19.42% KWPs. Furthermore, pleiotropy analysis showed that the positive allele at QFFS.sau-MC-1A simultaneously increased the spike length, spikelet number per spike, and thousand-kernel weight. QFFS.sau-MC-1A represents a novel QTL for marker-assisted selection with the potential for improving wheat yield. Four genes, TraesCS1A03G0012700, TraesCS1A03G0015700, TraesCS1A03G0016000, and TraesCS1A03G0016300, which may affect spike development, were predicted in the physical interval harboring QFFS.sau-MC-1A. Our results will help in further fine mapping QFFS.sau-MC-1A and be useful for improving wheat yield.

Identification and characterization of QSFS.sau-MC-5A for sterile florets genetically independent of fertile ones per spike in wheat.

KEY MESSAGE: A major and stable QTL for sterile florets per spike and sterile florets per spikelet was identified, it was mapped within a 2.22-Mb interval on chromosome 5AL, and the locus was validated using two segregating populations with different genetic backgrounds. Both the number of fertile florets per spike (FFS) and the number of sterile florets per spike (SFS) significantly influence the final yield of wheat (Triticum aestivum L.), and a trade-off theoretically exists between them. To enhance crop yield, wheat breeders have historically concentrated on easily measurable traits such as FFS, spikelets per spike, and spike length. Other traits of agronomic importance, including SFS and sterile florets per spikelet (SFPs), have been largely overlooked. In the study, reported here, genetic bases of SFS and SFPs were investigated based on the assessment of a population of recombinant inbred lines (RILs) population. The RIL population was developed by crossing a spontaneous mutant with higher SFS (msf) with the cultivar Chuannong 16. A total of 10 quantitative trait loci (QTL) were identified, with QSFS.sau-MC-5A for SFS and QSFPs.sau-MC-5A for SFPs being the major and stable ones, and they were co-located on the long arm of chromosome 5A. The locus was located within a 2.22-Mb interval, and it was further validated in two additional populations based on a tightly linked Kompetitive Allele-Specific PCR (KASP) marker, K_sau_5A_691403852. Expression differences and promoter sequence variations were observed between the parents for both TraesCS5A03G1247300 and TraesCS5A03G1250300. The locus of QSFS.sau-MC-5A/QSFPs.sau-MC-5A showed a significantly positive correlation with spike length, florets in the middle spikelet, and total florets per spike, but it showed no correlation with either kernel number per spike (KNS) or kernel weight per spike. Appropriate nitrogen fertilizer application led to reduced SFS and increased KNS, supporting results from previous reports on the positive effect of nitrogen fertilizer on wheat spike and floret development. Based on these results, we propose a promising approach for breeding wheat cultivars with multiple fertile florets per spike, which could increase the number of kernels per spike and potentially improve yield. Collectively, these findings will facilitate further fine mapping of QSFS.sau-MC-5A/QSFPs.sau-MC-5A and be instrumental in strategies to increase KNS, thereby enhancing wheat yield.

Effects of the Timing of Intense Physical Activity on Hypertension Risk in a General Population: A UK-Biobank Study.

PURPOSE OF REVIEW: It has recently been suggested that the timing of exercise is important in the subsequent development of hypertension. We used the UK Biobank database which prospectively collates data in over 500,000 people aged between 40 and 69 years to determine the relationship between the chronoactivity pattern of exercise and the risk of incident hypertension. RECENT FINDINGS: We analyzed data from 70,617 participants with 7-day Axivity AX3 triaxial accelerometry information available. Comparisons were made by a K-means clustering analysis separating groups according to the daily timing of physical activity and intensity. Subgroup, sensitivity analyses, and Cox proportional hazard model were performed. The mean age of the cohort was 61.17 (± 7.89) years with 40.05% men, and there was a mean follow-up of 7.54 (± 1.65) years. Participants were separated into 4 clusters with 6341 developing hypertension. Cluster 1 (early morning physical activity) and Cluster 2 (early morning and later physical activity) had a significantly reduced risk of incident hypertension (adjusted HR 0.870 [95%CI 0.812-0.932) vs. 0.895 [95%CI 0.825-0.972], respectively) when compared with Cluster 3 (physical activity intensity spread evenly throughout the day). Cluster 1 and Cluster 2 cases with High Intensity physical activity had a lower risk of hypertension; however, Low Intensity physical activity in Cluster 1 still reduced the risk of incident hypertension. There was a lower risk of hypertension in Cluster 1 and Cluster 2 in both morning and evening sleep chronotypes. The development of incident hypertension is significantly reduced in those who engage in some level of physical activity earlier in the day. Hypertension (high blood pressure) is a global problem with a high economic health burden that has been shown to be a major risk factor for diabetes, cardiovascular, and kidney disease. Our study has used a large maintained UK biological database to determine the impact of physical exercise on reducing the subsequent development of hypertension during follow-up from data provided by more than 70,000 participants. When we segregated patients into clusters of exercise timing, we found that the risk of developing hypertension over time was reduced for patients who performed exercise earlier in the morning than at other times of the day. This benefit was still evident even when the intensity of regular physical activity was low.

The Impact of Hydrogen Sulfide in the Paraventricular Nucleus on the MAPK Pathway in High Salt-Induced Hypertension.

ABSTRACT: The hypothalamic paraventricular nucleus (PVN) plays a central role in regulating cardiovascular activity and blood pressure. We administered hydroxylamine hydrochloride (HA), a cystathionine-ß-synthase inhibitor, into the PVN to suppress endogenous hydrogen sulfide and investigate its effects on the mitogen-activated protein kinase (MAPK) pathway in high salt (HS)-induced hypertension. We randomly divided 40 male Dahl salt-sensitive rats into 4 groups: the normal salt (NS) + PVN vehicle group, the NS + PVN HA group, the HS + PVN vehicle group, and the HS + PVN HA group, with 10 rats in each group. The rats in the NS groups were fed a NS diet containing 0.3% NaCl, while the HS groups were fed a HS diet containing 8% NaCl. The mean arterial pressure was calculated after noninvasive measurement using an automatic sphygmomanometer to occlude the tail cuff once a week. HA or vehicle was infused into the bilateral PVN using Alzet osmotic mini pumps for 6 weeks after the hypertension model was successfully established. We measured the levels of H 2 S in the PVN and plasma norepinephrine using enzyme linked immunosorbent assay. In addition, we assessed the parameters of the MAPK pathway, inflammation, and oxidative stress through western blotting, immunohistochemical analysis, or real-time polymerase chain reaction. In this study, we discovered that decreased levels of endogenous hydrogen sulfide in the PVN contributed to the onset of HS-induced hypertension. This was linked to the activation of the MAPK signaling pathway, proinflammatory cytokines, and oxidative stress in the PVN, as well as the activation of the sympathetic nervous system.

19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans.

Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using 19F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma. Of the administered dose, 55.4% (54.3% of M0) was recovered in urine, while 36.7% (4.57% of M0) was excreted in feces. UPLC/Q-TOF MS was used to identify metabolites in human plasma, urine and feces. Notably, oxidative metabolites catalyzed by CYP3A were scarcely detected in these matrixes. The amide hydrolyzed metabolite M9 and the cyano hydrolyzed metabolite M10 were recognized as the predominant metabolites, with the main excretion being through feces (19.0% and 12.7% of the administered dose, respectively). In vitro experiments indicated that M10 is primarily formed in the duodenum and jejunum, with further metabolism to M9 by microbiota in the large intestine. Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota.

Biochar alleviates inhibition effects of humic acid on anaerobic digestion: Insights to performances and mechanisms.

To recover methane from waste activated sludge through anaerobic digestion (AD) is one promising alternative to achieve carbon neutrality for wastewater treatment plants. However, humic acids (HAs) are one of the major compositions in waste activated sludge, and their accumulation performs inhibition effects on AD. This study investigated the potentials of biochar (BC) in alleviating inhibition effects of HAs on AD. Results showed that although the accumulated HAs reduced methane yield by 9.37% compared to control, the highest methane yield, 132.6 mL CH4/g VSS, was obtained after adding BC, which was 45.9% higher than that in HA group. Mechanism analysis showed that BC promoted the activities of hydrolase such as protease and α-glucosidase, which were 69.7% and 29.7% higher than those in HA group, respectively. The conversion of short-chain fatty acids was accelerated. In addition, the evolutions of electroactive microorganisms like Clostridium_sensu_stricto_13 and Methanosaeta were consistent with the activitiies of electron transfer and the contents of cytochrome c. Furthermore, parts of HAs rather than all of them were adsorbed by BC, and the remaining free HAs and BC formed synergistic effects on methanogenesis, then both CO2 reduction and acetoclastic methanogenesis pathways were improved. The findings may provide some solutions to alleviate inhibition effects of HAs on AD.

Biochar derived from alkali-treated sludge residue regulates anaerobic digestion: Enhancement performance and potential mechanisms.

Biochar produced from bio-wastes has been widely used to promote the performance of anaerobic digestion. Waste activated sludge (WAS) is considered as a kind of popular precursor for biochar preparation, but the abundant resources in WAS were neglected previously. In this study, the roles of biochar prepared from raw, pretreated, and fermented sludge on anaerobic digestion were investigated. That is, parts of carbon sources and nutrients like polysaccharides, proteins, and phosphorus were firstly recovered after sludge pretreatment or fermentation, and then the sludge residuals were used as raw material to prepare biochar. The methane yield improved by 22.1% with adding the biochar (AK-BC) prepared by sludge residual obtained from alkaline pretreatment. Mechanism study suggested that the characteristics of AK-BC like specific surface area and defect levels were updated. Then, the conversion performance of intermediate metabolites and electro-activities of extracellular polymeric substances were up-regulated. As a result, the activity of electron transfer was increased with the presence of AK-BC, with increase ratio of 21.4%. In addition, the electroactive microorganisms like Anaerolineaceae and Methanosaeta were enriched with the presence of AK-BC, and the potential direct interspecies electron transfer was possibly established. Moreover, both aceticlastic and CO2-reducing methanogenesis pathways were improved by up-regulating related enzymes. Therefore, the proposed strategy can not only obtain preferred biochar but also recover abundant resources like carbon source, nutrients, and bioenergy.

Biomarker Screening by LCMS and Liquid Chip Technology in Acute Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a serious disease. Previous study, the use of peripheral blood biomarkers to diagnose AD showed strong clinical feasibility, but the possible molecular mechanism is unclear. METHODS: Sera from 79 healthy subjects, 73 patients with well-established AD, and 74 patients with well-established acute myocardial infarction (AMI) were investigated by Liquid Chromatograph-Mass Spectrometer to detect metabolites (AFMK, Glycerophosphocholine, Inosine, SPH). The cell factor expression in the 3 group were detected by Liquid Chip Technology. RESULTS: The serum content trends of 4 metabolic indexes in patients with AMI and AD group were used as the diagnostic models, and the effective diagnosis rate was 97.8%. The diagnosis rate is 89.8% in distinguishing patients with AMI from patients with AD. The expression in serum of the 3 groups showed that there were significant differences in the expression of 23 cytokines. By correlation analysis, it was found that miP-1, IL-7, MIP-1ß, EGF and other cytokines were significantly correlated with the 4 metabolic molecules. CONCLUSIONS: AFMK, Glycerophosphocholine, Inosine, Sphingfungin B (SPH) metabolites are potential biomarkers for AD, and the influence of related metabolic process may be related to the expression of miP-1, IL-7, MIP-1ß, EGF, and other cytokines.

Screening and staging of chronic obstructive pulmonary disease with deep learning based on chest X-ray images and clinical parameters.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed with the current gold standard measure pulmonary function test (PFT). A more sensitive and simple option for early detection and severity evaluation of COPD could benefit practitioners and patients. METHODS: In this multicenter retrospective study, frontal chest X-ray (CXR) images and related clinical information of 1055 participants were collected and processed. Different deep learning algorithms and transfer learning models were trained to classify COPD based on clinical data and CXR images from 666 subjects, and validated in internal test set based on 284 participants. External test including 105 participants was also performed to verify the generalization ability of the learning algorithms in diagnosing COPD. Meanwhile, the model was further used to evaluate disease severity of COPD by predicting different grads. RESULTS: The Ensemble model showed an AUC of 0.969 in distinguishing COPD by simultaneously extracting fusion features of clinical parameters and CXR images in internal test, better than models that used clinical parameters (AUC = 0.963) or images (AUC = 0.946) only. For the external test set, the AUC slightly declined to 0.934 in predicting COPD based on clinical parameters and CXR images. When applying the Ensemble model to determine disease severity of COPD, the AUC reached 0.894 for three-classification and 0.852 for five-classification respectively. CONCLUSION: The present study used DL algorithms to screen COPD and predict disease severity based on CXR imaging and clinical parameters. The models showed good performance and the approach might be an effective case-finding tool with low radiation dose for COPD diagnosis and staging.

Genetic Analysis of Stripe Rust Resistance in the Chinese Wheat Cultivar Luomai 163.

Stripe or yellow rust (YR) caused by Puccinia striiformis tritici (Pst) is an important foliar disease affecting wheat production globally. Resistant varieties are the most economically and environmentally effective way to manage this disease. The common winter wheat (Triticum aestivum L.) cultivar Luomai 163 exhibited resistance to Pst races CYR32 and CYR33 at the seedling stage and showed a high level adult plant resistance in the field. To understand the genetic basis of YR resistance in this cultivar, 142 F5 recombinant inbred lines (RILs) derived from cross Apav#1 × LM163 and both parents were genotyped with the 16K SNP array and bulked segregant analysis sequencing (BSA-Seq). The analysis detected a major gene, YrLM163, at the seedling stage associated with the 1BL.1RS translocation. Additionally, three genes for resistance at the adult plant stage were detected on chromosome arms 1BL (Lr46/Yr29/Pm39/Sr58), 6BS and 6BL in Luomai 163, whereas Apav#1 contributed resistance at a QTL on 2BL. These QTL explained YR disease severity variations ranging from 6.9 to 54.8%. KASP markers KASP-2BL, KASP-6BS and KASP-6BL for three novel loci QYr.hzau-2BL, QYr.hzau-6BS and QYr.hzau-6BL were developed and validated. QYr.hzau-1BL, QYr.hzau-2BL and QYr.hzau-6BS showed varying degrees of resistance to YR when present individually or in combination based on genotype and phenotype analysis of a panel of 570 wheat accessions. Six RILs combining resistance alleles of all QTL, showing higher resistance to YR in the field than Luomai 163 with disease severities of 10.7-16.0%, are important germplasm resources for breeding programs to develop YR resistant wheat varieties with good agronomic traits.

Roles of quorum-sensing molecules in methane production from anaerobic digestion aided by biochar.

Biochar has been used to enhance methane generation from anaerobic digestion through establishing direct interspecific electron transfer between microorganisms. However, the microbial communication is still inadequate, thereby limiting further methane production improvement contributed by biochar. This study investigated the roles of quorum-sensing molecules, acylated homoserine lactone (AHL), in anaerobic digestion of waste activated sludge aided by biochar. Results showed that the co-addition of separated biochar and AHL achieved best methane production performance, with the maximal methane yield of 154.7 mL/g volatile suspended solids, which increased by 51.9%, 47.2%, 17.9%, and 39.4% respectively compared to that of control, AHL-loaded biochar, sole AHL, and sole biochar groups. The reason was that the co-addition of separated biochar and AHL promoted the stages of hydrolysis and acidification, promoting the conversion of organic matters and short-chain fatty acids, and optimizing the accumulation of acetate acid. Moreover, the methanogenesis stage also performed best among experimental groups. Correspondingly, the highest activities of electron transfer and coenzyme F420 were obtained, with increase ratios of 33.2% and 27.2% respectively compared to that of control. Furthermore, biochar did more significant effects on the evolution of microbial communities than AHL, and the direct interspecific electron transfer between fermentative bacteria and methanogens were possibly promoted.

Riboflavin improves grain yield, 2-acetyl-1-pyrroline accumulation, and antioxidative properties of fragrant rice.

BACKGROUND: Riboflavin, a vital water-soluble vitamin with antioxidative activity, plays a critical role in maintaining overall bodily health and defense responses. However, its impact on fragrant rice yield and aroma remains unexplored. RESULTS: In a 2022 pot experiment with Meixiangzhan and Yuxiangyouzhan fragrant rice cultivars, we applied riboflavin foliar treatments at concentrations of 0 (CK), 10 (R10), 20 (R20), and 40 (R40) mg L-1 during the initial heading stage. Riboflavin increased rice yield, 2-acetyl-1-pyrroline (2-AP) content, and antioxidative properties. It boosted 2-AP level by 13.1-50.1% for Meixiangzhan and 22.3-35.3% for Yuxiangyouzhan, with the highest levels in R20 and R10 treatments. This increase is significantly correlated with elevated levels of proline, pyrroline-5-carboxylic acid, pyrroline, and methylglyoxal, as well as heightened enzyme activities, including those of proline dehydrogenase, ornithine aminotransferase, and pyrroline-5-carboxylic acid synthetase (P5CS). The R20 treatment resulted in the highest yield due to an improved seed-setting rate. Importantly, a positive correlation emerged between 2-AP content and yield, both significantly linked to superoxide dismutase, proline, hydrogen peroxide, P5CS, catalase, and pyrroline. CONCLUSION: Riboflavin maintained enzyme activities, regulated substance synthesis pathways, and increased 2-AP and yield, especially in the R20 treatment. These insights advance fragrant rice production theory by uncovering riboflavin's role in the development of fragrant rice. © 2023 Society of Chemical Industry.

Epigenomic analysis of Alzheimer's disease brains reveals diminished CTCF binding on genes involved in synaptic organization.

Epigenetic aberrations are suggested to play an important role in transcriptional alterations in Alzheimer's disease (AD). One of the key mechanisms of epigenetic regulation of gene expression is through the dynamic organization of chromatin structure via the master genome architecture protein, CCCTC-binding factor (CTCF). By forming chromatin loops, CTCF can influence gene transcription in a complex manner. To find out whether genome-wide DNA binding sites for CTCF are altered in AD, we compared CTCF chromatin immunoprecipitation sequencing (ChIP-Seq) data from frontal cortex of human AD patients and normal controls (n = 9 pairs, all females). We have revealed that CTCF-binding affinity on many genes is significantly reduced in AD patients, and these genes are enriched in synaptic organization, cell adhesion, and actin cytoskeleton, including synaptic scaffolding molecules and receptors, such as SHANK2, HOMER1, NRXN1, CNTNAP2 and GRIN2A, and protocadherin (PCDH) and cadherin (CDH) family members. By comparing transcriptomic data from AD patients, we have discovered that many of the synaptic and adhesion genes with reduced CTCF binding in AD are significantly reduced in their mRNA expression. Moreover, a significant overlap of genes with the diminished CTCF binding and the reduced H3K27ac is identified in AD, with the common genes enriched in synaptic organization. These data suggest that the CTCF-controlled 3D chromatin organization is perturbed in AD, which may be linked to the diminished expression of target genes, probably through changes in histone modification.

Deep Learning-Based Classification of Hepatocellular Nodular Lesions on Whole-Slide Histopathologic Images.

BACKGROUND & AIMS: Hepatocellular nodular lesions (HNLs) constitute a heterogeneous group of disorders. Differential diagnosis among these lesions, especially high-grade dysplastic nodules (HGDNs) and well-differentiated hepatocellular carcinoma (WD-HCC), can be challenging, let alone biopsy specimens. We aimed to develop a deep learning system to solve these puzzles, improving the histopathologic diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma), and background tissues (nodular cirrhosis, normal liver tissue). METHODS: The samples consisting of surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2 to 3 subspecialists. Four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) were used. Their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was further verified by comparing with that of 9 pathologists. RESULTS: We obtained 213,280 patches from 1115 whole-slide images of 738 patients. An optimal model was finally chosen based on F1 score and area under the curve value, named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists' majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. CONCLUSIONS: We first developed a deep learning diagnostic model for HNLs, which performed well and contributed to enhancing the diagnosis rate of early HCC and risk stratification of patients with HNLs. Furthermore, HnAIM had significant advantages in patch-level recognition, with important diagnostic implications for fragmentary or scarce biopsy specimens.

CITEdb: a manually curated database of cell-cell interactions in human.

MOTIVATION: The interactions among various types of cells play critical roles in cell functions and the maintenance of the entire organism. While cell-cell interactions are traditionally revealed from experimental studies, recent developments in single-cell technologies combined with data mining methods have enabled computational prediction of cell-cell interactions, which have broadened our understanding of how cells work together, and have important implications in therapeutic interventions targeting cell-cell interactions for cancers and other diseases. Despite the importance, to our knowledge, there is no database for systematic documentation of high-quality cell-cell interactions at the cell type level, which hinders the development of computational approaches to identify cell-cell interactions. RESULTS: We develop a publicly accessible database, CITEdb (Cell-cell InTEraction database, https://citedb.cn/), which not only facilitates interactive exploration of cell-cell interactions in specific physiological contexts (e.g. a disease or an organ) but also provides a benchmark dataset to interpret and evaluate computationally derived cell-cell interactions from different tools. CITEdb contains 728 pairs of cell-cell interactions in human that are manually curated. Each interaction is equipped with structured annotations including the physiological context, the ligand-receptor pairs that mediate the interaction, etc. Our database provides a web interface to search, visualize and download cell-cell interactions. Users can search for cell-cell interactions by selecting the physiological context of interest or specific cell types involved. CITEdb is the first attempt to catalogue cell-cell interactions at the cell type level, which is beneficial to both experimental, computational and clinical studies of cell-cell interactions. AVAILABILITY AND IMPLEMENTATION: CITEdb is freely available at https://citedb.cn/ and the R package implementing benchmark is available at https://github.com/shanny01/benchmark. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic analysis of stripe rust resistance in the common wheat line Kfa/2*Kachu under a Chinese rust environment.

KEY MESSAGE: We mapped a new race-specific seedling stripe rust resistance gene on wheat chromosome 5BL and a new APR locus QYr.hazu-2BS from CIMMYT wheat line Kfa/2*Kachu. Breeding resistant wheat (Triticum aestivum) varieties is the most economical and efficient way to manage wheat stripe rust, but requires the prior identification of new resistance genes and development of associated molecular markers for marker-assisted selection. To map stripe rust resistance loci in wheat, we used a recombinant inbred line population generated by crossing the stripe rust-resistant parent 'Kfa/2*Kachu' and the susceptible parent 'Apav#1'. We employed genotyping-by-sequencing and bulked segregant RNA sequencing to map a new race-specific seedling stripe rust resistance gene, which we designated YrK, to wheat chromosome arm 5BL. TraesCS5B02G330700 encodes a receptor-like kinase and is a high-confidence candidate gene for YrK based on virus-induced gene silencing results and the significant induction of its expression 24 h after inoculation with wheat stripe rust. To assist breeding, we developed functional molecular markers based on the polymorphic single nucleotide polymorphisms in the coding sequence region of YrK. We also mapped four adult plant resistance (APR) loci to wheat chromosome arms 1BL, 2AS, 2BS and 4AL. Among these APR loci, we determined that QYr.hazu-1BL and QYr.hazu-2AS are allelic to the known pleiotropic resistance gene Lr46/Yr29/Pm39 and the race-specific gene Yr17, respectively. However, QYr.hazu-2BS is likely a new APR locus, for which we converted closely linked SNP polymorphisms into breeder-friendly Kompetitive allele-specific PCR (KASP) markers. In the present study, we provided new stripe rust resistance locus/gene and molecular markers for wheat breeder to develop rust-resistant wheat variety.

A promising QTL QSns.sau-MC-3D.1 likely superior to WAPO1 for the number of spikelets per spike of wheat shows no adverse effects on yield-related traits.

KEY MESSAGE: A likely new locus QSns.sau-MC-3D.1 associated with SNS showing no negative effect on yield-related traits compared to WAPO1 was identified and validated in various genetic populations under multiple environments. The number of spikelets per spike (SNS) is one of the crucial factors determining wheat yield. Thus, improving our understanding of the genes that regulate SNS could help develop wheat varieties with higher yield. In this study, a recombinant inbred line (RIL) population (MC) containing 198 lines derived from a cross between msf and Chuannong 16 (CN16) was used to construct a genetic linkage map using the GenoBaits Wheat 16 K Panel. The genetic map contained 5,991 polymorphic SNP markers spanning 2,813.25 cM. A total of twelve QTL for SNS were detected, and two of them, i.e., QSns.sau-MC-3D.1 and QSns.sau-MC-7A, were stably expressed. QSns.sau-MC-3D.1 had high LOD values ranging from 4.99 to 11.06 and explained 9.71-16.75% of the phenotypic variation. Comparison of QSns.sau-MC-3D.1 with previously reported SNS QTL suggested that it is likely a novel one, and two kompetitive allele-specific PCR (KASP) markers were further developed. The positive effect of QSns.sau-MC-3D.1 was also validated in three biparental populations and a diverse panel containing 388 Chinese wheat accessions. Genetic analysis indicated that WHEAT ORTHOLOG OFAPO1 (WAPO1) was a candidate gene for QSns.sau-MC-7A. Pyramiding of QSns.sau-MC-3D.1 and WAP01 had a great additive effect increasing SNS by 7.10%. Correlation analysis suggested that QSns.sau-MC-3D.1 was likely independent of effective tiller number, plant height, spike length, anthesis date, and thousand kernel weight. However, the H2 haplotype of WAPO1 may affect effective tiller number and plant height. These results indicated that utilization of QSns.sau-MC-3D.1 should be given priority for wheat breeding. Geographical distribution analysis showed that the positive allele of QSns.nsau-MC-3D.1 was dominant in most wheat-producing regions of China, and it has been positively selected among modern cultivars released in China since the 1940s. Gene prediction, qRT-PCR analysis, and sequence alignment suggested that TraesCS3D03G0216800 may be the candidate gene of QSns.nsau-MC-3D.1. Taken together, these results enrich our understanding of the genetic basis of wheat SNS and will be useful for fine mapping and cloning of the gene underlying QSns.sau-MC-3D.1.