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Abstract Corneal infection is a major public health concern worldwide and the most common cause of unilateral corneal blindness. Toxic effects of different microorganisms, such as bacteria and fungi, worsen keratitis leading to corneal perforation even with optimal drug treatment. The cornea forms the main refractive surface of the eye. Diseases affecting the cornea can cause severe visual impairment. Therefore, it is crucial to analyze the risk of corneal perforation and visual impairment in corneal ulcer patients for making early treatment strategies. The modeling of a fully automated prognostic model system was performed in two parts. In the first part, the dataset contained 4973 slit lamp images of corneal ulcer patients in three centers. A deep learning model was developed and tested for segmenting and classifying five lesions (corneal ulcer, corneal scar, hypopyon, corneal descementocele, and corneal neovascularization) in the eyes of corneal ulcer patients. Further, hierarchical quantification was carried out based on policy rules. In the second part, the dataset included clinical data (name, gender, age, best corrected visual acuity, and type of corneal ulcer) of 240 patients with corneal ulcers and respective 1010 slit lamp images under two light sources (natural light and cobalt blue light). The slit lamp images were then quantified hierarchically according to the policy rules developed in the first part of the modeling. Combining the above clinical data, the features were used to build the final prognostic model system for corneal ulcer perforation outcome and visual impairment using machine learning algorithms such as XGBoost, LightGBM. The ROC curve area (AUC value) evaluated the model’s performance. For segmentation of the five lesions, the accuracy rates of hypopyon, descemetocele, corneal ulcer under blue light, and corneal neovascularization were 96.86, 91.64, 90.51, and 93.97, respectively. For the corneal scar lesion classification, the accuracy rate of the final model was 69.76. The XGBoost model performed the best in predicting the 1-month prognosis of patients, with an AUC of 0.81 (95% CI 0.63–1.00) for ulcer perforation and an AUC of 0.77 (95% CI 0.63–0.91) for visual impairment. In predicting the 3-month prognosis of patients, the XGBoost model received the best AUC of 0.97 (95% CI 0.92–1.00) for ulcer perforation, while the LightGBM model achieved the best performance with an AUC of 0.98 (95% CI 0.94–1.00) for visual impairment.

Recently, the construction of the trisubstituted olefin-type probe molecules has elicited the attention of many researchers. However, the synthesis of the trisubstituted olefin-type probes containing two N-heterocycles simultaneously has been rarely reported. In this study, starting from the inexpensive mucobromic acid 1 and N-heterocyclic compound 2, we first utilized a simple one-step reaction to synthesize a series of trisubstituted olefin-type compounds 3 simultaneously bearing with the structure of two N-heterocyclic rings in the absence of transition metal catalysts with a yield of 62–86%. The optimal reaction conditions were systematically explored, and the structure of the obtained compounds 3 were well characterized with 1H NMR, 13C NMR, X-ray single-crystal and HR-MS. The preliminary observation showed that, in the presence of base, mucobromic acid 1 reacts as its ring-opening structure, and the successive nucleophilic substitution reaction and Michael addition reaction can generate the target product 3. Considering that the aldehyde group in the molecular structure of the trisubstituted olefin-type compounds 3 may react with malononitrile, we carried out some relevant investigations so as to realize the visual detection of malononitrile. Interestingly, among the products, compounds 3a–3c can be prepared in portable test strips through a simple process and used to achieve the naked-eye detection of malononitrile in environmental systems as designed.

Objectives: To update recent information on contamination levels of mycotoxins in South Korea. Materials and methods: A total of 208 samples sourced from the feeds of swine farms were collected. The contamination levels of mycotoxins, which are aflatoxin (Afla), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEN), fumonisin (FUM), and T-2 toxin, were investigated by enzyme-linked immunosorbent assays (ELISAs). Results: The detection levels of the total samples were 78.91% for DON, 75.24% for Afla, 47.02% for ZEN, 68.31% for FUM, and 5.94% for OTA and T-2, which were not detected at all. Most of the analyzed mycotoxins showed significant high occurrences in 47.02%–78.91% of the swine feed samples. 11 of the 152 alfa-positive samples exceeded the maximum residue limit (MRL) of Afla proposed by the Korean regulation. In the analysis of mycotoxin detection levels by growth stage, ZEN was found in the nursery stage at a remarkably high concentration level (126.46 ± 63.76 ppb), exceeding the MRL of ZEN for piglets proposed by the European Commission. This mycotoxin was also found in the samples from the gestation barn (89.04 ± 46.05 ppb) and the farrowing house (105.58 ± 94.12) at a high concentration level. Afla was found in the nursery stage at a high concentration (8.00 ± 2.22 ppb), approaching the MRL (10 ppb) of Afla proposed by the Korean regulation. Conclusion: These results indicate that many swine farms in South Korea are still exposed to mycotoxin risk, and special attention and surveillance are necessary for these mycotoxin risks in swine farms. [J Adv Vet Anim Res 2024; 11(1.000): 125-131]

Abstract Alternative polyadenylation can occur in introns, termed intronic polyadenylation (IPA), has been implicated in diverse biological processes and diseases, as it can produce noncoding transcripts or transcripts with truncated coding regions. However, a reliable method is required to accurately characterize IPA. Here, we propose a computational method called InPACT, which allows for the precise characterization of IPA from conventional RNA-seq data. InPACT successfully identifies numerous previously unannotated IPA transcripts in human cells, many of which are translated, as evidenced by ribosome profiling data. We have demonstrated that InPACT outperforms other methods in terms of IPA identification and quantification. Moreover, InPACT applied to monocyte activation reveals temporally coordinated IPA events. Further application on single-cell RNA-seq data of human fetal bone marrow reveals the expression of several IPA isoforms in a context-specific manner. Therefore, InPACT represents a powerful tool for the accurate characterization of IPA from RNA-seq data.

Fungal diseases form perforated disease spots in tobacco plants, resulting in a decline in tobacco yield and quality. The present study investigated the antagonistic effect of Bacillus subtilis CTXW 7-6-2 against Rhizoctonia solani, its ability to promote the growth of tobacco seedlings, and the expression of disease resistance-related genes for efficient and eco-friendly plant disease control. Our results showed that CTXW 7-6-2 had the most vigorous growth after being cultured for 96 h, and its rate of inhibition of R. solani growth in vitro was 94.02%. The volatile compounds produced by CTXW 7-6-2 inhibited the growth of R. solani significantly (by 96.62%). The fungal growthinhibition rate of the B. subtilis CTXW 7-6-2 broth obtained after high-temperature and no-high-temperature sterile fermentation was low, at 50.88% and 54.63%, respectively. The lipopeptides extracted from the B. subtilis CTXW 7-6-2 fermentation broth showed a 74.88% fungal growth inhibition rate at a concentration of 100 mg/l. Scanning and transmission electron microscopy showed some organelle structural abnormalities, collapse, shrinkage, blurring, and dissolution in the R. solani mycelia. In addition, CTXW 7-6-2 increased tobacco seedling growth and improved leaf and root weight compared to the control. After CTXW 7-6-2 inoculation, tobacco leaves showed the upregulation of the PDF1.2, PPO, and PAL genes, which are closely related to target spot disease resistance. In conclusion, B. subtilis CTXW 7-6-2 may be an efficient biological control agent in tobacco agriculture and enhance plant growth potential.

Reliable communication and intensive computing power cannot be provided effectively by temporary hot spots in disaster areas and complex terrain ground infrastructure. Mitigating this has greatly developed the application and integration of UAV and Mobile Edge Computing (MEC) to the Internet of Things (IoT). However, problems such as multi-user and huge data flow in large areas, which contradict the reality that a single UAV is constrained by limited computing power, still exist. Due to allowing UAV collaboration to accomplish complex tasks, cooperative task offloading between multiple UAVs must meet the interdependence of tasks and realize parallel processing, which reduces the computing power consumption and endurance pressure of terminals. Considering the computing requirements of the user terminal, delay constraint of a computing task, energy constraint, and safe distance of UAV, we constructed a UAV-Assisted cooperative offloading energy efficiency system for mobile edge computing to minimize user terminal energy consumption. However, the resulting optimization problem is originally nonconvex and thus, difficult to solve optimally. To tackle this problem, we developed an energy efficiency optimization algorithm using Block Coordinate Descent (BCD) that decomposes the problem into three convex subproblems. Furthermore, we jointly optimized the number of local computing tasks, number of computing offloaded tasks, trajectories of UAV, and offloading matching relationship between multi-UAVs and multiuser terminals. Simulation results show that the proposed approach is suitable for different channel conditions and significantly saves the user terminal energy consumption compared with other benchmark schemes.

Abstract The theories for substrate recognition in enzyme catalysis have evolved from lock-key to induced fit, then conformational selection, and conformational selection followed by induced fit. However, the prevalence and consensus of these theories require further examination. Here we use cryogenic electron microscopy and African swine fever virus type 2 topoisomerase (AsfvTop2) to demonstrate substrate binding theories in a joint and ordered manner: catalytic selection by the enzyme, conformational selection by the substrates, then induced fit. The apo-AsfvTop2 pre-exists in six conformers that comply with the two-gate mechanism directing DNA passage and release in the Top2 catalytic cycle. The structures of AsfvTop2-DNA-inhibitor complexes show that substantial induced-fit changes occur locally from the closed apo-conformer that however is too far-fetched for the open apo-conformer. Furthermore, the ATPase domain of AsfvTop2 in the MgAMP-PNP-bound crystal structures coexist in reduced and oxidized forms involving a disulfide bond, which can regulate the AsfvTop2 function.

Abstract The chromosome 20 long arm (20q) is one of the genomic hotspots where copy number alterations frequently occur in multiple types of tumors. However, it remains elusive which genes are implicated in 20q-related tumorigenesis. Here, by querying TCGA and GEO databases, we observed frequent copy number amplification at 20q and the chromosome subband 20q13.33 was amplificated in multiple cancers. Among those genes at 20q13.33, PSMA7 was found with the strongest correlation with cancers. Further analysis revealed that PSMA7 amplification was the most frequent genetic alteration event conferring adverse prognosis in various cancers. Consistent with the strong positive correlation between PSMA7 amplification and gene expression, elevated PSMA7 expression was observed in 20 of 33 types of cancers with a close link to adverse outcomes in certain tumors. In addition, PSMA7 was essential for the growth of almost 1095 cancer lines. Mechanistically, aberrant PSMA7 most probably influenced the proteasome and protease-related pathways to promote tumorigenesis and might be antagonized by several compounds, e.g., Docetaxel in relevant cancers. The current in-depth pan-cancer analysis refines our understanding of the crucial oncogenic role of copy number amplifications at PSMA7 loci at the novel chromosome amplicon 20q13.33 across different tumors.

Abstract Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.

Abstract Background Biological processes are controlled by groups of genes acting in concert. Investigating gene–gene interactions within different cell types can help researchers understand the regulatory mechanisms behind human complex diseases, such as tumors. Methods We collected extensive single-cell RNA-seq data from tumors, involving 563 patients with 44 different tumor types. Through our analysis, we identified various cell types in tumors and created an atlas of different immune cell subsets across different tumor types. Using the SCINET method, we reconstructed interactome networks specific to different cell types. Diverse functional data was then integrated to gain biological insights into the networks, including somatic mutation patterns and gene functional annotation. Additionally, genes with prognostic relevance within the networks were also identified. We also examined cell–cell communications to investigate how gene interactions modulate cell–cell interactions. Results We developed a data portal called CellNetdb for researchers to study cell-type-specific interactome networks. Our findings indicate that these networks can be used to identify genes with topological specificity in different cell types. We also found that prognostic genes can deconvolved into cell types through analyzing network connectivity. Additionally, we identified commonalities and differences in cell-type-specific networks across different tumor types. Our results suggest that these networks can be used to prioritize risk genes. Conclusions This study presented CellNetdb, a comprehensive repository featuring an atlas of cell-type-specific interactome networks across 44 human tumor types. The findings underscore the utility of these networks in delineating the intricacies of tumor microenvironments and advancing the understanding of molecular mechanisms underpinning human tumors.

Abstract Objective Our study aims to evaluate the predictive accuracy of functional liver remnant volume (FLRV) in post‐hepatectomy liver failure (PHLF) among surgically‐treated jaundiced patients with hilar cholangiocarcinoma (HCCA). Methods We retrospectively reviewed surgically‐treated jaundiced patients with HCCA between June, 2000 and June, 2018. The correlation between FRLV and PHLF were analyzed. The optimal cut off value of FLRV in jaundiced HCCA patients was also identified and its impact was furtherly evaluated. Results A total of 224 jaundiced HCCA patients who received a standard curative resection (43 patients developed PHLF) were identified. Patients with PHLF shared more aggressive clinic‐pathological features and were generally in a more advanced stage than those without PHLF. An obvious inconsistent distribution of FLRV in patients with PHLF and those without PHLF were detected. FLRV (continuous data) had a high predictive accuracy in PHLF. The newly‐acquired cut off value (FLRV = 53.5%, sensitivity = 81.22%, specificity = 81.4%) showed a significantly higher predictive accuracy than conventional FLRV cut off value (AUC: 0.81 vs. 0.60, p

Background: Compliance to sublingual immunotherapy (SLIT) is generally low, resulting in reduced short- and long-term clinical efficacy. Compliance is a critical factor determining the success of allergic rhinitis (AR) treatment. Objective: To analyze the compliance of patients with house dust mite (HDM)-induced AR to SLIT and the impact of coronavirus disease 2019 (COVID-19) on compliance. Methods: The clinical data of 3117 patients with HDM-induced AR who started SLIT between July 2018 and April 2022 were retrospectively reviewed. We assessed the reasons for non-compliance and the changes in non-compliance during the COVID-19 pandemic compared to the pre-pandemic period. Results: Of 3117 patients, 507 (16.27%) patients (ages, 5–67 years) were identified as non-compliant. The most common reason for non-compliance was poor efficacy (27.22%). The non-compliance rate was highest during 24–36 months of SLIT (28.13%, 153/544), followed by 12–24 months (7.02%, 91/1296). Non-compliance was significantly higher in adolescents/adults than in children (P = 0.000). Although the generalized linear model analysis indicated that compliance was affected by the COVID-19 pandemic during 3–6 months of SLIT, the overall compliance to SLIT was not significantly affected by the pandemic, according to the Kaplan-Meier survival analysis. Conclusions: The non-compliance rate of SLIT in this study was low, and poor efficacy was the most common reason for non-compliance. The compliance of adolescents/adults was lower than that of children. The COVID-19 pandemic did not significantly impact compliance to SLIT, which is an appropriate strategy for the home treatment of AR patients during major public health events.

Background Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC).Methods TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance.Results The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p

Redox-responsive hydropersulfide prodrugs are designed to enable a more controllable and efficient hydropersulfide (RSSH) supply and to thoroughly explore their biological and therapeutic applications in oxidative damage. To obtain novel activation patterns triggered by redox signaling, we focused on NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1), a canonical antioxidant enzyme, and designed NQO1-activated RSSH prodrugs. We also performed a head-to-head comparison of two mainstream structural scaffolds with solid quantitative analysis of prodrugs, RSSH, and metabolic by-products by LC-MS/MS, confirming that the perthiocarbamate scaffold was more effective in intracellular prodrug uptake and RSSH production. The prodrug was highly potent in oxidative stress management against cisplatin-induced nephrotoxicity. Strikingly, this prodrug possessed potential feedback activation properties by which the delivered RSSH can further escalate the prodrug activation via NQO1 upregulation. Our strategy pushed RSSH prodrugs one step further in the pursuit of efficient release in biological matrices and improved druggability against oxidative stress.

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural–functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.

Electroacupuncture (EA) is an effective alternative for the treatment of functional dyspepsia (FD). It reduces low-grade duodenal inflammation and improves the symptoms of FD by downregulating the expression of NF-κB p65 and NLRP3, but its mechanism needs to be elucidated. To examine the regulatory effect of electroacupuncture (EA) on intestinal flora and NF-κB p65/NLRP3 pyroptosis pathway in FD rats. The FD rat model was established via multi-factor stress intervention for two weeks. The rats were randomly divided into the NC group, model group, NF-kB inhibitor group (NF-κB inhibitor BAY 11–7082 was administered), EA group, and EA + NF-kB inhibitor group. After 14 days of treatment, the rats were sacrificed, and the protein and mRNA levels of NF-κB p65, IκB, and NLRP3 in the duodenum were evaluated by Western blotting assays and real-time fluorescent quantitative PCR. The Illumina MiSeq sequencing platform was used to analyze the V4 region of the 16S rRNA gene of intestinal flora and predict functional genes. The concentration of short-chain fatty acids (SCFAs) in feces was assessed by metabolomics. EA can decrease low-grade duodenal inflammation and promote gastrointestinal motility in FD rats. This effect is mediated by inhibition of the NF-κB p65/NLRP3 pyroptosis pathway, an increase in the alpha and beta diversity of gut microbiota in the duodenum, an increase in the abundance of beneficial bacteria at the phylum and genus levels, and an increase in the content of SCFAs. The protective effect of EA against FD might involve multiple hierarchy and pathways. EA may remodel intestinal flora by inhibiting the NF-κB p65/NLRP3 pyroptosis pathway, thereby improving low-grade duodenal inflammation in FD rats.

Background There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk.Aims To explore the relationship between major depressive disorder (MDD) and fracture risk.Methods We conducted a nested case-control analysis (32 670 patients with fracture and 397 017 individuals without fracture) and a matched cohort analysis (16 496 patients with MDD and 435 492 individuals without MDD) in the same prospective UK Biobank data set. Further, we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools. We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci. We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study.Results We found that MDD was associated with a 14% increase in fracture risk (hazard ratio (HR) 1.14, 95% CI 1.14 to 1.15, p

C16H17N3O2, monoclinic, P21/n (no. 14), a = 9.3503(9) Å, b = 9.1998(8) Å, c = 17.7180(18) Å, β = 97.636(9)°, V = 1510.6(3) Å3, Z = 4, Rgt(F) = 0.0564, wRref(F2) = 0.1439, T = 293 K.

The survival rate and storage period of lactic acid bacteria (LAB) are affected by numerous factors in the vacuum freeze-drying process. Hence, optimizing the freeze-drying process and storage conditions is an effective method to improve the survival rate and prolong the storage period of LAB. This paper reviews the factors that influence the survival rate of LAB during the vacuum freeze-drying process and explores how to optimize the freeze-drying process and storage conditions to improve the survival rate and extend the storage period of LAB. We expect that this review will provide a basis and reference for the preparation of lyophilized LAB formulations with high activity and good storage stability.