O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis.

O-linked GlcNAc (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalk with phosphorylation and ubiquitination to orchestrate various biological processes. The mechanisms underlying the involvement of O-GlcNAc modifications in N6-methyladenosine (m6A) regulation are not fully characterized. Herein, we show that O-GlcNAc modifies the m6A mRNA reader YTH domain family 1 (YTHDF1) and fine-tunes its nuclear translocation by the exportin protein Crm1. First, we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified Ser196/Ser197/Ser198 as the YTHDF1 O-GlcNAcylation sites, as described in numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196A/S197F/S198A (AFA) mutant, which significantly attenuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 promotes the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT-YTHDF1-c-Myc axis underlies colorectal cancer tumorigenesis.

Mitochondrial deoxyguanosine kinase is required for female fertility in mice.

Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleosides in mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. Dguok loss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. In this study, we find that Dguok knockout results in female infertility. Mechanistically, DGUOK deficiency hinders ovarian development and oocyte maturation. Moreover, DGUOK deficiency in oocytes causes a significant reduction in mitochondrial DNA copy number and abnormal mitochondrial dynamics and impairs germinal vesicle breakdown. Only few DGUOK-deficient oocytes can extrude their first polar body during in vitro maturation, and these oocytes exhibit irregular chromosome arrangements and different spindle lengths. In addition, DGUOK deficiency elevates reactive oxygen species levels and accelerates oocyte apoptosis. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate DGUOK as a potential marker for the diagnosis of female infertility.

Comprehensive analyses of intraoral spindle cell carcinoma: A rare disease entity revisited.

OBJECTIVE: The present study was aimed to comprehensively characterize the epidemiological, clinicopathological characteristics, treatments, and prognosis of intraoral spindle cell carcinoma (SpCC). MATERIALS AND METHODS: Patients diagnosed with intraoral SpCC at our institution in the past 15 years (2005-2019) were screened from inpatient disease registry. All relevant data concerning patients with intraoral SpCC were retrieved. Previous reports about intraoral SpCC with adequate clinicopathological data in both English literature and Chinese literature were collected. Eligible cases were further reviewed and pooled for statistical analyses. RESULTS: Six patients (5 females and 1 male; average age: 59 years) with intraoral SpCC were histopathologically diagnosed and surgically treated at our institution. The literature review identified another 63 published cases from 34 articles. Most cases were presented in the fifth to seventh decade of life with a male preponderance. Gingiva (23/69, 33.3%) was the most common site followed by the tongue (19/69, 27.5%) and buccal mucosa (8/69, 11.6%). Complete surgical ablation remains the primary treatment option. Tumor size, pathological grades, cervical node metastasis, and distant metastasis were significantly associated with reduced survival. CONCLUSIONS: Intraoral SpCC is an uncommon and aggressive malignancy with dismal prognosis. Much attention and effort are needed to characterize this rare entity and improve its clinical outcomes.

Effects of feeding methods on growth and slaughter performance, blood biochemical indices, and intestinal morphology in Minxinan black rabbits (Oryctolagus cuniculus).

Feed restriction after weaning is a common strategy used in commercial rabbit farms to improve feed efficiency, promote health, and reduce mortality. However, few studies have investigated the feed restrictions of Minxinan black rabbits (Oryctolagus cuniculus). Thus, the effects of feed restriction on growth and slaughter performance, intestinal morphology, and blood biochemical indices of Minxinan black rabbits were evaluated in this study. Rabbits in group A (control group) had ad libitum intake, while those in feed restriction groups (groups B, C, and D) were restricted to 80% of the average daily feed intake (ADFI) of group A the day before. The rabbits in group B were fed once per day at 8:00 am. Rabbits in groups C and D were fed twice per day at 8:00 am (50%) and 4:00 pm (50%) and 8:00 am (30%) and 4:00 pm (70%), respectively. The experimental period lasted for 8 weeks. Compared to that in group A, the diarrhea rate of group C was significantly decreased (P < 0.05), and the ADFI, feed conversion ratio, abdominal fat weight, abdominal fat rate, total protein, albumin, globulin, alanine aminotransferase (ALT), low-density lipoprotein, and intestinal crypt depth of all feed restriction groups were significantly reduced (P < 0.01). Feed conversion ratio in group D was significantly better than that in groups B and C (P < 0.05). The efficiency index (EI) of groups C and D was higher than that of groups A and B (P < 0.01). Triglyceride levels in groups C and D were significantly lower than those in group A. The villus length to crypt depth of the duodenum and jejunum in group D was significantly higher than that in group A (P < 0.01). In conclusion, the following parameters can be improved by feed restriction: feed conversion ratio, diarrhea rate, abdominal fat rate, serum ALT, lipid indices and intestinal health of Minxinan black rabbits, and the EI of the farm. Feeding twice per day, 30% at 8:00 am and 70% at 4:00 pm, had the best comprehensive effects.

Caenorhabditis elegans NHR-14/HNF4α regulates DNA damage-induced apoptosis through cooperating with cep-1/p53.

BACKGROUND: Nuclear hormone receptors are involved in transcriptional regulation and many important cellular processes including development and metabolism. However, its role in DNA damage-induced apoptosis remains elusive. METHODS: Synchronized young adult animals were irradiated with different doses of gamma-Ray, and then put back to culture at 20 °C. Germline cell apoptosis was scored at different time point. RESULTS: Deletion of nhr-14 led to decreased DNA damage-induced germline apoptosis, but not the physiological programmed cell death. We also demonstrate that nhr-14 functions downstream of the DNA damage checkpoint pathway. Moreover, we show that nhr-14 regulates egl-1 and ced-13 transcription upon DNA damage. Mechanistically, NHR-14 forms a complex with CEP-1/p53 and binds directly to the egl-1 promoter to promote egl-1 transcription.. CONCLUSIONS: Our results indicate that NHR-14/HNF4α cooperates with CEP-1/p53 to regulate DNA damage-induced apoptosis. Video abstract.

Pathogenic and genomic characterisation of a rabbit sourced Pasteurella multocida serogroup F isolate s4.

BACKGROUND: Pasteurella multocida is one of the most significant pathogens for a number of animals. In rabbits, the infection is generally associated with the P. multocida serogroups A and D, and the knowledge about the serogroup F is limited. In the present study, a P. multocida serogroup F isolate designated s4 was recovered from the lungs of rabbits died of respiratory disease in Fujian, in the southeast of China. The pathogenicity and genomic features of the s4 were then determined. RESULTS: The serotype and sequence type of s4 were F:L3 and ST12, respectively. The s4 was pathogenic for rabbits, but it was a low virulent strain comparing to the previously reported highly pathogenic P. multocida serogroup F strains J-4103, C21724H3km7, P-4218 and HN07. The whole genome of the s4 was then sequenced to understand the genomic basis for pathogenicity. Particularly, a large-sized fragment of approximate 275 kb in length was truncated from the chromosome to form a plasmid. Moreover, the in-frame deletion of natC and N-terminal redundance of gatF would resulted in the production of a mutant L3 outer core structure that was distinct from those of the other P. multocida strains belonging to the lipopolysaccharide genotype L3. We deduced that these features detected in the genome of s4 might impair the pathogenicity of the bacterium. CONCLUSIONS: This study evaluated the pathogenicity and determined the genomic features of the rabbit sourced P. multocida serogroup F isolate s4, the observations and findings would helpful for the understanding of the pathogenicity variability and genetic diversity of P. multocida.

Atlas of receptor genes expressed by the bovine morula and corresponding ligand-related genes expressed by uterine endometrium.

Regulation of the mammalian embryo involves cell-signaling molecules produced by the maternal oviduct and endometrium. Here, datasets on the transcriptome of the gestational Days 5 and 6 bovine morula and Day 5 maternal endometrium were examined to identify receptor genes expressed by the morula and expression of the corresponding ligand-related genes in the endometrium. A total of 175 receptor genes were identified in the morula, including 48 encoding for growth factors or WNT signaling molecules, 25 for cytokines and chemokines, 35 involved in juxtacrine and matricellular signaling and 25 encoding for receptors for small molecules. Some of the highly-expressed pairs of endometrial ligand and embryo receptor genes included MDK and its receptors ITGB1, SDC4 and LRP2, WNT5A (RYK), VEGFA (ITGB1), GPI (AMFR), and the hedgehog proteins IHH and DHH (HHIP). The most highly expressed receptors for small molecules were GPRC5C (retinoic acid receptor), PGRMC1 (progesterone), and CHRNB2 (acetylcholine). There were also 84 genes encoding for cell signaling ligands expressed by the morula, with the most highly expressed being GPI, AIMP1, TIMP1, IK, and CCN2. The atlas of receptor and ligand genes should prove useful for understanding details of the communication between the embryo and mother that underlies optimal embryonic development.

Does low dose of etoricoxib play pre-emptive analgesic effect in third molar surgery? A randomized clinical trial.

BACKGROUND: How to prevent pain after the extraction of impacted teeth is a serious challenge for all patients. The purpose of this clinical trial was to investigate whether pre-emptive low dose of etoricoxib can reduce postoperative pain in patients undergoing third molars surgery. METHODS: Patients were randomised to receive etoricoxib 60 mg or placebo 30 min before surgery. Post-operative pain was recorded using a visual analogue scale during 24 h within the post-operative period. The total dose of ibuprofen rescue intake was recorded. Kaplan-Meier curves and log-rank analyses were used to evaluate the proportion of patients without rescue analgesic. RESULTS: Scores for the post-operative pain in the etoricoxib group were significantly lower than those in the placebo group during first 12 h (p < 0.05). The number of patients without analgesic rescue medication was significantly lower in the etoricoxib group than in the placebo group. The average amount of rescue medication in the etoricoxib group (0.4 ± 0.9 dose) was lower than that in the placebo group (1.1 ± 0.9 doses, p = 0.004). Etoricoxib resulted in the long-term survival of patients without rescue analgesic (p < 0.001). CONCLUSIONS: This study revealed that etoricoxib has a substantial pre-emptive analgesic effect, resulting in the reduced use of analgesics after third molar removal. TRIAL REGISTRATION: Registered on ChiCTR1900024503. Date of Registration: 13/07/2019.

Actions of putative embryokines on development of the preimplantation bovine embryo to the blastocyst stage.

Once it enters the uterus at d 4 to 5 after ovulation, the preimplantation bovine embryo is controlled in its development by regulatory signaling molecules from the mother called embryokines. Here, several cell-signaling molecules whose genes are expressed in the endometrium during d 5 to 7 after estrus were tested for the ability to affect the competence of the embryo for further development and the characteristics of the resultant blastocysts. Molecules tested were C-natriuretic peptide (CNP), IL-8, bovine morphogenetic protein 4 (BMP-4), IL-6, and leukemia inhibitory factor (LIF). None of the cell-signaling molecules tested improved the competence of the embryo to become a blastocyst; in fact, BMP-4 decreased development. All molecules modified attributes of the blastocyst formed in culture. In particular, CNP increased the number of cells in the ICM, whereas IL-8 decreased inner cell mass cell numbers and tended to increase the proportion of blastocysts that were hatching or hatched. In addition, BMP-4 decreased the proportion of blastocysts that were hatching. Interleukin-6 and, to a lesser extent, LIF activated the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the inner cell mass, and LIF increased the percent of cells in the blastocyst that were positive for both NANOG and phosphorylated (activated) STAT3. In conclusion, our results indicate that CNP, IL-8, IL-6, LIF, and BMP-4 can modify embryonic development of the cow in a manner that affects characteristics of the resultant blastocyst. Further research is required to understand how these changes in characteristics of the blastocyst would affect competence of the embryo to establish and maintain pregnancy.

Monolithic radio frequency SiN x self-rolled-up nanomembrane interdigital capacitor modeling and fabrication.

Monolithic capacitors operating at radio frequencies (RF) serve as critical components in integrated circuits for wireless communication. Design and fabrication innovations for high capacitance density RF capacitors are highly desired for the miniaturization of RFIC chips. However, practical and simple solutions are limited by existing capabilities in three-dimensional (3D) structure construction and the effective configuration of electrodes. We report a unique route to achieve unprecedentedly high capacitance density at a high operating frequency through a capacitor configuration of 3D coil interdigital electrodes using planar semiconductor processing compatible materials and fabrication methods. A systematic mechanical-electrical design principle is demonstrated, and fabricated devices show a maximum 21.5 pF capacitance, which is 17.2× larger after rolling up. The corresponding capacitance density is as large as 371 pF mm-2, with resonant frequency of 1.5 GHz. The performance could be improved significantly by simply rolling up more turns with minimal change to the area footprint.

Characterization of Pasteurella multocida isolated from dead rabbits with respiratory disease in Fujian, China.

BACKGROUND: Pasteurella multocida is one of the important pathogens that infect rabbits, causing major economic losses in commercial rabbit farming. In this study, 205 P. multocida isolates recovered from lungs of dead rabbits with respiratory disease were defined by capsular serogroups, lipopolysaccharide (LPS) genotypes, multi-locus sequence types and screened virulence factors by using PCR assays, and tested antimicrobial susceptibility. RESULTS: The 205 isolates were assigned into 2 capsular types, A and D, and 2 LPS genotypes, L3 and L6. When combining capsular types with LPS genotypes, 4 serotypes were detected. A:L3 (51.22%, 105/205) was the most predominant serotype, followed by A:L6 (24.88%, 51/205), D:L6 (19.02%, 39/205) and D:L3 (4.88%, 10/205). The 205 isolates were grouped into 3 sequence types, ST10, ST11 and ST12. ST12 (56.10%, 115/205) was the most prevalent sequence type, followed by ST10 (24.88%, 51/205) and ST11 (19.02%, 39/205). In the 205 isolates, virulence associated genes ptfA, fur, hgbB, ompA, ompH and oma87 were positive in the PCR screening, whereas the toxA and tbpA genes were negative. Notably, the 156 capsular serogroup A isolates carried the pmHAS gene. All the 205 isolates were susceptible to most of the used antibiotics, except for streptomycin, gentamycin, kanamycin and ceftriaxone, and the resistance rates of which were 27.80, 15.61, 9.27 and 2.44%, respectively. CONCLUSIONS: This study, for the first time, described the prevalence and characteristics of P. multocida causing respiratory disease in rabbits in Fujian Province, which might be useful for tracking the epidemic strains and development of efficient vaccines and methods to prevent and control the pathogen.

Balancing Between Aging and Cancer: Molecular Genetics Meets Traditional Chinese Medicine.

The biological consequences of cellular senescence and immortalization in aging and cancer are in conflict. Organisms have developed common cellular signaling pathways and surveillance mechanisms to control the processing of aging against tumorigenesis. The imbalance of any signals involved in this process may result in either premature aging or tumorigenesis and reduce the life span of the organism. In contrast, the balance between aging and tumorigenesis at a higher level (homeostatic-balance) may benefit the organism with tumor-free longevity. The focus of this perspective is to review the literature on the balance between "Yin" and "Yang" in traditional Chinese medicine. Modern cellular and molecular techniques now permit a more robust system to screen herbs in traditional Chinese medicine for their activity in balancing aging and tumorigenesis. The understanding of the crosstalk between aging and tumorigenesis and new perspectives on the application of Chinese medicine might shed light on anti-aging and tumor-free strategies. J. Cell. Biochem. 118: 2581-2586, 2017. © 2017 Wiley Periodicals, Inc.

Milk, yogurt, and lactose intake and ovarian cancer risk: a meta-analysis.

Inconclusive information for the role of dairy food intake in relation to ovarian cancer risk may associate with adverse effects of lactose, which has been hypothesized to increase gonadotropin levels in animal models and ecological studies. Up to now, several studies have indicated the association between dairy food intake and risk of ovarian cancer, but no identified founding was reported. We performed this meta-analysis to derive a more precise estimation of the association between dairy food intake and ovarian cancer risk. Using the data from 19 available publications, we examined dairy food including low-fat/skim milk, whole milk, yogurt and lactose in relation to risk of ovarian cancer by meta-analysis. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to assess the association. We observed a slightly increased risk of ovarian cancer with high intake of whole milk, but has no statistical significance (OR = 1.228, 95% CI = 1.031-1.464, P = 0.022). The results of other milk models did not provide evidence of positive association with ovarian cancer risk. This meta-analysis suggests that low-fat/skim milk, whole milk, yogurt and lactose intake has no associated with increased risk of ovarian cancer. Further studies with larger participants worldwide are needed to validate the association between dairy food intake and ovarian cancer.

Tentative identification of sex-specific antibodies and their application for screening bovine sperm proteins for sex-specificity.

Our previous studies indicated that a purified rabbit antiserum against X-sperm contained sex-specific antibodies (SSAbs) which preferentially bound to sex-sorted X-sperm. The specificity of sex-specific antiserum was initially demonstrated using flow cytometry only, which resulted in uncertainty. In this study, the putative SSAbs against bovine X-sperm (XSSAb) were produced by a series of immunological approaches, and the effectiveness of separation of sperm using putative XSSAb was validated. Subsequently, the XSSAb was used to immunoprecipitate sex-specific proteins (SSPs) in bovine sperm, followed by two-dimensional gel electrophoresis. The results showed 7.6, 15.2 and 52.1 % of sex-sorted Y-sperm, sex-sorted X-sperm and unsorted sperm were recognized by the neutralized rabbit antisera against X-sperm, respectively. Also the purity of separation of sperm using putative XSSAb reached 74.3 % when the immunologically separated sperm were injected into oocytes. In addition, three candidate SSP sports about 30 kDa were captured by the XSSAb. Our results confirmed that the putative XSSAb contained SSAbs, and implied that these three protein sports might be SSPs in bovine X-sperm. This provides a potentially more efficient method for sorting sperm and lays a foundation for future search for SSPs.

Dual effects of gonadotropin-inhibitory hormone on testicular development in prepubertal Minxinan Black rabbits (Oryctolagus cuniculus).

Gonadotropin-inhibitory hormone (GnIH) is a neurohormone that not only suppresses reproduction at the brain level but also regulates steroidogenesis and gametogenesis at the gonad level. However, its function in gonadal physiology has received little attention in rabbits. The main objective of this study was to evaluate the effects of GnIH on testicular development and function in prepubertal Minxinan Black rabbits (Oryctolagus cuniculus). In the present study, we investigated the serum reproductive hormone concentration, testicular parameters, morphology of seminiferous tubules, apoptosis of testicular cells, and expression of reproductive-related genes in male prepubertal Minxinan Black rabbits intraperitoneally administered with 0, 0.5, 5, or 50 µg quail GnIH-related peptides (qGnIH) for 10 days. Compared with the vehicle, administration with 5 µg of qGnIH downregulated the serum testosterone concentration and mRNA levels of spermatogenic genes (PCNA, FSHR, INHßA, HSF1, and AR) and upregulated the apoptosis rate of testicular cells; administration with 50 µg of qGnIH decreased the serum testosterone concentration and hypothalamic GnIH gene mRNA level and increased the serum LH concentration, pituitary LHß gene mRNA level, testicular weight, gonadosomatic index (GSI), and spermatogenic cell layer thickness. It is concluded that GnIH could exert dual actions on testicular development depending on the male prepubertal rabbits receiving different intraperitoneal doses.

OLR-Net: Object Label Retrieval Network for principal diagnosis extraction.

BACKGROUND: Extracting principal diagnosis from patient discharge summaries is an essential task for the meaningful use of medical data. The extraction process, usually by medical staff, is laborious and time-consuming. Although automatic models have been proposed to retrieve principal diagnoses from medical records, many rare diagnoses and a small amount of training data per rare diagnosis provide significant statistical and computational challenges. OBJECTIVE: In this study, we aimed to extract principal diagnoses with limited available data. METHODS: We proposed the OLR-Net, Object Label Retrieval Network, to extract principal diagnoses for discharge summaries. Our approach included semantic extraction, label localization, label retrieval, and recommendation. The semantic information of discharge summaries was mapped into the diagnoses set. Then, one-dimensional convolutional neural networks slid into the bottom-up region for diagnosis localization to enrich rare diagnoses. Finally, OLR-Net detected the principal diagnosis in the localized region. The evaluation metrics focus on the hit ratio, mean reciprocal rank, and the area under the receiver operating characteristic curve (AUROC). RESULTS: 12,788 desensitized discharge summary records were collected from the oncology department at Hainan Hospital of Chinese People's Liberation Army General Hospital. We designed five distinct settings based on the number of training data per diagnosis: the full dataset, the top-50 dataset, the few-shot dataset, the one-shot dataset, and the zero-shot dataset. The performance of our model had the highest HR@5 of 0.8778 and macro-AUROC of 0.9851. In the limited available (few-shot and one-shot) dataset, the macro-AUROC were 0.9833 and 0.9485, respectively. CONCLUSIONS: OLR-Net has great potential for extracting principal diagnosis with limited available data through label localization and retrieval.

Effect of laser process parameters on the pores, surface roughness, and hardness of laser selective melting of dental cobalt-chrome alloys.

OBJECTIVES: To address the quality problems caused by high porosity in the preparation of dental cobalt-chrome alloy prosthetics based on selective laser melting (SLM) technology, we investigated the influence mechanism of different forming process parameters on the microstructure and properties of the materials. Moreover, the range of forming process parameters that can effectively reduce defects was precisely defined. METHODS: The effects of laser power, scanning speed, and scanning distance on the pore properties, surface roughness, and hardness of dental cobalt-chrome alloy were investigated by adjusting the printing parameters in the process of SLM. Through metallographic analysis, image analysis, and molten pool simulation, the pore formation mechanism was revealed, and the relationship between the porosity and energy density of SLM dental cobalt-chrome alloy was elucidated. RESULTS: When the linear energy density was higher than 0.18 J/mm, the porosity defect easily appeared at the bottom of the molten pool. When the laser energy density was lower than 0.13 J/mm, defects occurred in the gap of the molten pool due to insufficient melting of powder. In particular, when the linear energy density exceeded the threshold of 0.30 J/mm or was below 0.12 J/mm, the porosity increased significantly to more than 1%. In addition, we observed a negative correlation between free surface roughness and energy density and an inverse relationship between macroscopic hardness and porosity. CONCLUSIONS: On the basis of the conditions of raw materials and molding equipment used in this study, the key process parameters of SLM of molding parts with porosity lower than 1% were successfully determined. Specifically, these key parameters included the line energy density, which ranged from 0.13 J/mm to 0.30 J/mm, and the scan spacing should be strictly controlled below 90 µm.

Pathogenic and genomic characterization of rabbit-sourced Pasteurella multocida serogroup F isolates recovered from dead rabbits with respiratory disease.

Pasteurella multocida serogroup F can infect a number of animals. However, the pathogenicity and genomic features of this serogroup are still largely unknown. In the present study, the pathogenicity and genomic sequences of 19 rabbit-sourced P. multocida serogroup F isolates were determined. The 19 isolates were highly pathogenic for rabbits causing severe pathologic lesions and high mortality in inoculated rabbits. Nevertheless, the pathologic lesions in rabbits caused by the 19 isolates were distinct from those caused by the previously reported high-virulent serogroup F strains J-4103 (rabbit), P-4218 (turkey), and C21724H3km7 (chicken). Moreover, the 19 isolates were avirulent to white feather broilers. The genomes of the 19 isolates were determined to understand the pathogenicity of these isolates. The finding of a number of functional genes in the 19 isolates by comparison with the low-virulent rabbit-sourced serogroup F strain s4 might contribute to the high virulence of these isolates. Notably, polymorphisms were determined in the lipopolysaccharide outer core biosynthetic genes natC and gatF among the serogroup F strains of different hosts. However, the sequences of natC and gatF from rabbit-sourced strains (except for SD11) were identical, which might be responsible for the host specific of the 19 isolates. The observations and findings in this study would be helpful for the understanding of the pathogenicity variation and host predilection of P. multocida. IMPORTANCE: The 19 rabbit-sourced Pasteurella multocida serogroup F isolates showing high virulence to rabbits were avirulent to the broilers. Notably, polymorphisms were determined in the lipopolysaccharide outer core biosynthetic genes natC and gatF among all serogroup F strains of different hosts. However, the sequences of natC and gatF from rabbit-sourced strains (except for SD11) were identical, which might be responsible for the host specific of the 19 isolates.

Enhanced ICD-10 code assignment of clinical texts: A summarization-based approach.

BACKGROUND: Assigning International Classification of Diseases (ICD) codes to clinical texts is a common and crucial practice in patient classification, hospital management, and further statistics analysis. Current auto-coding methods mainly transfer this task to a multi-label classification problem. Such solutions are suffering from high-dimensional mapping space and excessive redundant information in long clinical texts. To alleviate such a situation, we introduce text summarization methods to the ICD coding regime and apply text matching to select ICD codes. METHOD: We focus on the tenth revision of the ICD (ICD-10) coding and design a novel summarization-based approach (SuM) with an end-to-end strategy to efficiently assign ICD-10 code to clinical texts. In this approach, a knowledge-guided pointer network is purposed to distill and summarize key information in clinical texts precisely. Then a matching model with matching-aggregation architecture follows to align the summary result with code, tuning the one-vs-all scenario to one-vs-one matching so that the large-label-space obstacle laid in classification approaches would be avoided. RESULT: The 12,788 ICD-10 coded discharge summaries from a Chinese hospital were collected to evaluate the proposed approach. Compared with existing methods, the purposed model achieves the greatest coding results with Micro AUC of 0.9548, MRR@10 of 0.7977, Precision@10 of 0.0944, and Recall@10 of 0.9439 for the TOP-50 Dataset. Results on the FULL-Dataset remain consistent. Also, the proposed knowledge encoder and applied end-to-end strategy are proven to facilitate the whole model to gain efficacy in selecting the most suitable code. CONCLUSION: The proposed automatic ICD-10 code assignment approach via text summarization can effectively capture critical messages in long clinical texts and improve the performance of ICD-10 coding of clinical texts.

EGF/EGFR-YAP1/TEAD2 signaling upregulates STIM1 in vemurafenib resistant melanoma cells.

Stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum Ca2+ sensor for store-operated calcium entry and is closely associated with carcinogenesis and tumor progression. Previously, we found that STIM1 is upregulated in melanoma cells resistant to the serine/threonine-protein kinase B-raf inhibitor vemurafenib, although the mechanism underlying this upregulation is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR)-Yes-associated protein 1 (YAP1)/TEA domain transcription factor 2 (TEAD2) signaling axis. Vemurafenib resistance can lead to an increase in EGF and EGFR levels, causing activation of the EGFR signaling pathway, which promotes YAP1 nuclear localization to increase the expression of STIM1. Our findings not only reveal the mechanism by which vemurafenib resistance promotes STIM1 upregulation, but also provide a rationale for combined targeting of the EGF/EGFR-YAP1/TEAD2-STIM1 axis to improve the therapeutic efficacy of BRAF inhibitor in melanoma patients.