DeepFace: Deep learning-based framework to contextualize orofacial cleft-related variants during human embryonic craniofacial development.

Orofacial clefts (OFC) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the 'casual' variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson Correlation Coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50 to 0.83. Specifically, our model revealed that SNPs significantly associated with OFC tended to exhibit higher SAD scores across various variant categories compared to less-related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFC. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFC, and the model that can be extended to study other complex diseases or traits.

Personalized Composite Dosimetric Score-Based Machine Learning Model of Severe Radiation-Induced Lymphopenia among Esophageal Cancer Patients.

PURPOSE: Radiation-induced lymphopenia (RIL) is common among patients undergoing radiotherapy (RT), and severe RIL has been linked with adverse outcomes. The severity and risk of RIL can be predicted from baseline clinical characteristics and dosimetric parameters. However, dose-volume (DV) indices are highly correlated with one another and are only weakly associated with RIL. Here we introduce the novel concept of "composite dosimetric score" (CDS) as the index that condenses the dose distribution in immune tissues of interest to study the dosimetric dependence of RIL. We derived an improved multivariate classification scheme for risk of grade 4 (G4) RIL, based on this novel RT dosimetric feature, for patients receiving chemoRT for esophageal cancer. METHODS AND MATERIALS: DV indices were extracted for 734 patients who received chemoRT for biopsy-proven esophageal cancer. Non-negative matrix factorization was used to project the DV indices of lung, heart, and spleen into a single CDS; XGBoost was employed to explore significant interactions among predictors; and logistic regression was applied to combine the resultant CDS along with baseline clinical factors and interaction terms to facilitate individualized prediction of immunotoxicity. Five-fold cross-validation was applied to evaluate the model performance. RESULTS: The CDS for selected immune organs at risk (OARs, i.e., heart, lung, and spleen) (1.791, 95 CI [1.350,2.377]) was a statistically significant risk determinant for G4RIL. Pearson correlation coefficients for CDS vs. G4RIL risk for individual immune OARs were greater than any single DV indices. Personalized prediction of G4RIL based on CDS and 4 clinical risk factors yielded an area under the curve value of 0.78. Interaction between age and CDS revealed that G4RIL risk increased more sharply with increasing CDS for patients ≥65. CONCLUSIONS: Risk of immunotoxicity for patients undergoing chemoRT for esophageal cancer can be predicted by CDS. The CDS concept can be extended to immunotoxicity in other cancer types and in dose-response models currently based on DV indices. Personalized treatment planning should leverage CDS methods rather than using individual or subsets of DV indices.

Iron-containing nanominerals for sustainable phosphate management: A comprehensive review and future perspectives.

Adsorption, which is a quick and effective method for phosphate management, can effectively address the crisis of phosphorus mineral resources and control eutrophication. Phosphate management systems typically use iron-containing nanominerals (ICNs) with large surface areas and high activity, as well as modified ICNs (mICNs). This paper comprehensively reviews phosphate management by ICNs and mICNs in different water environments. mICNs have a higher affinity for phosphates than ICNs. Phosphate adsorption on ICNs and mICNs occurs through mechanisms such as surface complexation, surface precipitation, electrostatic ligand exchange, and electrostatic attraction. Ionic strength influences phosphate adsorption by changing the surface potential and isoelectric point of ICNs and mICNs. Anions exhibit inhibitory effects on ICNs and mICNs in phosphate adsorption, while cations display a promoting effect. More importantly, high concentrations and molecular weights of natural organic matter can inhibit phosphate adsorption by ICNs and mICNs. Sodium hydroxide has high regeneration capability for ICNs and mICNs. Compared to ICNs with high crystallinity, those with low crystallinity are less likely to desorb. ICNs and mICNs can effectively manage municipal wastewater, eutrophic seawater, and eutrophic lakes. Adsorption of ICNs and mICNs saturated with phosphate can be used as fertilizers in agricultural production. Notably, mICNs and ICNs have positive and negative effects on microorganisms and aquatic organisms in soil. Finally, this study introduces the following: trends and prospects of machine learning-guided mICN design, novel methods for modified ICNs, mICN regeneration, development of mICNs with high adsorption capacity and selectivity for phosphate, investigation of competing ions in different water environments by mICNs, and trends and prospects of in-depth research on the adsorption mechanism of phosphate by weakly crystalline ferrihydrite. This comprehensive review can provide novel insights into the research on high-performance mICNs for phosphate management in the future.

LPAR6 Participates in Neuropathic Pain by Mediating Astrocyte Cells via ROCK2/NF-κB Signal Pathway.

Neuropathic pain (NPP) is a common type of chronic pain. Glial cells, including astrocytes (AS), are believed to play an important role in the progression of NPP. AS cells can be divided into various types based on their expression profiles, among which A1 and A2 types have clear functions. A1-type AS cells are neurotoxic, while A2-type AS cells exert neuroprotective functions. Some types of lysophosphatidic acid receptors (LPAR) have been shown to play a role in NPP. However, it remains unclear how AS cells and LPAR6 affect the occurrence and progression of NPP. In this study, we established a mouse model of chronic constriction injury (CCI) to simulate NPP. It was found that the expression of LPAR6 in AS cells of the spinal dorsal horn was increased in the CCI model, and the thresholds of mechanical and thermal pain were elevated after knocking out LPAR6, indicating that LPAR6 and AS cells participated in the occurrence of NPP. The experiment involved culturing primary AS cells and knocking down LPAR6 by Lentivirus. The results showed that the NF-κB signal pathway was activated and the number of A1-type AS cells increased in the CCI model. However, LPAR6 knockdown inhibited the NF-κB signal pathway and A1-type AS cells. The results of the mRNA sequencing and immunoprecipitation test indicate an interaction between LPAR6 and ROCK2. Inhibiting ROCK2 by Y-27632 increased mechanical and thermal pain thresholds and alleviated NPP at the molecular level. The study presents evidence that LPAR6 activates the NF-κB pathway through ROCK2 and contributes to the progression of NPP by increasing A1-type AS and decreasing A2-type AS. This suggests that LPAR6 could be a potential therapeutic target for alleviating NPP. Clinical applications that are successful can offer new therapeutic options, enhance the quality of life for patients, and potentially uncover new mechanisms for pain modulation.

Helicobacter pylori vacA affects the expression of COX-2 in the duodenal mucosa of patients with duodenitis.

Duodenitis refers to inflammation that occurs in the duodenum. Helicobacter pylori (Hp) is a known risk factor for duodenitis. This paper attempted to analyze the correlation between Hp virulence genotypes and the initiation and development of duodenal bulbar inflammation (DBI) to lay the foundation for the management of duodenitis induced by Hp infection. Total RNA was extracted from duodenal samples of 156 Hp-positive patients [70 with DBI and 86 with duodenal bulbar ulcer (DBU)] and 80 Hp-free DBI patients, followed by RT-qPCR detection of COX-2 mRNA expression and the presence of virulence factors. The cagA positive (62.2%), vacAs1 (21.79%), vacAm2 (23.72%), vacAs1m2 (19.87%) and iceA1 (55.80%) genotypes were dominant in 156 Hp-positive samples. Statistical difference was observed in vacAs and vacA mixtures between DBI and DBU patients. Gastric metaplasia had an association with vacA allelotypes, and its occurrence had strong correlations with vacAs1 and vacAs1m2 genotypes. The vacAs1 and vacAs1m2 genotypes were correlated with gastric metaplasia occurrence (all p<0.05). There were significant correlations between vacAs and vacA mixtures with cagA genotypes, and between iceA genotypes with vacA mixtures (all p<0.05). COX-2 was strongly expressed in Hp-infected duodenal mucosa and showed correlations with vacA genotype. COX-2 was differentially expressed in vacAs1- and vacAs2-positive patients. COX-2 was more highly upregulated in vacAs1m1- and vacAs1m2-positive patients than vacAs2m2-positive patients. Overall, Hp virulence genotype vacA was correlated with DBI and DBU initiation and development.

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. METHODS AND MATERIALS: Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P = .003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P = .002), and planning treatment volume (P = .033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P = .011). CONCLUSIONS: This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

Non-volatile and volatile compound changes in blueberry juice inoculated with different lactic acid bacteria strains.

BACKGROUND: Lactic acid bacteria (LABs) are widely present in foods and affect the flavour of fermented cultures. This study investigates the effects of fermentation with Lactobacillus acidophilus JYLA-16 (La), Lactobacillus plantarum JYLP-375 (Lp), and Lactobacillus rhamnosus JYLR-005 (Lr) on the flavour profile of blueberry juice. RESULTS: This study showed that all LABs strains preferentially used glucose rather than fructose as the carbon source during fermentation. Lactic acid was the main fermentation product, reaching 7.76 g L-1 in La-fermented blueberry juice, 5.86 g L-1 in Lp-fermented blueberry juice, and 6.41 g L-1 in Lr-fermented blueberry juice. These strains extensively metabolized quinic acid, whereas oxalic acid metabolism was almost unaffected. Sixty-four volatile compounds were identified using gas chromatography-ion mobility spectrometry (GC-IMS). All fermented blueberry juices exhibited decreased aldehyde levels. Furthermore, fermentation with La was dominated by alcohols, Lp was dominated by esters, and Lr was dominated by ketones. Linear discriminant analysis of the electronic nose and principal component analysis of the GC-IMS data effectively differentiated between unfermented and fermented blueberry juices. CONCLUSION: This study informs LABs selection for producing desirable flavours in fermented blueberry juice and provides a theoretical framework for flavour detection. © 2023 Society of Chemical Industry.

Pan-Cancer Analysis of the LOX Family Reveals that LOX Affects Tumor Prognosis by Affecting Immune Infiltration.

The lysyl oxidase (LOX) gene family encodes for a group of copper-dependent enzymes that play a crucial role in the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM). Dysregulation of LOX gene expression has been implicated in various pathological conditions, including cancer. Several studies have shown that the LOX gene family is involved in cancer progression and metastasis. The goal of this article is to conduct a comprehensive analysis of the LOX family's role in pan-cancer multiplexes. We utilized pan-cancer multi-omics sequencing data from TCGA to investigate the relationship between LOX family genes and tumors at four different levels: mutation, copy number variation, methylation, and gene expression. In addition, we also examined the relationship between LOX family genes and tumors at the cell line level using tumor cell line sequencing data from CCLE. Taking into account the impact of LOX family genes on lung cancer, we developed a LOX family lung cancer prognostic model to forecast the disease's prognosis. Our findings revealed that LOXL2 had the highest mutation frequency in tumors, while all four LOX family genes experienced some degree of copy number variation in diverse tumors. We observed that LOX, LOXL1 to LOXL3 were predominantly highly expressed in tumors including LUAD. The expression trends of LOX and LOXL1 to LOXL3 were consistent across tumor cell lines, but differed somewhat from LOXL4. Utilizing 25 LOX family-related genes, we constructed a LOX family prognostic model that performed well in predicting the prognosis of lung cancer. Through pan-cancer analysis, we gain further knowledge of the role of LOX family genes in different tumors, offering a novel pathway for future research into the relationship between LOX family genes and tumors.

Acute pancreatitis in intraductal papillary mucinous neoplasm: a single-center retrospective cohort study with systematic review and meta-analysis.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is a cystic tumor of the pancreas arising from abnormal papillary proliferation of ductal epithelial cells, and is a precancerous lesion of pancreatic malignancy. This study aimed to evaluate associations between acute pancreatitis (AP) and histologic subtypes of IPMN. METHODS: In the clinical study, patients with IPMN confirmed by surgical resection specimens at our institute between 2009 and 2021 were eligible for inclusion. Associations and predictive accuracy of AP on the presence of HGD were determined by logistic regressions. In addition, a systematic review and meta-analysis was conducted through literatures upon search in PubMed, Embase, CENTRAL, China National Knowledge Infrastructure (CKNI), and Wanfang database, up to June, 2023. Pooled effects of the associations between AP and HGD and intestinal epithelial subtype subtype, shown as odds ratios (ORs) with 95% confidence intervals (CIs), were calculated using random effects model. RESULTS: The retrospective cohort study included 47 patients (32 males, 15 females) diagnosed with IPMN at our center between 2009 and 2021, including 11 cases with AP (median 62 years) and 36 cases (median 64.5 years) without. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AP in predicting HGD were 78.7%, 57.1%, 82.5%, 36.4%, and 91.7%, respectively. Univariate logistic regression analysis showed that AP group had greater odds of presence of HGD (OR: 6.29,95% CI: 1.14-34.57) than non-AP group. Meta-analysis of five case-control studies in the literature included 930 patients and showed that AP-IPMN patients had higher odds for HGD (OR: 2.13, 95% CI 1.38-3.29) and intestinal epithelial subtype (OR: 5.38, 95% CI: 3.50-8.27) compared to non-AP IPMN. CONCLUSIONS: AP is predictive of malignancy in patients with IPMN.

Trichinella spiralis cathepsin L induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of newborn larvae.

BACKGROUND: During the early stages of Trichinella spiralis infection, macrophages predominantly undergo polarization to the M1-like phenotype, causing the host's inflammatory response and resistance against T. spiralis infection. As the disease progresses, the number of M2-type macrophages gradually increases, contributing to tissue repair processes within the host. While cysteine protease overexpression is typically associated with inflammation, the specific role of T. spiralis cathepsin L (TsCatL) in mediating macrophage polarization remains unknown. The aim of this study was to assess the killing effect of macrophage polarization mediated by recombinant T. spiralis cathepsin L domains (rTsCatL2) on newborn larvae (NBL). METHODS: rTsCatL2 was expressed in Escherichia coli strain BL21. Polarization of the rTsCatL2-induced RAW264.7 cells was analyzed by enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), western blot, immunofluorescence and flow cytometry. The effect of JSH-23, an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), on rTsCatL2-induced M1 polarization investigated. Cytotoxic effects of polarized macrophages on NBL were observed using in vitro killing assays. RESULTS: Following the co-incubation of rTsCatL2 with RAW264.7 murine macrophage cells, qPCR and ELISA revealed increased transcription and secretion levels of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1ß and tumor necrosis factor alpha (TNF-α) in macrophages. Western blot analysis showed a significant increase in iNOS protein expression, while the expression level of arginase-1 protein remained unchanged. Flow cytometry revealed a substantial increase in the number of CD86-labeled macrophages. The western blot results also indicated that rTsCatL2 increased the expression levels of phospho-NF-κB and phospho-nuclear factor-κB inhibitor alpha (IκB-α) proteins in a dose-dependent manner, while immunofluorescence revealed that rTsCatL2 induced nuclear translocation of the p65 subunit of NF-κB (NF-κB p65) protein in macrophages. The inhibitory effect of JSH-23 suppressed and abrogated the effect of rTsCatL2 in promoting M1 macrophage polarization. rTsCatL2 mediated polarization of macrophages to the M1-like phenotype and enhanced macrophage adhesion and antibody-dependent cell-mediated cytotoxicity (ADCC) killing of NBL. CONCLUSIONS: The results indicated that rTsCatL2 induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of NBL. This study provides a further understanding of the interaction mechanism between T. spiralis and the host.

Identification of the dominant loop of a dual-loop macro-reentry left atrial flutter without prior intervention using high-density mapping technology: A case report.

BACKGROUND: Left atrial flutter without prior cardiac interventions is uncommon, especially dual-loop macro-reentry atrial flutter. The critical step to ablate dual-loop macro-reentry atrial flutter is to identify the dominant loop and key isthmus. Although entrainment mapping could help identify the dominant loop and key isthmus, it may alter or terminate tachycardia. High-density mapping allows the generation of electroanatomic maps without altering or terminating tachycardia. CASE SUMMARY: Here, we report a case of symptomatic left atrial flutter without prior intervention. In this case, high-density mapping revealed a dual-loop macro-reentry around the mitral annulus and central scar of the anterior wall. The propagation result showed that the dominant loop was around the mitral annulus, and the key isthmus was between the central scar and mitral annulus. The atrial flutter terminated successfully after ablation was performed. CONCLUSION: In this case, we demonstrate that high-density mapping technology may help identify the dominant loop of dual-loop atrial flutter without entrainment, which makes ablation easier.

Incorporating Heterogeneous Features into the Random Subspace Method for Bearing Fault Diagnosis.

In bearing fault diagnosis, machine learning methods have been proven effective on the basis of the heterogeneous features extracted from multiple domains, including deep representation features. However, comparatively little research has been performed on fusing these multi-domain heterogeneous features while dealing with the interrelation and redundant problems to precisely discover the bearing faults. Thus, in the current study, a novel diagnostic method, namely the method of incorporating heterogeneous representative features into the random subspace, or IHF-RS, is proposed for accurate bearing fault diagnosis. Primarily, via signal processing methods, statistical features are extracted, and via the deep stack autoencoder (DSAE), deep representation features are acquired. Next, considering the different levels of predictive power of features, a modified lasso method incorporating the random subspace method is introduced to measure the features and produce better base classifiers. Finally, the majority voting strategy is applied to aggregate the outputs of these various base classifiers to enhance the diagnostic performance of the bearing fault. For the proposed method's validity, two bearing datasets provided by the Case Western Reserve University Bearing Data Center and Paderborn University were utilized for the experiments. The results of the experiment revealed that in bearing fault diagnosis, the proposed method of IHF-RS can be successfully utilized.

Non-invasive arterial blood pressure measurement and SpO2 estimation using PPG signal: a deep learning framework.

BACKGROUND: Monitoring blood pressure and peripheral capillary oxygen saturation plays a crucial role in healthcare management for patients with chronic diseases, especially hypertension and vascular disease. However, current blood pressure measurement methods have intrinsic limitations; for instance, arterial blood pressure is measured by inserting a catheter in the artery causing discomfort and infection. METHOD: Photoplethysmogram (PPG) signals can be collected via non-invasive devices, and therefore have stimulated researchers' interest in exploring blood pressure estimation using machine learning and PPG signals as a non-invasive alternative. In this paper, we propose a Transformer-based deep learning architecture that utilizes PPG signals to conduct a personalized estimation of arterial systolic blood pressure, arterial diastolic blood pressure, and oxygen saturation. RESULTS: The proposed method was evaluated with a subset of 1,732 subjects from the publicly available ICU dataset MIMIC III. The mean absolute error is 2.52 ± 2.43 mmHg for systolic blood pressure, 1.37 ± 1.89 mmHg for diastolic blood pressure, and 0.58 ± 0.79% for oxygen saturation, which satisfies the requirements of the Association of Advancement of Medical Instrumentation standard and achieve grades A for the British Hypertension Society standard. CONCLUSIONS: The results indicate that our model meets clinical standards and could potentially boost the accuracy of blood pressure and oxygen saturation measurement to deliver high-quality healthcare.

Technique of using Cionni-modified capsular tension ring in the management of severely traumatic lens subluxation.

AIM: To investigate the effect of Cionni-modified capsular tension ring (CTR) implantation in patients with severely traumatic subluxated cataracts. METHODS: All patients who totally had traumatic cataracts and lost zonule support and underwent cataract surgery were retrospectively analyzed. Corrected distance visual acuity (CDVA), extent of zonulysis, intraocular lens (IOL) position, intraoperative presentation, and complications were assessed. The primary outcomes included IOL centration stability and other postoperative complications. RESULTS: Twenty patients (20 eyes) were included in this study. The mean age in this study was 58.0±11.3y, and the average follow-up time was 17.3±12.8mo. Capsule bags were saved by Cionni-modified CTR. Nine eyes (45%) underwent simultaneously anterior vitrectomy due to the presence of vitreous in the anterior chamber. The preoperative mean CDVA was 0.83±0.24 logMAR, and the postoperative average CDVA was 0.23±0.30 logMAR (P<0.05). The horizontal and vertical IOL decentration after surgery was 0.27±0.12 mm and 0.41±0.19 mm, respectively; the vertical and horizontal IOL tilt after surgery was 5.5°±2.5° and 6.1°±2.2°, respectively. None of the eyes had obvious IOL decentration during the follow-up time. Eight eyes (40%) had posterior capsule opacification (PCO) that was severe enough to cause poor vision. Neodymium: YAG laser capsulotomy were performed on these eyes when the CTR was stabilized. CONCLUSION: With the help of Cionni-modified CTR, capsular bag preservation and better IOL concentration can be achieved without major complications in patients with severely traumatic subluxated cataracts.

Herbs for lochia discharge used among postpartum women in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: In the traditional Taiwanese culture of "postpartum confinement", the term "lochia discharge" is a synonym for assisting postpartum uterine involution. Postpartum women in Taiwan consult traditional Chinese medicine (TCM) pharmacies to obtain various TCM formulations that facilitate lochia discharge. AIM OF THE STUDY: As an ethnopharmacy study, we aimed to conduct field investigations to explore the herbal composition of TCM formulations for lochia discharge provided by TCM pharmacies in Taiwan and to identify the pharmaceutical implications of these TCM formulations. MATERIALS AND METHODS: Through stratified sampling, we collected 98 formulations for postpartum lochia discharge from TCM pharmacies, which used a total of 60 medicinal materials. RESULTS: The most common plant families of the medicinal materials found in Taiwanese lochia discharge formulations were Fabaceae and Lauraceae. Abiding by the TCM theory of nature and flavor, most drugs were warm in nature and sweet in flavor, and predominantly focused on the traditional functions of qi tonifying and blood activating. Correlation and network analyses of the medicinal components of lochia discharge formulations identified 11 core herbs, which, in the order of most to least frequently used, include Angelica sinensis, Ligusticum striatum, Glycyrrhiza uralensis, Zingiber officinale, Prunus persica, Eucommia ulmoides, Leonurus japonicus, Lycium chinense, Hedysarum polybotrys, Rehmannia glutinosa, and Paeonia lactiflora. These 11 herbs formed a total of 136 drug combinations in the 98 formulations, with 2-7 herbs in each combination. In addition, in the center of the network were A. sinensis and L. striatum, which jointly appeared in 92.8% of the formulations analyzed. CONCLUSIONS: To our knowledge, this is the first study to systematically review lochia discharge formulations in Taiwan. The results of this study could provide an important basis for subsequent research in the clinical efficacy of Taiwanese lochia discharge formulations and the pharmacological mechanisms of their herbal components.

FOXD3 suppresses the Proliferation of CRC Bone Metastatic Cells via the Ras/Raf/MEK/ERK Signaling Pathway.

BACKGROUND: The improvements in the treatment of colorectal cancer (CRC) and prolongation of survival time have improved the incidence of bone metastasis. Forkhead box D3 (FOXD3) is involved in the development of CRC. However, the role and mechanism of FOXD3 in CRC bone metastases development are unknown. OBJECTIVE: Using the combined bioinformatics and cytology experimental analyses, this study aimed to explore the mechanistic role of FOXD3 in the bone metastasis of colon cancer, thereby aiding in the treatment of colon cancer bone metastasis and identification of drug-targeting markers. METHODS: First, the changes in the expression levels of the FOXD3 gene and differentially expressed genes (DEGs) between the colon cancer samples and colon cancer metastases were obtained from The Cancer Genome Atlas (TCGA) database. Then, the correlations of the FOXD3 gene with the DEGs were identified. Next, the effects of the FOXD3 on the proliferation and invasion abilities of colon cancer bone metastatic cells were identified using Cell Counting Kit-8 (CCK8) and Transwell cell migration assays, respectively. In addition, Western blot analysis was used to identify the expression levels of the proteins related to the EGFR/Ras/Raf/MEK/ERK(EGFR/ERK) signaling pathway and epithelial-to-mesenchymal transition (EMT). RESULTS: FOXD3 was downregulated in colon cancer and could interact with multiple DEGs in colon cancer bone metastases. FOXD3 gene knockdown could increase the proliferation of human colon cancer bone metastatic cells and their invasive ability. FOXD3 gene knockdown could activate the expression of EGFR/ERK signaling pathway-related proteins and inhibit/promote the expression of EMT-related proteins, which in turn promoted the proliferation and metastasis of LoVo cells from colon cancer bone metastases. CONCLUSION: Overall, this study demonstrated that the downregulation of the FOXD3 gene might promote the proliferation of colon cancer bone metastatic cell lines through the EGFR/ERK pathway and promote their migration through EMT, thereby serving as a promising therapeutic target.

Skin infectome of patients with a tick bite history.

Introduction: Ticks are the most important obligate blood-feeding vectors of human pathogens. With the advance of high-throughput sequencing, more and more bacterial community and virome in tick has been reported, which seems to pose a great threat to people. Methods: A total of 14 skin specimens collected from tick-bite patients with mild to severe symptoms were analyzed through meta-transcriptomic sequencings. Results: Four bacteria genera were both detected in the skins and ticks, including Pseudomonas, Acinetobacter, Corynebacterium and Propionibacterium, and three tick-associated viruses, Jingmen tick virus (JMTV), Bole tick virus 4 (BLTV4) and Deer tick mononegavirales-like virus (DTMV) were identified in the skin samples. Except of known pathogens such as pathogenic rickettsia, Coxiella burnetii and JMTV, we suggest Roseomonas cervicalis and BLTV4 as potential new agents amplified in the skins and then disseminated into the blood. As early as 1 day after a tick-bite, these pathogens can transmit to skins and at most four ones can co-infect in skins. Discussion: Advances in sequencing technologies have revealed that the diversity of tick microbiome and virome goes far beyond our previous understanding. This report not only identifies three new potential pathogens in humans but also shows that the skin barrier is vital in preventing horizontal transmissions of tick-associated bacteria or virus communities to the host. It is the first research on patients' skin infectome after a tick bite and demonstrates that more attention should be paid to the cutaneous response to prevent tick-borne illness.

[Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome].

OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION: The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.