Possible opportunities and challenges for traditional Chinese medicine research in 2035.

The drug development process is poised for significant transformation due to the rapid advancement of modern biological and information technologies, such as artificial intelligence (AI). As these new technologies and concepts infiltrate every stage of drug development, the efficiency and success rate of research and development are expected to improve substantially. Traditional Chinese medicine (TCM), a time-honored therapeutic system encompassing herbal medicine, acupuncture, and qigong, will also be profoundly impacted by these advancements. Over the next decade, Traditional Chinese medicine research will encounter both opportunities and challenges as it integrates with modern technologies and concepts. By 2035, TCM is anticipated to merge with modern medicine through a more contemporary and open research and development model, providing substantial support for treating a broader spectrum of diseases.

Lethal variant in the C2A domain may cause severe SYT1-associated neurodevelopmental disorder in the newborns.

Synaptotagmin-1 (SYT1) plays a pivotal role in regulating presynaptic processes, including neurotransmitter release. SYT1 variants perturb synaptic vesicle endocytosis and exocytosis, resulting in a series of neurodevelopmental disorders defined as Baker-Gordon syndrome. Herein, we report the case of a newborn with dysmorphic facial appearance, severe hypotonia, poor feeding, gastroesophageal reflux, and an inability to eat and breathe, diagnosed with Baker-Gordon syndrome. A retrospective search was performed on a newborn with Baker-Gordon syndrome. Medical charts were reviewed, with focus on the clinical presentation, diagnostic process, and treatment outcomes. Whole-genome high-throughput DNA sequencing was performed to identify genetic variants. Whole-exome sequencing identified the likely pathogenic variant as SYT1 C.551 T > C(p.V184A). Sanger sequencing results indicated that this variant was a de novo mutation in a conservative site located in the C2A domain of the protein. The patient died at 57 days old because of severe feeding and breathing problems. Our findings of a novel lethal variant in the C2A domain of SYT1 in the youngest patient diagnosed infantile Baker-Gordon syndrome who presented with the most severe hypotonia reported to date expands the spectrum of SYT1- associated neurodevelopmental disorders.

The role of TREM2 in Alzheimer's disease: from the perspective of Tau.

Triggering receptor expressed on myeloid cells 2 (TREM2), a pattern recognition receptor abundantly expressed on microglia, has been identified as one of the risk factors for Alzheimer's disease (AD). Several studies have already demonstrated the relationship between TREM2 and Tau. TREM2 mutations and altered expression play an important role in Tau phosphorylation. Furthermore, the level of Tau phosphorylation is correlated with soluble TREM2 (sTREM2). However, in different stages of AD, TREM2 seems to have varying effects on Tau pathology. The explicit interaction between TREM2 and Tau, as well as how they affect AD pathology, remains unclear, and there is much evidence to the contrary that requires rational interpretation. Reviewing the dual roles of TREM2 in AD will help identify a more appropriate development strategy for targeting TREM2 to treat AD. Therefore, this review focuses on the interplay between Tau and TREM2 in relation to AD.

Radiomics optimizing the evaluation of endometrial receptivity for women with unexplained recurrent pregnancy loss.

Background: The optimization of endometrial receptivity (ER) through individualized therapies has been shown to enhance the likelihood of successful gestation. However, current practice lacks comprehensive methods for evaluating the ER of patients with recurrent pregnancy loss (RPL). Radiomics, an emerging AI-based technique that enables the extraction of mineable information from medical images, holds potential to offer a more objective and quantitative approach to ER assessment. This innovative tool may facilitate a deeper understanding of the endometrial environment and enable clinicians to optimize ER evaluation in RPL patients. Objective: This study aimed to identify ultrasound radiomics features associated with ER, with the purpose of predicting successful ongoing pregnancies in RPL patients, and to assess the predictive accuracy of these features against regular ER parameters. Methods: This retrospective, controlled study involved 262 patients with unexplained RPL and 273 controls with a history of uncomplicated full-term pregnancies. Radiomics features were extracted from ultrasound endometrial segmentation images to derive a radiomics score (rad-score) for each participant. Associations between rad-scores, baseline clinical variables, and sonographic data were evaluated using univariate and multivariate logistic regression analyses to identify potential indicators of RPL. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive accuracy of the rad-score and other identified indicators in discriminating RPL cases. Furthermore, the relationships between age and these identified indicators were assessed via Pearson correlation analysis. Results: From the 1312 extracted radiomics features, five non-zero coefficient radiomics signatures were identified as significantly associated with RPL, forming the basis of the rad-score. Following multivariate logistic regression analysis, age, spiral artery pulsatility index (SA-PI), vascularisation index (VI), and rad-score emerged as independent correlates of RPL (all P<0.05). ROC curve analyses revealed the superior discriminative capability of the rad-score (AUC=0.882) over age (AUC=0.778), SA-PI (AUC=0.771), and VI (AUC=0.595). There were notable correlations between age and rad-score (r=0.275), VI (r=-0.224), and SA-PI (r=0.211), indicating age-related variations in RPL predictors. Conclusion: This study revealed a significant association between unexplained RPL and elevated endometrial rad-scores during the WOI. Furthermore, it demonstrated the potential of rad-scores as a promising predictive tool for successful ongoing pregnancies in RPL patients.

Combining hydrochemistry and 13C analysis to reveal the sources and contributions of dissolved inorganic carbon in the groundwater of coal mining areas, in East China.

East China is a highly aggregated coal-grain composite area where coal mining and agricultural production activities are both flourishing. At present, the geochemical characteristics of dissolved inorganic carbon (DIC) in groundwater in coal mining areas are still unclear. This study combined hydrochemical and carbon isotope methods to explore the sources and factors influencing DIC in the groundwater of different active areas in coal mining areas. Moreover, the 13C isotope method was used to calculate the contribution rates of various sources to DIC in groundwater. The results showed that the hydrochemical types of groundwater were HCO3-Ca·Na and HCO3-Na. The main water‒rock interactions were silicate and carbonate rock weathering. Agricultural areas were mainly affected by the participation of HNO3 produced by chemical fertilizer in the weathering of carbonate rocks. Soil CO2 and carbonate rock weathering were the major sources of DIC in the groundwater. Groundwater in residential areas was primarily affected by CO2 from the degradation of organic matter from anthropogenic inputs. Sulfate produced by gypsum dissolution, coal gangue accumulation leaching and mine drainage participated in carbonate weathering under acidic conditions, which was an important factor controlling the DIC and isotopic composition of groundwater in coal production areas. The contribution rates of groundwater carbonate weathering to groundwater DIC in agricultural areas and coal production areas ranged from 57.46 to 66.18% and from 54.29 to 62.16%, respectively. In residential areas, the contribution rates of soil CO2 to groundwater DIC ranged from 51.48 to 61.84%. The results will help clarify the sources and circulation of DIC in groundwater under the influence of anthropogenic activities and provide a theoretical reference for water resource management.

LncRNA TUG1 promotes pulmonary fibrosis progression via up-regulating CDC27 and activating PI3K/Akt/mTOR pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with an unclear pathogenesis. This study aimed to elucidate the function and potential mechanisms of TUG1 in IPF progression. Cell viability and migration were detected by CCK-8 and transwell assays. Autophagy, fibrosis, or EMT-related proteins were measured by Western blotting. Pro-inflammatory cytokine levels were assessed by ELISA kits. The subcellular localization of TUG1 was observed by FISH assay. RIP assay detected the interaction between TUG1 and CDC27. TUG1 and CDC27 was up-regulated in TGF-ß1-induced RLE-6TN cells. TUG1 depletion suppressed pulmonary fibrosis via attenuating inflammation, EMT, inducing autophagy and inactivating PI3K/Akt/mTOR pathway in vitro and in vivo. TUG1 knockdown prevented CDC27 expression. TUG1 silencing ameliorated pulmonary fibrosis by reducing CDC27 expression and inhibiting PI3K/Akt/mTOR pathway.

China's drug clinical trial institution record-keeping system: Qualification requirements for PI are the key.

It has been 3 years since China implemented new management regulations for drug clinical trial institutions in December 2019, the most important of which is to change the qualification recognition of drug clinical trial institutions into record-keeping system. The original intention of the institution record-keeping system was to solve the shortage of clinical trial resources in China, effectively expand the number of clinical trial institutions, and effectively alleviate the contradiction between medical treatment and scientific research. After implementing the record-keeping system, although these goals have been achieved to a certain extent, there are still areas worthy of optimization and improvement. Therefore, we evaluated the new process, in particular the requirements, in order to see what possible barriers in the record-keeping system of institutions. We find that the requirements for principal investigator (PI) qualifications are the key to the record-keeping system. This reflects the shift of Chinese regulators' supervision of clinical trials to supervision of the ability to conduct clinical trials. However, the ambiguity of the definition of PI qualification has hindered implementation of the record-keeping system and reduced the release of clinical trial resources.

Breast milk jaundice affects breastfeeding: From the perspective of intestinal flora and SCFAs-GPR41/43.

Breast milk jaundice (BMJ) is one of the main factors leading to interruption or early termination of breastfeeding. Interrupting breastfeeding to treat BMJ may increase the adverse consequences for infant growth and disease prevention. The Intestinal flora and metabolites are increasingly recognized as a potential therapeutic target in BMJ. First, dysbacteriosis can lead to a decrease in the metabolite short-chain fatty acids. At the same time, SCFA can act on specific G protein-coupled receptors 41 and 43 (GPR41/43), and a decrease in SCFA downregulates the GPR41/43 pathway, leading to a diminished inhibition of intestinal inflammation. In addition, intestinal inflammation leads to a decrease in intestinal motility and a large amount of bilirubin enters the enterohepatic circulation. Ultimately, these changes will result in the development of BMJ. In this review, we will describe the underlying pathogenetic mechanism of the intestinal flora effects on BMJ.

Endoscope ear pick: An emerging but neglected medical device.

Earwax (cerumen), a normal bodily secretion, can become a problem when it obstructs the ear canal. Earwax removal is a difficult task for specialists because of the ear's unique location and the ear canal's intricate structure. Using ear scoops or cotton swabs to dig out ear wax in daily life is like "a blind man walking on a cliff." Improper operation may damage the ear canal or the eardrum. Thus, we need a pair of visible "eyes," otoscopes, to help us see earwax intuitively. As opposed to traditional otoscopes, which only serve as a visual aid, the endoscopic ear pick allows us to not only view the ear canal but also remove wax or other obstructions from the ear. In this review, we discussed endoscope ear pick pros and cons and discussed their future role.

Metagenomic Next-Generation Sequencing for the Diagnosis of Neonatal Infectious Diseases.

Infectious diseases pose a fatal risk to neonates. Timely and accurate pathogen detection is crucial for proper clinical diagnosis and therapeutic strategies. Limited sample volumes from neonatal patients seriously hindered the accurate detection of pathogens. Here, we unravel that metagenomic next-generation sequencing (mNGS) of cell-free DNA (cfDNA) and RNA can achieve unbiased detection of trace pathogens from different kinds of body fluid samples and blood samples. We enrolled 168 neonatal patients with suspected infections from whom blood samples (n = 153), cerebrospinal fluid samples (n = 127), and respiratory tract samples (RTSs) (including bronchoalveolar lavage fluids, sputa, and respiratory secretions) (n = 51) were collected and analyzed using mNGS. High rates of positivity (70.2%; 118/168) of mNGS were observed, and the coincidence rate against the final clinical diagnosis in positive mNGS cases reached 68.6% (81/118). The most common causative pathogens were Klebsiella pneumoniae (n = 12), Escherichia coli (n = 12), and Streptococcus pneumoniae (n = 8). mNGS using cfDNA and RNA can identify microbes that cannot be detected by conventional methods in different body fluid and blood samples, and more than 50% of these microbes were identified as causative pathogens. Further local polynomial regression fitting analysis revealed that the best timing for mNGS detection ranged from 1 to 3 days after the start of continuous antimicrobial therapy. Diagnosed and guided by mNGS results, the therapeutic regimens for 86 out of 117 neonatal patients were changed, most of whom (80/86) completely recovered and were discharged, while 44 out of 86 patients completely or partially stopped unnecessary medication. Our findings highlight the importance of mNGS in detecting causative DNA and RNA pathogens in infected neonatal patients. IMPORTANCE To the best of our knowledge, this is the first report on evaluating the performance of mNGS using cfDNA and RNA from body fluid and blood samples for diagnosing neonatal infections. mNGS of RNA and cfDNA can achieve the unbiased detection and identification of trace pathogens from different kinds of neonatal body fluid and blood samples with a high total coincidence rate (226/331; 68.3%) against final clinical diagnoses by sample. The best timing for mNGS detection in neonatal infections ranged from 1 to 3 days, rather than 0 days, after the start of continuous antimicrobial therapy. Our findings highlight the importance of mNGS in detecting causative DNA and RNA pathogens, and the extensive application of mNGS for the diagnosis of neonatal infections can be expected.

Analysis of Convolutional Neural Network Segmentation Algorithm of Adenomyoma.

Adenomoma is a common disease occurring in the female uterus. The symptoms and pain of adenomoma seriously troubled the physical and mental health of contemporary women. However, because of the significant advantages of nondestructive and low price, ultrasound examination is used as the main imaging method for clinical diagnosis of gynecological diseases at the present stage and is often used in the initial screening and postoperative diagnosis and treatment of uterine diseases. Imaging provides a very rich information in the medical diagnosis of tumor and is a very important basis for the disease diagnosis and treatment at this stage. Ultrasound images are different from medical images such as X-ray and MRI. Because of the characteristics of imaging principles and noise interference, ultrasound images need to rely on rich clinical experience of doctors in the process of disease diseases, which increases the difficulty and work burden of doctors to some extent. Therefore, the project aims to study the deep learning segmentation method suitable for ultrasonic images. Combined with the Deeplab network in the convolutional neural network, comparing the results of the FCN network, and then finding that the Deeplab network has obvious advantages as an image segmentation model of uterine adenomyoma. In clinical practice, it can reduce the work burden of doctors and try in the direction of uterine adenomyomas ultrasound image segmentation, to fill the gap in this field.

Programmable RNA base editing with a single gRNA-free enzyme.

Programmable RNA editing enables rewriting gene expression without changing genome sequences. Current tools for specific RNA editing dependent on the assembly of guide RNA into an RNA/protein complex, causing delivery barrier and low editing efficiency. We report a new gRNA-free system, RNA editing with individual RNA-binding enzyme (REWIRE), to perform precise base editing with a single engineered protein. This artificial enzyme contains a human-originated programmable PUF domain to specifically recognize RNAs and different deaminase domains to achieve efficient A-to-I or C-to-U editing, which achieved 60-80% editing rate in human cells, with a few non-specific editing sites in the targeted region and a low level off-target effect globally. The RNA-binding domain in REWIREs was further optimized to improve editing efficiency and minimize off-target effects. We applied the REWIREs to correct disease-associated mutations and achieve both types of base editing in mice. As a single-component system originated from human proteins, REWIRE presents a precise and efficient RNA editing platform with broad applicability.

Analysis of Mechanism of Action of Cuprous Oxide Nanoparticles in Treatment of Cervical Cancer under Real-time Ultrasound Elastography.

It aimed to explore the adoption value of cuprous oxide nanoparticles (Cu2O NPs) in the clinical treatment of cervical cancer under the evaluation of real-time ultrasound elastography. In this experiment, the solution of Cu2O NPs was synthesized and used in 90 selected mouse models of cervical cancer. It was found that Cu2O NPs can significantly control the reproduction of various types of cervical cancer cells, effectively stopping the cycle of cervical cancer cell lines in the G1/G0 phase. In addition, the tumor weight of 0.25g in the Cu2O NPs group was notably lighter than that of 1.1g in the control group. The weight change of the mouse was 21g compared with 15g of the cis-dichlorodiamine platinum (CDDP) group, and it was proved that Cu2O NPs were less cytotoxic to the body and have few side effects. Moreover, real-time ultrasound elastography showed that there were 26 cases with a tumor elasticity score no less than 2 in the Cu2O NPs group, accounting for 87%, which was better than that of the CDDP group (17 cases, 57%), and the difference was substantial (P<0.05). The shear wave velocity of Cu2O NPs (1.46±0.48 m/s) was also lower than that (1.73±0.62 m/s) of the CDDP group, which suggested that the tumor body hardness of mice in the Cu2O NPs group was lower, and the difference was considerable (P<0.05). In short, Cu2O NPs had good functions such as inhibiting the proliferation and spread of tumor cells and blocking the cell cycle. Moreover, the toxic and side effects of the drug were slight, and it was an ideal new type of treatment for cervical cancer.

A COVID-19 CXR image recognition method based on MSA-DDCovidNet.

Currently, coronavirus disease 2019 (COVID-19) has not been contained. It is a safe and effective way to detect infected persons in chest X-ray (CXR) images based on deep learning methods. To solve the above problem, the dual-path multi-scale fusion (DMFF) module and dense dilated depth-wise separable (D3S) module are used to extract shallow and deep features, respectively. Based on these two modules and multi-scale spatial attention (MSA) mechanism, a lightweight convolutional neural network model, MSA-DDCovidNet, is designed. Experimental results show that the accuracy of the MSA-DDCovidNet model on COVID-19 CXR images is as high as 97.962%, In addition, the proposed MSA-DDCovidNet has less computation complexity and fewer parameter numbers. Compared with other methods, MSA-DDCovidNet can help diagnose COVID-19 more quickly and accurately.

Development of a Nomogram for Predicting Intravasation Before Transvaginal 4-Dimensional Hysterosalpingo-Contrast Sonography.

Background: Intravasation during transvaginal 4-dimensional hysterosalpingo-contrast sonography (TVS 4D-HyCoSy) may lead to false-negative results in tubal patency evaluation. Although the influencing factors associated with intravasation have been investigated, some factors are only identified during 4D-HyCoSy, thus currently no studies on preventing intravasation. However, several preprocedural features can be collected in advance, which may be valuable in predicting intravasation. Objective: The purpose of this study is to establish a nomogram incorporating the preprocedural features to predict the risk of intravasation before TVS 4D-HyCoSy. Methods: The data of 276 infertile women with patent fallopian tubes were analyzed retrospectively. They were assigned to the study group (n = 62) and the control group (n = 214) according to the development of intravasation. The preprocedural characteristics were collected to investigate the predictors independently associated with intravasation, which were then served as the construction of a nomogram. The performance of the nomogram was verified internally. Results: History of uterine curettage (OR = 2.341, P = 0.009), endometrial thickness (OR = 0.587, P < 0.001), and examination schedule (OR = 0.790, P = 0.024) were found to be the independent influencing factors associated with intravasation. The established nomogram incorporating these preprocedural features was useful for predicting the risk of intravasation prior to 4D-HyCoSy. It yielded net benefits when the predicted probability was less than 50%. Conclusion: The nomogram incorporating the preprocedural characteristics achieved a net benefit for clinical decision-making when the estimated risk was less than 50%. It is recommended to change the examination schedule for patients with an estimated risk greater than 50% and perform 4D-HyCoSy when the risk is less than 50%.

TGF-ß1/SMADs signaling involved in alleviating inflammation induced by nanoparticulate titanium dioxide in BV2 cells.

There are increasing safety concerns accompanying the widespread use of nanoparticulate titanium dioxide (nano-TiO2). It has been demonstrated that nano-TiO2 can cross the blood-brain barrier and enter the brain, causing damage to the nervous system, consisting mainly of neuroinflammation and neuronal apoptosis. Several studies have linked the TGF-ß1/SMADs signaling to the development of inflammatory response in various organs. However, no studies have connected the induction of microglial inflammation by nano-TiO2 to this signaling. Therefore, this study aimed to investigate the role of TGF-ß1/SMADs signaling in microglia inflammatory response induced by nano-TiO2. The results showed that nano-TiO2 increased the secretions of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α) and decreased the expressions of TGF-ß1 and SMAD1/2/3 proteins in BV2 cells. When TGF-ß1/SMADs signaling was inhibited, the inflammatory effect induced by nano-TiO2 increased, suggesting a suppressive effect of this signaling on the inflammation. In addition, exogenous TGF-ß1 upregulated the expressions of TGF-ß1 and SMADs1/2/3 proteins as well as decreased the secretions of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α) compared to BV2 cells treated with only nano-TiO2. Our results suggest that nano-TiO2 may inhibit the TGF-ß1/SMADs signaling by suppressing the intracellular secretion of active TGF-ß1, leading to microglial activation and the induction or exacerbation of inflammatory responses.

Correction: A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

Correction for 'A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy' by Yujie Zhang et al., Biomater. Sci., 2021, 9, 1232-1236, DOI: 10.1039/D0BM02099K.

Genome-wide analysis of growth-regulating factors (GRFs) in Triticum aestivum.

The Growth-Regulating Factor (GRF) family encodes a type of plant-specific transcription factor (TF). GRF members play vital roles in plant development and stress response. Although GRF family genes have been investigated in a variety of plants, they remain largely unstudied in bread wheat (Triticum aestivum L.). The present study was conducted to comprehensively identify and characterize the T. aestivum GRF (TaGRF) gene family members. We identified 30 TaGRF genes, which were divided into four groups based on phylogenetic relationship. TaGRF members within the same subgroup shared similar motif composition and gene structure. Synteny analysis suggested that duplication was the dominant reason for family member expansion. Expression pattern profiling showed that most TaGRF genes were highly expressed in growing tissues, including shoot tip meristems, stigmas and ovaries, suggesting their key roles in wheat growth and development. Further qRT-PCR analysis revealed that all 14 tested TaGRFs were significantly differentially expressed in responding to drought or salt stresses, implying their additional involvement in stress tolerance of wheat. Our research lays a foundation for functional determination of TaGRFs, and will help to promote further scrutiny of their regulatory network in wheat development and stress response.

A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

A mitochondria-targeted dual-functional aggregation-induced emission luminogen, TPP-TPEDCH, was rationally designed and developed for intracellular mitochondrial imaging and photodynamic therapy. TPP-TPEDCH clearly showed the movements of mitochondria at various time points. Moreover, both in vitro and in vivo results demonstrated its excellent ROS generation ability and strong antitumor activity.

TransCirc: an interactive database for translatable circular RNAs based on multi-omics evidence.

TransCirc (https://www.biosino.org/transcirc/) is a specialized database that provide comprehensive evidences supporting the translation potential of circular RNAs (circRNAs). This database was generated by integrating various direct and indirect evidences to predict coding potential of each human circRNA and the putative translation products. Seven types of evidences for circRNA translation were included: (i) ribosome/polysome binding evidences supporting the occupancy of ribosomes onto circRNAs; (ii) experimentally mapped translation initiation sites on circRNAs; (iii) internal ribosome entry site on circRNAs; (iv) published N-6-methyladenosine modification data in circRNA that promote translation initiation; (v) lengths of the circRNA specific open reading frames; (vi) sequence composition scores from a machine learning prediction of all potential open reading frames; (vii) mass spectrometry data that directly support the circRNA encoded peptides across back-splice junctions. TransCirc provides a user-friendly searching/browsing interface and independent lines of evidences to predicte how likely a circRNA can be translated. In addition, several flexible tools have been developed to aid retrieval and analysis of the data. TransCirc can serve as an important resource for investigating the translation capacity of circRNAs and the potential circRNA-encoded peptides, and can be expanded to include new evidences or additional species in the future.