Characteristics and whole-genome analysis of a novel Pseudomonas syringae pv. tomato bacteriophage D6 isolated from a karst cave.

Pseudomonas syringae is a gram-negative plant pathogen that infects plants such as tomato and poses a threat to global crop production. In this study, a novel lytic phage infecting P. syringae pv. tomato DC3000, named phage D6, was isolated and characterized from sediments in a karst cave. The latent period of phage D6 was found to be 60 min, with a burst size of 16 plaque-forming units per cell. Phage D6 was stable at temperatures between 4 and 40 °C but lost infectivity when heated to 70 °C. Its infectivity was unaffected at pH 6-10 but became inactivated at pH ≤ 5 or ≥ 12. The genome of phage D6 is a linear double-stranded DNA of 307,402 bp with a G + C content of 48.43%. There is a codon preference between phage D6 and its host, and the translation of phage D6 gene may not be entirely dependent on the tRNA library provided by the host. A total of 410 open reading frames (ORFs) and 14 tRNAs were predicted in its genome, with 92 ORFs encoding proteins with predicted functions. Phage D6 showed low genomic similarity to known phage genomes in the GenBank and Viral sequence databases. Genomic and phylogenetic analyses revealed that phage D6 is a novel phage. The tomato plants were first injected with phage D6, and subsequently with Pst DC3000, using the foliar spraying and root drenching inoculum approach. Results obtained after 14 days indicated that phage D6 inoculation decreased P. syringae-induced symptoms in tomato leaves and inhibited the pathogen's growth in the leaves. The amount of Pst DC3000 was reduced by 150- and 263-fold, respectively. In conclusion, the lytic phage D6 identified in this study belongs to a novel phage within the Caudoviricetes class and has potential for use in biological control of plant diseases.

First Report of Powdery Mildew on Viburnum chinshanense Caused by Erysiphe pseudoviburni in China.

Viburnum chinshanense, a deciduous shrub in the family Caprifoliaceae, is a dominant tree distributed mainly in the North-Central and South-Central regions of China (Zhu et al. 2023). Because of its lush white flowers and vibrant red fruits, V. chinshanense is used widely as ornamental tree in China. In May 2022, severe powdery mildew symptoms were observed on V. chinshanense on the Huaxi Campus of Guizhou Normal University, Guiyang, China. The incidence was approximately 75% among 80 V. chinshanense plants observed. White mycelia were present on both adaxial and abaxial leaf sides, but not on fruits, petioles, or stems. Infected leaves showed slight chlorosis and twisting. The mycelia were amphigenous, forming small-to-large patches, often sparse on the upper leaf surface, but mostly confluent on the lower leaf surface. Hyphae were hyaline, 4-7 µm wide. Hyphal appressoria were lobed to multilobed, in opposite pairs or solitary. Conidiophores were erect, straight, or somewhat flexuous, 60-130 µm long (n = 30). Foot cells were subcylindrical to slightly curved-sinuous at the base, 20-40 × 6-10 µm (n = 30) in size, followed by 1-3 shorter cells. Conidia formed singly, occasionally two to three in a chain. Conidia were ellipsoid to ovoid, cylindrical, and 24-40 × 16-20 µm (n = 50). No fibrosin bodies were observed on the conidia. Chasmothecia were subglobose, 56-115 µm in diameter. The appendages were 35-70 µm long. Based on these morphological characteristics, the powdery mildew fungus was identified as Erysiphe pseudoviburni (Bradshaw et al. 2020). To confirm the identification, the ribosomal DNA internal transcribed spacer (ITS) and the ribosomal large subunit (LSU) region were amplified and sequenced using the ITS1/ITS4 primer pair (White et al. 1990) and the NL1/NL4 primer pair (Ziemiecki et al. 1990), respectively. The obtained 643-bp ITS sequence (GenBank accession no. ON729292) had 99.84% identity with E. pseudoviburni strains KUS-F27310 (MN431595) and MUMH0001 (LC009904). The obtained 593-bp LSU sequence (ON729293) had 99.83% identity with E. pseudoviburni (LC009904 and MN431595). Based on the phylogenetic analysis of the combined ITS and LSU dataset (Bradshaw et al. 2020), the isolate (GZVD-1) was grouped in a clade with the E. pseudoviburni strains KUS-F27319, KUS-F27310, and MUMH0001. To fulfill Koch's postulates, leaves of three healthy potted V. chinshanense plants were inoculated by gently pressing with diseased leaves. Non-contact plants were used as controls. All plants were incubated in a greenhouse at 25 ± 2°C, 80% relative humidity. Similar powdery mildew symptoms were observed on the inoculated plants 12 days after inoculation, whereas the control plants remained symptomless. The reisolated fungus from the inoculated plants was morphologically identical to that on originally diseased plants. ITS and LSU sequences of the reisolated fungus showed 100% identity with ON729292 and ON729293, respectively. E. pseudoviburni has previously been reported to infect some Viburnum species, including V. sieboldii in Japan (Takamatsu et al. 2015) and V. odoratissimum in South Korea (Bradshaw et al. 2020). To the best of our knowledge, this is the first report of powdery mildew caused by E. pseudoviburni on V. chinshanense in China. This work expands the known host range of E. pseudoviburni in the Viburnum genus.

First Report of Powdery Mildew on Berchemia floribunda Caused by Erysiphe berchemiae in China.

The genus Berchemia (family Rhamnaceae), a group of climbing plants, is mainly distributed in Asia, Africa, and South America. Berchemia plants are widely used in traditional medicine in some Asian countries (Inoshiri et al. 1987). For example, in Japan, B. racemosa (synonym B. floribunda) is used for the treatment of gallstones, liver diseases, neuralgia, and stomach cramps, and in China, B. floribunda is used for the treatment of rheumatism and lumbago. In August 2022, typical powdery mildew symptoms were observed on wild B. floribunda plants in Huaxi District, Guiyang, Guizhou Province, China. The incidence was approximately 60% among 100 B. floribunda plants observed outdoors. White colonies almost entirely covered on both adaxial and abaxial surfaces of all leaves on symptomatic plants. Infected leaves appeared curled or chlorotic, infection occasionally leading to defoliation. To describe the pathogen morphologically, fungal samples were collected from two individual B. floribunda plants and microscopically characterized. In these samples, hyphae were flexuous to straight, branched, septate, 3-6 µm wide, with lobed hyphal appressoria. Conidiophores were erect, flexuous to straight, and 50-160 µm long (n = 30). Foot cells were subcylindrical to slightly curved-sinuous at the base, 20-40 µm long (n = 30), followed by 2-3 shorter cells. Conidia formed singly, occasionally 2-3 in a chain. Conidia were ellipsoid to ovoid, 20-42 × 12-18 µm (n = 50), without fibrosin bodies. Chasmothecia were not found. For molecular identification, the ribosomal DNA internal transcribed spacers (ITSs) of the two fungal samples were amplified and sequenced using the ITS1/ITS4 primer pair (White et al. 1990). The obtained 649-bp ITS sequences (GenBank accession nos. OR414364 and OR414365, respectively) shared 100% identity, and they showed 99.52% identity with the ITS sequence (GenBank accession no. LC009934) of Erysiphe berchemiae. Phylogenetic analysis grouped OR414364 and OR414365 in a clade with LC009934. Based on morphological and molecular characteristics, the powdery mildew fungus from B. floribunda was identified as E. berchemiae (Braun and Cook 2012). The voucher specimen (accession no. GZNU-BFEE/0820/2022) were deposited at the School of Life Sciences, Guizhou Normal University. Pathogenicity was assessed by gently pressing naturally diseased leaves of B. floribunda onto leaves of three healthy potted 1-year-old B. floribunda plants. Three non-inoculated healthy plants were used as controls. The plants were incubated in a greenhouse at 25 ± 2°C, 80% relative humidity. Similar powdery mildew symptoms were observed on the inoculated plants 9 days after inoculation, whereas the control plants remained symptomless. The reisolated fungus from inoculated leaves was morphologically identical to that observed on the original diseased leaves, and the ITS sequence of the reisolated fungus shared 100% identity with OR414364 and OR414365, fulfilling Koch's postulates. E. berchemiae has previously been described as a powdery mildew pathogen on B. yunnanensis (Chen et al. 1987) and B. kulingensis (Chen 1993) in China and B. racemosa (synonym B. floribunda) in Japan (Braun and Cook 2012; Takamatsu et al. 2015), but this is the first report of E. berchemiae causing disease of B. floribunda in China. This work suggests that E. berchemiae is an important pathogen of Berchemia plants, at least for some species in the genus Berchemia.

First Report of Rust Disease on Alcea rosea caused by Puccinia modiolae in China.

Alcea rosea, belonging to the Alcea genus in the Malvaceae family, originated from China, but it is now grown worldwide. A. rosea has been widely used in traditional Chinese medicine to alleviate constipation, pain, swelling, and sores. In February 2023, typical symptoms of fungal infection were observed on A. rosea at Guizhou Normal University in Guiyang, Guizhou Province, China. The disease incidence was over 90% (n = 100) for the surveyed A. rosea plants, and the disease severity range from 30% to 90%. The initial symptoms of A. rosea rust were the appearance of chlorotic spots on the leaves. Subsequently, numerous reddish to dark-brown erumpent pustules (telia) were observed. Gradually, the entire plant was covered by rust and the center of each lesion turned brown, necrotic, and ruptured over times, eventually causing defoliation. Voucher specimens of infected A. rosea leaves as representative samples have been deposited at Guizhou Normal University (GNU2023LS008). Telia are round in shape, mostly aggregated in mass, with a diameter of 0.28-0.78 mm (0.46 mm, n = 20). They range in color from reddish-brown to dark brown, and are mainly hypophyllous but occasionally formed on the adaxial leaf surface. The teliospores are fusoid with dimensions of 31.3-93.8 × 10.9-21.3 µm (57.5 × 15.1 µm average, n = 50), hyaline or yellowish to light-brown in color, mostly two-celled, with a smooth wall (1.5-3.0 µm) and a thickened apex (3.0-9.0 µm). However, teliospores which are one-, three-, or four-celled with a notch at the apex, are rarely observed. The morphological characteristics of host symptoms and teliospores were similar to those of Puccinia modiolae (Aime and Abbasi 2018; Albu et al. 2019). For phylogenetic analysis, genomic DNA was extracted from the teliospores of infected leaves. To confirm the species-level identification, PCR was performed on the extracted DNA to amplify the ribosomal DNA internal transcribed spacer (ITS) and large subunit (LSU) regions using primer pairs ITS1/ITS4 (Schoch et al. 2012) and NL1/NL4 (Ziemiecki et al. 1990), respectively. The resulting ITS DNA sequence (GenBank accession no. OR607960) showed 100% identity with P. modiolae sequences (OP369291.1), when the query coverage was 100%. The LSU DNA sequence obtained (OR607961.2) shared 99.85% similarity with P. modiolae (MK458702.1). A phylogenetic tree was constructed using MEGA7.0 and the maximum likelihood method based on the ITS and LSU sequences. The fungal isolates collected in this study and several reference sequences of P. modiolae were grouped within a clade that included the isolates reported on A. rosea in Korea (Ryu et al. 2023), with 100% bootstrap support. Pathogenicity testing was conducted by gently pressing spore powder of naturally diseased leaves onto young leaves of three healthy A. rosea plants, with three noninoculated healthy plants serving as controls. The inoculated and noninoculated plants were kept in a growth chamber at the 26°C with a 12 hour light/dark cycle and 80% humidity. After 2 weeks, all inoculated A. rosea plants showed characteristic disease symptoms of rust infection and telia of P. modiolae, while control plants remained symptomless. The pathogen was identical to that observed on the original diseased leaves. The study results indicate that the causal fungus responsible for the disease is P. modiolae, which has been previously reported on Malvaceae plants (Farr and Rossman 2022). To the best of our knowledge, this is the first report of P. modiolae on A. rosea in China. This study will contribute to an increased understanding of the host range of Puccinia modiolae.

Cucurbitacin B suppresses hepatocellular carcinoma progression through inducing DNA damage-dependent cell cycle arrest.

BACKGROUND: The mortality rate of liver cancer ranks third in the world, and hepatocellular carcinoma (HCC) is a malignant tumor of the digestive tract. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae spp., is the main active component of Chinese patent medicine the Cucurbitacin Tablet, which has been widely used in the treatment of various malignant tumors in clinics, especially HCC. PURPOSE: This study explored the role and mechanism of CuB in the suppression of liver cancer progression. METHODS: Cell Counting Kit-8 (CCK-8) and colony formation assays were used to detect the inhibitory function of CuB in Huh7, Hep3B, and Hepa1/6 hepatoma cells. Calcein-AM/propidium iodide (PI) staining and lactate dehydrogenase (LDH) measurement assays were performed to determine cell death. Mitochondrial membrane potential (Δψm) was measured, and flow cytometry was performed to evaluate cell apoptosis and cell cycle. Several techniques, such as proteomics, Western blotting (WB), and ribonucleic acid (RNA) interference, were utilized to explore the potential mechanism. The animal experiment was performed to verify the results of in vitro experiments. RESULTS: CuB significantly inhibited the growth of Huh7, Hep3B, and Hepa1/6 cells and triggered the cell cycle arrest in G2/M phage without leading to cell death, especially apoptosis. Knockdown of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a target of CuB, did not reverse CuB elicited cell cycle arrest. CuB enhanced phosphorylated ataxia telangiectasia mutated (p-ATM) and phosphorylated H2A histone family member X (γ-H2AX) levels. Moreover, CuB increased p53 and p21 levels and decreased cyclin-dependent kinase 1 (CDK1) expression, accompanied by improving phosphorylated checkpoint kinase 1 (p-CHK1) level and suppressing cell division cycle 25C (CDC25C) protein level. Interestingly, these phenomena were partly abolished by a deoxyribonucleic acid (DNA) protector methylproamine (MPA). Animal studies showed that CuB also significantly suppressed tumor growth in BALB/c mice bearing Hepa1/6 cells. In tumor tissues, CuB reduced the expression levels of proliferating cell nuclear antigen (PCNA) and γ-H2AX but did not change the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) level. CONCLUSION: This study demonstrated for the first time that CuB could effectively impede HCC progression by inducing DNA damage-dependent cell cycle arrest without directly triggering cell death, such as necrosis and apoptosis. The effect was achieved through ataxia telangiectasia mutated (ATM)-dependent p53-p21-CDK1 and checkpoint kinase 1 (CHK1)-CDC25C signaling pathways. These findings indicate that CuB may be used as an anti-HCC drug, when the current findings are confirmed by independent studies and after many more clinical phase 1, 2, 3, and 4 testings have been done.

Development of Chinese herbal medicine for sensorineural hearing loss.

According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to a severe impact on individual life quality and national economies. Sensorineural hearing loss (SNHL) occurs commonly as a result of noise exposure, aging, and ototoxic drugs, and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear, which is mainly triggered by reactive oxygen species accumulation, inflammation, and mitochondrial dysfunction. Though recent advances have been made in understanding the ability of cochlear repair and regeneration, there are still no effective therapeutic drugs for SNHL. Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine. Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL, and elucidate their molecular mechanisms of action, to pave the way for further research and development of novel effective drugs in this field.

Compound-composed Chinese medicine of Huachansu triggers apoptosis of gastric cancer cells through increase of reactive oxygen species levels and suppression of proteasome activities.

BACKGROUND: Huachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula. PURPOSE: To discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells. METHOD: Network pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot. RESULTS: CCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways. CONCLUSION: CCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.

Research progress on invasive cervical resorption / 口腔疾病防治

@#Tooth absorption can be divided into physiological absorption and pathological absorption. Root absorption of mature deciduous teeth is physiological absorption. Pathological absorption includes internal absorption and external absorption. Internal absorption, also known as intramedullary absorption, includes inflammatory absorption and alternative absorption. External tooth absorption originates from the outer surface of the root or the neck of the tooth and can be divided into inflammatory absorption, alternative absorption, pressure resorption and invasive cervical resorption. Invasive cervical resorption (ICR) is pathological damage caused by many factors, which usually begins in the cemento-enamel junction and extends peripherally or horizontally in the dentin. It hardly invades the pulp. Orthodontic devices, trauma, bleaching, systemic diseases, and the use of certain medications can all lead to invasive cervical resorption. The clinical manifestations of ICR are usually asymptomatic or not obvious, and most of which are found in imaging examinations. Because caries and internal absorption are often misdiagnosed through plain apical radiography, cone beam computed tomography (CBCT) can help to better understand the situation of invasive cervical resorption. Because the pathogenesis and etiology of invasive cervical resorption are not fully understood, clinical negligence and inadequate treatment of invasive cervical resorption can even cause unnecessary tooth loss. This article reviews the latest research progress on the histopathologic features, pathogenic mechanism, susceptibility factors, diagnosis and treatment of ICR, with special emphasis on susceptibility factors and their mechanisms.

Cancer stem cells and their niche in cancer progression and therapy.

High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.

Light therapy for sleep disturbance comorbid depression in relation to neural circuits and interactive hormones-A systematic review.

AIM: To provide an overview of the evidence on the effect of light therapy on sleep disturbance and depression, identify the light-active neural and hormonal correlates of the effect of light therapy on sleep disturbance comorbid depression (SDCD), and construct the mechanism by which light therapy alleviates SDCD. METHODS: Articles published between 1981 and 2021 in English were accessed using Science Direct, Elsevier, and Google Scholar following a three-step searching process via evolved keywords. The evidence level, reliability, and credibility of the literature were evaluated using the evidence pyramid method, which considers the article type, impact factor, and journal citation report (JCR) partition. RESULTS: A total of 372 articles were collected, of which 129 articles fit the inclusion criteria and 44% were at the top of the evidence pyramid hierarchy; 50% were in the first quarter of the JCR partitions. 114 articles provided specific neural and hormonal evidence of light therapy and were further divided into three groups: 37% were related to circadian regulation circuits, 27% were related to emotional regulation circuits, and 36% were related to hormones. CONCLUSIONS: First, neural and hormonal light-active pathways for alleviating sleep disturbance or depression were identified, based on which the neural correlates of SDCD were located. Second, the light responses and interactions of hormones were reviewed and summarized, which also provided a way to alleviate SDCD. Finally, the light-active LHb and SCN exert extensive regulation impacts on the circadian and emotional circuits and hormones, forming a dual-core system for alleviating SDCD.

CXCL6: A potential therapeutic target for inflammation and cancer.

Chemokines were originally defined as cytokines that affect the movement of immune cells. In recent years, due to the increasing importance of immune cells in the tumor microenvironment (TME), the role of chemokines has changed from a single "chemotactic agent" to a key factor that can regulate TME and affect the tumor phenotype. CXCL6, also known as granulocyte chemoattractant protein-2 (GCP-2), can recruit neutrophils to complete non-specific immunity in the process of inflammation. Cancer-related genes and interleukin family can promote the abnormal secretion of CXCL6, which promotes tumor growth, metastasis, epithelial mesenchymal transformation (EMT) and angiogenesis in the TME. CXCL6 also has a role in promoting fibrosis and tissue damage repair. In this review, we focus on the regulatory network affecting CXCL6 expression, its role in the progress of inflammation and how it affects tumorigenesis and progression based on the TME, in an attempt to provide a potential target for the treatment of diseases such as inflammation and cancer.

Immuno-genomic-radiomics to predict response of biliary tract cancer to camrelizumab plus GEMOX in a single-arm phase II trial.

Background & Aims: Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Methods: Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. Results: CT radiomics correlated with CD8+ T cells (r = -0.72-0.71, p = 0.004-0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = -0.58-0.57, p = 0.020-0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09-3.81; p = 0.011-0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p <0.001], ARID1A (HR = 3.31, p = 0.013), and blood TMB (HR = 1.13, p = 0.023) were independent predictors of PFS. Radiomics signature (HR = 6.58, p <0.001) and CD8+ T cells (HR = 0.22, p = 0.004) were independent predictors of OS. Prognostic models integrating these features achieved concordance indexes of 0.677 and 0.681 for PFS and OS, respectively. Conclusions: Radiomics could act as a non-invasive immuno-genomic surrogate of BTC, which could further aid in response prediction for patients with BTC treated with immunotherapy. However, multicenter and larger sample studies are required to validate these results. Impact and implications: Immunotherapy is an alternative for the treatment of advanced BTC, whereas tumour response is heterogeneous. In a post hoc analysis of the single-arm phase II clinical trial (NCT03486678), we found that CT radiomics features were associated with the tumour microenvironment and that IGR expression was a promising marker for tumour response and long-term survival. Clinical trial number: Post hoc analysis of NCT03486678.

Multimodality neuroimaging in vascular mild cognitive impairment: A narrative review of current evidence.

The vascular mild cognitive impairment (VaMCI) is generally accepted as the premonition stage of vascular dementia (VaD). However, most studies are focused mainly on VaD as a diagnosis in patients, thus neglecting the VaMCI stage. VaMCI stage, though, is easily diagnosed by vascular injuries and represents a high-risk period for the future decline of patients' cognitive functions. The existing studies in China and abroad have found that magnetic resonance imaging technology can provide imaging markers related to the occurrence and development of VaMCI, which is an important tool for detecting the changes in microstructure and function of VaMCI patients. Nevertheless, most of the existing studies evaluate the information of a single modal image. Due to the different imaging principles, the data provided by a single modal image are limited. In contrast, multi-modal magnetic resonance imaging research can provide multiple comprehensive data such as tissue anatomy and function. Here, a narrative review of published articles on multimodality neuroimaging in VaMCI diagnosis was conducted，and the utilization of certain neuroimaging bio-markers in clinical applications was narrated. These markers include evaluation of vascular dysfunction before tissue damages and quantification of the extent of network connectivity disruption. We further provide recommendations for early detection, progress, prompt treatment response of VaMCI, as well as optimization of the personalized treatment plan.

Strategies to inTerrupt RAbies Transmission for the Elimination Goal by 2030 In China (STRATEGIC): a modelling study.

BACKGROUND: A global plan has been set to end human deaths from dog-mediated rabies by 2030 ("Zero-by-30"), but whether it could be achieved in some countries, such as China, remains unclear. Although elimination strategies through post-exposure prophylaxis (PEP) use, dog vaccination, and patient risk assessments with integrated bite case management (IBCM) were proposed to be cost-effective, evidence is still lacking in China. We aim to evaluate the future burdens of dog-mediated human rabies deaths in the next decade and provide quantitative evidence on the cost-effectiveness of different rabies-control strategies in China. METHODS: Based on data from China's national human rabies surveillance system, we used decision-analytic modelling to estimate dog-mediated human rabies death trends in China till 2035. We simulated and compared the expected consequences and costs of different combination strategies of the status quo, improved access to PEP, mass dog vaccination, and use of IBCM. RESULTS: The predicted human rabies deaths in 2030 in China will be 308 (95%UI: 214-411) and remain stable in the next decade under the status quo. The strategy of improved PEP access alone could only decrease deaths to 212 (95%UI: 147-284) in 2028, remaining unchanged till 2035. In contrast, scaling up dog vaccination to coverage of 70% could eliminate rabies deaths by 2033 and prevent approximately 3,265 (95%UI: 2,477-3,687) extra deaths compared to the status quo during 2024-2035. Moreover, with the addition of IBCM, the "One Health" approach through mass dog vaccination could avoid unnecessary PEP use and substantially reduce total cost from 12.53 (95%UI: 11.71-13.34) to 8.73 (95%UI: 8.09-9.85) billion US dollars. Even if increasing the total costs of IBCM from 100 thousand to 652.10 million US dollars during 2024-2035, the combined strategy of mass dog vaccination and use of IBCM will still dominate, suggesting the robustness of our results. CONCLUSIONS: The combined strategy of mass dog vaccination and IBCM requires collaboration between health and livestock/veterinary sectors, and it could eliminate Chinese rabies deaths as early as 2033, with more deaths averted and less cost, indicating that adding IBCM could reduce unnecessary use of PEP and make the "One Health" rabies-control strategy most cost-effective.

Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents.

BACKGROUND: Macrophages are one of the major cell types in the immune system and are closely related to tumor development, which can be polarized into M1 type with anti-tumor activity or M2 type with pro-tumor activity. The infiltration of more macrophages into tumor predicts poorer prognosis due to their more exhibition of M2 phenotype under the influence of many factors in the tumor microenvironment (TME). Therefore, reverse of M2 macrophage polarization in TME is conducive to the suppression of tumor deterioration and understanding the influencing factors of macrophage polarization is helpful to provide new ideas for the subsequent targeting macrophages for tumor therapy. PURPOSE: This review summarizes the effects of TME on macrophage polarization and natural products against M2 macrophage polarization, which may provide some directions for tumor therapy. METHODS: The search of relevant literature was conducted using the PubMed, Science Direct, CNKI and Web of Science databases with the search terms "macrophage", "tumor microenvironment", "natural product" and "tumor". RESULTS: The mutual transformation of M1 and M2 phenotypes in macrophages is influenced by many factors. Tumor cells affect the polarization of macrophages by regulating the expression of genes and proteins and the secretion of cytokines. The expression of some genes or proteins in macrophages is also related to their own polarization. Many natural products can reverse M2 polarization of macrophages which has been summarized in this review. CONCLUSION: Regulation of macrophage polarization in TME can inhibit tumor development, and natural products have the potential to impede tumor development by regulating macrophage polarization.

Effectiveness of peripheral defocus spectacle lenses in myopia control: a Meta-analysis and systematic review.

AIM: To evaluate the effectiveness of peripheral defocus spectacle lenses (PDLs) in myopia control. METHODS: Literature retrieval on PubMed, Cochrane Library, Embase, and Web of Science databases, and the search time limit was from the establishment of each database to December 29, 2021 were conducted. Change of spherical equivalent refraction (SER) and axial change (AL) were extracted from the literatures that met the inclusion criteria, and RevMan5.3 software was used for Meta-analysis. RESULTS: A total of 4 randomized controlled trials (RCTs) were included in this Meta-analysis, involving 770 myopic children. The results showed that PDLs could delay the progression of myopia in children with myopia compared with single vision spectacle lenses (SVLs; WMD=0.21 D, 95%CI: 0.01, 0.41, P=0.04). However, there was no significant difference in controlling the growth of axial length (AL) in myopic children (WMD=-0.10 mm, 95%CI: -0.21, 0.01, P=0.07). The results of the effectiveness of myopia control between the two spectacle lenses showed that PDLs were more effective in controlling the progression of myopia (OR=5.73, 95%CI: 2.58, 12.70, P<0.001) and delaying the growth of AL (OR=44.25, 95%CI: 8.84, 221.58, P<0.001) than SVLs, and the differences were statistically significant. CONCLUSION: PDLs can control the progression of myopia compared with SVLs, but cannot delay the growth of AL, and the effectiveness of PDLs in myopia control better than SVLs.

Comparison of intravitreal aflibercept and dexamethasone implant in the treatment of macular edema associated with diabetic retinopathy or retinal vein occlusion: a Meta-analysis and systematic review.

AIM: To compare the efficacy and safety of intravitreal aflibercept with dexamethasone implant in the treatment of macular edema (ME) associated with diabetic retinopathy (DR) or retinal vein occlusion (RVO). METHODS: A comprehensive search of studies comparing dexamethasone and aflibercept in patients with ME was conducted at PubMed, Embase, and Cochrane Central Register of Controlled Trials from the beginning of library to April 16, 2021. Extracting the data including best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of injections and serious adverse events (SAEs) from the final qualified articles. RevMan 5.3 software was used for Meta-analysis of the included studies. RESULTS: Totally 7 studies with 369 eyes were included. The causes of ME in the final screening study included RVO and DR. Compared with the aflibercept treatment group, the BCVA of the dexamethasone implant treatment group showed no significant difference in the follow-up for 3mo [mean difference (MD): -0.05, 95% confidence interval (CI): -0.11, 0.02; P=0.17] and 12mo (MD: -0.01, 95%CI: -0.38, 0.37; P=0.98), but it was slightly worse than the aflibercept group at 6mo (MD: 0.12, 95%CI: 0.03, 0.21; P=0.008). In terms of CRT reduction, there was no significant difference between the two groups at 3mo (MD: -28.14, 95%CI: -79.95, 23.67; P=0.29), 6mo (MD: 27.67, 95%CI: -84.89, 140.24; P=0.63), and 12mo (MD: -59.00, 95%CI: -127.37, 9.37; P=0.09). However, dexamethasone implant had fewer injections, but more adverse events such as elevated intraocular pressure (IOP) and cataract. CONCLUSION: Intravitreal injection of aflibercept and dexamethasone implant can both effectively increase BCVA and reduce CRT. Compared with aflibercept, dexamethasone implant is not inferior in improving vision and reducing CRT in the initial treatment period (3mo) and long-term treatment period (12mo). Besides, it has fewer injections and more likely to cause elevated IOP and cataract.

TED: Two-stage expert-guided interpretable diagnosis framework for microvascular invasion in hepatocellular carcinoma.

Microvascular invasion (MVI) has been clinically recognized as a prognostic factor for hepatocellular carcinoma (HCC) after surgical treatment. Detection of MVI before surgical operation greatly benefit patients' prognosis and survival. Most of the existing methods for automatic diagnosis of MVI directly use deep neural networks to make predictions, which do not take into account clinical knowledge and lack of interpretability. To simulate the radiologists' decision process, this paper proposes a Two-stage Expert-guided Diagnosis (TED) framework for MVI in HCC. Specifically, the first stage aims to predict key imaging attributes for MVI diagnosis, and the second stage leverages these predictions as a form of attention as well as soft supervision through a variant of triplet loss, to guide the fitting of the MVI diagnosis network. The attention and soft supervision are expected to jointly guide the network to learn more semantically correlated representations and thereafter increase the interpretability of the diagnosis network. Extensive experimental analysis on a private dataset of 466 cases has shown that the proposed method achieves 84.58% on AUC and 84.07% on recall, significantly exceeding the baseline methods.

Forsythiasides: A review of the pharmacological effects.

Forsythiasides are a kind of phenylethanol glycosides existing in Forsythia suspensa (Thunb.) Vahl, which possesses extensive pharmacological activities. According to the different groups connected to the nucleus, forsythiasides can be divided into A-K. In recent years, numerous investigations have been carried out on forsythiasides A, B, C, D, E, and I, which have the effects of cardiovascular protection, anti-inflammation, anti-oxidation, neuroprotection, et al. Mechanistically, forsythiasides regulate toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappaB (NF-κB), nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and other signaling pathways, as well as the expression of related cytokines and kinases. Further exploration and development may unearth more treatment potential of forsythiasides and provide more evidence for their clinical applications. In summary, forsythiasides have high development and application value.