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The latest review published in Nature Reviews Drug Discovery by Michael W. Mullowney and co-authors focuses on the use of artificial intelligence techniques, specifically machine learning, in natural product drug discovery. The authors discussed various applications of AI in this field, such as genome and metabolome mining, structural characterization of natural products, and predicting targets and biological activities of these compounds. They also highlighted the challenges associated with creating and managing large datasets for training algorithms, as well as strategies to address these obstacles. Additionally, the authors examine common pitfalls in algorithm training and offer suggestions for avoiding them.

The latest study published in Nature by Andrew R. Burns, Peter J. Roy and co-authors is highlighted in this paper, they investigated a series of novel nematicidal compounds, including Selectivin-A and Selectivin-E, and explored their mechanism of action. Experiments have displayed that the Selectivin compound is inactive to human cells, fish, fungi, insects and even beneficial nematodes. In the exploration of its mechanism of action, it was found that the mechanism of action of Selectivin is different with those of commercial nematocides: Selectivin needs to be activated by biotin produced by nematodes, after that they can be transformed into compounds with high nematicidal activity. This proves that the family of Selectivin compounds has the advantages of high selectivity and environmental friendliness, and their mechanism of action is completely new, proposing a completely new path for the development of new nematicides.

Summary: Obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia (CIH) and is not well addressed by current therapies. The genioglossus (GG) is the largest upper airway dilator controlling OSA pathology, making its repair a potential treatment. This study investigates dental pulp stem cells (DPSCs) in repairing GG injury in a CIH mouse model. We induced DPSCs to myogenic lineage cells (iDPSCs) and transplanted them into GG of CIH mice. DPSCs/iDPSCs grafts improved EMGGG and muscle type transitions while reducing tumor necrosis factor α (TNF-α), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK) levels, improving body weight. Moreover, iDPSCs increased Pax7+/Ki67+ and human-derived STEM121 cells in the GG compared with DPSCs. DPSCs/iDPSCs enhanced Desmin+ myotube formation in myoblasts under hypoxia in vitro, with iDPSCs increased human-derived myogenic markers and nuclei in myotubes. These results indicate that iDPSCs, beyond their paracrine effects like DPSCs, directly participate in myogenic differentiation, supporting the potential use of DPSCs for OSA treatment.

Crops will be harmed by fungi, pests and weeds during their growth. In the past half century, scientists have conducted in-depth research on natural products extracted from microorganisms, plants or animals, and used natural products and their derivatives as the lead for pesticides discovery. Natural product pesticides have the advantages of easy degradation in the environment, selective control and safety to non-target organisms. This review summarizes the studies on natural products pesticides in recent years, including natural products of chemical modification and biosynthesis, mainly fungicides, herbicides, insecticides and acaricides. We classify natural products according to their active fragments, and discuss their effects on the control of agricultural fungi, pests and weeds. Ultimately, we found that lead discovery based on natural products has great advantages in pesticide development.

Due to rapid urbanization, population growth, industrialization, and agricultural activities, there is an increasing demand for freshwater resources, leading to heightened pressure on watershed ecosystems. This study focused on the Nishan Reservoir, Qufu Sihe River, and Qufu Yihe River, conducting field investigations on these water bodies during the spring of 2021 and 2022. Water samples were collected and analyzed for key water quality indicators, including chemical oxygen demand (COD), biochemical oxygen demand (BOD), total nitrogen (TN), total phosphorus (TP), ammonia nitrogen (AN), chlorophyll A, and algal cell density. This study unveiled notable correlations among various water quality parameters, including positive associations between BOD and COD, chlorophyll A and algal cell density, and inverse relationships with total phosphorus. Moreover, significant positive correlations were identified between total nitrogen and ammonia nitrogen, as well as between ammonia nitrogen and chlorophyll A. The study highlighted that the TP concentration surpassed the threshold of 0.20 mg/L in 2021, potentially exacerbating the proliferation of algae, leading to algal blooms and adversely affecting the aquatic ecosystem. This study emphasizes the significance of broadening the geographical scope and utilizing long-term datasets to discern trends, determinants, and management approaches pertinent to water quality. Furthermore, this study underscores the imperative of investigating the influence of nitrogen-to-phosphorus nutrient ratios on the composition and proliferation of algal populations, while also taking into account the potential impact of additional factors like light availability, temperature, and water flow on the dynamics of algal communities.

Benzoxaborole, a five-membered oxaborole ring fused with a phenyl ring, has demonstrated potent pharmacological activity. In order to explore their potential applications in agriculture, five-membered and six-membered benzoxaborole derivatives were synthesized and evaluated for their fungicidal activity against six common plant pathogenic fungi in vitro. The bioassay results showed that most of the target compounds exhibited significant fungicidal activity at concentrations below 50 μg/mL, particularly the highlighted compounds 4b and 4e, which demonstrated impressive fungicidal activity superior to those of the positive controls. Molecular docking was also performed to confirm the practical value of the active compound as a potential inhibitor of Leucyl-tRNA Synthetase (LeuRS). This study indicates that the designed benzoxaborole derivatives could serve as template molecules for the development of novel fungicides.

ObjectiveTo explore the potential of walking alone milestone combined reading-frame rule to improve the early diagnosis of Duchenne muscular dystrophy (DMD).MethodTo retrospectively describe the genotype and phenotype of Duchenne and Becker muscular dystrophies (BMD) patients with deletions and duplicates in the dystrophin gene. The sensitivity and specificity of the reading frame rule were calculated and compared to that of the combined reading frame rule and walking alone milestone. The diagnostic coincidence rate of two different methods was analyzed.ResultOne hundred sixty-nine male DMD/BMD patients were enrolled, including 17 cases of BMD and 152 cases of DMD. The diagnostic coincidence rate, diagnostic sensitivity, and specificity of the reading-frame rule for DMD/BMD were 85.2, 86.8, and 70.59%, respectively. The sensitivity and specificity of the reading frame principle combined with the walking alone milestone for DMD/BMD were 96.05 and 70.59%, respectively. The diagnostic coincidence rate increased to 93.49%, significantly different from that predicted by reading- frame rule (P < 0.05).ConclusionThe reading-frame rule combined with the walking alone milestone significantly improved the early diagnosis rate of DMD.

We describe the case of a 7-year-old girl with anti-leucine-rich glioma-inactivated 1 (anti-LGI1) antibodies (Abs) who presented with isolated epileptic seizures. Her refractory focal seizures did not respond to anti-seizure medicines but responded rapidly to immunotherapy. She remained seizure-free at 2 years follow-up. Reviewing the literature, isolated epileptic seizures have not been reported as the phenotype of anti-LGI1 autoimmunity in children. Our study indicated that screening for anti-LGI1 Abs is necessary for children with severe and/or drug-resistant new-onset focal epileptic seizures.

This study explores the relationship between China's reproductive health policy and the rate of return on urban education by using fixed-effect, mediating-effect, and breakpoint regression models. The authors study the impact of China's reproductive health policy on individual years of education, income, return on education, the impact of reproductive health policy on population health, and overall human development. The empirical results show that the implementation of China's reproductive health policy can improve the rate of return on urban education and increase the average length of education of urban residents by 0.29 years. Under the breakpoint regression model, the educational return rate of urban residents is approximately 12.2% higher than the ordinary least squares (OLS) estimate. China's reproductive health policy has significantly promoted the return rate of residents' education and simultaneously effectively promoted the income of urban residents. With the development of the economy, the government should properly adjust reproductive health policies and improve the population health rate so that the adjustment of reproductive health policies can comprehensively promote the health of residents of all ages. The overall relaxation of family restrictions on children's human capital investment will likely reduce the negative impact of the overall relaxation of family planning, not only improving the health of the population but also contributing to sustainable economic development.

Background: Accumulated experimental evidence suggests that resveratrol may have an effect on diabetic nephropathy by inhibiting inflammation and decreasing oxidative stress. However, the credibility of the evidence for this practice is unclear. Thus, we aimed to perform a systematic review and meta-analysis of animal studies to evaluate the antioxidant and anti-inflammatory properties of resveratrol when used in the treatment of diabetic nephropathy.Methods: Electronic bibliographic databases including PubMed, EMBASE, and Web of Science were searched for relevant studies. The methodological quality of animal studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Risk of Bias (SYRCLE’s RoB) tool. A meta-analysis was performed based on the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.4 software. This study was registered within International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42021293784.Results: Thirty-six qualified studies involving 726 animals were included. There was a significant association of resveratrol with the levels of blood glucose (BG), serum creatinine (Scr), blood urea nitrogen (BUN), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and interleukin-1β (IL-1β). Nevertheless, resveratrol treatment did not effectively decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, more remarkable antioxidant and hypoglycemic effects were observed in type 2 diabetic nephropathy rather than in type 1 diabetic nephropathy based on subgroup analysis.Conclusion: In this meta-analysis, resveratrol can exert its antioxidant activities by reducing the levels of MDA and recovering the activities of SOD, CAT, GSH, and GPx. With regard to pro-inflammatory cytokines, resveratrol had a positive effect on the reduction of IL-1β. However, the analysis indicated that resveratrol had no effect on IL-6 and TNF-α levels, probably because of the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory properties of resveratrol, but its relationship with the levels of some inflammatory cytokines such as IL-6 and TNF-α in animals with diabetic nephropathy needs further elucidation.

Kartagener’s syndrome is a subgroup of primary ciliary dyskinesia (PCD), a genetically heterogeneous condition characterised by sinusitis, bronchiectasis, and situs in versus. Genetic testing has importance for their diagnosis. Here, we report a chinese patient with Kartagener’s syndrome. Transthoracic echocardiography showed severely elevated right ventricular systolic pressure. Right heart catheterisation demonstrated a pre-capillary pulmonary hypertension. Whole-exome sequencing indicated that she had a novel homozygous nonsense mutation, c.2845C > T, p.Gln949*, in exon 18 of CCDC40 and a heterozygotic mutation, c.73G > A, p.Ala25Thr, in exon 1 of DNAH11. She was diagnosed as Kartagener’s syndrome with pulmonary hypertension. Her symptoms improved significantly by treatment of antibiotics, expectorant drugs, bronchodilators, and oxygen therapy treatment. Our findings extend the mutation spectrum of CCDC40 gene related Kartagener’s syndrome, which is very important for gene diagnosis of the disease.

The effects of hydrogen sulfide (H2S) on diabetic metabolic disorders are still controversial, and the mechanisms underlying these effects remain largely unknown. This study was conducted to investigate the potential relationship between the gut microbiota and the improvement of diabetic metabolic disorders by exogenous H2S in obese db/db mice. The db/db mice were treated with sodium hydrosulfide (NaHS) (80 μmol/kg), or vehicle for 16 weeks, respectively. We measured the serum H2S, obesity parameters, glucose homeostasis, and triglyceride. The sequencing of bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) in the cecal contents of NaHS-treated mice was performed to evaluate the gut microbial communities. We found that supplying exogenous H2S for 16 weeks significantly inhibited the increase of serum triglyceride, blood glucose, and insulin levels and altered specifically the gut bacterial microbiota structure in db/db mice. The relative abundance of some bacterial genera was correlated with the H2S or blood glucose level. Indeed, exogenous H2S increased Firmicutes and decreased Bacteroidetes at the phylum level along with changes of abundance of multifarious genera. Among them, Unclassified_Enterobacteriaceae, Prevotella, and Lactobacillus decreased and Unclassified_Ruminococcaceae, Oscillospira, Ruminococcus, Sutterella, and Desulfovibrio increased. For fungi, exogenous H2S decreased the abundance of Candida and Aspergillus. Here we demonstrated that, in diabetes, microbial dysbiosis may not be just limited to bacteria due to the inter-linked metabolic interactions among bacteria and fungi in the gut. The beneficial effects of exogenous H2S on diabetic metabolic disorders are likely associated with the alterations of specific microbiota.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate—it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 μg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this study, pimprinine and streptochlorin were used as parent structures with the combination strategy of their structural features. Three series of target compounds were designed and synthesized. Subsequent evaluation for antifungal activity against six common phytopathogenic fungi showed that some of thee compounds possessed excellent effects, and this is highlighted by compounds 4a and 5a, displaying 99.9% growth inhibition against Gibberella zeae and Alternaria Leaf Spot under 50 μg/mL, respectively. EC50 values indicated that compounds 4a, 5a, 8c, and 8d were even more active than Azoxystrobin and Boscalid. SAR analysis revealed the relationship between 5-(3′-indolyl)oxazole scaffold and antifungal activity, which provides useful insight into the development of new target molecules. Molecular docking models indicate that compound 4a binds with leucyl-tRNA synthetase in a similar mode as AN2690, offering a perspective on the mode of action for the study of its antifungal activity. These results suggest that compounds 4a and 5a could be regarded as novel and promising antifungal agents against phytopathogens due to their valuable potency.

Coumarin compounds have a variety of biological activities such as anti-tumor, anti-coagulation, anti-HIV, anti-fungal, and insecticidal. Amide and sulfonamide compounds have been used as fungicides for half a century, and dozens of varieties have been developed so far. This study focused on the introduction of carboxamide and sulfonamide moieties in a coumarin core to discover novel derivatives. Based on this strategy, we synthesized two series of novel carboxamide and sulfonamide substituted coumarin derivatives, and their fungicidal activity was also investigated. Some designed compounds possessed potential activities against six phytopathogenic fungi in the primary assays, highlighted by compound 6r. Compound 6r exhibited stronger fungicidal activity against Botrytis cinerea (EC50 = 20.52 µg/mL) and will be the lead structure for further study.

Glioma is the most common and malignant primary brain tumor. Patients with malignant glioma usually have a poor prognosis due to drug resistance and disease relapse. Cancer stem cells contribute to glioma initiation, progression, resistance, and relapse. Hence, quick identification and efficient understanding of glioma stem cells (GSCs) are of profound importance for therapeutic strategies and outcomes. Ideally, therapeutic approaches will only kill cancer stem cells without harming normal neural stem cells (NSCs) that can inhibit GSCs and are often beneficial. It is key to identify the differences between cancer stem cells and normal NSCs. However, reports detailing an efficient and uniform protocol are scarce, as are comparisons between normal neural and cancer stem cells. Here, we compared different protocols and developed a fast and efficient approach to obtaining high-purity glioma stem cell by tracking observation and optimizing culture conditions. We examined the proliferative and differentiative properties confirming the identities of the GSCs with relevant markers such as Ki67, SRY-box containing gene 2, an intermediate filament protein member nestin, glial fibrillary acidic protein, and s100 calcium-binding protein (s100-beta). Finally, we identified distinct expression differences between GSCs and normal NSCs including cyclin-dependent kinase 4 and tumor protein p53. This study comprehensively describes the features of GSCs, their properties, and regulatory genes with expression differences between them and normal stem cells. Effective approaches to quickly obtaining high-quality GSCs from patients should have the potential to not only help understand the diseases and the resistances but also enable target drug screening and personalized medicine for brain tumor treatment.

Objective: Variant non-ketotic hyperglycinaemia (NKH) is a rare disorder characterized by variable clinical, biochemical, and imaging features. The variant form of NKH is rare and characterized by variable clinical, biochemical and imaging features.Subjects: Herein, we report a girl with variant NKH with two mutations in glutaredoxin 5 (GLRX5), which has been described in only three patients.Results: The clinical and biochemical phenotypes of the patient are also described. She suffered from developmental regression associated with spasticity, developmental delay, anemia and optic atrophy. The mitochondrial leukoencephalopathy was used to designate these disorders. An increased T2 signal from the medulla oblongata to the C6 spinal region was also observed on spinal cord MRI. Tandem mass analysis of a dried blood sample revealed elevated levels of glycine. The patient has two compound heterozygous mutations (c.151_153 del AAG and c.196C>T) in the GLRX5 gene. The c.196C>T mutation led to a stop codon (p.Q66Ter). Activities of mitochondrial respiratory chain (MRC) complexes II+III in the patient's fibroblasts were abnormal.Conclusions: We present the case of a girl with variant NKH who manifested spasticity and bilateral cavitating leukoencephalopathy. The patient had a deficiency of a respiratory chain enzyme, and this is the first report. Genetic testing is important for physicians to evaluate suspected variant NKH patients and to provide proper genetic counseling.

This report presents a very rare case of fibrous tumour in the pulmonary artery. A 32-year-old male patient presented at the First Hospital of Jilin University with the chief complaint of chest pain accompanied by cough and haemoptysis. Laboratory test results showed a D-dimer level of 60 ng/ml, and protein S activity of 51.0%. Echocardiography and enhanced computed tomography (CT) of the lung revealed a thrombus-like mass in the main pulmonary artery trunk, and the left pulmonary artery and its branches. The patient was initially diagnosed with pulmonary embolism, but after performing arterial endarterectomy, the presence of a tumour in the corresponding areas was confirmed. Histopathology and immunohistochemistry indicated the presence of a malignant solitary fibrous tumour. Chemotherapeutic agents were administered following surgery. The patient was prescribed ongoing oral Apatinib (250 mg, once daily) as a tumour-targeting therapy. The patient refused permission for postoperative CT. The patient was still alive at the 2-year follow-up.

Familial hemophagocytic lymphohistiocytosis Type 2 (FHL2) associated central nervous system (CNS) involvement is less understood in children, especially when considering neurologic manifestations as part of the initial presentation. We conducted a retrospective review of the clinical manifestations and genetic abnormality of four Han Chinese children with FHL2 who were patients at the neurology department of Beijing Children’s Hospital from November 2015 to October 2018. These four patients initially manifested CNS symptoms in their disease presentation, and all four patients were misdiagnosed as having ademyelinating disease, such as acute disseminated encephalomyelitis and multiple sclerosis. Given these misdiagnoses, it is important that general physicians and pediatricians maintain awareness of the possibility of FHL2 as a differential diagnosis. These four cases included neurologic manifestations including seizures, ataxia, spasticity, gait disorder, and coma. Bilateral abnormal signals in the cerebrum, including in white matter, gray matter, and junctions were discovered. Enhanced magnetic resonance imaging (MRI) in these patients showed spot or ring enhancement and/or hemorrhage. These patients all possessed a compound heterozygote mutation PRF1 gene. Whole exome sequencing analysis revealed seven different mutations (three novel mutations) spread over the PRF1 gene and a heterozygous missense mutation c.1349C > T [p.T450M] that was present in two patients. Three novel mutations, c.634T > C[p.Y212H], c.1083_1094del[p.361_364del], and c.1306G > T [p.D436Y], were discovered and through in silico analysis were discovered to be deleterious. Neurologic manifestations were the initial symptoms of FHL2 in these patients in addition to the expected leukopenia and hepatosplenomegaly. Whole exome sequencing of PRF1 for patients with similar presentations would facilitate prompt and accurate diagnosis and treatment.

Aging of population brings related social problems, such as muscle attenuation and regeneration barriers with increased aging. Muscle repair and regeneration depend on muscle stem cells (MuSCs). Obstructive sleep apnea (OSA) rises in the aging population. OSA leads to hypoxia and upper airway muscle injury. However, little is known about the effect of increasing age and hypoxia to the upper airway muscle. The genioglossus (GG) is the major dilator muscle to keep the upper airway open. Here, we reported that muscle fiber and MuSC function declined with aging in GG. Increasing age also decreased the migration and proliferation of GG MuSCs. p53 and p21 were high expressions both in muscle tissue and in GG MuSCs. We further found that hypoxia inhibited GG MuSC proliferation and decreased myogenic differentiation. Then, hypoxia enhanced the inhibition effect of aging to proliferation and differentiation. Finally, we investigated that hypoxia and aging interact to form a vicious circle with upregulation of p53 and p21. This vicious hypoxia plus aging damage accelerated upper airway muscle injury. Aging and hypoxia are the major damage elements in OSA patients, and we propose that the damage mechanism of hypoxia and aging in GG MuSCs will help to improve upper airway muscle regeneration.

Neuronal Ceroid Lipofuscinoses (NCLs) are progressive degenerative diseases mainly affect brain and retina. They are characterized by accumulation of autofluorescent storage material, mitochondrial ATPase subunit C, or sphingolipid activator proteins A and D in lysosomes of most cells. Heterogenous storage material in NCLs is not completely disease-specific. Most of CLN proteins and their natural substrates are not well-characterized. Studies have suggested variants of Late-Infantile NCLs (LINCLs) include the major type CLN2 and minor types CLN5, CLN6, CLN7, and CLN8. Therefore, combination of clinical and molecular analysis has become a more effective diagnosis method. We studied 4 late-infantile NCL siblings characterized by seizures, ataxia as early symptoms, followed by progressive regression in intelligence and behavior, but mutations are located in different genes. Symptoms and progression of 4 types of LINCLs are compared. Pathology of LINCLs is also discussed. We performed Nest-Generation Sequencing on these phenotypically similar families. Three novel variants c.1551+1insTGAT in TPP1, c.244G>T in CLN6, c.554-5A>G in MFSD8 were identified. Potential outcome of the mutations in structure and function of proteins are studied. In addition, we observed some common and unique clinical features of Chinese LINCL patient as compared with those of Western patients, which greatly improved our understanding of the LINCLs.

A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by 1H-NMR, 13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternariasolani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 μg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 μg/mL, which was obviously better than Osthole (33.20 μg/mL) and Azoxystrobin (64.95 μg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 μg/mL, which was better than Osthole (67.18 μg/mL) and equivalent to Azoxystrobin (21.34 μg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.

Hepatic involvement in aggressive systemic mastocytosis (ASM) is relatively common, and the main clinical features of this disease include hepatomegaly, portal hypertension, ascites, and fibrosis. Cirrhosis is a rare ASM symptom. We report an ASM case that initially mimicked cirrhosis based on clinical and radiographic analyses. The portal tract was expanded by mononuclear inflammatory cells, and an increase in collagen amount was observed in routine histological sections of the biopsied liver. A diagnosis of systemic mastocytosis (SM) was made after ancillary tests for mast cells using bone marrow aspirates. Extensive involvement of the liver and gastrointestinal tract was observed. Clinicians and pathologists need to consider ASM as a diagnosis or differential diagnosis in a clinical case of cirrhosis with unknown etiology. The diagnosis can be confirmed or disregarded by immunohistochemical staining and molecular analysis.

Aims: Calcium-sensing receptor (CaR) acts as a G protein coupled receptor that mediates the increase of the intracellular Ca2+ concentration. The expression of CaR has been confirmed in various cell types, including cardiomyocytes, smooth muscle cells, neurons and vascular endothelial cells. However, whether CaR is expressed and functions in cardiac fibroblasts has remained unknown. The present study investigated whether CaR played a role in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion, both in cultured rat neonatal cardiac fibroblasts and in a model of cardiac hypertrophy induced by isoproterenol (ISO). Methods and Results: Immunofluorescence, immunohistochemistry and Western blot analysis revealed the presence of CaR in cardiac fibroblasts. Calcium and calindol, a specific activator of CaR, elevated the intracellular calcium concentration in cardiac fibroblasts. Pretreatment of cardiac fibroblasts with calhex231, a specific inhibitor of CaR, U73122 and 2-APB attenuated the calindol- and extracellular calcium-induced increase in intracellular calcium ([Ca2+]i). Cardiac fibroblast proliferation and migration were assessed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cell count and the cell scratch assay. ECM production was detected by expression of matrix metalloproteinase-3 and -9 (MMP-3 and -9). Activation of CaR promoted cardiac fibroblast proliferation and migration and ECM secretion. More importantly, calhex231, suppressed cardiac fibroblast proliferation and migration and MMP-3 and -9 expression. To further investigate the effect of CaR on cardiac fibrosis, a model of ISO-induced cardiac hypertrophy was established. Pretreatment with calhex231 prevented cardiac fibrosis and decreased the expression of MMP-3 and -9 expression. Conclusions: Our results are the first report that CaR plays an important role in Ca2+ signaling involved in cardiac fibrosis through the phospholipase C- inositol 3,4,5 phosphate (PLC-IP3) pathway.

Aims: Alterations in calcium homeostasis in the intracellular endo/sarcoplasmic reticulum (ER/SR) and mitochondria of cardiomyocytes cause cell death via the SR and mitochondrial apoptotic pathway, contributing to ventricular dysfunction. However, the role of the calcium-sensing receptor (CaR) in cardiac hypertrophy and heart failure has not been studied. This study examined the possible involvement of CaR in the SR and mitochondrial apoptotic pathway in an experimental model of heart failure. Methods and Results: In Wistar rats, cardiac hypertrophy and heart failure were induced by subcutaneous injection of isoproterenol (Iso). Calindol, an activator of CaR, and calhex231, an inhibitor of CaR, were administered by caudal vein injection. Cardiac remodeling and left ventricular function were then analyzed in these rats. After 2, 4, 6 and 8 weeks after the administration of Iso, the rats developed cardiac hypertrophy and failure. The cardiac expression of ER chaperones and related apoptotic proteins was significantly increased in the failing hearts. Furthermore, the expression of ER chaperones and the apoptotic rate were also increased with the administration of calindol, whereas the expression of these proteins was reduced with the treatment of calhex231. We also induced cardiac hypertrophy and failure via thoracic aorta constriction (TAC) in mice. After 2 and 4 weeks of TAC, the expression of ER chaperones and apoptotic proteins were increased in the mouse hearts. Furthermore, Iso induced ER stress and apoptosis in cultured cardiomyocytes, while pretreatment with calhex231 prevented ER stress and protected the myocytes against apoptosis. To further investigate the effect of CaR on the concentration of intracellular calcium, the calcium concentration in the SR and mitochondria was determined with Fluo-5N and x-rhod-1 and the mitochondrial membrane potential was examined with JC-1 using laser confocal microscopy. After treatment with Iso for 48 hours, activation of CaR reduced [Ca2+]SR, increased [Ca2+]m, decreased the mitochondrial membrane potential, increased the expression of ER stress chaperones and related apoptotic proteins, and induced the release of cytochrome c from the mitochondria. Conclusions: Our results demonstrated that CaR activation caused Ca2+ release from the SR into the mitochondria and induced cardiomyocyte apoptosis through the SR and mitochondrial apoptotic pathway in failing hearts.

Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

A series of linear furanocoumarins with different substituents have been designed and synthesized. Their structures were confirmed by 1H-NMR spectroscopy, high resolution mass spectra (EI-MS), IR, and X-ray single-crystal diffraction. All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Botrytis cinerea, Alternaria solani, Gibberella zeae, Cucumber anthrax, and Alternaria leaf spot at 100 μg/mL, and some of the designed compounds exhibited potential antifungal activities. Compound 3a (67.9%) exhibited higher activity than the control Osthole (66.1%) against Botrytis cinerea. Furthermore, compound 4b (62.4%) represented equivalent antifungal activity as Osthole (69.5%) against Rhizoctonia solani. The structure-activity relationship (SAR) study demonstrates that linear furanocoumarin moiety has an important effect on the antifungal activity, promoting the idea of the coumarin ring as a framework that might be exploited in the future.

BACKGROUND: No specific antiviral agent against hand foot and mouth disease (HFMD) is available for clinical practice today. OBJECTIVE: To evaluate the efficacy and safety of Jinzhen oral solution in treating uncomplicated HFMD. METHODS: In this randomized, double-blind, placebo-controlled trial, 399 children aged 1 to 7 years with laboratory confirmed HFMD were randomized to receive Jinzhen oral liquid or placebo 3 times daily for 7 days with a 3-day follow-up. The primary outcomes were time to the first disappearance of oral ulcers and vesicles on hand or foot and time to the first normalization of temperature (fever clearance). RESULTS: There were 199 children enrolling into the Jinzhen group including 79 with fever and 200 into the placebo group including 93 with fever. Jinzhen reduced the time to the first disappearance of oral ulcers and vesicles on hand or foot to 4.9 days (95% CI, 4.6 to 5.2 days), compared with 5.7 days (95% CI, 5.4 to 6.0 days) in the placebo group (P = 0.0036). The median time of fever clearance was shorter in the 79 children who received Jinzhen (43.41 hrs, 95% CI, 37.05 to 49.76) than that in the 93 children who received placebo (54.92 hrs, 95% CI, 48.16 to 61.68) (P = 0.0161). Moreover, Jinzhen reduced the risk of symptoms by 28.5% compared with placebo (HR, 0.7150, 95% CI, 0.5719 to 0.8940, P = 0.0032). More importantly, treatment failure rate was significantly lower in the Jinzhen group (8.04%) compared with that in the placebo group (15.00%) (P = 0.0434). The incidence of serious adverse events did not differ significantly between the two groups (9 in Jinzhen group vs. 18 in placebo, P = 0.075). CONCLUSIONS: Children with HFMD may benefit from Jinzhen oral liquid treatment as compared with placebo. TRIAL REGISTRATION: Chinese Clinical Trial Registry (http://www.chictr.org/en/) ChiCTR-TRC-10000937.

Based on our initial design, we synthesized two series of coumarin ring-opening derivatives by the reactions of hydrolysis and methylation. Results of antifungal screening in vitro showed that the target compounds exhibited potent activity against the six common pathogenic fungi. Compounds 6b, 6e, 6g, 6i, 7b and 7c were identified as the most active ones, and the EC50 values of these active compounds were further tested. Compared to the commonly used fungicide Azoxystrobin (0.0884 µM), compounds 6b (0.0544 µM) and 6e (0.0823 µM) displayed improved activity against Botrytis cinerea.

This paper introduces a non-contact method for detecting contact force between pantograph and catenary (PAC), based on image processing and Kalman filter. A non-contact method for detecting contact force of PAC, which only utilizes the vertical displacement of the collector head, is proposed. First, the images of the collector head area are collected by adding an image acquisition system on the roof of the vehicle. Second, combined with target tracking and template matching, the vertical displacement of the pantograph's collector head is identified. Finally, based on the Kalman filter considering least squares method and the PAC dynamics model, a method for detecting contact force is constructed. The estimation of the PAC's dynamic contact force is realized only by using the vertical displacement of the collector head obtained from the image identification. The results of simulation and test-bed results show that the Kalman filter considering least squares significantly has higher accuracy and better robustness compared with the traditional Kalman filter. [ABSTRACT FROM AUTHOR]