Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

Identification of neuropeptides and their G protein-coupled receptors in the predatory stink bug, Arma custos (Hemiptera: Pentatomidae).

The predatory stink bug Arma custos has been selected as an effective biological control agent and has been successfully massly bred and released into fields for the control of a diverse insect pests. As a zoophytophagous generalist, A. custos relies on a complex neuropeptide signaling system to prey on distinct food and adapt to different environments. However, information about neuropeptide signaling genes in A. custos has not been reported to date. In the present study, a total of 57 neuropeptide precursor transcripts and 41 potential neuropeptide G protein-coupled receptor (GPCR) transcripts were found mainly using our sequenced transcriptome data. Furthermore, a number of neuropeptides and their GPCR receptors that were enriched in guts and salivary glands of A. custos were identified, which might play critical roles in feeding and digestion. Our study provides basic information for an in-depth understanding of biological and ecological characteristics of the predatory bug and would aid in the development of better pest management strategies based on the effective utilization and protection of beneficial natural enemies.

Rifampicin synergizes the toxicity of insecticides against the green peach aphid, Myzus persicae.

Myzus persicae is an important pest that has developed resistance to nearly all currently used insecticidal products. The employment of insecticide synergists is one of the effective strategies that need to be developed for the management of this resistance. Our study showed that treatment with a combination of the antibiotic, rifampicin, with imidacloprid, cyantraniliprole, or clothianidin significantly increased their toxicities against M. persicae, by 2.72, 3.59, and 2.41 folds, respectively. Rifampicin treatment led to a noteworthy reduction in the activities of multifunctional oxidases (by 32.64%) and esterases (by 23.80%), along with a decrease in the expression of the CYP6CY3 gene (by 58.57%) in M. persicae. It also negatively impacted the fitness of the aphids, including weight, life span, number of offspring, and elongation of developmental duration. In addition, bioassays showed that the combination of rifampicin and a detoxification enzyme inhibitor, piperonyl butoxide, or dsRNA of CYP6CY3 further significantly improved the toxicity of imidacloprid against M. persicae, by 6.19- and 7.55-fold, respectively. The present study suggests that development of active ingredients such as rifampicin as candidate synergists, show promise to overcome metabolic resistance to insecticides in aphids.

Chiral growth of adherent filopodia.

Adherent filopodia are elongated finger-like membrane protrusions, extending from the edges of diverse cell types and participating in cell adhesion, spreading, migration, and environmental sensing. The formation and elongation of filopodia are driven by the polymerization of parallel actin filaments, comprising the filopodia cytoskeletal core. Here, we report that adherent filopodia, formed during the spreading of cultured cells on galectin-8-coated substrates, tend to change the direction of their extension in a chiral fashion, acquiring a left-bent shape. Cryoelectron tomography examination indicated that turning of the filopodia tip to the left is accompanied by the displacement of the actin core bundle to the right of the filopodia midline. Reduction of the adhesion to galectin-8 by treatment with thiodigalactoside abolished this filopodia chirality. By modulating the expression of a variety of actin-associated filopodia proteins, we identified myosin-X and formin DAAM1 as major filopodia chirality promoting factors. Formin mDia1, actin filament elongation factor VASP, and actin filament cross-linker fascin were also shown to be involved. Thus, the simple actin cytoskeleton of filopodia, together with a small number of associated proteins are sufficient to drive a complex navigation process, manifested by the development of left-right asymmetry in these cellular protrusions.

Differential cellular responses to adhesive interactions with galectin-8- and fibronectin-coated substrates.

The mechanisms underlying the cellular response to extracellular matrices (ECMs) that consist of multiple adhesive ligands are still poorly understood. Here, we address this topic by monitoring specific cellular responses to two different extracellular adhesion molecules - the main integrin ligand fibronectin and galectin-8, a lectin that binds ß-galactoside residues  - as well as to mixtures of the two proteins. Compared with cell spreading on fibronectin, cell spreading on galectin-8-coated substrates resulted in increased projected cell area, more-pronounced extension of filopodia and, yet, the inability to form focal adhesions and stress fibers. These differences can be partially reversed by experimental manipulations of small G-proteins of the Rho family and their downstream targets, such as formins, the Arp2/3 complex and Rho kinase. We also show that the physical adhesion of cells to galectin-8 was stronger than adhesion to fibronectin. Notably, galectin-8 and fibronectin differently regulate cell spreading and focal adhesion formation, yet act synergistically to upregulate the number and length of filopodia. The physiological significance of the coherent cellular response to a molecularly complex matrix is discussed. This article has an associated First Person interview with the first author of the paper.

Facilitating combined biopsy and percutaneous microwave ablation of pulmonary ground-glass opacities using lipiodol localisation.

OBJECTIVES: Whether preoperative localisation is necessary and valuable for the microwave ablation (MWA) of small pulmonary lesions with ground-glass opacity (GGO) remains unclear. This study aimed to explore the role of the Chiba needle and lipiodol localisation techniques in facilitating MWA and biopsy. METHODS: This retrospective before-after study included patients with GGOs who underwent conventional MWA and biopsy treatment in our hospital between January 2018 and December 2019 (group A) or who underwent the Chiba needle and lipiodol localisation treatment before MWA and biopsy between January 2020 and December 2020 (group B). The characteristics of each patient and GGO lesion were collected and analysed to evaluate the safety and effectiveness of the localisation technique. RESULTS: A total of 122 patients with 152 GGOs and 131 patients with 156 GGOs underwent MWA and biopsy in groups A and B, respectively. The primary technique efficacy rate of MWA differed significantly between the two groups (A vs. B: 94.1% vs. 99.4%; p = 0.009). The positive biopsy rate in the two groups was determined by the difference (A vs. B: 93.4% vs. 98.1%; p = 0.042). The incidence of complications did not increase in group B. CONCLUSIONS: Compared with the unmarked group, the Chiba needle and lipiodol localisation technique improved the positive rate of biopsy and the initial effective rate of MWA, without significantly increasing the complication rate. KEY POINTS: • The localisation of the Chiba needle and lipiodol could improve the positive biopsy rate and the initial effective rate of MWA. • The localisation of the Chiba needle and lipiodol does not affect the subsequent MWA and biopsy and does not increase the incidence of pneumothorax and haemorrhage.

Associated Risk Factors and Diagnostic Value of Fiberoptic Bronchoscopy for Protracted Bacterial Bronchitis in Children.

Objective: Untreated protracted bacterial bronchitis (PBB), a chronic wet cough prevalent in children, may lead to chronic suppurative lung disease. However, clinical diagnostic criteria are currently nonspecific; thus, PBB may be misdiagnosed. Thus, we assessed the diagnostic value of fiberoptic bronchoscopy (FOB) and the risk factors associated with PBB. Methods: Children with chronic cough at The First Affiliated Hospital of Anhui Medical University from January 2015 to May 2020 were enrolled and allocated to a suspected PBB (n = 141) or a non-PBB (n = 206) group. All children underwent extensive laboratory, chest imaging, and allergen tests. Children with suspected PBB underwent FOB with bronchoalveolar lavage; lavage and sputum samples were cultured. Results: All 347 children had a chronic wet cough for approximately 2 months. Of 141 children with suspected PBB, 140 received FOB with bronchoalveolar lavage. Visible tracheal changes included pale mucosa, mucosal congestion, edema, swelling, and increased secretions attached to the wall. Sputum was visible primarily in the left main bronchus (78.7%), left lower lobe (59.6%), right upper lobe (62.4%), and right lower lobe (64.5%). Sputum properties and amounts significantly differed between children with vs. without PBB (P < 0.05). Dermatophagoides (odds ratio (OR), 2.642; 95% CI, 1.283-5.369), milk protein (OR, 2.452; 95% CI, 1.243-4.836) allergies, and eczema (OR, 1.763; 95% CI, 1.011-3.075) were risk factors significantly associated with PBB. Conclusion: Dermatophagoides, milk protein, and eczema were associated with an increased risk of PBB. Sputum distribution and tracheal wall changes observed through FOB may distinguish PBB and assist in its diagnosis.

Influence of artificial diets on biological characteristics and digestive enzymes of Coccinella septempunctata L.

In order to improve the rearing of Coccinella septempunctata L. (Coleoptera: Coccinellidae), nutrients such as shrimp, pollen, honey, and lard were added to the basic artificial diet, and the effects of the artificial diet on biological parameters and digestive enzymes were evaluated. The results show that beetles feeding on the supplemented diet exhibited pupation, emergence, fecundity, and hatching rates that were 102.69%, 125.02%, 162.33%, and 119.90% of those supplied with the basic diet, respectively. The addition of shrimp and pollen to the basal diet improved protease, trypsin, chymotrypsin, and aminopeptidase activity in larvae and female adults. The addition of lard improved lipase activity in female adults, and the addition of honey improved invertase activity in adults of both sexes. This study provides guidance for improving the nutritional benefits of ladybug artificial diets.

A Study of the Mechanisms and Characteristics of Fluorescence Enhancement for the Detection of Formononetin and Ononin.

In this work, the origins for the spectral difference between two isoflavones, formononetin (F) and ononin (FG), are revealed via a comparison study of the fluorescence molecular structure. The fluorescence enhancement of FG in hot alkaline conditions is reported for the first time. For F, there is almost no fluorescence under acidic conditions, but when the pH is >4.8, its fluorescence begins to increase due to the deprotonation of 7-OH. Under a pH between 9.3 and 12.0, the anionic form of F produces a strong and stable fluorescence. The fluorescence quantum yield (Yf) of F is measured to be 0.042. FG shows only weak fluorescence in aqueous solutions under a wide range of pH until it is placed in hot alkaline solutions, which is attributed to the cleavage reaction of the γ-pyrone ring in FG. The Yf of FG is determined to be 0.020. Based on the fluorescence sensitization methods of F and FG, the quantitative analysis and detection of two substances can be realized. The limit of the detections for F and FG are 2.60 ng·mL-1 and 9.30 ng·mL-1, respectively. The linear detection ranges of F and FG are 11.7~1860 ng·mL-1 and 14.6~2920 ng·mL-1, respectively. Although the structural relationship between F and FG is glycoside and aglycone, under hot alkaline conditions, the final products after the cleavage and hydrolysis reactions are essentially different. The different fluorescence characteristics between F and FG pave a way for further identification and a quantitative analysis of the corresponding components in Chinese herbal medicine.

Functional analysis of islet cells in vitro, in situ, and in vivo.

The islet of Langerhans contains at least five types of endocrine cells producing distinct hormones. In response to nutrient or neuronal stimulation, islet endocrine cells release biochemicals including peptide hormones to regulate metabolism and to control glucose homeostasis. It is now recognized that malfunction of islet cells, notably insufficient insulin release of ß-cells and hypersecretion of glucagon from α-cells, represents a causal event leading to hyperglycemia and frank diabetes, a disease that is increasing at an alarming rate to reach an epidemic level worldwide. Understanding the mechanisms regulating stimulus-secretion coupling and investigating how islet ß-cells maintain a robust secretory activity are important topics in islet biology and diabetes research. To facilitate such studies, a number of biological systems and assay platforms have been developed for the functional analysis of islet cells. These technologies have enabled detailed analyses of individual islets at the cellular level, either in vitro, in situ, or in vivo.

Microwave ablation treatment for medically inoperable stage I non-small cell lung cancers: long-term results.

OBJECTIVES: In the present study, we aim to show the results of microwave ablation (MWA) for medically inoperable stage I non-small cell lung cancers (NSCLCs) with long-term follow-up. METHODS: From Feb 2011 to Mar 2016, patients with histologically proven clinical stage I NSCLC were treated with CT-guided MWA and retrospectively analyzed. The primary end point was overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and complications. RESULTS: A total of 105 patients with 105 lesions underwent MWA. The mean age was 70.7 years (range: 40-86 years), and the mean diameter of all lesions was 2.40 cm (range: 0.9-4.0 cm). Adenocarcinoma was the most common histological type (77, 73.3%), followed by squamous cell carcinomas (21, 20%) and undefined NSCLC (7, 6.7%). With a median follow-up of 54.8 months, the median DFS was 36.0 months, and 1-, 3-, and 5-year DFS rates were 89.5%, 49.4%, and 42.7%, respectively. The median CSS and OS were 89.8 and 64.2 months, respectively. The OS rate was 99% at 1 year, 75.6% at 3 years, and 54.1% at 5 years, while the CSS rates were 99%, 78.9%, and 60.9%, respectively. Patients with stage IB lesions had significant shorter DFS (22.3 months vs. undefined, HR: 11.5, 95%CI: 5.85-22.40) and OS (37.3 vs. 89.8 months, HR: 8.64, 95% CI: 4.49-16.60) than IA disease. CONCLUSION: MWA is a safe, effective, and potentially curative therapy for medically inoperable stage I NSCLC patients. KEY POINTS: • In this multicenter retrospective study which included 105 patients, we found the median overall survival (OS) was 64.2 months. The OS rate was 99% at 1 year, 75.6% at 3 years, and 54.1% at 5 years. • Procedures were technically successful and well tolerated in all patients. Most MWA complications were mild or moderate.

Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes.

Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and mitochondrial dysfunction. Studies over the last few decades have highlighted the role played by ceramides in pancreatic islet ß-cell apoptosis, especially under glucolipotoxic and inflammatory conditions. This review focuses on ceramides and adiponectin receptor signaling, summarizing recent advancements in our understanding of their roles in islet ß-cells and the discovery of zinc-dependent lipid hydrolase (ceramidase) activity of adiponectin receptors. The therapeutic potential of targeting these events to prevent islet ß-cell loss for treating diabetes is discussed.

Fluorescence, Absorption, Chromatography and Structural Transformation of Chelerythrine and Ethoxychelerythrine in Protic Solvents: A Comparative Study.

Chelerythrine (CH) and ethoxychelerythrine (ECH) are chemical reference substances for quality control of Chinese herbal medicines, and ECH is the dihydrogen derivative of CH. In this study, their fluorescence and absorption spectra, as well as their structural changes in different protic solvents were compared. It was observed that their emission fluorescence spectra in methanol were almost the same (both emitted at 400 nm), which may be attributed to the nucleophilic and exchange reactions of CH and ECH with methanol molecules with the common product of 6-methoxy-5,6-dihydrochelerythrine (MCH). When diluted with water, MCH was converted into CH, which mainly existed in the form of positively charged CH+ under acidic and near-neutral conditions with the fluorescence emission at 550 nm. With the increase of pH value of the aqueous solution, CH+ converted to 6-hydroxy-5,6-dihydrochelerythrine (CHOH) with the fluorescence emission at 410 nm. The fluorescence quantum yields of MCH and CHOH were 0.13 and 0.15, respectively, and both the fluorescence intensities were much stronger than that of CH+. It is concluded that CH and ECH can substitute each other in the same protic solvent, which was further verified by high-performance liquid chromatography. This study will help in the investigation of structural changes of benzophenanthridine alkaloids and will provide the possibility for the mutual substitution of standard substances in relevant drug testing.

Alteration of Biomolecular Conformation by Aluminum-Implications for Protein Misfolding Disease.

The natural element aluminum possesses a number of unique biochemical and biophysical properties that make this highly neurotoxic species deleterious towards the structural integrity, conformation, reactivity and stability of several important biomolecules. These include aluminum's (i) small ionic size and highly electrophilic nature, having the highest charge density of any metallic cation with a Z2/r of 18 (ionic charge +3, radius 0.5 nm); (ii) inclination to form extremely stable electrostatic bonds with a tendency towards covalency; (iii) ability to interact irreversibly and/or significantly slow down the exchange-rates of complex aluminum-biomolecular interactions; (iv) extremely dense electropositive charge with one of the highest known affinities for oxygen-donor ligands such as phosphate; (v) presence as the most abundant metal in the Earth's biosphere and general bioavailability in drinking water, food, medicines, consumer products, groundwater and atmospheric dust; and (vi) abundance as one of the most commonly encountered intracellular and extracellular metallotoxins. Despite aluminum's prevalence and abundance in the biosphere it is remarkably well-tolerated by all plant and animal species; no organism is known to utilize aluminum metabolically; however, a biological role for aluminum has been assigned in the compaction of chromatin. In this Communication, several examples are given where aluminum has been shown to irreversibly perturb and/or stabilize the natural conformation of biomolecules known to be important in energy metabolism, gene expression, cellular homeostasis and pathological signaling in neurological disease. Several neurodegenerative disorders that include the tauopathies, Alzheimer's disease and multiple prion disorders involve the altered conformation of naturally occurring cellular proteins. Based on the data currently available we speculate that one way aluminum contributes to neurological disease is to induce the misfolding of naturally occurring proteins into altered pathological configurations that contribute to the neurodegenerative disease process.

PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions.

The pleiotropic actions of adiponectin in improving cell survival and metabolism have motivated the development of small-molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of the adiponectin receptors, yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic ß-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high-fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared with AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.

Binary and ternary toxicological interactions of clothianidin and eight commonly used pesticides on honey bees (Apis mellifera).

Although many toxicological evaluations have been conducted for honey bees (Apis mellifera), most of these studies have only focused on the effects of individual chemicals. However, honey bees are usually exposed to pesticide mixtures under field conditions. In this study, we examined the effects of individual pesticides and mixtures of clothianidin (CLO) with eight other pesticides [carbaryl (CAR), thiodicarb (THI), chlorpyrifos (CHL), beta-cyfluthrin (BCY), gamma-cyhalothrin (GCY), tetraconazole (TET), spinosad (SPI) and indoxacarb (IND)] on honey bees using a feeding method. Toxicity tests of a 4-day exposure to individual pesticides revealed that CLO had the highest toxicity to A. mellifera, with an LC50 value of 0.24 µg a.i. mL-1, followed by IND and CHL with LC50 values of 3.40 and 3.56 µg a.i. mL-1, respectively. SPI and CAR had relatively low toxicities, with LC50 values of 7.19 and 8.42 µg a.i. mL-1, respectively. In contrast, TET exhibited the least toxicity, with an LC50 value of 258.7 µg a.i. mL-1. Most binary mixtures of CLO with other pesticides exerted additive and antagonistic effects. However, all the ternary mixtures containing CLO and TET (except for CLO+TET+THD) elicited synergistic responses to bees. Either increased numbers of components in the mixture or/and a unique mode of action appeared to be responsible for the higher toxicity of mixtures. Our findings emphasized the need for risk assessment of pesticide mixtures rather than the individual chemicals. Our data also provided information that might help growers avoid increased toxicity and unnecessary injury to pollinators.

Microwave ablation or plus monochemotherapy in elderly advanced non-small-cell lung cancer patients.

OBJECTIVE: To evaluate the efficacy of microwave ablation (MWA) and MWA plus monochemotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with advanced NSCLC aged ≥70 years were retrospectively enrolled. MWA was performed at the primary tumor site. The end points included progression-free survival (PFS), response to MWA and overall survival (OS). RESULTS: Fifty-four patients were enrolled; of these, 36 received monochemotherapy. Complete ablation was achieved in 42 patients (77.8%). The median PFS and OS were 4.9 months and 21.8 months, respectively. Univariate analyses showed that female patients had superior PFS (31.9 months [95% confidence interval (CI): 0.8-63.0]) vs. 5.0 months in male patients (95% CI: 2.0-8.0), p = .002). Female sex was associated with better OS (not reached vs. 10.8 months, 95% CI: 9.3-12.3, p = .003). Moreover, patients with primary tumor size <3.5 cm had better OS than those with tumor size ≥3.5 cm (not reached vs. 10.9 months, 95% CI: 8.2-13.6, p = .006). Multivariate analyses showed that no characteristics were independent prognostic factors of PFS, but sex and primary tumor size were independent prognostic factors of OS. CONCLUSION: MWA was effective in the treatment of elderly patients with advanced NSCLC.

[Innovation of traditional Chinese medicine compounds and patent layout strategy with Lianhua Qingwen Formula as example].

The innovation and patent layout of traditional Chinese medicine compounds reflects the innovation level of the traditio-nal Chinese medicine industry to a certain extent. Lianhua Qingwen Formula was taken as an example to analyze the innovation and patent layout of traditional Chinese medicine compounds. The study first proposed an innovative technology system for traditional Chinese medicine compounds, and then analyzed the advantages and disadvantages of Lianhua Qingwen Formula in innovation and patent layout based on 56 patents and other relevant patents. The analysis results showed that Lianhua Qingwen Formula had the following characte-ristics in terms of patent layout. In terms of innovation technical route, the patented technical route of Lianhua Qingwen Formula was mainly based on the composition and preparation of granules as the first choice, followed by corresponding process improvements, new uses, and detection methods as the main improvement routes. In terms of the corresponding patent layout, the basic patent protection scope of Lianhua Qingwen Formula completely covered marketed drugs, and then took new functions as the main layout strategy for subsequent patent applications. With the advancement of modern technical means, the preparation process and testing methods have been optimized continuously. At the same time, the international patent layout was given the priority in domestic patent application. Based on the above characteristics, the study gave suggestions for follow-up innovation and patent work for Lianhua Qingwen Formula, so as to provide enlightenment for other traditional Chinese medicine companies in exploring original innovation of traditional Chinese medicine compounds, improving innovative methods, and enhancing the ability of patent layout of innovative achievements.

Atropa belladonna Expresses a microRNA (aba-miRNA-9497) Highly Homologous to Homo sapiens miRNA-378 (hsa-miRNA-378); both miRNAs target the 3'-Untranslated Region (3'-UTR) of the mRNA Encoding the Neurologically Relevant, Zinc-Finger Transcription Factor ZNF-691.

Recent advances in ethnobotanical and neurological research indicate that ingested plants from our diet may not only be a source of nutrition but also a source of biologically relevant nucleic-acid-encoded genetic information. A major source of RNA-encoded information from plants has been shown to be derived from small non-coding RNAs (sncRNAs) such as microRNAs (miRNAs) that can transfer information horizontally between plants and humans. In human hosts, the 3'-untranslated region (3'-UTR) of messenger RNAs (mRNAs) is targeted by these miRNAs to effectively down-regulate expression of that mRNA target in the host CNS. In this paper, we provide evidence that the Atropa belladonna aba-miRNA-9497 (miRBase conserved ID: bdi-miRNA-9497) is highly homologous to the CNS-abundant Homo sapiens miRNA-378 (hsa-miRNA-378) and both target the zinc-finger transcription factor ZNF-691 mRNA 3'-UTR to down-regulate ZNF-691 mRNA abundance. We speculate that the potent neurotoxic actions of the multiple tropane alkaloids of Atropa belladonna may be supplemented by the neuroregulatory actions of aba-miRNA-9497 on ZNF-691, and this may be followed by the modulation in the expression of ZNF-691-sensitive genes. This is the first example of a human brain-enriched transcription factor, ZNF-691, targeted and down-regulated by a naturally occurring plant microRNA, with potential to modulate gene expression in the human CNS and thus contribute to the neurotoxicological-and-psychoactive properties of the Atropa belladonna species of the deadly nightshade Solanaceae family.

Microwave ablation plus chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a multicenter, randomized, controlled, phase III clinical trial.

OBJECTIVES: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. MATERIALS AND METHODS: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. RESULTS: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups. CONCLUSIONS: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone. KEY POINTS: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.