NCPAD2 is a favorable predictor of prognostic and immunotherapeutic biomarker for multiple cancer types including lung cancer.

BACKGROUND: Non-SMC condensin I complex subunit D2 (NCAPD2) belongs to the chromosomal structural maintenance family. While the different contribution of NCAPD2 to chromosome in mitosis have been thoroughly investigated, much less is known about the expression of NCAPD2 in pan-cancer. Thus, we used a bioinformatics dataset to conduct a pan-cancer analysis of NCAPD2 to determine its regulatory role in tumors. METHODS: Multiple online databases were analyzed NCAPD2 gene expression, protein level, patient survival and functional enrichment in pan-cancer. Genetic alteration and tumor stemness of NCAPD2 were analyzed using cBioPortal and SangerBox. The GSCA and CellMiner were used to explore the relationship between NCAPD2 and drug sensitivity. The diagnostic value of prognosis was evaluated by ROC curve. Subsequently, the immune infiltration level and immune subtype of NCAPD2 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were analyzed using TIMER1 and TISIDB. RESULTS: NCAPD2 gene expression was significantly higher in most cancers and associated with clinical stage and poor prognosis. Genomic heterogeneity of NCAPD2 promoted the occurrence and development of tumors. GO enrichment analysis suggested NCAPD2 might be involved in DNA repair and immune response. NCAPD2 was involved in immune infiltration of LUAD and LUSC. ROC curves showed that NCAPD2 has important prognosis diagnostic value in LUAD and LUSC. Moreover, NCAPD2 was drug sensitive to topotecan, which may be an optimize immunotherapy. CONCLUSIONS: It was found that NCAPD2 was overexpressed in pan-cancers, which was associated with poor outcomes. Importantly, NCAPD2 could be a diagnostic marker and an immune related biomarker for LUAD and LUSC.

miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability.

BACKGROUND: T lymphoma invasion and metastasis 1 (Tiam1) is a tumor related gene that specifically activates Rho-like GTPases Rac1 and plays a critical role in the progression of various malignancies. Glycolysis plays an important role in cancer progression, it is crucial for supplying energy and producing metabolic end products, which can maintain the survival of tumor cells. As yet, however, the mechanism of Tiam1 in glycolysis reprogramming of pancreatic cancer (PC) remains to be clarified. Here, we investigated the functional role of Tiam1 in PC cell proliferation, metastasis and glycolysis reprogramming. It is expected to provide a new direction for clinical treatment. METHODS: The clinical relevance of Tiam1 was evaluated in 66 patients with PC, the effect of Tiam1 on cell proliferation was detected via 5-Ethynyl-2'-deoxyuridine (EdU) and colony formation. The ability of cell migration was detected by the wound healing and Transwell. Quantitative real time polymerase chain reaction (qRT-PCR) and luciferase reporter gene experiments clarify the regulatory relationship of miR-590-5p inhibiting Tiam1. Detection of the molecular mechanism of Tiam1 regulating glucose metabolism reprogramming in PC by glucose metabolism kit. RNA sequencing and Co-Immunoprecipitation (CoIP) have identified glucose transporter protein 3 (SLC2A3) as a key downstream target gene for miR-590-5p/Tiam1. RESULTS: We found that Tiam1 expression increased in PC tissues and was associated with lymph node metastasis. The silencing or exogenous overexpression of Tiam1 significantly altered the proliferation, invasion, and angiogenesis of PC cells through glucose metabolism pathway. In addition, Tiam1 could interact with the crucial SLC2A3 and promote the evolution of PC in a SLC2A3-dependent manner. Moreover, miR-590-5p was found to exacerbate the PC cell proliferation, migration and invasion by targeting Tiam1. Furthermore, the reversing effects on proliferation, migration and invasion were found in PC cells with miR-590-5p/Tiam1 overexpression after applying glucose metabolism inhibition. CONCLUSIONS: Our findings demonstrate the critical role of Tiam1 in PC development and the miR-590-5p/Tiam1/SLC2A3 signaling pathway may serve as a target for new PC therapeutic strategies.

The Deadly Toxin Arsenal of the Tree-Dwelling Australian Funnel-Web Spiders.

Australian funnel-web spiders are amongst the most dangerous venomous animals. Their venoms induce potentially deadly symptoms, including hyper- and hypotension, tachycardia, bradycardia and pulmonary oedema. Human envenomation is more frequent with the ground-dwelling species, including the infamous Sydney funnel-web spider (Atrax robustus); although, only two tree-dwelling species induce more severe envenomation. To unravel the mechanisms that lead to this stark difference in clinical outcomes, we investigated the venom transcriptome and proteome of arboreal Hadronyche cerberea and H. formidabilis. Overall, Hadronyche venoms comprised 44 toxin superfamilies, with 12 being exclusive to tree-dwellers. Surprisingly, the major venom components were neprilysins and uncharacterized peptides, in addition to the well-known ω- and δ-hexatoxins and double-knot peptides. The insecticidal effects of Hadronyche venom on sheep blowflies were more potent than Atrax venom, and the venom of both tree- and ground-dwelling species potently modulated human voltage-gated sodium channels, particularly NaV1.2. Only the venom of tree-dwellers exhibited potent modulation of voltage-gated calcium channels. H. formidabilis appeared to be under less diversifying selection pressure compared to the newly adapted tree-dweller, H. cerberea. Thus, this study contributes to unravelling the fascinating molecular and pharmacological basis for the severe envenomation caused by the Australian tree-dwelling funnel-web spiders.

Prognostic value of MTV and TLG of 18 F-FDG PET in patients with head and neck squamous cell carcinoma: A meta-analysis.

BACKGROUND: The current systematic review and meta-analysis explored the value of metabolic tumor volume (MTV) as well as total lesion glycolysis (TLG) in predicting the prognosis of head and neck squamous cell carcinoma (HNSCC) using 18 F-FDG PET parameters. METHODS: This work identified relevant studies in the English language by searching several electronic databases, like Cochrane Library, EMBASE, and PubMed. In addition, pooled hazard ratios (HRs) were also calculated to analyze whether MTV and TLG were significant in predicting prognosis. RESULTS: The present study included 15 primary studies involving HNSCC cases. As for the elevated TLG, it attained the pooled HR of 1.85 (95% confidence interval [CI], 1.16-2.94; P = .000; I2 = 78.3%) in predicting overall survival (OS), whereas that for elevated MTV was1.22 (95%CI, 1.09-1.36; P = .000; I2 = 82.4%). Besides, for elevated MTV, it attained the pooled HR of 1.34 (95%CI, 1.15-1.56, P = .000; I2 = 86.0%) in predicting disease-free survival (DFS); while the elevated TLG was related to DFS. Sensitivity analysis confirmed that our results are reliable. As for MTV, the ROC-stratified subgroups for DFS and multivariate analyses-stratified subgroups for OS showed statistically significant differences, with no obvious heterogeneities across different studies. For TLG, other methods-stratified subgroups for OS showed statistically significant differences, with no obvious heterogeneity across different studies. CONCLUSION: This work indicated that PET/CT is of predictive significance across HNSCC cases. Although the included articles used different methods and recruited HNSCC cases with high clinical heterogeneity; however, our findings confirmed that an elevated MTV can predict the increased risk of side reactions or even death among HNSCC cases and that an elevated TLG can predict a higher death risk.

Visualization of Sodium Metal Anodes via Operando X-Ray and Optical Microscopy: Controlling the Morphological Evolution of Sodium Metal Plating.

Because of the abundance and cost effectiveness of sodium, rechargeable sodium metal batteries have been widely studied to replace current lithium-ion batteries. However, there are some critical unresolved issues including the high reactivity of sodium, an unstable solid-electrolyte interphase (SEI), and sodium dendrite formation. While several studies have been conducted to understand sodium plating/stripping processes, only a very limited number of studies have been carried out under operando conditions. We have employed operando X-ray and optical imaging techniques to understand the mechanistic behavior of Na metal plating. The morphology of sodium metal plated on a copper electrode depends strongly on the salts and solvents used in the electrolyte. The addition of a fluorine-containing additive to a carbonate-based electrolyte, NaClO4 in propylene carbonate (PC):fluoroethylene carbonate (FEC), results in uniform sodium plating processes and much more stable cycling performance, compared to NaClO4 in PC, because of the formation of a stable SEI containing NaF. A NaF layer, on top of the sodium metal, leads to a much more uniform deposition of sodium and greatly enhanced cyclability.

Discovery of novel peptide neurotoxins from sea anemone species.

As primitive metazoa, sea anemones are rich in various bioactive peptide neurotoxins. These peptides have been applied to neuroscience research tools or directly developed as marine drugs. To date, more than 1100 species of sea anemones have been reported, but only 5% of the species have been used to isolate and identify sea anemone peptide neurotoxins. There is an urgent need for more systematic discovery and study of peptide neurotoxins in sea anemones. In this review, we have gathered the currently available methods from crude venom purification and gene cloning to venom multiomics, employing these techniques for discovering novel sea anemone peptide neurotoxins. In addition, the three-dimensional structures and targets of sea anemone peptide neurotoxins are summarized. Therefore, the purpose of this review is to provide a reference for the discovery, development, and utilization of sea anemone peptide neurotoxins.

The Allosteric Activation of α7 nAChR by α-Conotoxin MrIC Is Modified by Mutations at the Vestibular Site.

α-conotoxins are 13-19 amino acid toxin peptides that bind various nicotinic acetylcholine receptor (nAChR) subtypes. α-conotoxin Mr1.7c (MrIC) is a 17 amino acid peptide that targets α7 nAChR. Although MrIC has no activating effect on α7 nAChR when applied by itself, it evokes a large response when co-applied with the type II positive allosteric modulator PNU-120596, which potentiates the α7 nAChR response by recovering it from a desensitized state. A lack of standalone activity, despite activation upon co-application with a positive allosteric modulator, was previously observed for molecules that bind to an extracellular domain allosteric activation (AA) site at the vestibule of the receptor. We hypothesized that MrIC may activate α7 nAChR allosterically through this site. We ran voltage-clamp electrophysiology experiments and in silico peptide docking calculations in order to gather evidence in support of α7 nAChR activation by MrIC through the AA site. The experiments with the wild-type α7 nAChR supported an allosteric mode of action, which was confirmed by the significantly increased MrIC + PNU-120596 responses of three α7 nAChR AA site mutants that were designed in silico to improve MrIC binding. Overall, our results shed light on the allosteric activation of α7 nAChR by MrIC and suggest the involvement of the AA site.

Venom duct origins of prey capture and defensive conotoxins in piscivorous Conus striatus.

The venom duct origins of predatory and defensive venoms has not been studied for hook-and-line fish hunting cone snails despite the pharmacological importance of their venoms. To better understand the biochemistry and evolution of injected predatory and defensive venoms, we compared distal, central and proximal venom duct sections across three specimens of C. striatus (Pionoconus) using proteomic and transcriptomic approaches. A total of 370 conotoxin precursors were identified from the whole venom duct transcriptome. Milked defensive venom was enriched with a potent cocktail of proximally expressed inhibitory α-, ω- and µ-conotoxins compared to milked predatory venom. In contrast, excitatory κA-conotoxins dominated both the predatory and defensive venoms despite their distal expression, suggesting this class of conotoxin can be selectively expressed from the same duct segment in response to either a predatory or defensive stimuli. Given the high abundance of κA-conotoxins in the Pionoconus clade, we hypothesise that the κA-conotoxins have evolved through adaptive evolution following their repurposing from ancestral inhibitory A superfamily conotoxins to facilitate the dietary shift to fish hunting and species radiation in this clade.

Globular and ribbon isomers of Conus geographus α-conotoxins antagonize human nicotinic acetylcholine receptors.

The short disulfide-rich α-conotoxins derived from the venom of Conus snails comprise a conserved CICII(m)CIII(n)CIV cysteine framework (m and n, number of amino acids) and the majority antagonize nicotinic acetylcholine receptors (nAChRs). Depending on disulfide connectivity, α-conotoxins can exist as either globular (CI-CIII, CII-CIV), ribbon (CI-CIV, CII-CIII) or bead (CI-CII, CIII-CIV) isomers. In the present study, C. geographus α-conotoxins GI, GIB, G1.5 and G1.9 were chemically synthesized as globular and ribbon isomers and their activity investigated at human nAChRs expressed in Xenopus oocytes using the two-electrode voltage clamp recording technique. Both the globular and ribbon isomers of the 3/5 (m/n) α-conotoxins GI and GIB selectively inhibit heterologous human muscle-type α1ß1δε nAChRs, whereas G1.5, a 4/7 α-conotoxin, selectively antagonizes neuronal (non-muscle) nAChR subtypes particularly human α3ß2, α7 and α9α10 nAChRs. In contrast, globular and ribbon isomers of G1.9, a novel C-terminal elongated 4/8 α-conotoxin exhibited no activity at the human nAChR subtypes studied. This study reinforces earlier observations that 3/5 α-conotoxins selectively target the muscle nAChR subtypes, although interestingly, GIB is also active at α7 and α9 α10 nAChRs. The 4/7 α-conotoxins target human neuronal nAChR subtypes whereas the pharmacology of the 4/8 α-conotoxin remains unknown.

Venom chemistry underlying the painful stings of velvet ants (Hymenoptera: Mutillidae).

Velvet ants (Hymenoptera: Mutillidae) are a family of solitary parasitoid wasps that are renowned for their painful stings. We explored the chemistry underlying the stings of mutillid wasps of the genus Dasymutilla Ashmead. Detailed analyses of the venom composition of five species revealed that they are composed primarily of peptides. We found that two kinds of mutillid venom peptide appear to be primarily responsible for the painful effects of envenomation. These same peptides also have defensive utility against invertebrates, since they were able to incapacitate and kill honeybees. Both act directly on cell membranes where they directly increase ion conductivity. The defensive venom peptides of Dasymutilla bear a striking similarity, in structure and mode of action, to those of the ant Myrmecia gulosa (Fabricius), suggesting either retention of ancestral toxins, or convergence driven by similar life histories and defensive selection pressures. Finally, we propose that other highly expressed Dasymutilla venom peptides may play a role in parasitisation, possible in delay or arrest of host development. This study represents the first detailed account of the composition and function of the venoms of the Mutillidae.

Chemical Synthesis and NMR Solution Structure of Conotoxin GXIA from Conus geographus.

Conotoxins are disulfide-rich peptides found in the venom of cone snails. Due to their exquisite potency and high selectivity for a wide range of voltage and ligand gated ion channels they are attractive drug leads in neuropharmacology. Recently, cone snails were found to have the capability to rapidly switch between venom types with different proteome profiles in response to predatory or defensive stimuli. A novel conotoxin, GXIA (original name G117), belonging to the I3-subfamily was identified as the major component of the predatory venom of piscivorous Conus geographus. Using 2D solution NMR spectroscopy techniques, we resolved the 3D structure for GXIA, the first structure reported for the I3-subfamily and framework XI family. The 32 amino acid peptide is comprised of eight cysteine residues with the resultant disulfide connectivity forming an ICK+1 motif. With a triple stranded ß-sheet, the GXIA backbone shows striking similarity to several tarantula toxins targeting the voltage sensor of voltage gated potassium and sodium channels. Supported by an amphipathic surface, the structural evidence suggests that GXIA is able to embed in the membrane and bind to the voltage sensor domain of a putative ion channel target.

The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation.

Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (NaV) channels, however relatively few venom-derived peptides with activity at the mammalian NaV1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of ß-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV1.8. Eo1a is a 37-residue peptide that increases NaV1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50-20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50-15.5 ± 1.8 mV). At a concentration of 10 µM, Eo1a has varying effects on the peak current and channel gating of NaV1.1-NaV1.7, although its activity is most pronounced at NaV1.8. Investigations into the binding site of Eo1a using NaV1.7/NaV1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV1.8.

Electrolyte screening studies for Li metal batteries.

From 60 solvent electrolyte combinations tested, we find that Li metal anodes, tested in 1 M LiFSI in DOL:DME exhibit an outstanding cycling performance (>500 cycles) even at high current densities (3 mA cm-2). The excellent performance is ascribed, at least in part, to a low Li nucleation overpotential and a low charge transfer resistance during cycling.

Structural and Thermodynamic Understandings in Mn-Based Sodium Layered Oxides during Anionic Redox.

A breakthrough utilizing an anionic redox reaction (O2-/On-) for charge compensation has led to the development of high-energy cathode materials in sodium-ion batteries. However, its reaction results in a large voltage hysteresis due to the structural degradation arising from an oxygen loss. Herein, an interesting P2-type Mn-based compound exhibits a distinct two-phase behavior preserving a high-potential anionic redox (≈4.2 V vs Na+/Na) even during the subsequent cycling. Through a systematic series of experimental characterizations and theoretical calculations, the anionic redox reaction originating from O 2p-electron and the reversible unmixing of Na-rich and Na-poor phases are confirmed in detail. In light of the combined study, a critical role of the anion-redox-induced two-phase reaction in the positive-negative point of view is demonstrated, suggesting a rational design principle considering the phase separation and lattice mismatch. Furthermore, these results provide an exciting approach for utilizing the high-voltage feature in Mn-based layered cathode materials that are charge-compensated by an anionic redox reaction.

Clinical characteristics of patients diagnosed with COVID-19 in Beijing.

This study aimed to determine the clinical characteristics of patients diagnosed with the coronavirus disease 2019 (COVID-19). Clinical data of COVID-19 patients diagnosed between January 28, 2020 and February 23, 2020 at the Beijing You'an Hospital were summarized and analyzed. Overall, 45 (18 men and 27 women) patients were included in this study. The average age of patients was 58 years (range, 7-94 years). Furthermore, 21 patients (47%) experienced underlying chronic diseases, with another four patients (9%) having three or more chronic diseases simultaneously. The first symptoms appeared at the onset of illness onset include fever in 36 patients (80%), cough in 23 patients (51%), and expectoration in 15 patients (33%), respectively. Patients may experience hepatic and renal injury as well as abnormal myocardial enzymes in varying degrees. Senior patients (≥58) and accompanying chronic diseases were considered as independent predictors for developing a severe and critically ill population with increased mortality. Laboratory results regarding the NEU percentage, NLR, ALC, and C-reactive protein levels were considered significant in predicting clinically critical disease or for prognosis assessment and thus require further studies. COVID-19 may affect multiple organs of the human body. Glucocorticoid is considered effective in the treatment of patients diagnosed with severe COVID-19.

Bi-MOF derived micro/meso-porous Bi@C nanoplates for high performance lithium-ion batteries.

Micro/meso-porous Bi@C nanoplates are synthesized by pyrolyzing Bi-based metal-organic frameworks (MOFs) prepared by a microwave-assisted hydrothermal method to overcome huge volume expansion and pulverization of anode materials during battery operation. The Bi@C nanoplates are composed of ∼10-50 nm Bi nanoparticles in an amorphous carbon shell. The material shows very high capacity (556 mA h g-1) after 100 cycles at 100 mA g-1 and good cycling performance. Moreover, the Bi@C nanoplates perform well at high current densities and have excellent cyclic stability; their capacity is 308 mA h g-1 after 50 cycles and 200 mA h g-1 after 1000 cycles at 3000 mA g-1. The outstanding performance of this anode is due to the nanosized Bi and amorphous carbon shell. The nanosized Bi reduces the diffusion length of Li ions, while the amorphous carbon shell improves the electrical conductivity of the anode and also restrains the pulverization and aggregation of the metal during cycling. The proposed hierarchical micro/meso-porous materials derived from MOFs are a new type of nanostructures that can aid the development of novel Bi-based anodes for LIBs.

Sn(salen)-derived SnS nanoparticles embedded in N-doped carbon for high performance lithium-ion battery anodes.

By simple pyrolysis of a tin salen complex [Sn(salen)] and sulfur powder at 700 °C, SnS nanoparticles with ∼20 nm thickness homogeneously embedded in nitrogen-doped carbon are prepared. When applied as lithium-ion battery anodes, the SnS/N-C nanocomposites exhibited long cycling stability and excellent rate capability.

Effect of Jinhua Qinggan granules on novel coronavirus pneumonia in patients.

OBJECTIVE: To evaluate the effectiveness and safety of Jinhua Qinggan granules in the treatment of patients with novel coronavirus pneumonia (COVID-19). METHODS: Eighty cases of COVID-19 diagnosed from January 24 to February 17, 2020 in Beijing YouAn Hospital Affiliated to Capital Medical University were retrospectively analyzed. All 80 patients received symptomatic and supportive treatment. Among them, 44 patients took Jinhua Qinggan granules (treatment group) within 24 h of admission, and the remaining 36 patients either did not take Jinhua Qinggan granules or took the granules for less than 2 d (control group). In this study, we compared the duration of viral nucleic acid detection and of pneumonia absorption improvement between the two groups. RESULTS: Among the 80 cases, 37 were male (46%) and 43 were female (54%) with age ranging from 15 to 86 years, with an average age of 51.19 years. The average duration of viral nucleic acid detection was (7 ± 4) d in the Jinhua Qinggan administration group and (10 ± 4) d for the control group (P = 0.010), following which, nucleic acid tests were negative. Of the two groups, 56.82% in the Jinhua Qinggan treatment group and 27.78% in the control group demonstrated negative nucleic acid tests within 7 d or less. The 7-day viral clearance rate was significantly higher in the Jinhua Qinggan group compared with the control group (P = 0.009). Furthermore, the pneumonia recovery time indicated by chest CT was (8 ± 4) d in the Jinhua Qinggan group, which was significantly shorter than the control group, at (10 ± 5) d (P = 0.021). No adverse reactions were found in the treatment group after taking this medicine. CONCLUSION: In patients with COVID-19, Jinhua Qinggan granules can effectively shorten the duration of nucleic acid detection and promote the absorption of pneumonia inflammatory exudate without obvious adverse reactions.

Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.

The role of voltage-gated sodium (NaV) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms NaV1.8 and NaV1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat NaV1.8 and mouse NaV1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant NaV isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human NaV1.8 and NaV1.9, and lacked analgesic efficacy in a murine model of inflammatory pain.