A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) ...is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.
Abstract
Background
Cyclin-dependent kinase inhibitor 2C (CDKN2C) was identified to participate in the occurrence and development of multiple cancers; however, its roles in small cell lung carcinoma ...(SCLC) remain unclear.
Methods
Differential expression analysis of CDKN2C between SCLC and non-SCLC were performed based on 937 samples from multiple centers. The prognosis effects of
CDKN2C
in patients with SCLC were detected using both Kaplan–Meier curves and log-rank tests. Using receiver-operating characteristic curves, whether
CDKN2C
expression made it feasible to distinguish SCLC was determined. The potential mechanisms of
CDKN2C
in SCLC were investigated by gene ontology terms and signaling pathways (Kyoto Encyclopedia of Genes and Genomes). Based on 10,080 samples, a pan-cancer analysis was also performed to determine the roles of
CDKN2C
in multiple cancers.
Results
For the first time, upregulated CDKN2C expression was detected in SCLC samples at both the mRNA and protein levels (
p
of Wilcoxon rank-sum test < 0.05; standardized mean difference = 2.86 95% CI 2.20–3.52). Transcription factor FOXA1 expression may positively regulate
CDKN2C
expression levels in SCLC. High
CDKN2C
expression levels were related to the poor prognosis of patients with SCLC (hazard ratio > 1,
p
< 0.05) and showed pronounced effects for distinguishing SCLC from non-SCLC (sensitivity, specificity, and area under the curve ≥ 0.95).
CDKN2C
expression may play a role in the development of SCLC by affecting the cell cycle. Furthermore, the first pan-cancer analysis revealed the differential expression of
CDKN2C
in 16 cancers (breast invasive carcinoma, etc
.
) and its independent prognostic significance in nine cancers (
e.g
., adrenocortical carcinoma).
CDKN2C
expression was related to the immune microenvironment, suggesting its potential usefulness as a prognostic marker in immunotherapy.
Conclusions
This study identified upregulated CDKN2C expression and its clinical significance in SCLC and other multiple cancers, suggesting its potential usefulness as a biomarker in treating and differentiating cancers.
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•Combined effects of MPs and BHA on zebrafish embryos/larvae were evaluated.•MPs promoted the accumulation of BHA in zebrafish larvae.•MPs enhanced the toxicity of BHA in larvae ...development.•Coexposure disturbed arachidonic acid, glycerophospholipid, and lipids metabolism.
Coexposure of MPs and other contaminants adsorbed from the environment has raised many attentions, but the understanding of the combined effects of MPs and plastic additives are limited. Butylated hydroxyanisole (BHA), a widely used synthetic phenolic antioxidant in plastics, has gained high concerns due to their unintended environmental release and potential threat to aquatic organisms. This study was conducted to reveal the influences of MPs on the bioaccumulation and developmental toxicity of BHA in zebrafish larvae. As a result, MPs promoted the accumulation of BHA in zebrafish larvae and enhanced the toxicity of BHA in larvae development manifested by reduced hatching rates, increased malformation rates and decreased calcified vertebrae. Although the concentration of MPs was not sufficient to cause obvious developmental toxicity, the impacts of MPs on thyroid hormones status might contribute to the aggravated join toxicity. The metabolomic mechanism was revealed to be that the coexposure of BHA and MPs affected the development of zebrafish larvae via disturbing the metabolism of arachidonic acid, glycerophospholipid, and lipids. Our results emphasized that MPs, even at the nontoxic concentrations, in combination with additives caused health risk that should not be ignored.
To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L ...(CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.
Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of ...mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by
. However, BNP also binds to its cognate receptor, NPRC encoded by
with equal potency. Moreover, natriuretic peptides (NP) signal through the G
-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that
expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via G
-couped PLCβ-Ca
signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca
responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.
The present study was carried out to investigate the hypoglycemic effect of soy isoflavones from hypocotyl in GK diabetic rats. A single administration and long-term administration tests were ...conducted in GK diabetic rats to test the hypoglycemic effect of soy isoflavones. At the end of long-term administration trial, blood protein, cholesterol, triglyceride, glycosylated serum protein, C-reactive protein, insulin, aminotransferase, lipid peroxide, interleukin-6, tumor necrosis factor-α were estimated. Inhibition of soy isoflavones against α-amylase and α-glucosidase, as well as on glucose uptake into brush border membrane vesicles or Caco-2 cells were determined in vitro. In single administration experiment, soy isoflavones reduced postprandial blood glucose levels in GK rats. In long-term administration, hypoglycemic effect of soy isoflavones was first observed at week 12 and maintained till week 16. A significant reduction in fasting blood glucose, C-reactive protein, and lipid peroxide was noted at week 16. However, there was no significant treatment effect on blood insulin. Furthermore, soy isoflavone administration resulted in significant decreases in glycosylated serum protein, tumor necrosis factor-α, and interleukin-6. Other biochemical parameters, such as protein, cholesterol, triglyceride and aminotransferases were not modified, however. The results in vitro showed that soy isoflavones showed a potent inhibitory effect on intestinal α-glucosidase, but not on pancreatic α-amylase. Soy isoflavones also decreased glucose transport potency into brush border membrane vesicles or Caco-2 cells. It is concluded that soy isoflavones from hypocotyl, performs hypoglycemic function in GK rats with type 2 diabetes, maybe via suppression of carbohydrate digestion and glucose uptake in small intestine.
Tin‐based halide perovskite materials have been successfully employed in lead‐free perovskite solar cells, but the overall power conversion efficiencies (PCEs) have been limited by the high carrier ...concentration from the facile oxidation of Sn2+ to Sn4+. Now a chemical route is developed for fabrication of high‐quality methylammonium tin iodide perovskite (MASnI3) films: hydrazinium tin iodide (HASnI3) perovskite film is first solution‐deposited using presursors hydrazinium iodide (HAI) and tin iodide (SnI2), and then transformed into MASnI3 via a cation displacement approach. With the two‐step process, a dense and uniform MASnI3 film is obtained with large grain sizes and high crystallization. Detrimental oxidation is suppressed by the hydrazine released from the film during the transformation. With the MASnI3 as light harvester, mesoporous perovskite solar cells were prepared, and a maximum power conversion efficiency (PCE) of 7.13 % is delivered with good reproducibility.
High‐quality, pinhole‐free CH3NH3SnI3 films are achieved from pristine NH2NH3SnI3 perovskite, and the oxidation of Sn2+ to Sn4+ can be efficiently suppressed owing to the reduction agent hydrazine generated inside the films in the conversion. With the CH3NH3SnI3 film as light absorber, mesoporous MASnI3 perovskite solar cells were fabricated with a maximum PCE of 7.13 %.
The forms of alkalis of the biochars produced from the straws of canola, corn, soybean and peanut at different temperatures (300, 500 and 700°C) were studied by means of oxygen-limited pyrolysis. The ...alkalinity and pH of the biochars increased with increased pyrolysis temperature. The X-ray diffraction spectra and the content of carbonates of the biochars suggested that carbonates were the major alkaline components in the biochars generated at the high temperature; they were also responsible for the strong buffer plateau-regions on the acid–base titration curves at 500 and 700°C. The data of FTIR–PAS and zeta potentials indicated that the functional groups such as –COO− (–COOH) and –O− (–OH) contained by the biochars contributed greatly to the alkalinity of the biochar samples tested, especially for those generated at the lower temperature. These functional groups were also responsible for the negative charges of the biochars.
After decades of molecular phylogenetic studies, the deep phylogeny of gymnosperms has not been resolved, and the phylogenetic placement of Gnetales remains one of the most controversial issues in ...seed plant evolution. To resolve the deep phylogeny of seed plants and to address the sources of phylogenetic conflict, we conducted a phylotranscriptomic study with a sampling of all 13 families of gymnosperms and main lineages of angiosperms. Multiple datasets containing up to 1 296 042 sites across 1308 loci were analysed, using concatenation and coalescence approaches. Our study generated a consistent and well-resolved phylogeny of seed plants, which places Gnetales as sister to Pinaceae and thus supports the Gnepine hypothesis. Cycads plus
is sister to the remaining gymnosperms. We also found that Gnetales and angiosperms have similar molecular evolutionary rates, which are much higher than those of other gymnosperms. This implies that Gnetales and angiosperms might have experienced similar selective pressures in evolutionary histories. Convergent molecular evolution or homoplasy is partially responsible for the phylogenetic conflicts in seed plants. Our study provides a robustly reconstructed backbone phylogeny that is important for future molecular and morphological studies of seed plants, in particular gymnosperms, in the light of evolution.
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