Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

Few-shot disease recognition algorithm based on supervised contrastive learning.

Diseases cause crop yield reduction and quality decline, which has a great impact on agricultural production. Plant disease recognition based on computer vision can help farmers quickly and accurately recognize diseases. However, the occurrence of diseases is random and the collection cost is very high. In many cases, the number of disease samples that can be used to train the disease classifier is small. To address this problem, we propose a few-shot disease recognition algorithm that uses supervised contrastive learning. Our algorithm is divided into two phases: supervised contrastive learning and meta-learning. In the first phase, we use a supervised contrastive learning algorithm to train an encoder with strong generalization capabilities using a large number of samples. In the second phase, we treat this encoder as an extractor of plant disease features and adopt the meta-learning training mechanism to accomplish the few-shot disease recognition tasks by training a nearest-centroid classifier based on distance metrics. The experimental results indicate that the proposed method outperforms the other nine popular few-shot learning algorithms as a comparison in the disease recognition accuracy over the public plant disease dataset PlantVillage. In few-shot potato leaf disease recognition tasks in natural scenarios, the accuracy of the model reaches the accuracy of 79.51% with only 30 training images. The experiment also revealed that, in the contrastive learning phase, the combination of different image augmentation operations has a greater impact on model. Furthermore, the introduction of label information in supervised contrastive learning enables our algorithm to still obtain high accuracy in few-shot disease recognition tasks with smaller batch size, thus allowing us to complete the training with less GPU resource compared to traditional contrastive learning.

Increasing N active sites by in-situ growing conformal C3N4 layer in hierarchical porous carbon-based networks for fast Li+ transfer and polysulfide anchoring in lithium-sulfur batteries.

Various challenges remain to be overcome in lithium-sulfur (Li-S) batteries, including the volume expansion and low conductivity of sulfur, the shuttle effect of lithium polysulfides and the sluggish redox reaction in the cell. Herein, we propose a multilayered conductive framework by the in situ growth of a conformal graphene-like C3N4 (GCN) coating on porous CNT@NC networks with carbon nanotubes (CNTs) as the core and N-doped carbon (NC) as the crosslinking shell. The abundant N in the GCN coating increased the surface N concentration of the framework from 14.38% to 18.77%, which enriched the active sites in the frameworks for the adsorption and catalysis conversion of LiPSs and Li2S with a low energy barrier. Furthermore, the scalable frameworks can provide an 85% porosity for a sufficient reaction interface and accommodate the volume expansion of sulfur. The synergistic effect between GCN and the highly conductive hierarchical structure can accelerate the transport of Li+ and electrons as well as the diffusion of electrolyte. Benefitting from the above advantages, the Al-free CNT@NC@GCN electrode exhibits a reversible capacity of 647.6 mAh g-1 after cycling for 450 cycles at 1C with a low capacity fading rate of 0.09% per cycle. This proposed facile strategy creates inspiring insights into the design of novel cathode materials for Li-S batteries.

Thiophilic-Lithiophilic Hierarchically Porous Membrane-Enabled Full Lithium-Sulfur Battery with a Low N/P Ratio.

Lithium-sulfur batteries stand out as the next-generation batteries because of their high energy density and low cost. However, the shuttle effect of lithium polysulfides (LiPSs), growth of lithium dendrites, and overuse of lithium resources still hinder their further application. To address these problems, we constructed a porous network structure in which Sn is melted and coated on a frame that has a carbon nanotube (CNT) core and a nitrogen-doped carbon (NC) coating as cross-linking shell (CNT@NC@Sn). This hierarchically porous membrane electrode, which has an ultrahigh porosity of approximately 90%, works as a matrix to strengthen the conductivity of Li+ and electrons and provides enough space for the conversion between sulfur and LiPSs. Moreover, the in situ thin coating of Sn not only promotes the adsorption and catalytic conversion of LiPSs but also provides lithiophilic binding sites and induces uniform lithium deposition. Thus, the thiophilic-lithiophilic porous membrane electrode with lithium loaded on the frame (in the form of Sn-Li alloy) by electroplating can replace lithium sheets, reduce the use of Li, and improve the safety performance of the battery. Additionally, these dual-functional membranes boost the reaction kinetics and conductivity of the cathode by dispersing the sulfur slurry in the porous membrane framework. As a result, the lithium-sulfur full battery assembled with the CNT@NC@Sn integrated membrane electrode exhibits stable cycling with a reversible capacity of 617.1 mAh g-1 after 200 cycles at 1 C. The capacity decay rate per cycle is 0.105%, and the N/P ratio is as low as 2.98.

Exploration of anti-chromium mechanism of marine Penicillium janthinellum P1 through combinatorial transcriptomic analysis and WGCNA.

Fungi have a promising application prospect in the remediation of heavy-metal wastewater pollution which is a sticky global problem. New marine-derived strain Penicillium janthinellum P1 is of high chromium resistance. However, a comprehensive study of the transcriptomics in Penicillium janthinellum P1 strains is lacking. Firstly, the changing trends of a series of physiological and biochemical indices of P1 strain at 0 M and 1 M Cr concentration were investigated to track the ROS variation. Secondly, transcriptome sequencing of P1 was performed by RNA-Seq sequencing technology. The transcriptome data indicated that 12,352 coding protein regions were predicted, and 6655 differentially expressed genes were identified by DESeq2, of which 4234 genes were up-regulated, and 2421 genes down-regulated. Through further co-expression network of WGCNA analysis, the filtered unigenes were clustered into 19 modules. Combined with the physiological and biochemical findings, the three modules with the highest correlation with the six traits were selected to construct the network, and 52 hub genes were obtained. Furthermore, 10 speculative hub genes related to chromium resistance were selected and verified by real-time PCR. The results were in line with the expected experimental assumption. These results improve our understanding of the transcriptomic dimensions of the high chromium resistance of Penicillium janthinellum P1 strains.

Alpha-lipoic acid could attenuate the effect of chemerin-induced diabetic nephropathy progression.

OBJECTIVES: Chemerin is associated with insulin resistance, obesity, and metabolic syndrome. α-lipoic acid (α-LA) is a potent antioxidant involved in the reduction of diabetic symptoms. This study aimed to investigate the relationship between chemerin and P38 MAPK in the progression of diabetic nephropathy (DN) and examine the effects of α-LA on chemerin-treated human mesangial cells (HMCs). MATERIALS AND METHODS: HMCs were transfected with a chemerin-overexpressing plasmid. HMCs were also treated with high-glucose, chemerin, α-LA, PDTC (pyrrolidine dithiocarbamate ammonium, NF-κB p65 inhibitor), and/or SB203580 (P38 MAPK inhibitor). Cell proliferation was tested using the Cell Counting Kit-8 assay. Collagen type IV and laminin were tested by ELISA. Chemerin expression was detected by qRT-PCR. The chemerin receptor was detected by immunohistochemistry. Interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), nuclear factor-κBp-p65 (NF-κB p-p65), transforming growth factor-ß (TGF-ß), and p-P38 mitogen-activated protein kinase (p-P38 MAPK) were evaluated by western blot. RESULTS: High-glucose culture increased the expression of the chemerin receptor. α-LA inhibited HMC proliferation. Chemerin overexpression increased collagen type IV and laminin expression. P38 MAPK signaling was activated by chemerin, resulting in up-regulation of IL-6, TNF-α, NF-κB p-p65, and TGF-ß. SB203580, PDTC, and α-LA reversed the effects of chemerin, reducing IL-6, TNF-α, NF-κB p-p65, and TGF-ß expression. CONCLUSION: Chemerin might be involved in the occurrence and development of DN. α-LA might prevent the effects of chemerin on the progression of DN, possibly via the P38 MAPK pathway.

Robust and Fast Lithium Storage Enabled by Polypyrrole-Coated Nitrogen and Phosphorus Co-Doped Hollow Carbon Nanospheres for Lithium-Ion Capacitors.

Lithium-ion capacitors (LICs) have been proposed as an emerging technological innovation that integrates the advantages of lithium-ion batteries and supercapacitors. However, the high-power output of LICs still suffers from intractable challenges due to the sluggish reaction kinetics of battery-type anodes. Herein, polypyrrole-coated nitrogen and phosphorus co-doped hollow carbon nanospheres (NPHCS@PPy) were synthesized by a facile method and employed as anode materials for LICs. The unique hybrid architecture composed of porous hollow carbon nanospheres and PPy coating layer can expedite the mass/charge transport and enhance the structural stability during repetitive lithiation/delithiation process. The N and P dual doping plays a significant role on expanding the carbon layer spacing, enhancing electrode wettability, and increasing active sites for pseudocapacitive reactions. Benefiting from these merits, the NPHCS@PPy composite exhibits excellent lithium-storage performances including high rate capability and good cycling stability. Furthermore, a novel LIC device based on the NPHCS@PPy anode and the nitrogen-doped porous carbon cathode delivers a high energy density of 149 Wh kg-1 and a high power density of 22,500 W kg-1 as well as decent cycling stability with a capacity retention rate of 92% after 7,500 cycles. This work offers an applicable and alternative way for the development of high-performance LICs.

microRNA-103 Contributes to Progression of Polycystic Ovary Syndrome Through Modulating the IRS1/PI3K/AKT Signal Axis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a frequent gynecological endocrine disorder, and the majority of PCOS patients experience different degrees of insulin resistance (IR). Nevertheless, the functions of microRNAs (miRNAs) in IR of PCOS remain unclear. In this study, we desired to elucidate the mechanisms of miR-103 in IR of PCOS. METHODS: The ovarian pathological morphology of established PCOS rats was detected by HE staining. Following miR-103 expression determination in the ovarian tissues of PCOS rats, the relationship between its expression and IR was studied. A PCOS/IR cell model was established, and the effect of miR-103 on granulosa cells was determined by CCK-8 assay and flow cytometry. Through online website prediction and consulting related literatures, the target gene of miR-103 and the pathway regulated by the target genes were discovered, which was verified by further experiments. RESULTS: PCOS rats showed polycystic changes in the ovary and a decrease in granulosa cells, and these symptoms were more pronounced in rats showed IR. miR-103 expressed highly in PCOS and was positively related to IR. miR-103 inhibitor led to improved PCOS-related symptoms. In addition, miR-103 directly targeted IRS1, which was poorly expressed in PCOS, and IRS1 silencing promoted PCOS development. Furthermore, miR-103 regulated the PI3K/AKT pathway by targeting IRS1, and PI3K/AKT pathway suppression reduced the therapeutic effect of miR-103 inhibitor. CONCLUSION: This study indicates that miR-103 disrupts the PI3K/AKT pathway activation by targeting IRS1, thereby aggravating PCOS development. miR-103 inhibition may be a promising molecular target for treatment of PCOS.

Anomalous expression of miR-103 in polycystic ovary syndrome influenced by hormonal, and metabolic variables.

BACKGROUND: Polycystic ovary syndrome (PCOS), a common endocrine disorder in reproductive-aged women, is correlated with obesity and insulin resistance (IR), androgens excess, chronic anovulation, and infertility. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNA molecules that participate in inflammation, reproduction and metabolism, may contribute to PCOS. Current study aiming to manifest the correlation of body mass index (BMI) and testosterone (T) with miR-103 expression before and after fat loss. METHODS: 46 controls (N = 23 with BMI < 24 kg/m2, N = 23 with BMI ≥ 28 kg/m2) and 46 patients with PCOS (N = 23 with BMI < 24 kg/m2, N = 23 with BMI ≥ 28 kg/m2) aged between 20 and 30 were recruited. Waist-to-hip (WHR) and Body fat% (BF%) was measured and calculated. Serum hormones, serum lipid, metabolism parameters, and serum miR-103 were measured. All the assessments were measured before and after fat loss in a three-month intervention period. RESULTS: miR-103 was correlated with BMI rather than testosterone (T), and there was a significant difference between the non-obese and obese groups in miR-103 expression. Compared to before fat loss, miR-103 expression showed a slight downward trend. CONCLUSIONS: Serum miR-103 differentially expressed between controls and PCOS subjects, miR-103 was positively correlated with BMI. There was significant difference between the non-obese and obese groups in miR-103 expression.

Association between vaspin level and coronary artery disease in patients with type 2 diabetes.

AIM: Adipokines contribute to the atherosclerotic process, connecting obesity and diabetes to cardiovascular disease. Vaspin is a recently discovered adipokine, so data about the relationship of vaspin to coronary artery disease in type-2 diabetes mellitus (T2DM) is limited. The current study was designed to evaluate the association of vaspin with the presence of coronary artery disease in T2DM. METHODS: We enrolled 228 patients with T2DM, with or without CAD, between March 2010 and July 2011, and 120 healthy control participants. Serum vaspin, homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiovascular risk factors were assayed. RESULTS: Vaspin levels were significantly increased in patients with T2DM compared to healthy individuals, and were further increased in patients with both T2DM and CAD compared to those with T2DM but without CAD. Moreover, vaspin correlated positively with body mass index, fasting plasma glucose, insulin and HOMA-IR in all patients with T2DM (P<0.05). Furthermore, in multivariate logistic regression analysis, vaspin level was associated with the presence of CAD in patients with T2DM. CONCLUSIONS: Vaspin correlates with CAD in T2DM.

Effect of Irbesartan on Chemerin in the Renal Tissues of Diabetic Rats.

BACKGROUND/AIMS: Chemerin was introduced as a novel adipokine that plays a crucial role in insulin signaling and diabetic nephropathy. Serum chemerin levels are significantly elevated in type 2 diabetes patients with macroalbuminuria. However, the underlying mechanisms remain unclear. We conducted a preliminary investigation of the effects of the renin-angiotensin system (RAS) on chemerin expression in streptozotocin-induced diabetic rats. METHODS: Streptozotocin-induced diabetic rats were randomized into control, diabetic, and irbesartan-treated groups. Real-time polymerase chain reaction was used to detect mRNA expression of chemerin, angiotensin II type 1a receptor (AT1a), angiotensin II type 1b receptor (AT1b) and angiotensin II type 2 receptor (AT2). Immunohistochemical staining was used to detect chemerin in renal tissues. RESULTS: Expression levels of chemerin in renal tissues were significantly elevated in the diabetic group compared to the control group. In the irbesartan-treated group, chemerin expression levels and RAS-related protein levels (i.e. AT1a and AT1b) were markedly decreased compared to the diabetic group. Irbesartan treatment reduced chemerin overexpression and RAS-related protein levels in diabetic rats (i.e. AT1a and AT1b). CONCLUSION: Irbesartan may inhibit intrarenal RAS in diabetic rats, which may affect the expression of chemerin in the kidneys; however, the precise underlying mechanism remains to be determined.

Damage to vascular endothelial cells by high insulin levels is associated with increased expression of ChemR23, and attenuated by PPAR-gamma agonist, rosiglitazone.

OBJECTIVE: This study investigated the effect of different insulin concentrations on the activity of vascular endothelial cells (VECs), and the role of PPARγ activator rosiglitazone (RGZ) on the expression of the chemerin receptor, ChemR23, in insulin-treated human umbilical vein endothelial cells (HUVECs). METHODS: Cell viability was determined in HUVECs treated with different insulin concentrations. Immunofluorescence staining was used to detect ChemR23 expression in insulin-treated HUVECs. Western blot assays were used to evaluate ChemR23 and PPARγ protein expression in insulin-treated HUVECs after pretreatment with PPARγ activator (RGZ) or inhibitor (GW9662). RESULTS: High insulin concentrations significantly inhibited HUVEC cell viability compared to low insulin concentrations, and this inhibition was attenuated by pretreatment with RGZ. High concentrations of insulin caused a significant upregulation of ChemR23 and a significant downregulation of PPARγ. These effects were attenuated by RGZ pretreatment, while PPARγ antagonist, GW9662 reversed this attenuation. CONCLUSION: ChemR23 upregulation may play a role in VEC damage caused by high concentrations of insulin. The protective effect of PPARγ activation in VECs may be mediated via ChemR23 downregulation.