Dynamic Structural Fluxionality in a Planar Tetracoordinate Carbon Cluster Stabilized by Boron Ligands.

The design of boron-based molecular rotors stems from boron-carbon binary clusters containing multiple planar hypercoordinate carbons (phCs, such as C2B8). However, the design of boron-coordinated phCs is challenging due to boron's tendency to occupy hypercoordinate centers more than carbon. Although this challenge has been addressed, the designed clusters of interest have not exhibited dynamic fluxionality similar to that of the initial C2B8. To address this issue, we report a σ/π doubly aromatic CB2H5 + cluster, the first global minimum containing a boron-coordinated planar tetracoordinate carbon atom with dynamic fluxionality. Dynamics simulations show that two ligand H atoms exhibit alternate rotation, resulting in an intriguing dynamic fluxionality in this cluster. Electronic structure analysis reveals the flexible bonding positions of the ligand H atoms because they do not participate in π delocalized bonding nor bond to any other non-carbon atom, highlighting this rotational fluxionality. Unprecedentedly, the fluxional process involves not only the usual conversion of the number of bonding atoms, but also the type of bonding (3c π bonds ↔4c σ bonds), which is an uncommon fluxional mechanism. The cluster represents an effort to apply phC species to molecular machines.

Tetracoordinate or tricoordinate? Planar tetracoordinate nitrogen in the NBe4H4- cluster stabilized by multicenter bonds.

Realization of planar tetracoordinate arrangements of nitrogen atoms is challenging because their preference for localized bonding (caused by its high electronegativity) makes them typically tricoordinate. This is especially true for the more electronegative oxygen atoms. Herein, we computationally designed two clusters NBe4H4- and OBe4H4; they contain a planar tetracoordinate nitrogen (ptN) and planar tetracoordinate oxygen (ptO) atom, respectively. Remarkably, the former is a dynamically stable global minimum, while the latter is not. The bonding analysis proves that planar tetracoordination in NBe4H4- favors over tricoordination because of the presence of multicenter delocalized bonds. In contrast, the planar tricoordination dominates due to its weak delocalized bonding ability of oxygen in the OBe4H4 cluster. Moreover, the 6σ/2π double aromaticity due to multicenter delocalized bonds allows the NBe4H4- cluster to obtain additional stability. This cluster is a promising synthetic due its dynamic and thermodynamic stability.

A Positioning Alarm System for Explosive Impact Debris Protective Suit Based on an Accelerometer Array.

Protection suits are vital for firefighters' safety. Traditional protection suits physically protect firemen from burns, but cannot locate the position of bodily injuries caused by impact debris. Herein, we present a wearable impact debris positioning system for firefighter protection suits based on an accelerometer array. Wearable piezoelectric accelerometers are distributed regularly on the suit to detect the vibration on different body parts, which is conducive to determining the position of injured body parts. In addition, the injured parts can be displayed on a dummy body model on the upper computer with a higher localization accuracy of 4 cm. The positioning alarm system has a rapid response time of 0.11 ms, attributed to the smart signal processing method. This work provides a reliable and smart method for locating and assessing the position of bodily injuries caused by impact debris, which is significant because it enables fire commanders to rescue injured firefighters in time.

Anlotinib dramatically improved pulmonary hypertension and hypoxia caused by Pulmonary Tumor Thrombotic Microangiopathy (PTTM) associated with gastric carcinoma: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, demonstrating rapid progression of pulmonary hypertension (PH) and respiratory failure. Although a number of treatments have been attempted for patients diagnosed with or suspected of having PTTM, successful-treated cases of PTTM were mainly from imatinib therapy, which was a PDGF receptor inhibitor. Anlotinib was a novel tyrosine kinase inhibitor that targets VEGFR, FGFR, PDGFR, and c-kit. CASE PRESENTATION: We reported a patient of PTTM associated with gastric carcinoma, whom were treated with anlotinib, thereby exhibiting significant improvement of PH and respiratory dysfunction. CONCLUSION: Our case provides a new understanding of therapy to PTTM, with implications for defining anlotinib as candidate drug for PTTM. Clinical diagnosis and prompt initiation of anlotinib might be one of the strategies in patients with unstable PTTM.

Binary mono-anions with unprecedented anti-aromatic planar tetracoordinate carbon and nitrogen atoms.

Global minima (CBe4- and NBe4-) with planar tetracoordinate carbon and nitrogen atoms are stabilized by multicentric bonds. Their unusual anti-aromaticity is due to the strong localized Be-Be bonds preventing the full delocalization of the electrons in the CBe4/NBe4 skeleton. These binary mono-anions are expected to be experimentally realized in the gas phase.

Agrin promotes the proliferation, invasion and migration of rectal cancer cells via the WNT signaling pathway to contribute to rectal cancer progression.

Rectal cancer is the most common malignant tumor in the digestive system with rapidly metastasis and highly recurrence. Agrin (AGRN) is a proteoglycan involving in a large number of human cancers. However, how AGRN regulates the progression of rectal cancer remains largely unknown. We aimed to determine the biological role of AGRN and its mechanism in rectal cancer. AGRN expression in rectal cancer tissues was detected based on TCGA. The survival curve was plotted using the Kaplan-Meier method. qRT-PCR and western blot were utilized to examine the expression level of AGRN in cells. Cell proliferation, clonogenic ability, invasion, and migration of rectal cancer cells were analyzed by CCK-8, colony formation and transwell experiments. GSEA was employed for the analysis of the potential pathways-related with AGRN in rectal cancer. The activity of WNT pathway was determined by western blot. AGRN expression was dramatically increased in rectal cancer, and its up-regulation was associated with poorer prognosis of rectal cancer patients. AGRN expression was an independent factor for the prognosis of rectal cancer. AGRN inhibition suppressed rectal cancer cell growth, invasion, and migration, whereas AGRN overexpression facilitated these behaviors of rectal cancer cells in vitro. Mechanistically, WNT signaling pathway was enriched in high AGRN-expressing patients with rectal cancer. AGRN elevated the activity of WNT pathway through increasing Cyclin D1, C-Myc, p-GSK-3ß, and p-ß-catenin expression. Our present study indicated that AGRN might function as an oncogenic indicator in rectal cancer via activating the WNT pathway, which would help develop optimized therapeutic therapies for rectal cancer.

Ajugol enhances TFEB-mediated lysosome biogenesis and lipophagy to alleviate non-alcoholic fatty liver disease.

Lipophagy is the autophagic degradation of lipid droplets. Dysregulated lipophagy has been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Ajugol is an active alkaloid isolated from the root of Rehmannia glutinosa which is commonly used to treat various inflammatory and metabolic diseases. This study aimed to investigate the effect of ajugol on alleviating hepatic steatosis and sought to determine whether its potential mechanism via the key lysosome-mediated process of lipophagy. Our findings showed that ajugol significantly improved high-fat diet-induced hepatic steatosis in mice and inhibited palmitate-induced lipid accumulation in hepatocytes. Further analysis found that hepatic steatosis promoted the expression of LC3-II, an autophagosome marker, but led to autophagic flux blockade due to a lack of lysosomes. Ajugol also enhanced lysosomal biogenesis and promoted the fusion of autophagosome and lysosome to improve impaired autophagic flux and hepatosteatosis. Mechanistically, ajugol inactivated mammalian target of rapamycin and induced nuclear translocation of the transcription factor EB (TFEB), an essential regulator of lysosomal biogenesis. siRNA-mediated knockdown of TFEB significantly abrogated ajugol-induced lysosomal biogenesis as well as autophagosome-lysosome fusion and lipophagy. We conclude that lysosomal deficit is a critical mediator of hepatic steatosis, and ajugol may alleviate NAFLD via promoting the TFEB-mediated autophagy-lysosomal pathway and lipophagy.

Attenuation of the hypoxia-induced miR-34a protects cardiomyocytes through maintenance of glucose metabolism.

Ischemic injury in the heart is associated with death of cardiomyocytes and even after decades of research there is no appropriate therapeutic intervention to treat ischemic injury. The microRNA miR-34a is known to be induced in cardiomyocytes following ischemic injury. Another hallmark of ischemic injury is impaired glycolysis. The objective of the current study was to investigate the effects of short- and long-term exposure to hypoxia on miR-34a expression on apoptosis and regulation of key glycolysis metabolic enzymes. Both repeated short-term (30 min) burst of hypoxia with intermittent reoxygenation (30 min) as well as long-term (4 h) exposure to hypoxia followed by 6 h of reoxygenation robustly induced miR-34a levels. Hypoxia induced changes in cardiac permeability and localization of the channel protein connexin 34 as well as induced apoptosis as evident by levels of cleaved-caspase 3/7 and impaired cell proliferation. Hypoxia was also associated with decreased expression of key glycolytic enzymes hexokinase-1, hexokinase-2, glucose-6-phosphate-isomerase, and pyruvate dehydrogenase kinase 1. Attenuation of hypoxia-induced miR-34a by anti-miR-34a antagomir, but not a control antagomir, decreased miR-34a levels to those observed under normoxia and also inhibited apoptosis, potentially by rescuing expression of the key glycolytic enzymes. Cumulatively, our results establish that therapeutic targeting of miR-34a via antagomir might be a potent therapeutic mechanism to treat ischemic injury in the heart.

Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats.

GLP-1-based treatment improves glycemia through stimulation of insulin secretion and inhibition of glucagon secretion. Recently, more and more findings showed that GLP-1 could also protect kidney from diabetic nephropathy. Most of these studies focused on glomeruli, but the effect of GLP-1 on tubulointerstitial and tubule is not clear yet. In this study, we examined the renoprotective effect of recombinant human GLP-1 (rhGLP-1), and investigated the influence of GLP-1 on inflammation and tubulointerstitial injury using diabetic nephropathy rats model of STZ-induced. The results showed that rhGLP-1 reduced urinary albumin without influencing the body weight and food intake. rhGLP-1 could increased the serum C-peptide slightly but not lower fasting blood glucose significantly. In diabetic nephropathy rats, beside glomerular sclerosis, tubulointerstitial fibrosis was very serious. These lesions could be alleviated by rhGLP-1. rhGLP-1 decreased the expression of profibrotic factors collagen I, α-SMA, fibronectin, and inflammation factors MCP-1 and TNFα in tubular tissue and human proximal tubular cells (HK-2 cells). Furthermore, rhGLP-1 significantly inhibited the phosphorylation of NF-κB, MAPK in both diabetic tubular tissue and HK-2 cells. The inhibition of the expression of TNFα, MCP-1, collagen I and α-SMA in HK-2 cells by GLP-1 could be mimicked by blocking NF-κB or MAPK. These results indicate that rhGLP-1 exhibit renoprotective effect by alleviation of tubulointerstitial injury via inhibiting phosphorylation of MAPK and NF-κB. Therefore, rhGLP-1 may be a potential drug for treatment of diabetic nephropathy.

Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

Recent studies have shown that KIF5B (conventional kinesin heavy chain) mediates glucose transporter type 4 translocation and adiponectin secretion in 3T3-L1 adipocytes, suggesting an involvement of KIF5B in the homeostasis of metabolism. However, the in vivo physiologic function of KIF5B in adipose tissue remains to be determined. In this study, adipose-specific Kif5b knockout (F-K5bKO) mice were generated using the Cre-LoxP strategy. F-K5bKO mice had similar body weights to controls fed on a standard chow diet. However, F-K5bKO mice had hyperlipidemia and significant glucose intolerance and insulin resistance. Deletion of Kif5b aggravated the deleterious impact of a high-fat diet (HFD) on body weight gain, hepatosteatosis, glucose tolerance, and systematic insulin sensitivity. These changes were accompanied by impaired insulin signaling, decreased secretion of adiponectin, and increased serum levels of leptin and proinflammatory adipokines. F-K5bKO mice fed on an HFD exhibited lower energy expenditure and thermogenic dysfunction as a result of whitening of brown adipose due to decreased mitochondria biogenesis and down-regulation of key thermogenic gene expression. In conclusion, selective deletion of Kif5b in adipose tissue exacerbates HFD-induced obesity and its associated metabolic disorders, partly through a decrease in energy expenditure, dysregulation of adipokine secretion, and insulin signaling.-Cui, J., Pang, J., Lin, Y.-J., Gong, H., Wang, Z.-H., Li, Y.-X., Li, J., Wang, Z., Jiang, P., Dai, D.-P., Li, J., Cai, J.-P., Huang, J.-D., Zhang, T.-M. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

Effect of Dietary Protein and Carbohydrates on Survival and Growth in Larvae of the Henosepilachna vigintioctopunctata (F.) (Coleoptera: Coccinellidae).

The ratio of protein and carbohydrate in an insect's nutritional regime can significantly influence its survival, growth, and fecundity. The effects of 11 different artificial diets containing protein (p): carbohydrate (c) ratios were determined in larvae of the phytophagus ladybug, Henosepilachna vigintioctopunctata (F.) (Coleoptera: Coccinellidae). We recorded the developmental times and survival rates of the larvae and weighed their pupae. When the concentration of carbohydrates was kept constant while the concentration of proteins was increased (p29:c20, p31:c20, p33:c20, and p35:c20), H. vigintioctopunctata could successfully complete the larval and pupal stages. The highest survival rate and greatest pupal mass of H. vigintioctopunctata were 72% and 19.5 mg, respectively, when reared on the p33:c20 diet. H. vigintioctopunctata larvae, however, were unable to develop into adults when the concentration of protein remained constant while the level of carbohydrates was increased (p20:c23, p20:c25, p20:c27, and p20:c29), or when the total amount (p + c) was kept at 48% (p22:c26, p 24:c24, p26:c22). Evidently, changing the availability of quality diet, especially the total protein levels, can significantly affect the performance to H. vigintioctopunctata. Our results indicated that the maximum development and survival of H. vigintioctopunctata larvae occurred within a narrow range-when the p:c ratio was (33:20).

Axl is not an indispensable factor for Zika virus infection in mice.

Recently, Zika virus (ZIKV) outbreak has been associated with a sharp increase in cases of Guillain-Barré syndrome and severe fetal abnormalities. However, the mechanism underlying the interaction of ZIKV with host cells is not yet clear. Axl, a receptor tyrosine kinase, is postulated as a receptor for ZIKV entry; however, its in vivo role during ZIKV infection and its impact on the outcome of the disease have not been fully characterized and evaluated. Moreover, there are contradictory results on its involvement in ZIKV infection. Here we utilized Axl-deficient mice (Axl-/-) and their littermates (Axl+/-) to study the in vivo role of Axl in ZIKV infection. Our results showed that both Axl+/- and Axl-/- suckling mice supported the replication of ZIKV and presented clinical manifestations. No significant difference has been found between Axl-deficient mice and their littermates in terms of the survival rate, clinical manifestations, viral load, ZIKV distribution and histopathological changes in major organs. These results therefore indicate that Axl is not an indispensable factor for ZIKV infection in mice.

Conventional kinesin KIF5B mediates adiponectin secretion in 3T3-L1 adipocytes.

Insulin stimulates adiponectin secretion and glucose transporter type 4 (GLUT4) translocation in adipocyte to regulate metabolism homeostasis. Similar to GLUT4 translocation, intracellular trafficking and release of adiponectin in adipocytes relies on the trans-Golgi network and endosomal system. Recent studies show that the heavy chain of conventional kinesin (KIF5B) mediates GLUT4 translocation in murine 3T3-L1 adipocytes, however, the motor machinery involved in mediating intracellular trafficking and release of adiponectin is unknown. Here, we examined the role of KIF5B in the regulation of adiponectin secretion. The KIF5B level was up-regulated during 3T3-L1 adipogenesis. This increase in cytosolic KIF5B was synchronized with the induction of adiponectin. Endogenous KIF5B and adiponectin were partially colocalized at the peri-nuclear and cytosolic regions. In addition, adiponectin-containing vesicles were co-immunoprecipitated with KIF5B. Knockdown of KIF5B resulted in a marked inhibition of adiponectin secretion and overexpression of KIF5B enhanced adiponectin release, whereas leptin secretion was not affected by changes in KIF5B expression. These data suggest that the secretion of adiponectin, but not leptin, is dependent on functional KIF5B.

Kif5b controls the localization of myofibril components for their assembly and linkage to the myotendinous junctions.

Controlled delivery of myofibril components to the appropriate sites of assembly is crucial for myofibrillogenesis. Here, we show that kinesin-1 heavy chain Kif5b plays important roles in anterograde transport of α-sarcomeric actin, non-muscle myosin IIB, together with intermediate filament proteins desmin and nestin to the growing tips of the elongating myotubes. Mice with Kif5b conditionally knocked out in myogenic cells showed aggregation of actin filaments and intermediate filament proteins in the differentiating skeletal muscle cells, which further affected myofibril assembly and their linkage to the myotendinous junctions. The expression of Kif5b in mutant myotubes rescued the localization of the affected proteins. Functional mapping of Kif5b revealed a 64-amino acid α-helix domain in the tail region, which directly interacted with desmin and might be responsible for the transportation of these proteins in a complex.

Site-Specific and High-Loading Immobilization of Proteins by Using Cohesin-Dockerin and CBM-Cellulose Interactions.

Immobilization of enzymes enhances their properties for application in industrial processes as reusable and robust biocatalysts. Here, we developed a new immobilization method by mimicking the natural cellulosome system. A group of cohesin and carbohydrate-binding module (CBM)-containing scaffoldins were genetically engineered, and their length was controlled by cohesin number. To use green fluorescent protein (GFP) as an immobilization model, its C-terminus was fused with a dockerin domain. GFP was able to specifically bind to scaffoldin via cohesin-dockerin interaction, while the scaffoldin could attach to cellulose by CBM-cellulose interaction. Our results showed that this mild and convenient approach was able to achieve site-specific immobilization, and the maximum GFP loading capacity reached ∼0.508 µmol/g cellulose.

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1.

AIM: Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. METHODS: Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 µmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg(-1)·d(-1)) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. RESULTS: Pretreatment with quercetin (3, 10, 30 µmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. CONCLUSION: Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and demonstrate the therapeutic potential of quercetin for treating this side effect.

Multiple Eruptive Pyogenic Granulomas Occurring in a Region of Scalded Skin.

We report a case of multiple eruptive pyogenic granulomas after scalding. A 4-year-old girl developed papules and nodules within the scalded areas after a hot soup burn. Although the occurrence of pyogenic granulomas after trauma to the skin is common, multiple lesions of pyogenic granuloma secondary to scalding are rare.

[Effect of ß-lactamase detection on reducing the incidence of antibiotic-associated diarrhea in children with severe bacterial pneumonia].

OBJECTIVE: To study the effect of ß-lactamase (BLs) detection and ß-lactam/ß-lactamase inhibitor (BL/BLI) on the incidence of antibiotic-associated diarrhea (AAD) in children with severe bacterial pneumonia. METHODS: The clinical data of the children with bacterial severe pneumonia were retrospectively studied. Of all the patients, 248 using amoxicillin/clavulanate but without BLs detection and 323 using amoxicillin (BLs negative) or amoxicillin/clavulanate (BLs positive) were used as the amoxicillin group; 208 patients using piperacillin/tazobactam but without BLs detection and 291 patients using piperacillin (BLs negative) or piperacillin/tazobactam (BLs positive) were used as the piperacillin group; and 191 patients using cefoperazone/sulbactam but without BLs detection and 341 patients using cefoperazone (BLs negative) or cefoperazone/sulbactam (BLs positive) were used as the cefoperazone group. The incidence and clinical symptoms of AAD between the undetected and detected BLs patients were compared. RESULTS: The incidences of AAD in the amoxicillin, piperacillin and cefoperazone groups without BLs detection groups were significantly higher than those in the corresponding groups with negative or positive results of BLs detection (P<0.01). The durations of diarrhea, antibiotic use and hospitalization stay in AAD patients receiving BLs detection were shorter than in those without receiving BLs detection (P<0.01). CONCLUSIONS: It is very important to detect BLs for reducing the incidence and relieving symptoms of AAD in children with severe bacterial pneumonia.

Stable knockdown of Kif5b in MDCK cells leads to epithelial-mesenchymal transition.

Polarization of epithelial cells requires vectorial sorting and transport of polarity proteins to apical or basolateral domains. Kif5b is the mouse homologue of the human ubiquitous Kinesin Heavy Chain (uKHC). To investigate the function of Kif5b in epithelial cells, we examined the phenotypes of Kif5b-deficient MDCK cells. Stable knockdown of Kif5b in MDCK cells resulted in reduced cell proliferation rate, profound changes in cell morphology, loss of epithelial cell marker, and gain of mesenchymal marker, as well as increased cell migration, invasion, and tumorigenesis abilities. E-cadherin and NMMIIA could interact with Kif5b in polarized MDCK cells, and their expression levels were decreased in Kif5b-deficient MDCK cells. Overexpression of E-cadherin and NMMIIA in Kif5b depleted MDCK cells could decrease mesenchymal marker expression and cell migration ability. These results indicate that stable knockdown of Kif5b in MDCK cells can lead to epithelial-mesenchymal transition, which is mediated by defective E-cadherin and NMMIIA expression.

C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis.

Type 1 diabetes mellitus (T1DM) is characterized by the deficiencies of insulin and C-peptide. Mounting evidences have proved the beneficial effects of C-peptide on the renal function in T1DM. However, it is still controversial about the roles of C-peptide in T2DM nephropathy since the level of C-peptide fluctuates greatly at different stages of T2DM. In the present study, we found that the serum C-peptide concentration was much lower in GK rats with diabetic nephropathy than that in normal counterparts. A sustained supplementation of C-peptide at a physiological level could ameliorate urinary albumin, independent of blood glucose control. C-peptide treatment improved glomerulosclerosis and podocyte morphology and reduced the thickness of glomerular basement membrane as compared with saline treatment control. Moreover, it decreased fibronectin synthesis in diabetic glomeruli and in cultured rat mesangial cells accompanied by a down-regulation of RAGE and an up-regulation of PKA. Interestingly, H-89, a PKA inhibitor, could reverse the inhibition effect of C-peptide on fibronectin production in cultured mesangial cells. These findings suggest that C-peptide level is low in T2DM rats with nephropathy and a treatment with a physiological dose of C-peptide can prevent renal injury in diabetic GK rats.