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Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy. [ABSTRACT FROM AUTHOR]

Thermal conductivity is one of the most significant criterion of three-dimensional carbon fiber-reinforced SiC matrix composites (3D C/SiC). Represent volume element (RVE) models of microscale, void/matrix and mesoscale proposed in this work are used to simulate the thermal conductivity behaviors of the 3D C/SiC composites. An entirely new process is introduced to weave the preform with three-dimensional orthogonal architecture. The 3D steady-state analysis step is created for assessing the thermal conductivity behaviors of the composites by applying periodic temperature boundary conditions. Three RVE models of cuboid, hexagonal and fiber random distribution are respectively developed to comparatively study the influence of fiber package pattern on the thermal conductivities at the microscale. Besides, the effect of void morphology on the thermal conductivity of the matrix is analyzed by the void/matrix models. The prediction results at the mesoscale correspond closely to the experimental values. The effect of the porosities and fiber volume fractions on the thermal conductivities is also taken into consideration. The multi-scale models mentioned in this paper can be used to predict the thermal conductivity behaviors of other composites with complex structures. [ABSTRACT FROM AUTHOR]

The photosynthesis of hydrogen peroxide (H2O2) through the selective 2e− oxygen reduction reaction (ORR) from O2 and H2O stands out as an environmentally sustainable and cost-effective method for generating this essential chemical. Unfortunately, the widespread application of most photocatalysts is impeded by their reliance on sacrificial agents. In this context, we present a noteworthy advancement in the form of a step-scheme (S-scheme) heterojunction involving a donor–acceptor (D–A)-conjugated polymer and manganese cadmium sulfide (BTz@MCS). This innovative configuration enables efficient photocatalytic H2O2 production within a non-sacrificial system, showcasing an impressive H2O2 yield of 5,368 µmol g−1 h−1 and an apparent quantum yield of 4.5% at 420 nm. Through insights gained from in-situ irradiated X-ray photoelectron spectroscopy (ISIXPS), in-situ diffuse reflectance infrared Fourier transformations spectroscopy (DRIFTS), and density function calculations (DFT), it is revealed that the sp2 C between thiazole–thiazole rings at the BTz and the concentrated holes at the MCS function as spatially separated redox centers. These centers catalyze the selective 2e− ORR and 4e− water oxidation reaction (WOR) concurrently. The O2 generated from the WOR is subsequently utilized by the ORR cycle, enabling the overall photosynthesis of H2O2 with accelerated total reaction kinetics. Furthermore, the high photocatalytic performance of the developed catalyst is attributed to well-designed S-scheme heterojunctions with tuned band structures. The spatially separated redox centers and effective transfer of photogenerated charge carriers facilitated by the internal electric field significantly enhance reaction kinetics. This study introduces a promising avenue for photocatalytic H2O2 production without sacrificial agents, providing valuable insights into the underlying mechanisms in S-scheme heterojunctions. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice. [ABSTRACT FROM AUTHOR]

Hyalectan cleavage may play an important role in extracellular matrix remodeling. However, the proteolytic enzyme responsible for hyalectan degradation for fetal membrane rupture at parturition remains unknown. Here, we reveal that versican (VCAN) is the major hyalectan in the amnion, where its cleavage increases at parturition with spontaneous rupture of membrane. We further reveal that ADAMTS4 is a crucial proteolytic enzyme for VCAN cleavage in the amnion. Inflammatory factors may enhance VCAN cleavage by inducing ADAMTS4 expression and inhibiting ADAMTS4 endocytosis in amnion fibroblasts. In turn, versikine, the VCAN cleavage product, induces inflammatory factors in amnion fibroblasts, thereby forming a feedforward loop between inflammation and VCAN degradation. Mouse studies show that intra-amniotic injection of ADAMTS4 induces preterm birth along with increased VCAN degradation and proinflammatory factors abundance in the fetal membranes. Conclusively, there is enhanced VCAN cleavage by ADAMTS4 in the amnion at parturition, which can be reenforced by inflammation. ADAMTS4 is crucial for VCAN cleavage in the amnion at parturition, which participates not only in extracellular matrix remodeling but also in inflammatory reactions of the fetal membranes. [ABSTRACT FROM AUTHOR]

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Purpose: Methylenetetrahydrofolate dehydrogenase (MTHFD1), a key enzyme on the folate pathway, has been implicated in the tumor development of distinct types of cancers. The single nucleotide polymorphism (SNP) of 1958G > A mutation in the coding region of MTHFD1 (arginine 653 is mutated into glutamine) has been detected in a significant proportion of clinical samples of hepatocellular carcinoma (HCC). Methods : Hepatoma cell lines, 97H and Hep3B were used. The expression of MTHFD1 and SNP mutation protein was determined by immunoblotting analysis. The protein ubiquitination of MTHFD1 was detected by immunoprecipitation analysis. The post-translational modification sites and interacting proteins of MTHFD1 in the presence of G1958A SNP were identified by mass spectrometry. Metabolic flux analysis was used to detect the synthesis of relevant metabolites sourced from serine isotope. Results: The present study showed G1958A SNP of MTHFD1, encoding MTHFD1 R653Q, was associated with the attenuated protein stability caused by ubiquitination-mediated protein degradation. Mechanistically, MTHFD1 R653Q displayed an enhanced binding to the E3 ligase TRIM21, which was responsible for the augmented ubiquitination, and MTHFD1 K504 was identified to be the primary ubiquitination site. The subsequent metabolite analysis revealed MTHFD1 R653Q resulted in the repressed flux of serine-derived methyl group into metabolite precursors for purine synthesis, and the compromised purine synthesis was demonstrated to be responsible for the impeded growth capability in MTHFD1 R653Q-expressing cells. Moreover, the suppressive effect of MTHFD1 R653Q expression in tumorigenesis was verified by xenograft analysis, and the relationship between MTHFD1 G1958A SNP and its protein levels was revealed in clinical human liver cancer specimens. Conclusion: Our results uncovered an unidentified mechanism underlying of the impact of G1958A SNP on MTHFD1 protein stability and tumor metabolism in HCC. which provides a molecular basis for the according clinical management when considering MTHFD1 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives: Sterile inflammation of fetal membranes is an indispensable event of normal parturition. However, triggers of sterile inflammation are not fully resolved. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver. Fetal membranes can also synthesize SAA1 but its functions are not well defined. Given the role of SAA1 in the acute phase response to inflammation, we postulated that SAA1 synthesized in the fetal membranes may be a trigger of local inflammation at parturition. Methods: The changes of SAA1 abundance in parturition were studied in the amnion of human fetal membranes. The role of SAA1 in chemokine expression and leukocyte chemotaxis was examined in cultured human amnion tissue explants as well as primary human amnion fibroblasts. The effects of SAA1 on monocytes, macrophages and dendritic cells were investigated in cells derived from a human leukemia monocytic cell line (THP-1). Results: SAA1 synthesis increased significantly in human amnion at parturition. SAA1 evoked multiple chemotaxis pathways in human amnion fibroblasts along with upregulation of a series of chemokines via both toll-like receptor 4 (TLR4) and formyl peptide receptor 2 (FPR2). Moreover, SAA1-conditioned medium of cultured amnion fibroblasts was capable of chemoattracting virtually all types of mononuclear leukocytes, particularly monocytes and dendritic cells, which reconciled with the chemotactic activity of conditioned medium of cultured amnion tissue explants collected from spontaneous labor. Furthermore, SAA1 could induce the expression of genes associated with inflammation and extracellular matrix remodeling in monocytes, macrophages and dendritic cells derived from THP-1. Conclusions: SAA1 is a trigger of sterile inflammation of the fetal membranes at parturition. [ABSTRACT FROM AUTHOR]

Fluorescence bioimaging based on rare-earth-doped nanocrystals (RENCs) in the shortwave infrared (SWIR, 1000–3000 nm) region has aroused intense interest due to deeper penetration depth and clarity. However, their downshifting emission rarely shows sufficient brightness beyond 1600 nm, especially in NIR-IIc. Here, we present a class of thulium (Tm) self-sensitized RENC fluorescence probes that exhibit bright downshifting luminescence at 1600–2100 nm (NIR-IIb/c) for in vivo bioimaging. An inert shell coating minimizes surface quenching and combines strong cross-relaxation, allowing LiTmF4@LiYF4 NPs to emit these intense downshifting emissions by absorbing NIR photons at 800 nm (large Stokes shift ~1000 nm with a absolute quantum yield of ~14.16%) or 1208 nm (NIR-IIin and NIR-IIout). Furthermore, doping with Er3+ for energy trapping achieves four-wavelength NIR irradiation and bright NIR-IIb/c emission. Our results show that Tm-based NPs, as NIR-IIb/c nanoprobes with high signal-to-background ratio and clarity, open new opportunities for future applications and translation into diverse fields. Fluorescence imaging in the near-infrared region yields high-quality images that overcome the current depth limitations. Here, the authors report a Tm3 + -based nanoprobe for NIR-IIb/c imaging, providing references to future bioimaging beyond 1700 nm. [ABSTRACT FROM AUTHOR]

Myristic acid (MA) was used as the phase change material (PCM) and expanded graphite (EG) was used as the additive substrate. 21 kinds of EG/MA shaped composite PCM samples with different ratios were prepared by means of "melt blending-press forming" method with different molding pressure and pressing technology. The microstructure of the samples was characterized and analyzed, and then the samples were subjected to thermal property testing and thermal stability analysis to explore the relationship between the microstructure and thermal properties. Relevant experiments showed that EGII with high expansion degree not only improved the distribution uniformity of MA, but also significantly improved the liquid phase encapsulation during the phase transition. Better thermal stability was shown in the 50-cycle stability test. The melting point and enthalpy of the shaped composite PCM sample (24 wt% EGΙΙ/MA) were 53.98 ℃ and 199.1 J g−1, respectively. The addition of EG and the change of the pressing process can adjust the radial thermal conductivity and axial thermal conductivity of the samples. The radial thermal conductivity of the 16 wt% and 24 wt% EGII/MA samples consistently increased with increasing pressure in the molding pressure range of 10 MPa to 50 MPa, which is due to the larger pore volume of the more expansive EGII and the higher compressibility of the graphite flake layer in the composites. When the pressure was increased to 50 MPa, the radial thermal conductivity of 24 wt% EGII/MA slightly increased to 26.21 W m−1·K−1, which was about 140 times higher than the thermal conductivity value of 0.18 W m−1·K−1 for pure MA. [ABSTRACT FROM AUTHOR]

Sex is a key biological variable in traumatic brain injury (TBI) and plays a significant role in neuroinflammatory responses. However, the molecular mechanisms contributing to this sexually dimorphic neuroinflammatory response remain elusive. Here we describe a significant and previously unreported tissue enrichment and sex-specific alteration of a set of inflammatory microRNAs (miRNAs) in CD11b+ cells of brain and bone marrow isolated from naïve mice as well as mice subjected to TBI. Our data from naïve mice demonstrated that expression levels of miR-146a-5p and miR-150-5p were relatively higher in brain CD11b+ cells, and that miR-155-5p and miR-223-3p were highly enriched in bone marrow CD11b+ cells. Furthermore, while miR-150-5p and miR-155-5p levels were higher in male brain CD11b+ cells, no significant sexual difference was observed for miR-146a-5p and miR-223-3p. However, TBI resulted in sex-specific differential responses of these miRNAs in brain CD11b+ cells. Specifically, miR-223-3p levels in brain CD11b+ cells were markedly elevated in both sexes in response to TBI at 3 and 24 h, with levels in females being significantly higher than males at 24 h. We then focused on analyzing several miR-223-3p targets and inflammation-related marker genes following injury. Corresponding to the greater elevation of miR-223-3p in females, the miR-223-3p targets, TRAF6 and FBXW7 were significantly reduced in females compared to males. Interestingly, anti-inflammatory genes ARG1 and IL4 were higher in females after TBI than in males. These observations suggest miR-223-3p and other inflammatory responsive miRNAs may play a key role in sex-specific neuroinflammatory response following TBI. [ABSTRACT FROM AUTHOR]

Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO3; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 μL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 μL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68+ (macrophages) cells (p = 0.0012), CD3+ (lymphocytes) cells (p = 0.0011), p-mTOR+ cells (p = 0.0019), PCNA+ cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions. [ABSTRACT FROM AUTHOR]

Chemical sensing for the sensitive and reliable detection of mercury(II) ions (Hg2+) is of great importance in environmental protection, food safety, and biomedical applications. Due to the bio-enrichment property of Hg2+ in organisms, it is particularly meaningful to develop an effective tool that can in situ and rapidly monitor the level of Hg2+ in living organisms. In this work, we report ligand functionalized gold-silver bimetallic nanoclusters with bright red fluorescence as intracellular probes for imaging Hg2+ in living cells and zebrafish. The bimetallic nanoclusters of DTT-GSH@Au/AgNCs (DG-Au/AgNCs) with strong fluorescence that benefited from the synergistic effect of Au and Ag atoms were obtained through a one-pot synthesis method, incorporating glutathione (GSH) and dithiothreitol (DTT) as the reducers and functionalized ligands. Attractively, the bright red fluorescence of DG-Au/AgNCs could be rapidly and selectively quenched by Hg2+ within 1 min with a very low detection limit of 1.01 nM. Additionally, DG-Au/AgNCs had a great advantage in the detection of Hg2+ in living cells and zebrafish owing to its notably strong red fluorescence at 665 nm, which could avoid effectively auto-fluorescence interference from the organism. Such easily prepared bimetallic fluorescent nanoclusters would be expected to provide a noninvasive and sensitive approach in the detection of heavy metals in situ for environmental protection. [ABSTRACT FROM AUTHOR]

To investigate the combustion behavior of furfurylated wood in the presence of montmorillonite (MMT) and its char properties, original, MMT-treated, furfuryl alcohol (FA)-treated (i.e., furfurylated), and MMT/FA-treated wood were pyrolyzed and carbonized using thermo-gravimetry and cone calorimeter, respectively. Results on thermal stability, gas emission, microstructure, surface area, porosity, and chemical components confirmed that MMT dramatically affected the pyrolysis features of both control and furfurylated wood, and increased the char yield due to the catalytic activity and barrier effect of the clay sheets. Furfurylated wood released massive carbon-containing compounds and heat during combustion, which supported burning. The flame retardancy index (FRI) values of MMT/FA-treated wood were increased by 65.6% compared with the furfurylated wood, suggesting that MMT inhibited the spreading of gases and heat and promoted the formation of protective char layer. MMT uniformly distributed in wood cell lumina, promoted the effective carbonization of cellulose, and restrained the formation of carbon gaseous species, thus exerting a pronounced effect on char formation. The microstructure and chemical composition of the char residue indicated that due to the acid catalysis and barrier property of MMT sheets and the wrap of furfuryl alcohol resin, the coherent surface and porous structure of the char residues with Si–O–C/C–Si structures dominated the char-forming process, which was conducive to the comprehensive utilization of modified wood waste. [ABSTRACT FROM AUTHOR]

Purposes: Distant metastasis from papillary thyroid microcarcinoma (PTMC) is extremely rare and the long-term outcomes and independent prognostic factors remain unclear. The present study aimed to investigate clinicopathological characteristics and evaluate the long-term outcomes and prognostic factors of PTMC patients with distant metastases (DM) who underwent surgery and radioactive iodine (131I) treatment. Methods: We retrospectively reviewed the medical records of 13,441 patients with thyroid cancer (including 1697 cases with PTMC) who underwent 131I treatment at our institution between January 2008 and December 2019. PTMC patients with distant metastases with sufficient clinical follow-up data were enrolled in this cohort study. The overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan–Meier method and the prognostic factors were assessed by Cox proportional hazards. Results: Thirty-three PTMC patients with DM were enrolled in this study. The median follow-up was 75 months (range: 5–151 months). The 5-year and 10-year OS rates were 96.97 and 81.41%, respectively, and the 5-year and 10-year PFS rates were 90.46 and 69.68%, respectively. Multivariate analysis showed that male sex (P = 0.005), radioactive iodine refractory PTMC (P = 0.033), and symptomatic DM (P = 0.022) were significantly associated with worse 10-year PFS in PTMC patients with DM. No independent predictor related to poor 10-year OS was found in the present study. Conclusions: The prognosis of PTMC patients becomes worse after the development of DM. Male sex, radioactive iodine refractory PTMC, and symptomatic DM were identified as independent factors associated with PFS. [ABSTRACT FROM AUTHOR]

The natural environment is a complex system, and there is never only one kind of nanomaterial entering the environment. However, many studies only considered the plant toxicity of one kind of nanomaterial and do not consider the influence of two or more kinds of nanomaterials on plant toxicity. Multi-walled carbon nanotubes (MWCNTs) and zinc oxide nanoparticles (ZnO NPs) are two common and widely used nanomaterials in water environment, so these two kinds of nanomaterials were chosen to explore the effects of their combined toxicity on cabbage. This study investigated the toxicity of MWCNTs combined with ZnO NPs on cabbage by measuring the length of roots and stems, chlorophyll content, oxidative stress, antioxidant enzyme activity, metal element content, and root scanning electron microscopy. The toxicity of single MWCNTs toward cabbage was attributed to direct oxidative damage, while the toxicity of single ZnO NPs toward cabbage was due to the high level of zinc concentration. Moreover, ZnO NPs (10 mg/L) ameliorated MWCNTs toxicity toward cabbage by improving the activity of antioxidant enzymes. ZnO NPs (50 and 100 mg/L) because of the high content of zinc disrupted the balance of other metals in the plant and increased the toxicity of MWCNTs. In conclusion, the combined toxicity of different concentrations and types of nanomaterials should be considered for a more accurate assessment of environmental risks. [ABSTRACT FROM AUTHOR]

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450–458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic. Neutralizing antibodies are currently one versatile strategy to treat SARS-CoV-2 infection. Here, Li et al. characterize three monoclonal antibodies neutralizing authentic virus infection in vitro and in vivo by targeting the receptor binding domain as evidenced by Cryo-EM. [ABSTRACT FROM AUTHOR]

Small diameter (< 6 mm) prosthetic vascular grafts continue to show very low long-term patency, but bioengineered vascular grafts show promising results in preclinical experiments. To assess a new scaffold source, we tested the use of decellularized fish swim bladder as a vascular patch and tube in rats. Fresh goldfish (Carassius auratus) swim bladder was decellularized, coated with rapamycin and then formed into patches or tubes for implantation in vivo. The rapamycin-coated patches showed decreased neointimal thickness in both the aorta and inferior vena cava patch angioplasty models. Rapamycin-coated decellularized swim bladder tubes implanted into the aorta showed decreased neointimal thickness compared to uncoated tubes, as well as fewer macrophages. These data show that the fish swim bladder can be used as a scaffold source for tissue-engineering vascular patches or vessels. Bai et al. employ a fish bladder-derived decellularized matrix for the engineering of vascular grafts. The authors show that rapamycin-coated bladder-derived vascular grafts can be implanted as an interposition graft in rats, and that these vascular grafts showed decreased neointimal thickness both in artery and veins. [ABSTRACT FROM AUTHOR]

Rock-support interaction is one of the most core issues in underground engineering, which is of major interest to supporting structure design, construction safety and cost, as well as environmental protection. In order to study the rock-support interaction in deep tunnel under complex geological conditions, taking Xianglushan Tunnel of Yunnan Water Diversion Project in China as the engineering background, two true three-dimensional physical model tests were conducted. The model test results show: (1) the surrounding rock and support are a pair of opposite and united contradictions, which are both antagonistic and cooperative; (2) the rock-lining interaction and rock-bolt interaction are distinctly different. The lining is a type of outside supporting structure to bear the load from surrounding rock and the bolt is a kind of inside supporting structure to reinforce and protect surrounding rock; (3) the impacts of weak fault on mechanical behavior of surrounding rock and supporting structure are significant. The load bearing effects of surrounding rock and support system exhibit different characteristic depending on the corresponding geological conditions. The results can contribute to the development of construction scheme and optimization of support design, and also provide an ideal data set for the calibration and validation of numerical models to simulate the rock-support interaction. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play important roles in post-transcriptional regulation as well as in various biological and metabolic processes. Lilium pumilum originated from northern China with a high ornamental value, and is important for Lilium resistance breeding. The dormancy of the bulbs has a serious effect on flowering quality. In this study, the miRNAs from samples at 0 days (S1 stage), 30 days (S2 stage), 60 days (S3 stage) and 90 days (S4 stage) of cold storage were sequenced to reveal the dormancy mechanism of Lilium pumilum. Through ultrastructural observation and physiological index measurement, we found that Lilium pumilum bulbs were released from dormancy during low-temperature storage. We further conducted miRNAs sequencing; a total of 17 conserved miRNAs were identified from 12 families, two nonconserved miRNAs were found that belonged to two families, and 38 novel miRNAs were predicted. MiRNA-target pairs analysis showed that some biological processes, including antioxidant reactions, epigenetic modification and abiotic stress, were induced in response to low-temperature conditions. Some transcription factors, plant hormone signalling pathways, and enzymes involved in plant growth and development were also activated to break the bulb dormancy. The study initially revealed the complex regulatory mechanisms of miRNAs for dormancy release during low-temperature storage. Comprehensive sequence information and target gene data were obtained by miRNAs sequencing, which determined that miRNAs regulation of bulb dormancy release in low temperature. [ABSTRACT FROM AUTHOR]

LiErF4 was commonly used as a dipolar-coupled antiferromagnet, and was rarely considered as a luminescent material. Herein, we achieved the strong red upconversion emission of LiErF4 simply by an inert shell coating, i.e., LiErF4@LiYF4. Owing to the unique and intrinsic ladder-like energy levels of Er3+ ions, this LiErF4 core-shell nanostructures present red emission (∼ 650 nm) under multi-band excitation in the near-infrared (NIR) region (∼ 808, ∼ 980, and ∼ 1,530 nm). A brighter and monochromic red emission can be further obtained via doping 0.5% Tm3+ into the LiErF4 core, i.e., LiErF4: 0.5% Tm3+@LiYF4. The enriched Er3+ ions and strong monochromic red emission natures make LiErF4: 0.5% Tm3+@LiYF4 nanocrystals very sensitive for trace water probing in organic solvents with detection limit of 30 ppm in acetonitrile, 50 ppm in dimethyl sulfoxide (DMSO), and 58 ppm in N, N-dimethylformamide (DMF) under excitation of 808 nm. Due to their superior chemical and physical stability, these nanoprobes exhibit excellent antijamming ability and recyclability, offering them suitable for real-time and long-term water monitoring. [ABSTRACT FROM AUTHOR]

Vein traits influence photosynthesis and drought resistance and are sensitive to climate change. It is unclear whether vein traits, similar to other leaf traits, have obvious regional characteristics and covariance with other leaf traits, especially in Tibetan Plateau grasslands. We collected 66 species from 37 sites in late July of 2012 and early August of 2013 to investigate leaf vein traits and their relationships with other leaf traits in comparison with the available global database data and to elucidate vein investment of plants with different vein types. The average vein length per area (VLA) of plants in the Tibetan Plateau was within the range of the global dataset, and the relationships among vein traits and other leaf traits of alpine plants were consistent with the global models. The VLAs of parallel-veined grasses and pinnate-veined forbs were significantly lower and higher than the global mean value, respectively. The leaf mass per area and total nitrogen content of parallel-veined grasses were significantly lower and higher, respectively, than the global mean values; the opposite was observed in pinnate-veined forbs. The parallel-veined grasses exhibited almost a four-fold higher vein biomass investment (i.e., vein mass per leaf mass) than pinnate-veined forbs in the same region. The average VLA and its relationships with other leaf traits of the alpine grassland plants on the Tibetan Plateau had no regional characteristics, suggesting a convergence in plant leaf functioning. Plants with different leaf types differ in their adaptation strategies to plateau environments, and this may relate to biomass investment into leaf veins. Our study fills the gap with regard to vein density in alpine grassland species and provides a new perspective for understanding plant physiology and ecology by calculating and comparing the proportion of vein investment among different vein types. [ABSTRACT FROM AUTHOR]

We prepared the H3PW12O40-doped pyromellitic diimide (PMDI) photocatalysts via thermal transformation using urea phosphotungstate and pyromellitic dianhydride as precursors (UPWPI) and calcination of PMDI with phosphotungstic acid directly (UPIPW). The influences of the strategies on the morphology, light absorption, and visible-light photocatalytic degradation efficiency of H3PW12O40-doped PMDI are systematically investigated by various characterization methods. By comparing the structure of UPWPI and UPIPW, the adoption of urea phosphotungstate as precursors can promote the separation of PMDI into small particles and the inclusion of phosphotungstic acid. Moreover, the visible-light (λ > 420 nm) absorption efficiency of UPWPI is also enhanced compared with that of UPIPW because of the improved photogenerated electron transfer efficiency between PMDI and HPW. With a catalyst dosage of 100 mg and the degradation time of 3 h, the photocatalytic degradation efficiency of imidacloprid on UPWPI was 97.12% and the degradation rate constant was 0.93 h−1. [ABSTRACT FROM AUTHOR]

The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands. [ABSTRACT FROM AUTHOR]

Hydrophilicity of fast-growing plantation wood is the major restriction for its outdoor applications. Herein, a novel method is reported for improving the hydrophobicity of Cathay poplar (Populus cathayana Rehd.) by using a paraffin/carnauba (5:5 and 7:3)-mixed wax emulsion system. The poplar samples were impregnated in the single or mixed wax O/W emulsions of 4% solid content with subsequent drying treatment at 70 °C, which was higher than the paraffin wax melting point but lower than that of carnauba wax. The images obtained by field emission scanning electron microscopy confirmed that the mixed wax emulsion treatment developed textured surfaces in the inner lumen surface of wood cells and on the external surfaces of the samples comprising a continuous paraffin wax film with carnauba wax micropillars embedded in it. Contact angle analysis and water absorption tests show that the textured surface imparted the mixed wax emulsion-treated wood good hydrophobicity, rendering the initial contact angle greater than 140° and improving not only the surface property but also the long-term (120 or 192 h immersion) water repellency. In addition, free and bound water fractions in the treated wood were measured quantitatively using low-field nuclear magnetic resonance. The results show that the mixed wax emulsion treatment significantly decreased the free water content and delayed the bound water adsorption. In conclusion, this mixed wax emulsion treatment can be potentially utilized as a highly efficient wood hydrophobization method for expanding wood applications outdoors. [ABSTRACT FROM AUTHOR]

Cross-coupling reactions have developed into powerful approaches for carbon–carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki–Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process. Migratory cross-coupling reactions are powerful tools to form bonds at predictable positions. Here the authors report a nickel-catalyzed migratory Suzuki–Miyaura cross-coupling of unactivated alkyl electrophiles with aryl and vinyl boron reagents and provide experimental and computational mechanistic evidence. [ABSTRACT FROM AUTHOR]

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Extranodal natural killer/T-cell lymphoma (ENKTCL), nasal type, is rare and aggressive and often involves the nose, nasopharynx, and upper aerodigestive tract. The non-nasal type can affect the skin, salivary glands, gut, testes, brain, salivary glands, and other sites. Primary ENKTCL of the lung is rare. Here, we report a 68-year-old non-smoking female who presented with fever, dry cough, and night sweats. The chest image showed lung consolidation in the right lower lung field. Pulmonary biopsy showed diffuse abnormal lymphocyte infiltrate in the necrotic exudate. Immunohistochemical data indicated that the tumour cells were positive for CD56, granzyme B, CD3, and TIA. Using in situ hybridization, Epstein–Barr virus-encoded ribonucleic acid (EBER) was detected. There was no evidence to indicate extrathoracic lymphoma involvement. Primary pulmonary ENKTCL was therefore diagnosed. The patient underwent chemotherapy using the P-GEMOX regimen (pegaspargase, gemcitabine, and oxaliplatin) and is still alive. [ABSTRACT FROM AUTHOR]

Antibiotics are the front-line treatment against many bacterial infectious diseases in human. The excessive and long-term use of antibiotics in human cause several side effects. It is important to understand the underlying molecular mechanisms of action of antibiotics in the host cell to avoid the side effects due to the prevalent uses. In the current study, we investigated the crosstalk between mitochondria and lysosomes in the presence of widely used antibiotics: erythromycin (ERM) and clindamycin (CLDM), which target the 50S subunit of bacterial ribosomes. We report here that both ERM and CLDM induced caspase activation and cell death in several different human cell lines. The activity of the mitochondrial respiratory chain was compromised in the presence of ERM and CLDM leading to bioenergetic crisis and generation of reactive oxygen species. Antibiotics treatment impaired autophagy flux and lysosome numbers, resulting in decreased removal of damaged mitochondria through mitophagy, hence accumulation of defective mitochondria. We further show that over-expression of transcription factor EB (TFEB) increased the lysosome number, restored mitochondrial function and rescued ERM- and CLDM-induced cell death. These studies indicate that antibiotics alter mitochondria and lysosome interactions leading to apoptotsis and may develop a novel approach for targeting inter-organelle crosstalk to limit deleterious antibiotic-induced side effects. [ABSTRACT FROM AUTHOR]

Phenol and butanolone catalyzed by different SOH-functionalized ionic liquids (ILs) for synthesis of raspberry ketone (RK) had been investigated. The influences of different ionic liquids, reaction time, reaction temperature, reactant ratio, the amount of ionic liquid were investigated. The yield of raspberry ketone was 82.5% under the optimum reaction condition. In addition, the ILs (3-sulfo)propyltriamine bisulfate ([TEA-PS][HSO]) can be recycled up to five consecutive times without loss of activity. This method had the advantages of mild conditions, high product yield, easy to separate from the product, as well as environmentally friendly procedure. At the same time, the possible reaction mechanism was discussed. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) expression varies in association with different tissue types and in diseases. Having been found in body fluids including blood and cerebrospinal fluid (CSF), miRNAs constitute potential biomarkers. CSF miRNAs have been proposed as biomarkers for neurodegenerative diseases; however, there is a lack of consensus about the best candidate miRNA biomarkers and there has been variability in results from different research centers, perhaps due to technical factors. Here, we sought to optimize technical parameters for CSF miRNA studies. We examined different RNA isolation methods and performed miRNA expression profiling with TaqMan® miRNA Arrays. More specifically, we developed a customized CSF-miRNA low-density array (TLDA) panel that contains 47 targets: miRNAs shown previously to be relevant to neurodegenerative disease, miRNAs that are abundant in CSF, data normalizers, and controls for potential blood and tissue contamination. The advantages of using this CSF-miRNA TLDA panel include specificity, sensitivity, fast processing and data analysis, and cost effectiveness. We optimized technical parameters for this assay. Further, the TLDA panel can be tailored to other specific purposes. We tested whether the profile of miRNAs in the CSF resembled miRNAs isolated from brain tissue (hippocampus or cerebellum), blood, or the choroid plexus. We found that the CSF miRNA expression profile most closely resembles that of choroid plexus tissue, underscoring the potential importance of choroid plexus-derived signaling through CSF miRNAs. In summary, the TLDA miRNA array panel will enable evaluation and discovery of CSF miRNA biomarkers and can potentially be utilized in clinical diagnosis and disease stage monitoring. [ABSTRACT FROM AUTHOR]

Cremastra appendiculata (D. Don) Makino is a mainly vegetative propagation terrestrial orchid that is a typical representative of the warm-temperate vegetation in China. In this experiment, we investigated the growth and development process of C. appendiculata leaf buds and examined their biochemical components (proteins, auxin, and cytokinin) to gain insight into the 'shoot branching' of C. appendiculata pseudobulb string. The results showed that the metabolic activity of C. appendiculata pseudobulbs became lower with the increase of pseudobulb age. However, biennial and triennial pseudobulbs have higher auxin levels than annual pseudobulbs in the intact plant ( P < 0.05). After decapitation, the auxin rapidly reduces in biennials. The reduction of auxin level promotes cytokinin biosynthesis, which makes the biennial dormant buds start to germinate 18 days after decapitation. These data and phenomena suggested that auxin plays important roles in regulating shoot branching of C. appendiculata, although further studies are needed to consolidate this viewpoint. Our data indirectly support the classical apical dominance theory whereby biennial pseudobulbs are strongly dependent on reduced auxin to initiate leaf bud outgrowth. [ABSTRACT FROM AUTHOR]

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n = 1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases ( p < 0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker. [ABSTRACT FROM AUTHOR]

A series of Cu-based catalysts were prepared and employed in the N-ethylation of ethylenediamine with ethanol in a fixed-bed reactor. Satisfying results were obtained using Cu-Zn-La/Al2O3 as a catalyst. In addition, Cu-Zn-La/SiO2, Cu-Zn-La/Al2O3 and Cu-Zn-La/HZSM-5 were characterized by the Brunauer-Emmett-Teller method (BET), H2- temperature program reduction (H2-TPR), X-ray diffraction (XRD), transmission electron microscopic measurements (TEM) and NH3-temperature programmed desorption (NH3-TPD) in order to investigate the influence of supports on their catalytic performance. It was found that both the BET surface area and the acidity of the support are key factors in the catalytic performance. Moreover, reaction parameters including temperature, hydrogen pressure and liquid hourly space velocity were optimized. Under optimal conditions, a 73.3 % conversion of ethylenediamine and a 71.2 % selectivity of N-ethylethylenediamine were achieved. Finally, the lifetime of the catalysts was evaluated and the reaction proceeded continuously for over 200 h. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2 (wildtype) and ACE2 (heterozygote) mice. Pressure overload in ACE2 mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2 cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2 hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2 mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2 vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Key message: [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 ( ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance ( p = 1.4 × 10), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 ( GRN) and OR = 1.22 rs1990622 ( TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database ( n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology ( p = 0.03). Thus, we describe a novel and targetable dementia risk factor. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available. [ABSTRACT FROM AUTHOR]

EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity Ca2+ buffer in many biological systems. Given the centrality of Ca2+ signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: Mg2+ affinity increased, whereas Ca2+ affinity decreased, forming a new ultra-delayed Ca2+ buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular Ca2+ signaling could benefit many biological systems with abnormal Ca2+ handling, including the diseased heart. [ABSTRACT FROM AUTHOR]

A 59-year-old Chinese male patient was admitted at diagnosis of type1 diabetes with ketoacidosis. During the normalization of blood glucose with insulin, the patient developed acute hemolysis. The factors predisposing to hemolysis were not found, except the significantly diminished activity of glucose-6-phosphate dehydrogenase (G6PD). DNA analysis did not show any coding or intronic mutation in the G6PD gene. This is the first reported case of a Chinese patient in diabetic ketoacidosis with hemolysis induced by G6PD deficiency in the absence of mutations in the G6PD gene. [ABSTRACT FROM AUTHOR]

A novel angiotensin-converting enzyme (ACE) homolog, named ACE2, is a monocarboxypeptidase which metabolizes several peptides. ACE2 degrades Angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang-(1-7), which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. In addition, as ACE2 is a multifunctional enzyme and its actions on other vasoactive peptides can also contribute to its vasoactive effects including the apelin-13 and apelin-17 peptides. The discovery of ACE2 corroborates the establishment of two counter-regulatory arms within the renin-angiotensin system. The first one is formed by the classical pathway involving the ACE-Ang II-AT receptor axis and the second arm is constituted by the ACE2-Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction. The ACE2-Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and cardiovascular diseases. In this review, we will summarize the biochemical and pathophysiological aspects of ACE2 with a focus on its role in diastolic and systolic heart failure. [ABSTRACT FROM AUTHOR]

Survivin belongs to the family of genes known as inhibitors of apoptosis, and although it has been implicated in the prevention of cancer, its potential role in burn-induced cardiac injury is unknown. In this study, we investigated the effects of survivin blockade on burn-induced cardiac apoptosis. Using a standardized Sprague-Dawley rat model of third-degree burn injury over 40% of total body surface area, apoptosis was measured in vivo followed by in vitro assessment of burn serum-stimulated cardiomyocytes. Based on the Western blot analyses, real-time PCR, ELISA, and TUNEL, apoptosis and caspase activation both in vivo and in vitro were significantly increased after severe burn injury, while survivin expression was increased (up to 2.90-fold) during the early stage of burn injury and was almost completely abolished 8 h after the burn. Survivin-deficient cardiomyocytes, as well as hearts from rats treated with the survivin inhibitor YM155, exhibited increased caspase-3 protein and mRNA expression and apoptosis ratio at different times after the burn. Furthermore, inhibition of ERK, phosphoinositol 3-kinase contributed the burn serum-induced increase in apoptosis and caspase-3 protein expression, and decreased survivin expression, whereas burn serum-induced increase in apoptosis was attenuated by P38 mitogen-activated protein kinase inhibition. These data identify survivin as a critical anti-apoptotic regulator of cardiomyocytes after burn injury. ERK, P38 MAPK and PI3K were found to be upstream regulators of survivin. [ABSTRACT FROM AUTHOR]