The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and ...respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
Next-generation sequencing has generated a need for a broadly applicable method to remove unwanted high-abundance species prior to sequencing. We introduce DASH (Depletion of Abundant Sequences by ...Hybridization). Sequencing libraries are 'DASHed' with recombinant Cas9 protein complexed with a library of guide RNAs targeting unwanted species for cleavage, thus preventing them from consuming sequencing space. We demonstrate a more than 99 % reduction of mitochondrial rRNA in HeLa cells, and enrichment of pathogen sequences in patient samples. We also demonstrate an application of DASH in cancer. This simple method can be adapted for any sample type and increases sequencing yield without additional cost.
Background
Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important ...role. The aim of this study was to evaluate whether postoperative infective complications influence long‐term survival after liver resection for hepatocellular carcinoma (HCC).
Methods
Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence‐free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection.
Results
Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021).
Conclusion
Postoperative infective complications decreased long‐term OS and RFS in patients treated with liver resection for HCC.
From a multi‐institutional database, 2442 patients who underwent resection with curative intent for hepatocellular carcinoma between 2003 and 2016 were analysed retrospectively. Among them, 332 patients (13·6 per cent) had postoperative infective complications within 30 days after surgery. Multivariable Cox regression revealed that postoperative infective complications decreased long‐term overall and recurrence‐free survival after liver resection for hepatocellular carcinoma.
Complications decrease long‐term overall survival
In the inductive power transfer systems (IPTSs) of wireless electric vehicles (WEV), the electromagnetic field (EMF) should be lowered for the safety of pedestrians. In general, the EMF should be ...canceled for every space, time, and load condition of interest. Three generalized design methods for cancelling the EMF of WEV are proposed in this paper. By adding active EMF cancel coils to each primary main coil and secondary main coil, respectively, the EMF generated from each main coil can be independently cancelled by their corresponding cancel coils. Moreover, the EMF can be successfully mitigated if a dominant EMF source only is cancelled with 3-dB margin, which can be applied to any resonant type wireless power transfer systems. Furthermore, no significant power drop may occur if the cancel coils are placed aside from magnetic coupling path. Design examples are shown for U-type and W-type IPTS as well as a wireless stationary EV charger. Experimental verifications are shown for a recently developed I-type IPTS, which has a narrow rail width structure with alternating magnetic polarity along with a roadway. The proposed design methods have been demonstrated, without the loss of generality, to only the secondary coil where relatively large EMF is generated due to high ampere turns. An optimum spacing for cancel coils from main coils and an optimum number of turns are determined. Through experiments, additional EMF mitigation techniques such as the magnetic mirror method, separating pick-up rectifiers, and passive Al plate are provided. Thus, the EMF at 1 m distance from the center of a pick-up becomes under 44 mG even for the maximum power of 12 kW.
N-doped highly microporous carbons have been successfully fabricated from N-rich microalgae by the combination of low-cost hydrothermal carbonization and industry-adopted KOH activation processes. ...The hydrothermal carbonization process was found to be an essential step for the successful conversion of microalgae into a carbon material. The materials thus synthesized showed BET surface areas in the range ∼1800–2200 m2 g−1 exclusively ascribed to micropores. The carbons showed N contents in the 0.7–2.7 wt.%, owing to the use of N-rich microalgae as a carbon precursor. When tested in symmetric double layer capacitors (occasionally called supercapacitors) based on aqueous LiCl electrolytes, pseudocapacitance was only observable for the sample synthesized at the lowest temperature, 650 °C, which is the one exhibiting the largest amount of N- and O-containing groups. The samples synthesized at 700–750 °C exhibited excellent rate capability (only 20% of capacitance loose at 20 A g−1), with specific capacitances of 170–200 F g−1 at 0.1 A g−1. These materials showed excellent long-term cycling stability under high current densities.
•Exclusively microporous carbons have been prepared.•Low cost hydrothermal carbonization step critical for successful porous carbon synthesis.•N-doping achieved through a N-rich microalgae, a fast-growing renewable precursor.•Excellent capacitance retention achieved in symmetric EDLCs operating in LiCl.
•Pb and Cu were mobilized but not hyperaccumulated by Noccaea caerulescens.•More Pb and Zn leached from pots with N. caerulescens than with Thlaspi arvense.•Magnetic field with intensity below 150 mT ...promoted the growth of N. caerulescens.•Magnetic field decreased the volume of leachate.•Less Pb and Zn leached from pots treated by magnetic field.
Hyperaccumulators can accumulate high amounts of specific metals and have been widely used to remediate metal polluted soil. However, organic acid secretion and soil acidification (two important mechanisms for hyperaccumulators to mobilize and extract metals) can also activate non-hyperaccumulated metals and then increase the leaching risk. The decontamination efficiency and leaching risk of using Noccaea caerulescens (formerly Thlaspi caerulescens) and Thlaspi arvense were compared in the present study. Although N. caerulescens accumulated significantly more Cd and Zn than T. arvense, it increased the leaching risk of Pb and Cu as well. Under magnetic fields of 30, 60, 120 and 150 mT, the biomass production of N. caerulescens was increased by 18.5, 48.9, 80.4, and 29.3% respectively, but decreased by 21.7% under 400 mT. Comparing with the control, plants raised from seeds pre-treated by magnetic fields accumulated 37.8–250.1% more metals and reduced the leachate volume and leached metals by 1.1–32.9% and 4.6–48.1% respectively. Considering remediation efficiency, environmental risk alleviation and energy consumption, N. caerulescens treated by 120 mT magnetic field is suited to remediate multi-metal polluted soil.
p53 is a central integrator of a plethora of signals and outputs these signals in the form of tumor suppression. It is well accepted that ubiquitination plays a major part in p53 regulation. ...Nonetheless, the molecular mechanisms by which p53 activity is controlled by ubiquitination are complex. Mdm2, a RING oncoprotein, was once thought to be the sole E3 ubiquitin ligase for p53, however recent studies have shown that p53 is stabilized but still degraded in the cells of Mdm2-null mice. Although the essential role of Mdm2 in p53 regulation is well established, there are an increasing number of other E3 ligases implicated in Mdm2-independent regulation of p53 by ubiquitination. The different types of ubiquitination on p53 by various E3 ligases have been linked to its differential effects on p53-mediated stress responses. In addition to proteasome-mediated degradation, ubiquitination of p53 acts as signals for degradation-independent functions, such as nuclear export. The function of ubiquitinated p53 varies in the nucleus and cytosol underlying the many potential contributions ubiquitinated p53 may have in promoting cell proliferation or death. Thus, p53 requires multiple layers of regulatory control to ensure correct temporal and spatial functions.
Hausp is a deubiquitinase that has been shown to regulate the p53-Mdm2 pathway. Cotransfection of p53 and Hausp stabilizes p53 through the removal of ubiquitin moieties from polyubiquitinated p53. ...Interestingly, knockout or RNA interference-mediated knockdown of Hausp in human cells also resulted in the stabilization of p53 due to the destabilization of Mdm2, suggesting a dynamic role of Hausp in p53 activation. To understand the physiological functions of Hausp, we generated hausp knockout mice. Hausp knockout mice die during early embryonic development between embryonic days E6.5 and E7.5. The hausp knockout embryos showed p53 activation, but no apparent increase in apoptosis. Embryonic lethality was caused by a dramatic reduction in proliferation and termination in development, in part due to p53 activation and/or abrogation of p53-independent functions. Although deletion of p53 did not completely rescue the embryonic lethality of the hausp knockout, embryonic development was extended in both hausp and p53 double knockout embryos. These data show that Hausp has a critical role in regulating the p53-Mdm2 pathway.
Cancer cells recruit monocytes, macrophages and other inflammatory cells by producing abundant chemoattractants and growth factors, such as macrophage colony-stimulating factor (M-CSF/CSF-1) and ...monocyte chemoattractant protein-1 (MCP-1/CCL2), to promote tumor growth and dissemination. An understanding of the mechanisms that target cancer cells and regulate tumor microenvironment is essential in designing anticancer therapies. Here, we showed that serum amyloid-A (SAA) and cathelicidin (LL-37) stimulated M-CSF and MCP-1 expression with or without lipopolysaccharide (LPS) administration; conversely, lipoxin-A(4) (LXA(4)) and annexin-A1 (ANXA1) inhibited LPS-induced M-CSF and MCP-1 production by human (HepG2) and mouse (H22) hepatocellular carcinoma cells (HCCs). The effects of LXA(4), ANXA1, SAA and LL-37 were dependent on the activation of their mutual cell-surface receptor formyl peptide receptor-2 (FPR2) and subsequent ROS-MAPK-NF-kB signalings. Furthermore, our results indicated that LPS switched macrophages into an IL-10(low)IL-12(high) M1 profile, whereas M-CSF+MCP-1 and FPR2 agonists skewed them into M2 (IL-10(high)IL-12(low)). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA(4) and ANXA1 induced monocyte differentiation into M2a+M2c-like cells and showed antitumorigenetic activities, whereas SAA, LL-37 and M-CSF+MCP-1 led to M2b- or M2d-like polarization, which exacerbated HCC invasion in vitro and in vivo, respectively. Our results suggest that FPR2 has an appreciable pleiotropic regulator role in tumor immunoediting.
Laboratory animals are often used to derive health risk from environmental exposure or to assess the therapeutic effect of a drug delivered by inhaled therapy. Knowledge of the in-situ distribution ...of deposited particles on airway and alveolar surfaces is essential in any assessment of these effects. A unique database including both high-resolution lung anatomy and deposition data in four strains of laboratory mice have been recently made publicly available to the research community (https://doi.org/10.25820/9arg-9w56). Using these data, we investigated the effect of particle size on the distribution of deposited particles at the lobar and near-acini level. Analysis was performed on a total of 33 mice where 3, 16 and 14 animals were exposed to 0.5 μm, 1 μm and 2 μm particles, respectively. Ratio of normalized deposition to normalized volume was calculated for each lobe (DVlobe). At the near-acini level, the skew and standard deviation of the frequency distribution of particle deposition were calculated. Significant deviation above 1 was found for DV ratio in the cranial lobe (DVCranial). DVMiddle, DVCaudal and DVAccessory were all significantly <1 and lower than DVleft (p < 0.01). At the near-acini level, skew and standard deviation were positively correlated with particle size and the presence of hot spots (high deposition) were mainly found in the apical region of the lung. These results highlight the uneven distribution of deposited particles in the mouse lung. Thus, depending on the lung sample location, individual analysis to determine overall deposition may either underestimate or overestimate total lung burden, at least for micron-sized particles.
•Volume-normalized deposition is highest in the cranial lobe of the mouse lung.•Heterogeneity of deposition patterns increases with increasing particle size.•Hot spots of deposition are mainly located in the apical region of the mouse lung.
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