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Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N(6)-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8(+) T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ–STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10–STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.

Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.

Left bundle branch area pacing (LBBAP) has developed in an effort to improve cardiac resynchronization therapy (CRT). We aimed to compare the long-term clinical outcomes between LBBAP and biventricular pacing (BIVP) in patients with heart failure (HF) and complete left bundle branch block (CLBBB). Consecutive patients with HF and CLBBB requiring CRT received either LBBAP or BIVP were recruited at the Second Affiliated Hospital of Nanchang University from February 2018 to May 2019. We assessed their implant parameters, electrocardiogram (ECG), clinical outcomes at implant and during follow-up at 1, 3, 6, 12, and 24 months. Forty-one patients recruited including 21 for LBBAP and 20 for BIVP. Mean follow-up duration was 23.71 ± 4.44 months. LBBAP produced lower pacing thresholds, shorter procedure time and fluoroscopy duration compared to BIVP. The QRS duration was significantly narrower after LBBAP than BIVP (129.29 ± 31.46 vs. 156.85 ± 26.37 ms, p = 0.005). Notably, both LBBAP and BIVP significantly improved LVEF, LVEDD, NYHA class, and BNP compared with baseline. However, LBBAP significantly lowered BNP compared with BIVP (416.69 ± 411.39 vs. 96.07 ± 788.71 pg/ml, p = 0.007) from baseline to 24-month follow-up. Moreover, patients who received LBBAP exhibited lower number of hospitalizations than those in the BIVP group (p = 0.019). In addition, we found that patients with moderately prolonged left ventricular activation time (LVAT) and QRS notching in limb leads in baseline ECG respond better to LBBAP for CLBBB correction. LBBAP might be a relative safe and effective resynchronization therapy and as a supplement to BIVP for patients with HF and CLBBB.

Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP.Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period.The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP.Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings.www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

The multi-generation heredity trait of hypertension in human has been reported, but the molecular mechanisms underlying multi-generational inheritance of hypertension remain obscure. Recent evidence shows that prenatal inflammatory exposure (PIE) results in increased incidence of cardiovascular diseases, including hypertension. In this study we investigated whether and how PIE contributed to multi-generational inheritance of hypertension in rats. PIE was induced in pregnant rats by intraperitoneal injection of LPS or Poly (I:C) either once on gestational day 10.5 (transient stimulation, T) or three times on gestational day 8.5, 10.5, and 12.5 (persistent stimulation, P). Male offspring was chosen to study the paternal inheritance. We showed that PIE, irrespectively induced by LPS or Poly (I:C) stimulation during pregnancy, resulted in multi-generational inheritance of significantly increased blood pressure in rat descendants, and that prenatal LPS exposure led to vascular remodeling and vasoconstrictor dysfunction in both thoracic aorta and superior mesenteric artery of adult F2 offspring. Furthermore, we revealed that PIE resulted in global alteration of DNA methylome in thoracic aorta of F2 offspring. Specifically, PIE led to the DNA hypomethylation of G beta gamma (Gβγ) signaling genes in both the F1 sperm and the F2 thoracic aorta, and activation of PI3K/Akt signaling was implicated in the pathologic changes and dysregulated vascular tone of aortic tissue in F2 LPS-P offspring. Our data demonstrate that PIE reprogrammed DNA methylome of cells from the germline/mature gametes contributes to the development of hypertension in F2 PIE offspring. This study broadens the current knowledge regarding the multi-generation effect of the cumulative early life environmental factors on the development of hypertension.

Background The most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective. Methods A prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups. Results Fewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p Conclusion Our results suggest that AmB-D combined with 5FC remains the more efficacious induction regimen compared to AmB-D plus Flu, and that VCZ + 5FC might be a potential alternative when the standard regimen is not readily available, accessible, tolerated, or effective. Clinical Trials: Registration number, ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362.

Broaching is commonly used for machining fir tree slots on turbine disk, which has outstandingadvantages and disadvantages, such as high quality machined surface, high manufacturing accuracy and highproductivity as well as fa st tool wear, extremely high processing costs and long preparation time, poor processflexibility. Utilizing the electroplated cubic boron nitride (CBN) profiled grinding wheels and single sided localprofiled grinding process, the experiments of FGH96 tur bine disk slots are carried out. The results show that thehigh precision of slot profile can be achieved by the developed process. Using the given experimental parametersn =48000 rpm, a p =0.002 mm, v f =100 mm/min and 600# electroplated CBN profiled wheel, the profile error ofFGH96 slots is within ±0.012 mm, and the grinding surface roughness is less than Ra0.8 μm. After four whole slotsare machined completely, the grinding wheel still has grinding capability, which proves that 600 # electroplatedCBN prof iled wheel can meet the grinding needs of FGH96 turbine disk slots.

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options.

High speed small hole electrical discharge machining (EDM) drilling processes can easily become unstable, due to changing flushing conditions, inappropriate preset electrical parameters, and machining debris residues. Although there are already successful attempts in controlling EDM processes, cost-effective adaptive control of high speed small hole EDM drilling has not been reported. Process stability can contribute to the improvement of machining efficiency and surface finish. To maintain a higher process stability, a minimum-variance self-tuning regulator (MVSTR) is designed based on an auto-regressive moving average exogenous (ARMAX) model. To determine specifications of the system, the time and frequency responses are analyzed, and the validation is executed for the offline system model. A series of high aspect ratio holes drilling experiments with different electrode diameters of 0.3 mm, 1.0 mm, and 3.0 mm show that, with the use of the MVSTR control scheme, a higher machining efficiency and a lower tool wear can be achieved as compared with the original controller. Microscopic pictures of drilled holes and electrodes show better surface quality.

N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

This paper presents a new dynamic two-axis interpolation test method for dynamic accuracy calibration of rotary axis in a five-axis machine tool based on the double ball bar(DBB). The proposed method only requires synchronous movement of a single rotary axis and a single linear axis which is parallel to the average line of the rotary axis. The measurement trajectory is a spatial curve formed by the intersection of spherical and cylindrical surface, which are the reachable operating space of the DBB and the reachable operating space of the two moving axes, respectively. Compared to the circular tests described in ISO10791.6, which need at least three axes to synchronize motion, the proposed method can be effectively applied to the matching of servo parameters and the adjusting of the dynamic errors of the rotary axis, without the interference of additional linear axes. Meanwhile, the error trajectory pattern obtained by this method has the characteristics of orthogonality and regular variation, which is similar to the circular test of linear axis. So it can guide the calibration and optimization of rotating axis conveniently and effectively. Simulation results show that the proposed method can effectively identify the inverse error, scaling mismatch error, servo mismatch error, squareness error, and other error sources of the rotary axis. The proposed method is verified through experiments on a five-axis machine tool.

SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells1. Here we identified a signaling pathway-involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes2,3-that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein. XBP1s bound to and recruited the transcription factor T-BET to the gene encoding granzyme B, leading to increased transcription. XBP1s positively regulated the cytolytic activity of NK cells against leukemia cells and was also required for IL-15-mediated NK cell survival through an anti-apoptotic mechanism. Thus, the newly identified IL-15-AKT-XBP1s signaling pathway contributes to enhanced effector functions and survival of human NK cells.

The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.

This study examined electrophysiological characteristics and outcomes of patients with sustained ventricular tachycardia (VT) in the setting of isolated ventricular noncompaction (IVNC). In patients with IVNC, VT has been associated with sudden cardiac death. However, the electrophysiological characteristics and optimal management of these VTs are only incompletely understood. This retrospective cohort study assessed arrhythmia characteristics and outcomes in IVNC patients with sustained monomorphic VTs. Data were obtained from five academic centers covering the time period from January 1, 2006, to December 31, 2016, with a median follow-up of 40 months. Eighteen consecutive IVNC patients with sustained VTs (12 males [66%], mean age of 44.4 ± 16.9 years) were enrolled. Seven (39%) patients underwent VT ablation (five males, mean age of 43.3 ± 15.5 years) and nine (50%) patients received ICD therapy. Six of 18 patients (33%) died during a median follow-up of 40 months. Of these, three had ICDs, two had undergone VT ablation, and one had received only antiarrhythmic drugs. Among the seven patients with prior VT ablation, five VTs in the RV (three RVOT and one tricuspid annulus) and two LV VTs (one anterolateral papillary muscle and one inferolateral wall) were localized by 3-D mapping and successfully ablated. In six of seven ablation cases (85.7%), the VTs were distant from the noncompaction zone. VTs appeared to be focal in 57% (4/7) and macro-reentry in 43% (3/7) of patients based on 3-D mapping and entrainment studies. The success rate of VT ablation was 85.7% with one VT recurrence and two deaths during the mean follow-up of 54 (28–115) months. IVNC Patients with sustained VTs appear to have a poor prognosis despite receiving ICD or apparently successful VT ablation therapy. Further, most VTs appear to arise remote from the noncompaction zone. Whether these VTs were “idiopathic” or related to IVNC was uncertain.

Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia

Methods for solving equations play an important role in scientific computation and cryptography. Usually, many cryptographic protocols and scientific computation problems can be reduced to some differential equation or linear equation systems. However, the above mentioned scientific computation needs very much computation resource. Hence, super computer technology such as grid technology, cloud computation is slow to emerge. Cloud computation has strong computation power and helps users to deals with this very difficult computation. For security, we need improve some conditional computation methods for numerical or scientific outsourcing computation. In this paper some special algebraic and differential equations are studied. And some new practical verifiably secure outsourcing protocols are designed, which are better than the previous methods in the following terms. First, they can protect more secret parameters for abstract equations. Second, based on previous methods, random function can be chosen in the different ways and hence better security and privacy is obtained. Third, for nonlinear equations, we find more applications and new methods. These tools help us to find more methods to deal with more linear or nonlinear equations. At last, some verifiably secure outsourcing computation for integral computation is designed. These results help to outsource the computation for solving differential equations.

In this work, metal oxide (MnO2, SnO2 and Co3O4)–graphene composite materials were successfully prepared via different synthesis methods. Uniform metal oxide nanoparticles were well dispersed on graphene sheets, and transmission electron microscopy characterizations showed that the average sizes of MnO2, SnO2, and Co3O4 particles were about 60, 5, and 10 nm, respectively. Reflection losses of graphene composites and pure graphene were systematically evaluated between 2 and 18 GHz, which revealed that all composites exhibited enhanced microwave absorption properties compared to pure graphene. The minimum reflection losses of MnO2-graphene, SnO2–graphene, and Co3O4–graphene composites with a thickness of 2.0 mm were −20.9, −15.28, and −7.3 dB at the frequency of 14.8, 15.94, and 9.6 GHz, respectively, whereas −4.5 dB for pure graphene. The enhanced absorption ability probably originated from the combined advantage of metal oxide particles and graphene, which proved beneficial to improve the impedance matching of permittivity and permeability. Besides, the intrinsic characteristics of MnO2, SnO2, and Co3O4 nanoparticles, the interface between nanostructured metal oxides and graphene sheets, and the multi-dielectric relaxation processes are all influence factors to improve the properties of microwave absorption.

Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.

Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention.

Nanoparticles have demonstrated great potential for enhancing drug delivery. However, the low drug encapsulation efficiency at high drug-to-nanoparticle feeding ratios and minimal drug loading content in nanoparticle at any feeding ratios are major hurdles to their widespread applications. Here we report a robust eukaryotic cell-like hybrid nanoplatform (EukaCell) for encapsulation of theranostic agents (doxorubicin and indocyanine green). The EukaCell consists of a phospholipid membrane, a cytoskeleton-like mesoporous silica matrix and a nucleus-like fullerene core. At high drug-to-nanoparticle feeding ratios (for example, 1:0.5), the encapsulation efficiency and loading content can be improved by 58 and 21 times, respectively, compared with conventional silica nanoparticles. Moreover, release of the encapsulated drug can be precisely controlled via dosing near infrared laser irradiation. Ultimately, the ultra-high (up to ∼87%) loading content renders augmented anticancer capacity both in vitro and in vivo. Our EukaCell is valuable for drug delivery to fight against cancer and potentially other diseases.

Mutations in the α-subunit of cardiac sodium channel gene SCN5A can lead to the overlapping phenotypes of both the Brugada and type 3 long QT syndromes. However, the combination of Brugada and a short QT phenotype resulting from mutation in SCN5A has not previously been described. A man with concomitant Brugada-like and short QT electrocardiogram (ECG) was identified and the SCN5A gene was sequenced. Whole-cell patch clamp analysis of human embryo kidney (HEK) 293 cells expressing a SCN5A channel with the patient's sequence was used to investigate the biophysical properties of the channel. The patient with the family history of sudden death showed Brugada-like and short QT interval ECG. Sequence anlaysis of the coding region of the SCN5A gene, identified a G to A heterozygous missense mutation at nucleotide site 2066 that resulted in a amino-acid substitution of arginine to histidine at amino-acid site 689 (R689H). Patch clamp analysis showed that the R689H failed to generate current when heterologously expressed in HEK293 cells, indicating it was a loss-of-function mutation. Our finding firstly showes that a heterozygous missense mutation R689H in SCN5A gene results in the loss of protein function and the coexistents of the Brugada-like and short QT interval ECG phenotypes.

Nanoparticles have demonstrated great potential for enhancing drug delivery. However, the low drug encapsulation efficiency at high drug-to-nanoparticle feeding ratios and minimal drug loading content in nanoparticle at any feeding ratios are major hurdles to their widespread applications. Here we report a robust eukaryotic cell-like hybrid nanoplatform (EukaCell) for encapsulation of theranostic agents (doxorubicin and indocyanine green). The EukaCell consists of a phospholipid membrane, a cytoskeleton-like mesoporous silica matrix and a nucleus-like fullerene core. At high drug-to-nanoparticle feeding ratios (for example, 1:0.5), the encapsulation efficiency and loading content can be improved by 58 and 21 times, respectively, compared with conventional silica nanoparticles. Moreover, release of the encapsulated drug can be precisely controlled via dosing near infrared laser irradiation. Ultimately, the ultra-high (up to ∼87%) loading content renders augmented anticancer capacity both in vitro and in vivo. Our EukaCell is valuable for drug delivery to fight against cancer and potentially other diseases., Nanoparticles have the potential for enhancing drug delivery; however, low drug encapsulation efficiency and drug loading content limit their application. Here, the authors engineer a complex nanostructure for drug delivery in cancer treatment and evaluate it in different conditions with encouraging results.

The rare-earth zirconates with the general formula of Ln2Zr2O7 (Ln = rare-earth elements) having considerable low thermal conductivity and exhibiting good phase stability at high temperature have attracted particular interest in thermal barrier coating (TBC) applications. The Sm2Zr2O7 coatings were deposited by plasma spraying, and the effect of thermal aging on their microstructure and mechanical properties was examined. The lamellar structure gradually disappeared with the temperature increasing for thermal aging. The evaluation by image analysis revealed that the amount of microcrack in coatings decreased with increasing aging temperature because of the increase in aspect ratio caused by microcrack healing, while no obvious change was observed in the spherical porosity. The as-sprayed Sm2Zr2O7 coating exhibited low microhardness and elastic modulus, which increased with rise in aging temperature because of the microstructure reconfiguration; in addition, the ratio of microhardness to elastic modulus decreased with aging temperature increase, indicating a promotion in plastic property.

Our goal was to evaluate a multi-pinhole (MPH) collimator which allows changing configurations for mouse imaging and rat imaging. The collimator length can be adjusted from 5 cm for rat imaging to a maximum of 8 cm for mouse imaging. Projections of mouse- and rat-size phantoms were simulated with collimator length of 8 cm, and the rat-size phantom was additionally simulated with collimator length of 5 cm. Bias and noise were assessed in the reconstructed images. Three physical phantoms were used to evaluate the axial sampling and resolutions for one-, four-, and five-pinhole single photon emission computed tomography (SPECT). Images of three different-sized rodents were also acquired. Simulations showed that for rat imaging, shorter collimator length provided an improved bias-noise trade-off compared to that of longer collimator length. Axial distortions were significantly reduced for MPH compared to single pinhole imaging. The smallest rods visible for mouse imaging and rat imaging were 1 and 1.6 mm, respectively, and their corresponding absolute sensitivities were 3.47% and 2.02% at the center field-of-view for 5-pinhole imaging. The count ratios were 1:3.78:4.42, respectively, for one-, four-, and five-pinhole for same acquisition time. Good image quality was observed in real animal studies. This collimator allows flexible single pinhole and MPH SPECT imaging for rodents, achieving high resolution and detection efficiency with minimal image artifacts.

The fabrication process of Cu/Al2O3/MgF2/Au double-barrier metal/insulator/metal junction (DMIMJ) was introduced, and more stable light emission from this junction was successfully observed. The light emission physical mechanism of the junction was discussed. Results show that light emission spectrum of this structure locates at wavelength of 250–700 nm with two peaks at around 460 nm and 640 nm, which moves towards shorter wavelength region in comparison with that of the Al/Al2O3/Au junction. The light emission efficiency of this junction ranges from 0.7×10−5–2.0×10−5, which is 1 to 2 orders higher than that of the single-barrier Al/Al2O3/Au junction. The improved properties of this structure should be due to the electrons resonant tunneling effect in the double-barrier.

Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.