CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses.

Efforts are being made worldwide to understand the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses because of different peptide conformations. T cell receptor (TCR) sequencing indicated that cross-reactivity was driven by private TCR repertoires with a bias for TRBV27 and a long CDR3ß loop. Our findings demonstrate the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity.

Increasing HbA1c is associated with reduced CD8+ T cell functionality in response to influenza virus in a TCR-dependent manner in individuals with diabetes mellitus.

Diabetes mellitus is on the rise globally and is a known susceptibility factor for severe influenza virus infections. However, the mechanisms by which diabetes increases the severity of an influenza virus infection are yet to be fully defined. Diabetes mellitus is hallmarked by high glucose concentrations in the blood. We hypothesized that these high glucose concentrations affect the functionality of CD8+ T cells, which play a key role eliminating virus-infected cells and have been shown to decrease influenza disease severity. To study the effect of hyperglycemia on CD8+ T cell function, we stimulated peripheral blood mononuclear cells (PBMCs) from donors with and without diabetes with influenza A virus, anti-CD3/anti-CD28-coated beads, PMA and ionomycin (PMA/I), or an influenza viral peptide pool. After stimulation, cells were assessed for functionality [as defined by expression of IFN-γ, TNF-α, macrophage inflammatory protein (MIP)-1ß, and lysosomal-associated membrane protein-1 (CD107a)] using flow cytometry. Our results showed that increasing HbA1c correlated with a reduction in TNF-α production by CD8+ T cells in response to influenza stimulation in a TCR-specific manner. This was not associated with any changes to CD8+ T cell subsets. We conclude that hyperglycemia impairs CD8+ T cell function to influenza virus infection, which may be linked with the increased risk of severe influenza in patients with diabetes.

Giant Enhancement of Hole Mobility for 4H-Silicon Carbide through Suppressing Interband Electron-Phonon Scattering.

4H-silicon carbide (4H-SiC) possesses a high Baliga figure of merit, making it a promising material for power electronics. However, its applications are limited by low hole mobility. Herein, we found that the hole mobility of 4H-SiC is mainly limited by the strong interband electron-phonon scattering using mode-level first-principles calculations. Our research indicates that applying compressive strain can reverse the sign of crystal-field splitting and change the ordering of electron bands close to the valence band maximum. Therefore, the interband electron-phonon scattering is severely suppressed and the electron group velocity is significantly increased. The out-of-plane hole mobility of 4H-SiC can be greatly enhanced by ∼200% with 2% uniaxial compressive strain applied. This work provides new insights into the electron transport mechanisms in semiconductors and suggests a strategy to improve hole mobility that could be applied to other semiconductors with hexagonal crystalline geometries.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

Evaluation of safety and efficacy of insulated-gate bipolar transistor holmium laser technology for prostate enucleation in canine model: a preliminary study.

The evolution of laser medical devices for benign prostatic hyperplasia (BPH) treatment aims to enhance vaporization, coagulation, or tissue removal. In this study, we aim to evaluate the effectiveness and safety of the innovative application of insulated-gate bipolar transistor (IGBT) xenon lamp-pulsed drive technology holmium laser in endoscopic prostate enucleation operations using canine models. Six canines were used as an experimental unit, the breed of the canine unit used was beagle. Each canine served as its own control to minimize the number of experimental units. Endoscopic enucleation, performed by a single surgeon, involved enucleating the left hemi-prostate, leaving the right hem-prostate untouched to serve as the control. Throughout the study period, all canines maintained good health. No adverse events were observed in all six canines. Postoperatively, there were no indications of redness, swelling, or other adverse effects at the surgical sites. No abnormalities were observed in the appearance and morphology of major organs. The prostate and bladder, removed for further pathological evaluation, exhibited no abnormalities in size, color, or texture. No abnormalities or inflammation were observed, and the tissues were free of adhesions, indicating successful healing. In conclusion, our comparison of preoperative and postoperative parameters in canines suggests that the IGBT pulsed laser, at a power setting of 100 W, demonstrates characteristics of safety, efficacy, minimal tissue damage, and no major postoperative complications. This study establishes a theoretical foundation for future applications in human settings, encouraging further exploration of the IGBT holmium laser's potential in clinical practice.

Glass-like Transport Dominates Ultralow Lattice Thermal Conductivity in Modular Crystalline Bi4O4SeCl2.

Crystalline Bi4O4SeCl2 exhibits record-low 0.1 W/mK lattice thermal conductivity (κL), but the underlying transport mechanism is not yet understood. Using a theoretical framework which incorporates first-principles anharmonic lattice dynamics into a unified heat transport theory, we compute both the particle-like and glass-like components of κL in crystalline and pellet Bi4O4SeCl2 forms. The model includes intrinsic three- and four-phonon scattering processes and extrinsic defect and extended defect scattering contributing to the phonon lifetime, as well as temperature-dependent interatomic force constants linked to phonon frequency shifts and anharmonicity. Bi4O4SeCl2 displays strongly anisotropic complex crystal behavior with dominant glass-like transport along the cross-plane direction. The uncovered origin of κL underscores an intrinsic approach for designing extremely low κL materials.

Electrocatalytic Decomposition of Lithium Oxalate-Based Composite Microspheres as a Prelithiation Additive in Lithium-Ion Batteries.

In conventional lithium-ion batteries (LIBs), the active lithium from the lithium-containing cathode is consumed by the formation of a solid electrolyte interface (SEI) at the anode during the first charge, resulting in irreversible capacity loss. Prelithiation additives can provide additional active lithium to effectively compensate for lithium loss. Lithium oxalate is regarded as a promising ideal cathode prelithiation agent; however, the electrochemical decomposition of lithium oxalate is challenging. In this work, a hollow and porous composite microsphere was prepared using a mixture of lithium oxalate, Ketjen Black and transition metal oxide catalyst, and the formulation was optimized. Owing to the compositional and structural merits, the decomposition voltage of lithium oxalate in the microsphere was reduced to 3.93 V; when being used as an additive, there is no noticeable side effect on the performance of the cathode material. With 4.2% of such an additive, the first discharge capacity of the LiFePO4‖graphite full cell increases from 139.1 to 151.9 mAh g-1, and the coulombic efficiency increases from 88.1% to 96.3%; it also facilitates the formation of a superior SEI, leading to enhanced cycling stability. This work provides an optimized formula for developing an efficient prelithiation agent for LIBs.

Baseline PSMA-PET/CT as a predictor of PSA persistence following radical prostatectomy in high-risk nonmetastatic prostate cancer patients receiving neoadjuvant therapy.

BACKGROUND: The precise staging and proper management of high-risk prostate cancer (PCa) continues to be a challenge. We aimed to demonstrate the prognostic value of baseline prostate-specific membrane antigen-ligand positron emission tomography/computed tomography (PSMA-PET/CT) in high-risk, nonmetastatic PCa patients who received neoadjuvant hormonal or chemohormonal treatment followed by radical prostatectomy (RP). METHODS: We performed retrospective analyses of 70 patients with high-risk, nonmetastatic PCa confirmed by biopsy between 2018 and 2021. All patients underwent neoadjuvant therapy followed by RP and pelvic lymph node dissection (PLND); PSMA-PET/CT was performed before initiation of neoadjuvant therapy. Acquired image information and clinical characteristics/outcomes were examined for possible associations. RESULTS: Among 70 high-risk PCa patients, median age was 69 years old and median prostate specific antigen (PSA) at presentation was 58.5 ng/mL. Thirty (42.9%) patients had uptake of the PSMA tracer only in the primary PCa lesions and 40 (57.1%) patients had PSMA-positive lesions in regional or distant sites. Sixteen (32%) localized PCa patients defined by pre-PET magnetic resonance imaging were found to have locally advanced PCa based on PSMA-PET/CT. Fifteen (30%) localized PCa patients and 7 (35%) locally advanced PCa patients were upstaged to metastatic PCa. The sensitivity and specificity of PSMA-PET/CT for the detection of lymph node involvement were 90.9% and 69.5%, respectively, with a positive prediction value of 35.7% and negative prediction value of 97.6%. The diagnostic accuracy was 72.9%. Univariate analysis showed upstaging, tumor stage, and metastasis location based on PSMA-PET/CT are predictors to PSA persistence after surgery, while multivariate logistic regression analysis showed only the tumor stage based on PSMA-PET/CT remained an independent predictor of the outcome. CONCLUSIONS: This study further highlights the accuracy and necessity of PSMA-PET/CT in newly diagnosed, high-risk, nonmetastatic PCa patients.

Outcomes of holmium laser enucleation of the prostate (HoLEP) for very large-sized benign prostatic hyperplasia (over 150 mL): open simple prostatectomy is dead.

INTRODUCTION: Our study aimed to describe the outcomes of transurethral enucleation of the prostate (HoLEP) for large-sized benign prostatic hyperplasia over 150 mL (bBPH). METHODS: We conducted a retrospective, descriptive, and analytical study of patients undergoing HoLEP for bBPH. The primary endpoint was the success of the procedure, defined by a mixed criteria: complete endoscopic enucleation of the prostate, absence of blood transfusion or reoperation for bleeding, post-operative improvement of quality of life (assessed by a ≥ 2 points increase at in the 8th question of the IPSS test) and post-operative continence (no pads use) at 3 months. RESULTS: Eighty-one patients were included with a mean age of 73.9 ± 7.3 and a mean measured prostate volume of 183.3 ± 34.5 cc. The mean operative time was 57.5 ± 29.7 min and the average wet weight of resected tissue removed was 151.8 ± 44.7 g. Mean hospitalization stay was 1.3 ± 0.7 days with a mean post-operative catheterization period of 1.9 ± 0.9 days. The success of the surgery was achieved in 77 patients (95%). Functional improvements were found at 1 and 6 months for Qmax, post-void residual, IPSS and QoL-IPSS. The 30-day complication rate was 9.9%. The average PSA level dropped from 14.8 ± 11.6 ng/mL at baseline to 0.8 ± 0.5 ng/mL at 6 months. CONCLUSION: HoLEP for bBPH is both safe and efficient. Regarding the benefit/risk balance, it should be highlighted as the gold standard for the management of big BPH.

Hypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) experience excess cardiovascular morbidity and mortality, and exacerbations further increase the risk of such events. COPD is associated with persistent blood and airway neutrophilia and systemic and tissue hypoxia. Hypoxia augments neutrophil elastase release, enhancing capacity for tissue injury. Objective: To determine whether hypoxia-driven neutrophil protein secretion contributes to endothelial damage in COPD. Methods: The healthy human neutrophil secretome generated under normoxic or hypoxic conditions was characterized by quantitative mass spectrometry, and the capacity for neutrophil-mediated endothelial damage was assessed. Histotoxic protein concentrations were measured in normoxic versus hypoxic neutrophil supernatants and plasma from patients experiencing COPD exacerbation and healthy control subjects. Measurements and Main Results: Hypoxia promoted PI3Kγ-dependent neutrophil elastase secretion, with greater release seen in neutrophils from patients with COPD. Supernatants from neutrophils incubated under hypoxia caused pulmonary endothelial cell damage, and identical supernatants from COPD neutrophils increased neutrophil adherence to endothelial cells. Proteomics revealed differential neutrophil protein secretion under hypoxia and normoxia, and hypoxia augmented secretion of a subset of histotoxic granule and cytosolic proteins, with significantly greater release seen in COPD neutrophils. The plasma of patients with COPD had higher content of hypoxia-upregulated neutrophil-derived proteins and protease activity, and vascular injury markers. Conclusions: Hypoxia drives a destructive "hypersecretory" neutrophil phenotype conferring enhanced capacity for endothelial injury, with a corresponding signature of neutrophil degranulation and vascular injury identified in plasma of patients with COPD. Thus, hypoxic enhancement of neutrophil degranulation may contribute to increased cardiovascular risk in COPD. These insights may identify new therapeutic opportunities for endothelial damage in COPD.

Transurethral columnar balloon dilation of the prostate combined with holmium laser incision for bladder neck contracture in day-surgery mode.

The study aimed to investigate the clinical effect of transurethral columnar balloon dilation of the prostate combined with holmium laser in the treatment of bladder neck contracture (BNC). This retrospective study included 41 patients with BNC, who had been treated with transurethral columnar balloon dilation and holmium laser in our hospital from June 2020 to June 2022. Admission, operation, and discharge of all the patients were completed in 24 h. The patients' satisfaction, postoperative complications, and chronic pain after operation were followed up. Clinical parameters, such as International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), quality of life (QoL), and post-void residual volume (PVR) in pre-operation, 1 month and 6 months after operation were recorded. All patients underwent the operations successfully. Six patients experienced urge incontinence and one patient experienced recurrence of BNC after 12 months. At 1 month and 6 months after the operation, IPSS, QoL, PVR, and Qmax of the patients were significantly better than those before the operation (P < 0.05). Transurethral columnar balloon dilation of the prostate combined with holmium laser can effectively treat BNC with simple performance and satisfactory clinical effects. It is a minimally invasive treatment that can be conducted by simple day surgery.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice.

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer's disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

Highly Dispersed Ru-Co Nanoparticles Interfaced With Nitrogen-Doped Carbon Polyhedron for High Efficiency Reversible Li-O2 Battery.

The lithium-oxygen (Li-O2 ) battery with high energy density of 3860 Wh kg-1 represents one of the most promising new secondary batteries for future electric vehicles and mobile electronic devices. However, slow oxygen reduction/oxygen evolution (ORR/OER) reaction efficiency and unstable cycling performance restrain the practical applications of the Li-O2 battery. Herein, Ru-modified nitrogen-doped porous carbon-encapsulated Co nanoparticles (Ru/Co@CoNx -C) are synthesized through reduction of Ru on metal-organic framework (MOFs) pyrolyzed derivatives strategies. Porous carbon polyhedra provide channels for reactive species and stable structure ensures the cyclic stability of the catalyst; abundant Co-Nx sites and high specific surface area (353 m2 g-1 ) provide more catalytically active sites and deposition sites for reaction products. Theoretical calculations further verify that Ru/Co@CoNx -C can regulate the growth of Li2 O2 to improve reversibility of Li-O2 batteries. Li-O2 batteries with Ru/Co@CoNx -C as cathode catalyst achieve small voltage gaps of 1.08 V, exhibit excellent cycle stability (205 cycles), and deliver high discharge specific capacity (17050 mAh g-1 ). Furthermore, pouch-type Li-O2 batteries that maintain stable electrochemical performance output even under conditions of bending deformation and corner cutting are successfully assembled. This study demonstrates Ru/Co@CoNx -C catalyst's great application potential in Li-O2 batteries.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Role of soluble endoglin in BMP9 signaling.

Endoglin (ENG) is a coreceptor of the transforming growth factor-ß (TGFß) family signaling complex, which is highly expressed on endothelial cells and plays a key role in angiogenesis. Its extracellular domain can be cleaved and released into the circulation as soluble ENG (sENG). High circulating levels of sENG contribute to the pathogenesis of preeclampsia (PE). Circulating bone morphogenetic protein 9 (BMP9), a vascular quiescence and endothelial-protective factor, binds sENG with high affinity, but how sENG participates in BMP9 signaling complexes is not fully resolved. sENG was thought to be a ligand trap for BMP9, preventing type II receptor binding and BMP9 signaling. Here we show that, despite cell-surface ENG being a dimer linked by disulfide bonds, sENG purified from human placenta and plasma from PE patients is primarily in a monomeric form. Incubating monomeric sENG with the circulating form of BMP9 (prodomain-bound form) in solution leads to the release of the prodomain and formation of a sENG:BMP9 complex. Furthermore, we demonstrate that binding of sENG to BMP9 does not inhibit BMP9 signaling. Indeed, the sENG:BMP9 complex signals with comparable potency and specificity to BMP9 on human primary endothelial cells. The full signaling activity of the sENG:BMP9 complex required transmembrane ENG. This study confirms that rather than being an inhibitory ligand trap, increased circulating sENG might preferentially direct BMP9 signaling via cell-surface ENG at the endothelium. This is important for understanding the role of sENG in the pathobiology of PE and other cardiovascular diseases.

Ultralow Thermal Conductivity in Two-Dimensional MoO3.

Monolayer molybdenum trioxide (MoO3) is an emerging two-dimensional (2D) material with high electrical conductivity but unexplored thermal conductivity. Using first-principles calculations and a Boltzmann transport theoretical framework, we predict a record low room-temperature phonon thermal conductivity (κp) of 1.57 and 1.26 W/mK along the principal in-plane directions of the MoO3 monolayer. The behavior is attributed to the combination of soft flexural and in-plane acoustic modes, which are coupled through the finite layer thickness, and to the strong bonding anharmonicity, which gives rise to significant 3- and 4-phonon scattering. These insights suggest new indicators for guiding the search of 2D materials with low κp and motivates κp measurements in MoO3 and its applications as a thermoelectric and thermally protective material.

Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins.

Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-ß.

A Meta-analysis on the Role of Children in Severe Acute Respiratory Syndrome Coronavirus 2 in Household Transmission Clusters.

The role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains highly controversial. To address this issue, we performed a meta-analysis of the published literature on household SARS-CoV-2 transmission clusters (n = 213 from 12 countries). Only 8 (3.8%) transmission clusters were identified as having a pediatric index case. Asymptomatic index cases were associated with a lower secondary attack in contacts than symptomatic index cases (estimate risk ratio [RR], 0.17; 95% confidence interval [CI], 0.09-0.29). To determine the susceptibility of children to household infections the secondary attack rate in pediatric household contacts was assessed. The secondary attack rate in pediatric household contacts was lower than in adult household contacts (RR, 0.62; 95% CI, 0.42-0.91). These data have important implications for the ongoing management of the COVID-19 pandemic, including potential vaccine prioritization strategies.