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Steering ultrafast electron dynamics with well-controlled laser fields is very important for generation of intense supercontinuum radiation. It can be achieved through coherent control of the symmetry of the interaction between strong-field laser fields and a metal nanotip. We employ a scheme of two-color laser pulses combined with a weak static field to realize the control of a single quantum path to generate high harmonic generation from a single solid-state nanoemitter. Moreover, a smooth and ultrabroad supercontinuum in the extreme ultraviolet region is obtained, which can produce a single attosecond pulse. Our findings are beneficial for efficient generation of isolated sub-100 as XUV pulses from solid-state sources. [ABSTRACT FROM AUTHOR]

Background. Since the first diagnosed case of infection with the novel coronavirus (SARS-CoV-2), there has been a rapid spread of the disease with an increasing number of cases confirmed every day, as well as a rising death toll. An association has been reported between acute kidney injury (AKI) and mortality in patients infected with SARS-CoV-2. Therefore, our study was conducted to explore possible risk factors of AKI as well as whether AKI was a risk factor for worse outcome, especially mortality among patients with coronavirus disease (COVID-19). Methods. We included all hospital admissions with confirmed or clinically diagnosed COVID-19 from January 29 to February 25, 2020. We collected demographic and epidemiological information, past medical history, symptoms, laboratory tests, treatments, and outcome data from electronic medical records. A total of 492 patients with diagnosed or clinically diagnosed COVID-19 were included in this study. Results. The prevalence rate of AKI was 7.32%. Among the factors associated with AKI, males versus females (aOR 2.73), chronic kidney disease (aOR 42.2), hypertension (aOR 2.82), increased leucocytes (aOR 6.08), and diuretic use (aOR 7.89) were identified as independent risk factors for AKI among patients infected by SARS-CoV-2. There was a significant difference in hospital fees and death in patients with and without AKI (p < 0.05). The mortality rate in patients with AKI was 63.9%. Conclusions. AKI was widespread among patients with COVID-19. The risk factors of AKI in COVID-19 patients included sex, chronic kidney disease, hypertension, infection, and diuretic use. AKI may be associated with a worse outcome, especially mortality in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19. [ABSTRACT FROM AUTHOR]

• Exosome of ectopic endometrial stromal cells promotes M2 macrophage polarization. • miR-146a-5p is increased in the exosome of ectopic endometrial stromal cells. • miR-146a-5p regulates M2 macrophage polarization via targeting TRAF6. • Exosomes of ectopic endometrial stromal cells promote endometriosis in rat. Ectopic endometrial stromal cells (ESCs) and M2 macrophages co-exist in the lesions of endometriosis and participate in the occurrence and progression of endometriosis. However, the interaction between ectopic ESCs and M2-type macrophage polarization is poorly understood. This study aims to investigate the effect of exosomes released from ectopic ESCs on M2 macrophage polarization and the potential mechanism. Human THP-1 monocytic cells induced macrophage differentiation (M0) and M2 polarization. Ectopic ESCs and their exosomes were used to stimulate M2 macrophages. M2 macrophage polarization was examined by detecting CD163 and ARG1 expression. Exosomal microRNAs were analyzed by small-RNA sequencing. Our in vitro results suggest that exosomes of ectopic ESCs promoted M2 macrophage polarization. Meanwhile, The miR-146a-5p level was highly increased in ectopic ESCs and their exosomes and promoted the role of exosomes in M2 macrophage polarization. As a target, TRAF6 overexpression inhibits the function of miR-146a-5p mimic on M2 macrophage polarization. In the rat model, exosomes from ectopic ESCs contribute to the development of endometriosis. It was suggested that exosomes derived from ectopic ESCs promote the M2 macrophage polarization by delivering miR-146a-5p targeting TRAF6 in the pathological process of endometriosis. [ABSTRACT FROM AUTHOR]

Abstract The presence of asbestos in the environment has caused concern because exposure to asbestos can cause diseases such as stomach and pancreatic cancer. However, suitable up-to-date methods for quantitatively analyzing asbestos and assessing the toxicity of asbestos have not been developed. In this study, asbestos in drinking water was characterized using a stepwise multiple differential infra-red spectra method and a partial least squares method. The in vivo migration of ingested asbestos in mice was then investigated using the technique. The quantification limit of six kinds of asbestos by using inductively coupled plasma optical emission spectrometry and Fourier-transform infrared spectroscopy in water are respectively from 0.0468 to 0.0705 mg/L, from 0.0039 to 0.0064 mg/L. The relative standard deviations were respectively less than 2.85% and 3.81%. The recoveries of the test asbestos were respectively more than 95.10% and 95.38%. Asbestos was found mainly to accumulate in the livers of mice. The Fourier-transform infra-red spectroscopy inductively coupled plasma optical emission spectrometry method can be used to detect and precisely quantify asbestos in water samples and in animal tissues. Graphical abstract Image 1 Highlights • A technique using Fourier-transform infrared spectroscopy for quantitatively analyzing asbestos was developed. • Asbestos was quantified (silicon dioxide present) using differential spectrum and partial least squares methods. • Migration of ingested asbestos in mouse organs and blood was investigated. • Asbestos fibers in water could pose unpredictable risks to humans. [ABSTRACT FROM AUTHOR]

Gallocatechin gallate (GCG) possesses multiple potential biological activities. However, the content of GCG in traditional green tea is too low which limits its in-depth pharmacological research and application. In the present study, a simple, efficient and environment-friendly chromatographic separation method was developed for preparative enrichment and separation of GCG from cocoa tea ( Camellia ptilophylla ) which contains high content of GCG. In the first step, the adsorption properties of selected resins were evaluated, and XAD-7HP resin was chosen by its adsorption and desorption properties for GCG. In order to maximize column efficiency for GCG collection, the operating parameters (e.g., flow rate, ethanol concentration, and bed height) were optimized. We found that the best combination was the feed concentration at 20 mg/mL, flow rate at 0.75 BV/h and the ratio of diameter to bed heights as 1:12. Under these conditions, the purity of GCG was 45% with a recovery of 89%. In order to obtain pure target, a second step was established using column chromatography with sephadex LH-20 gel and 55% ethanol–water solution as eluent. After this step, the purity of the GCG was 91% with a recovery of 68% finally. [ABSTRACT FROM AUTHOR]

Camellia ptilophylla, known as cocoa tea, is a natural decaffeinated tea plant which has been proved with potential bioactivities. This study was carried out to evaluate the safety of green cocoa tea water extract ( CWE) by determining its potential toxicity after subacute administration in SD rats. In the subacute toxicity study, oral administration of CWE up to 800 mg kg−1 body weight day−1 for twenty-eight consecutive days did not cause either mortality or toxicity in SD rats, regardless of gender. There were no adverse effects in body weight, food consumption, relative organ weight, haematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. Several parameters (e.g. neutrophils%, Ca2+, total Ca) in CWE-treated rats with high dosage were significantly different from the control groups, but still in a safety level. A dose of 800 mg kg−1 day−1 was identified as the no observed adverse effect level ( NOAEL) in this study. [ABSTRACT FROM AUTHOR]

Abstract: Three main types of cocoa tea derived from Camellia ptilophylla, white cocoa tea (WCT), green cocoa tea (GCT) and black cocoa tea (BCT) were prepared. A comparison between cocoa tea and commonly consumed tea Biluochun cha (BLC), Longjing cha (Lj), Qimenhong cha (Qmh) and Yinghong 9# (Yh9) was studied. Levels of catechins and purine alkaloids were determined by HPLC. Total polyphenol contents were determined by ferrous tartrate assay. Antioxidative activity was evaluated using ABTS decolorization assay, DPPH radical assay and ferric thiocyanate (FTC) method. The results showed that WCT contained the highest polyphenol content and showed the highest antioxidative activity. The radical scavenging ability of the tea extracts followed this order: WCT>GCT>Blc>Lj>BCT>Yh9>Qmh. Tea extracts measured by the linoleic acid system also showed the same patterns of activity as the ABTS and DPPH method. A high correlation between polyphenol content and antioxidative activity of tea extracts was observed. [Copyright &y& Elsevier]

Abstract: Interferon-omega (IFN-ω) may be a useful, promising and alternative antiviral agent, in addition to IFN-α-2a and IFN-α-2b. To improve the pharmacokinetics of IFN-ω for clinical use, the recombinant human IFN-ω-Fc fusion protein (rhIFN-ω-Fc) was expressed in a Chinese hamster ovary cell line (CHO-S), due to the longer serum half-life of rhIFN-ω-Fc compared to the native IFN-ω protein, and purified by affinity chromatography. Physicochemical characterization of the purified fusion protein was performed by SDS–PAGE electrophoresis, dot blot analysis and N-terminal amino acid sequence analysis. The results show that rhIFN-ω-Fc was highly expressed at the predicted size and with the N-terminal amino acid sequence. The antiviral activity was determined by the ability of IFNs to inhibit the cytopathic effects (CPEs) of vesicular stomatitis virus (VSV) on the human amnion WISH cells. The rhIFN-ω-Fc expressed in CHO-S cells has a specific activity of 1.6×107 IU/mg compared to rhIFN-ω expressed in yeast, which has a specific activity of 7×107 IU/mg. Equimolar concentrations of rhFN-ω and rhIFN-ω-Fc were administered to rabbits for pharmacokinetics comparison. The terminal half-life of rhIFN-ω-Fc was 35 times higher than that of rhIFN-ω. Thus, rhIFN-ω-Fc can be used as a prospective antiviral candidate especially for the treatment of chronic viral disease, such as hepatitis C virus (HCV) infection. [Copyright &y& Elsevier]

Abstract: Cervical cancer still remains a major health problem in women worldwide. Inhibitors of topoisomerase I have proven to be among the most promising new classes of anti-neoplastic agents introducing into the clinic in recent years. CPT-11 is one of the most widely used Camptothecin analogues and is converted to form the active metabolite SN-38. The study tried to explore the in vitro mechanisms of apoptosis induced by SN-38 in cervical cancer cell lines HeLa and SiHa. The results demonstrated here that SN-38 inhibited cell proliferation in a time- and dose-dependant manner. Western Blot showed that SN-38 down-regulated protein expression of p-Akt and increased protein expression of p53 and p21, but it had no effects on protein expression of Bax, Bcl-2 and Akt. Transfection of the full-length Akt cDNA into HeLa and SiHa cells resulted in the reduction of apoptosis induced by SN-38, and Akt kinase activity regulated the p53 pathway, indicating that inhibition of the Akt pathway played an important role in exhibition of SN-38-mediated cytotoxic effect. Our data suggested that SN-38 could induce apoptosis through a p53 pathway and that activation of p53 in response to S-38 is governed by Akt. [Copyright &y& Elsevier]

Purpose: The aim of this study was to explore role of PTEN gene in chemosensitivity to cisplatin in human ovarian cancer cells and related mechanisms.Method: A PTEN-targeted short hairpin RNA (shRNA) expression vector and a wild-type sense PTEN plasmid were constructed, human ovarian cisplatin-sensitive cancer cell line OV2008 and its resistant variant C13 * cells were transfected with PTEN shRNA or wild-type PTEN plasmid, respectively, and cells were then treated with cisplatin. Next, AKT activity was regulated with co-transfection of antisense or sense AKT plasmid in OV2008 /PTENshRNA cells or C13 */p-PTEN cells, respectively. Effects of transfection of above vectors on cell growth, apoptosis and expression of PTEN and AKT were evaluated.Results: Expression of PTEN in OV2008 cells was significantly higher than that in C13 * cells. Transfection of PTEN shRNA into OV2008 cells remarkably down-regulated expression of PTEN and up-regulated expression of phospho-AKT protein, with transfected cells being resistant to cisplatin. Overexpression of PTEN by transfection with sense PTEN obviously enhanced cisplatin-induced apoptosis of C13 * cells. Furthermore, decreased AKT activity could increase cisplatin-induced apoptosis in OV2008/PTENshRNA cells; while, transfection of pcDNA3.1-AKT plasmid into C13 */p-PTEN cells resulted in increased activity of AKT, with cisplatin-induced apoptosis being inhibited significantly.Conclusions: PTEN might reverse chemoresistance to cisplatin in human ovarian cancer cells through inactivation of the PI3K/AKT cell survival pathway and may serve as a potential molecular target for the treatment of chemoresistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor gene identified on human chromosome 10q23. Substantial studies have demonstrated that PTEN can inhibit cell proliferation, migration and invasion of many cancer cells. The purpose of this study was to determine whether upregulation of PTEN gene by transfection wild-type PTEN gene to ovarian cancer cells can inhibit growth and migration and to explore the potential for PTEN gene therapy of ovarian cancers.Method: Wild-type and phosphatase-inactive (C124A) PTEN plasmids were transfected into ovarian epithelial cancer A2780 cells, and their effects on cell apoptosis, cell proliferation, cell migration and cell invasion were analyzed by flow cytometry analysis, TUNEL assay, MTT assay, wound-healing assay and transwell assay.Results: Both wild-type and mutant PTEN can upregulate the expression of PTEN gene dramatically; however, it is wild-type PTEN not phosphatase-inactive PTEN that can induce apoptosis and decrease cell migration, invasion and proliferation in ovarian cancer cells.Conclusion: These results demonstrated that PTEN had played an important role in the cell proliferation, cell migration and invasion dependent on its phosphatase activity. Enhanced expression of PTEN by gene transfer is sufficient to reverse the malignant phenotype of ovarian cancer cells and transfection of ovarian cancer cells with wild-type PTEN gene might be another novel approach for therapeutic intervention in ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: The major aim of present study is to develop and evaluate chimeric virus-like particles (VLPs) displaying a neutralizing epitope of anthrax protective antigen (PA) as a potential vaccine against anthrax. The truncated hepatitis B virus core (HBc) protein (aa 1–144) was used as a carrier, and the 2β2–2β3 loop of the PA domain 2 (aa 302–325) which has been shown contains a dominant neutralizing epitope was inserted into the major immunodominant region (MIR) of the HBc. The recombinant protein HBc-N144-PA-loop2 was expressed in Escherichia coli, and was able to form HBc-like particles confirmed by electron microscopy. The immunogenicity of these chimeric particles was evaluated in mice and guinea pigs. In mice the HBc-N144-PA-loop2 was able to induce PA-epitope specific antibodies; in guinea pigs it was able to induce PA-epitope specific antibodies and anthrax toxin-neutralizing antibodies regardless of whether alum adjuvant was used or not, and was able to partially protect the immunized guinea pigs against virulent anthrax spores challenge. This study suggests chimeric HBc particles carrying a neutralizing epitope of PA can induce protective immunity against Bacillus anthracis. [Copyright &y& Elsevier]

Abstract: Anthrax toxin consists of three proteins, protective antigen (PA), lethal factor, and edema factor. PA is the major component in the current anthrax vaccine, but the antigenic epitopes on it are not well-defined. We generated a pool of toxin-neutralizing anti-PA monoclonal antibodies (MAbs) to analyze the neutralizing epitopes of PA. Nine toxin-neutralizing MAbs obtained were found bound to three different domains of PA respectively, among which three MAbs with the strongest toxin-neutralizing activity recognized the same epitope within domain 2. This epitope was fine mapped to the chymotrypsin-sensitive site, 312SFFD315, in the 2β2–2β3 loop of PA, using phage-displayed random peptide libraries and mutation analysis. The result demonstrated for the first time that the 2β2–2β3 loop, which is involved in the transition of PA oligomers from prepore to pore, contains a dominant neutralizing epitope. This work contributes to the immunological and functional analysis of PA and offers perspective for the development of a new epitope vaccine against anthrax. [Copyright &y& Elsevier]

• Five fully human neutralizing antibodies against tetanus neurotoxin were isolated from a vaccinated individual. • The neutralizing antibodies bind to different epitopes of tetanus toxoid with high affinities. • Three neutralizing antibodies conferred full protection in mice against tetanus neurotoxin challenge. Clostridium tetani causes life-threatening disease by producing tetanus neurotoxin (TeNT), one of the most toxic protein substances. Toxicosis can be prevented and cured by administration of anti-TeNT neutralizing antibodies. Here, we identified a series of monoclonal antibodies (mAbs) derived from memory B cells of a healthy adult immunized with the C-terminal domain of TeNT (TeNT-Hc). Thirteen mAbs bound to both tetanus toxoid (TT) and TeNT-Hc, while two mAbs recognized only TT. VH3-23 was the most frequently used germline gene in these TT-binding mAbs, and the pairwise identity values of the VH gene sequences ranged from 27% to 69%. Three of these mAbs—T3, T7, and T9-6—completely protected mice from challenge with 2× LD 50 of TeNT, and two (T2 and T18) significantly prolonged the survival time. The five neutralizing mAbs recognized distinct epitopes on TT, with binding affinities ranging from 0.123 to 11.9 nM. Our study provides promising therapeutic candidates for tetanus. [ABSTRACT FROM AUTHOR]

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X L ) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X L inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X L inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X L -targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X L -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X L -targeting agent to enter human clinical trials.

Angular streaking technique employs a close-to-circularly polarized laser pulse to build a mapping between the instant of maximum ionization and the most probable emission angle in the photoelectron momentum distribution, thereby enabling the probe of laser-induced electron dynamics in atoms and molecules with attosecond temporal resolution. Here, through the jointed experimental observations and improved Coulomb-corrected strong-field approximation statistical simulations, we identify that electrons emitted at different initial ionization times converge to the most probable emission angle due to the previously-unexpected Coulomb focusing triggered by the nonadiabatic laser-induced electron tunneling. We reveal that the Coulomb focusing induces the observed nonintuitive energy-dependent trend in the angular streaking measurements on the nonadiabatic tunneling, and that tunneling dynamics under the classically forbidden barrier can leave fingerprints on the resulting signals. Our findings have significant implications for the decoding of the intricate tunneling dynamics with attosecond angular streaking., (© 2024. The Author(s).)

Invasive hydatidiform mole, a form of gestational trophoblastic neoplasm in reproductive-age women, poses a significant threat to life due to its associated signs and symptoms. This case report details the management of a 24-year-old Chinese woman with no prior pregnancy history, who presented at our hospital 23 days postcurettage, experiencing persistent vaginal bleeding for 3 days. While two rounds of chemotherapy effectively reduced human chorionic gonadotropin levels, a subsequent magnetic resonance imaging (MRI) revealed suspicious growth lesions in the uterus. High-intensity focused ultrasound (HIFU) treatment was administered under ultrasound guidance, resulting in notable grayscale changes to optimize the efficacy of chemotherapy and restrict lesion progression. Subsequent ultrasound and MRI assessments during follow-up demonstrated a transparent texture in the muscle layer at the lesion site. This case suggests that the combination of chemotherapy and HIFU, guided by ultrasound, may represent a promising therapeutic approach for managing invasive hydatidiform mole., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Gynecology and Minimally Invasive Therapy.)

Addressing the existing gaps in our understanding of sex- and strain-dependent disparities in renal microhemodynamics, this study conducted an investigation into the variations in renal function and related biological oscillators. Using the genetically diverse mouse models BALB/c, C57BL/6, and Kunming, which serve as established proxies for the study of renal pathophysiology, we implemented laser Doppler flowmetry conjoined with wavelet transform analyses to interrogate dynamic renal microcirculation. Creatinine, urea, uric acid, glucose, and cystatin C levels were quantified to investigate potential divergences attributable to sex and genetic lineage. Our findings reveal marked sexual dimorphism in metabolite concentrations, as well as strain-specific variances, particularly in creatinine and cystatin C levels. Through the combination of Mantel tests and Pearson correlation coefficients, we delineated the associations between renal functional metrics and microhemodynamics, uncovering interactions in female BALB/c mice for creatinine and uric acid, and in male C57BL/6 mice for cystatin C. Histopathologic examination confirmed an augmented microvascular density in female mice and elucidating variations in the expression of estrogen receptor β among the strains. These data collectively highlight the influence of both sex and genetic constitution on renal microcirculation, providing an understanding that may inform the etiologic exploration of renal ailments., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Tunneling ionization is a crucial process in the interaction between strong laser fields and matter which initiates numerous nonlinear phenomena including high-order harmonic generation, photoelectron holography, etc. Both adiabatic and nonadiabatic tunneling ionization are well understood in atomic systems. However, the tunneling dynamics in solids, especially nonadiabatic tunneling, has not yet been fully understood. Here, we study the sub-cycle resolved strong-field tunneling dynamics in solids via a complex saddle-point method. We compare the instantaneous momentum at the moment of tunneling and the tunneling distances over a range of Keldysh parameters. Our results demonstrate that for nonadiabatic tunneling, tunneling ionization away from Γ point is possible. When this happens the electron has a nonzero initial velocity when it emerges in the conduction band. Moreover, consistent with atomic tunneling, a reduced tunneling distance as compared to the quasi-static case is found. Our results provide remarkable insight into the basic physics governing the sub-cycle electron tunneling dynamics with significant implications for understanding subsequent strong-field nonlinear phenomena in solids.

Background: The association between Interdialytic home blood pressure variability (BPV) and the prognosis of patients undergoing maintenance hemodialysis (MHD) largely unknown., Hypothesis: We proposed the hypothesis that interdialytic home BPV exert effect on cardiac and all-cause mortality among individuals undergoing MHD., Methods: A total of 158 patients receiving MHD at the hemodialysis unit of Wuhan Fourth Hospital between December 2019 and August 2020 were included in this prospective cohort study. Patients were divided into tertiles according to the systolic BPV (SBPV), and the primary endpoints were cardiac and all-cause death. Kaplan-Meier analysis was used to assess the relationship between long-term survival and interdialytic home SBPV. In addition, Cox proportional hazards regression models were used to identify risk factors contributing to poor prognosis., Results: The risk of cardiac death and all-cause death was gradually increased in patients according to tertiles of SBPV (3.5% vs. 14.8% vs. 19.2%, p for trend = .021; and 11.5% vs. 27.8% vs. 44.2%, p for trend <.001). The Cox regression analysis revealed that compared to Tertile 1, the hazard ratios for all-cause mortality in Tertile 2 and Tertile 3 were 3.13 (p = .026) and 3.24 (p = .021), respectively, after adjustment for a series of covariates., Conclusions: The findings revealed a positive correlation between increased interdialytic home SBPV and elevated mortality risk in patients with MHD., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

The vaccine-induced innate immune response is essential for the generation of an antibody response. To date, how Ad5-vectored vaccines are influenced by preexisting anti-Ad5 antibodies during activation of the early immune response remains unclear. Here, we investigated the specific alterations in GP 1,2 -specific IgG-related elements of the early immune response at the genetic, molecular, and cellular levels on days 0, 1, 3, and 7 after Ad5-EBOV vaccination. In a causal multiomics analysis, distinct early immune responses associated with GP 1,2 -specific IgG were observed in Ad5-EBOV recipients with a low level of preexisting anti-Ad5 antibodies. This study revealed the correlates of the Ad5-EBOV-induced IgG response and provided mechanistic evidence for overcoming preexisting Ad5 immunity during the administration of Ad5-vectored vaccines., Competing Interests: The authors declare no competing interests., (© 2024.)

As compared to the intuitive process that the electron emits straight to the continuum from its parent ion, there is an alternative route that the electron may transfer to and be trapped by a neighboring ionic core before the eventual release. Here, we demonstrate that electron tunnelling via the neighboring atomic core is a pronounced process in light-induced tunnelling ionization of molecules by absorbing multiple near-infrared photons. We devised a site-resolved tunnelling experiment using an Ar-Kr + ion as a prototype system to track the electron tunnelling dynamics from the Ar atom towards the neighboring Kr + by monitoring its transverse momentum distribution, which is temporally captured into the resonant excited states of the Ar-Kr + before its eventual releasing. The influence of the Coulomb potential of neighboring ionic cores promises new insights into the understanding and controlling of tunnelling dynamics in complex molecules or environment., (© 2024. The Author(s).)

Type 1 diabetes mellitus (T1DM) is predominantly managed using insulin replacement therapy, however, pancreatic microcirculatory disturbances play a critical role in T1DM pathogenesis, necessitating alternative therapies. This study aimed to investigate the protective effects of glycine supplementation on pancreatic microcirculation in T1DM. Streptozotocin-induced T1DM and glycine-supplemented mice (n = 6 per group) were used alongside control mice. Pancreatic microcirculatory profiles were determined using a laser Doppler blood perfusion monitoring system and wavelet transform spectral analysis. The T1DM group exhibited disorganized pancreatic microcirculatory oscillation. Glycine supplementation significantly restored regular biorhythmic contraction and relaxation, improving blood distribution patterns. Further-more, glycine reversed the lower amplitudes of endothelial oscillators in T1DM mice. Ultrastructural deterioration of islet microvascular endothelial cells (IMECs) and islet microvascular pericytes, including membrane and organelle damage, collagenous fiber proliferation, and reduced edema, was substantially reversed by glycine supplementation. Additionally, glycine supplementation inhibited the production of IL-6, TNF-α, IFN-γ, pro-MMP-9, and VEGF-A in T1DM, with no significant changes in energetic metabolism observed in glycine-supplemented IMECs. A statistically significant decrease in MDA levels accompanied by an increase in SOD levels was also observed with glycine supplementation. Notably, negative correlations emerged between inflammatory cytokines and microhemodynamic profiles. These findings suggest that glycine supplementation may offer a promising therapeutic approach for protecting against pancreatic microcirculatory dysfunction in T1DM., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fine particulate matter (PM 2.5 ) chemical composition has strong and diverse impacts on the planetary environment, climate, and health. These effects are still not well understood due to limited surface observations and uncertainties in chemical model simulations. We developed a four-dimensional spatiotemporal deep forest (4D-STDF) model to estimate daily PM 2.5 chemical composition at a spatial resolution of 1 km in China since 2000 by integrating measurements of PM 2.5 species from a high-density observation network, satellite PM 2.5 retrievals, atmospheric reanalyses, and model simulations. Cross-validation results illustrate the reliability of sulfate (SO 4 2- ), nitrate (NO 3 - ), ammonium (NH 4 + ), and chloride (Cl - ) estimates, with high coefficients of determination (CV-R 2 ) with ground-based observations of 0.74, 0.75, 0.71, and 0.66, and average root-mean-square errors (RMSE) of 6.0, 6.6, 4.3, and 2.3 μg/m 3 , respectively. The three components of secondary inorganic aerosols (SIAs) account for 21% (SO 4 2- ), 20% (NO 3 - ), and 14% (NH 4 + ) of the total PM 2.5 mass in eastern China; we observed significant reductions in the mass of inorganic components by 40-43% between 2013 and 2020, slowing down since 2018. Comparatively, the ratio of SIA to PM 2.5 increased by 7% across eastern China except in Beijing and nearby areas, accelerating in recent years. SO 4 2- has been the dominant SIA component in eastern China, although it was surpassed by NO 3 - in some areas, e.g., Beijing-Tianjin-Hebei region since 2016. SIA, accounting for nearly half (∼46%) of the PM 2.5 mass, drove the explosive formation of winter haze episodes in the North China Plain. A sharp decline in SIA concentrations and an increase in SIA-to-PM 2.5 ratios during the COVID-19 lockdown were also revealed, reflecting the enhanced atmospheric oxidation capacity and formation of secondary particles.

High-intensity focused ultrasound (HIFU) is commonly used to treat uterine fibroids and adenomyosis, but there is no evidence using metadata to compare fertility outcomes between conventional laparoscopic procedures and HIFU. The purpose of this study analysis is that evidence-based fertility outcomes may provide better treatment options for clinicians and patients considering fertility. The literature on fertility data for HIFU surgery versus laparoscopic myomectomy was searched in seven English language databases from January 1, 2010, to November 23, 2022. A total of 1375 articles were received in the literature, 14 of which were selected. We found that women who underwent HIFU surgery had higher rates of spontaneous pregnancy, higher rates of spontaneous delivery, and higher rates of full-term delivery but may have higher rates of miscarriage or postpartum complications than women who underwent laparoscopic myomectomy. Looking forward to future studies, it is hoped that the literature will examine endometrial differences in women who undergo HIFU and laparoscopic myomectomy to demonstrate the ability of endometrial repair. The location of fibroids in the sample should also be counted to allow for attribution statistics on the cause of miscarriage., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Gynecology and Minimally Invasive Therapy.)

Introduction: The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant and exhibits immune escape to current COVID-19 vaccines, the further boosting strategies are required., Methods: We have conducted a non-randomized, open-label and parallel-controlled phase 4 trial to evaluate the magnitude and longevity of immune responses to booster vaccination with intramuscular adenovirus vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines., Results: The aerosolized Ad5-nCoV induced the most robust and long-lasting neutralizing activity against Omicron variant and IFNg T-cell response among all the boosters, with a distinct mucosal immune response. SARS-CoV-2-specific mucosal IgA response was substantially generated in subjects boosted with the aerosolized Ad5-nCoV at day 14 post-vaccination. At month 6, participants boosted with the aerosolized Ad5-nCoV had remarkably higher median titer and seroconversion of the Omicron BA.4/5-specific neutralizing antibody than those who received other boosters., Discussion: Our findings suggest that aerosolized Ad5-nCoV may provide an efficient alternative in response to the spread of the Omicron BA.4/5 variant., Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=152729, identifier ChiCTR2200057278., Competing Interests: TZ is the employee of CanSino Biologics and has stock options in CanSino Biologics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Wu, Liu, Li, Fan, Song, Wang, Zhao, Zhang, Shang, Zhang, Xu, Li, Li, Zhang, Fu, Wang, Hao, Zhang, Long, Qiu, Zhu, Liu, Zhang, Shao, Lv, Yang, Zhao, Sun, Hou and Chen.)

Objective: This study aims to compare the results of cervical cancer screening in Shanghai General Hospital before and after the COVID-19 epidemic, and analyze the current status and related influencing factors of precervical cancer screening in our hospital under the COVID-19 pandemic., Methods: The data of 13,748 women of cervical precancer screening with HPV in Shanghai General Hospital were selected.The data included human papillomavirus (HPV), thin-layer liquid-based cytology test (TCT), colposcopy and cervical biopsy, and pathological diagnosis results after trachelectomy in 2019 and 2020, and were analyzed and compared., Results: The detection rates of precancerous lesions and cervical cancer were 2.9061/10,000 and 29.26/10,000 respectively. There was a significant difference in the rate of comparison ( χ 2  = 30.361, P  = 0.000; χ 2  = 7.682, P  = 0.006);(2) Missing detection rate: In 2020, other positive subtypes other than HPV 16 and 18 who need TCT, the colposcopy, and the histopathological examination missing detection rate were higher than those in 2019 ( P  < 0.05);(3) Abnormal rate of examination: the abnormal rate of HPV, TCT, and histopathology in 2020 was higher than those in 2019 ( P  < 0.05);(4) Histopathological analysis: The detection rate of high-grade lesions and invasive cancer in 2020 was higher than those in 2019, and the detection rate of low-grade lesions was lower than that in 2019 ( P  < 0.05); Conclusion: Health authorities should formulate intervention measures to cope with the safe and timely implementation of cervical cancer screening and subsequent follow-up management during public health emergency.

Introduction: Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa). Down-regulation of this process is critical, as excess thrombin can lead to life-threatening thrombotic events. FXa and FVa are inhibited by the anticoagulants tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (APC), respectively, and their common cofactor protein S (PS). However, prothrombinase is resistant to either of these inhibitory systems in isolation., Materials and Methods: We hypothesized that these anticoagulants function best together, and tested this hypothesis using purified proteins and plasma-based systems., Results: In plasma, TFPIα had greater anticoagulant activity in the presence of APC and PS, maximum PS activity required both TFPIα and APC, and antibodies against TFPI and APC had an additive procoagulant effect, which was mimicked by an antibody against PS alone. In purified protein systems, TFPIα dose-dependently inhibited thrombin activation by prothrombinase, but only in the presence of APC, and this activity was enhanced by PS. Conversely, FXa protected FVa from cleavage by APC, even in the presence of PS, and TFPIα reversed this protection. However, prothrombinase assembled on platelets was still protected from inhibition, even in the presence of TFPIα, APC, and PS., Conclusions: We propose a model of prothrombinase inhibition through combined targeting of both FXa and FVa, and that this mechanism enables down-regulation of thrombin activation outside of a platelet clot. Platelets protect prothrombinase from inhibition, however, supporting a procoagulant environment within the clot., Competing Interests: Declaration of competing interest J.P. Wood has an investigator-initiated grant through Pfizer, Inc., which funded part of this study. X. Li is now employed by GenScript Biotech Corp. but was not at the time of his participation in this study. All other authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still unclear. We explore the expression of FAM3A, a newly identified metabolic cytokine, and whether and how FAM3A regulates VSMC differentiation in AAA. We discover that FAM3A is decreased in the aortas and plasma in AAA patients and murine models. Overexpression or supplementation of FAM3A significantly attenuate the AAA formation, manifested by maintenance of the well-differentiated VSMC status and inhibition of VSMC transformation toward macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induces KLF4 ubiquitination and reduces its phosphorylation and nuclear localization. Here, we report FAM3A as a VSMC fate-shaping regulator in AAA and reveal the underlying mechanism associated with KLF4 ubiquitination and stability, which may lead to the development of strategies based on FAM3A to restore VSMC homeostasis in AAA., (© 2023. Springer Nature Limited.)

Since high-order harmonic generation (HHG) from atoms depends sensitively on the polarization of the driving laser field, the polarization gating (PG) technique was developed and applied successfully to generate isolated attosecond pulses from atomic gases. The situation is, however, different in solid-state systems as it has been demonstrated that due to collisions with neighboring atomic cores of the crystal lattice strong HHG can be generated even by elliptically- and circularly-polarized laser fields. Here we apply PG to solid-state systems and find that the conventional PG technique is inefficient for the generation of isolated ultrashort harmonic pulse bursts. In contrast, we demonstrate that a polarization-skewed laser pulse is able to confine the harmonic emission to a time window of less than one-tenth of the laser cycle. This method provides a novel way to control HHG and to generate isolated attosecond pulses in solids.

FLOURY ENDOSPERM 2 ( FLO2 ), encoding a tetratricopeptide repeat domain (TPR)-containing protein located in the nucleus, is considered to be a regulatory protein that controls the biosynthesis of seed storage substances. The diversity of flo2 allele is attributable for the variations in grain appearance, amylose content (AC), and physicochemical properties, influencing the eating and cooking quality (ECQ) of rice. In this study, we used CRISPR/Cas9 to introduce loss-of-function mutations into the FLOURY ENDOSPERM 2 gene in Suken118 (SK118), a widely cultivated elite japonica rice variety in Jiangsu, China. Physiochemical analyses of the flo2 mutants were congruent with previous studies, exhibiting lowered AC and viscosity, risen gel consistency (GC) and gelatinization temperature (GT) values, which were all instrumental to the improvement of ECQ. However, the wrinkled opaque appearance and the decrease in grain width, grain thickness and grain weight imply trade-offs in grain yield. Despite the ex-ante estimation for low yielding, the superior ECQ in these novel genotypes generated by using genome editing approach may have the potential for formulating high value specialty food., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Chen, Du, Li, Fei, Tao, Wang, Xu, Li, Wang, Liang, Zhou, Tan, Li and Yang.)

Propylparaben (PrP) is a widely used preservative that is constantly detected in aquatic environments and poses a potential threat to aquatic ecosystems. In the present work, adult male mosquitofish were acutely (4d) and chronically (32d) exposed to environmentally and humanly realistic concentrations of PrP (0, 0.15, 6.00 and 240 μg/L), aimed to investigate the toxic effects, endocrine disruption and possible mechanisms of PrP. Histological analysis showed time- and dose-dependent manners in the morphological injuries of brain, liver and testes. Histopathological alterations in the liver were found in 4d and severe damage was identified in 32d, including hepatic sinus dilatation, cytoplasmic vacuolation, cytolysis and nuclear aggregation. Tissue impairments in the brain and testes were detected in 32d; cell cavitation, cytomorphosis and blurred cell boundaries appeared in the brain, while the testes lesions contained spermatogenic cell lesion, decreased mature seminal vesicle, sperm cells gathering, seminiferous tubules disorder and dilated intercellular space. Furthermore, delayed spermatogenesis had occurred. The transcriptional changes of 19 genes along the hypothalamus-pituitary-gonadal-liver (HPGL) axis were investigated across the three organs. The disrupted expression of genes such as Ers , Ars , Vtgs , cyp19a , star , hsd3b , hsd17b3 and shh indicated the possible abnormal steroidogenesis, estrogenic or antiandrogen effects of PrP. Overall, the present results provided evidences for the toxigenicity and endocrine disruptive effects on the male mosquitofish of chronic PrP exposure, which highlights the need for more investigations of its potential health risks.

Adenovirus type 7 (HAdV7) is one of the most pathogenic human adenoviruses (HAdVs) and can cause severe illness and even death, particularly in people with weakened immune systems. Many countries worldwide have experienced epidemics of this highly contagious pathogen, including China and Sierra Leone; however, studies describing the seroprevalence of anti-HAdV7 neutralizing antibodies (nAbs) are still lacking. Herein, we established an efficient neutralization assay based on a recombinant luciferase-expressing HAdV7 virus (HAd7-Luc) to monitor historical HAdV7 infections and predict outbreak distributions. Among the 2,350 serum samples collected from eight sites in China and Sierra Leone in this cross-sectional serological survey, the overall proportion of anti-HAdV7-seropositive individuals was nearly 60%, with higher seroprevalence rates in Sierra Leone than in China. Regionally, HAdV7 nAb titers were higher in China than in Sierra Leone and showed a geographic variation across different regions. Regardless of the location, the seropositive rate of HAdV7 nAb was lower than that of HAdV5 nAb, as was the nAb titer. The prevalence rates of antibodies against HAdV7 and HAdV5 were both related to age but not to sex. In addition, serologic cross-reactions were rarely observed among people infected with HAdV7 and HAdV5. These results indicate a humoral immune response acquired through endemic HAdV7 infection and enrich the understanding of not only the epidemiological prevention and control of HAdV7 but also the clinical application of HAdV7-based vaccines or gene therapy tools., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Li, Wu, Wang, Chen, Zhai, Song, Zhao, Zhang, Zhang, Yu, Hou and Chen.)

Three degradation strains that can utilize β -Hexachlorocyclohexanes ( β -HCH) as the sole carbon source were isolated from the soil substrate of constructed wetland under long-term β -HCH stress, and they were named A1, J1, and M1. Strains A1 and M1 were identified as Ochrobactrum sp. and strain J1 was identified as Microbacterium oxydans sp. by 16S rRNA gene sequence analysis. The optimum conditions for degradation with these three strains, A1, J1, and M1, were pH = 7, 30 °C, and 5% inoculum amount, and the degradation rates of 50 μg/L β -HCH under these conditions were 58.33%, 51.96%, and 50.28%, respectively. Degradation characteristics experiments showed that root exudates could increase the degradation effects of A1 and M1 on β -HCH by 6.95% and 5.82%, respectively. In addition, the degradation bacteria A1 and J1 mixed in a ratio of 1:1 had the highest degradation rate of β -HCH, which was 69.57%. An experiment on simulated soil remediation showed that the compound bacteria AJ had the best effect on promoting the degradation of β -HCH in soil within 98 d, and the degradation rate of β -HCH in soil without root exudates was 60.22%, whereas it reached 75.02% in the presence of root exudates. The addition of degradation bacteria or degradation bacteria-root exudates during soil remediation led to dramatic changes in the community structure of the soil microorganisms, as well as a significant increase in the proportion of aerobic and Gram-negative bacterial groups. This study can enrich the resources of β -HCH degrading strains and provided a theoretical basis for the on-site engineering treatment of β -HCH contamination.

Attosecond time-resolved electron tunneling dynamics have been investigated by using attosecond angular streaking spectroscopy, where a clock reference to the laser field vector is required in atomic strong-field ionization and the situation becomes complicated in molecules. Here we reveal a resonant ionization process via a transient state by developing an electron-tunneling-site-resolved molecular attoclock in Ar-Kr^{+}. Two distinct deflection angles are observed in the photoelectron angular distribution in the molecular frame, corresponding to the direct and resonant ionization pathways. We find the electron is temporally trapped in the Coulomb potential wells of the Ar-Kr^{+} before finally releasing into the continuum when the electron tunnels through the internal barrier. By utilizing the direct tunneling ionization as a self-referenced arm of the attoclock, the time delay of the electron trapped in the resonant state is revealed to be 3.50±0.04  fs. Our results give an impetus to exploring the ultrafast electron dynamics in complex systems and also endow a semiclassical presentation of the electron trapping dynamics in a quantum resonant state.

The proper route for vaccine delivery plays an important role in activating a robust immune response. Several viral vector-based vaccines against Ebola disease administered intramuscularly have been found to have excellent immunogenicity and protectiveness. In this study, we evaluated different vaccine routes for Ad5-EBOV delivery by comparing humoral and cellular responses, germinal center reactions, dendritic cell activation and antigen expression. Mice injected intramuscularly with the vaccine exhibited an advantage in antigen expression, leading to more robust germinal center and humoral responses, while intradermal injection recruited more migrating DCs and induced a more polyfunctional cellular response. Our study provides more data for future use of viral vector-based vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Zhao, Wang, Wu, Wang, Zhang, Song, Chen, Lv and Hou.)

Highly divergent SARS-CoV-2 variants have continuously emerged and spread around the world, and updated vaccines and innovative vaccination strategies are urgently needed to address the global SARS-COV2 pandemic. Here, we established a series of Ad5-vectored SARS-CoV-2 variant vaccines encoding multiple spike proteins derived from the Alpha, Beta, Gamma, Epsilon, Kappa, Delta and Omicron lineages and analyzed the antibody immune responses induced by single-dose and prime-boost vaccination strategies against emerging SARS-CoV-2 variants of concern (VOCs). Single-dose vaccination with SARS-CoV-2 variant vaccines tended to elicit the optimal self-matched neutralizing effects, and Ad5-B.1.351 produced more broad-spectrum cross-neutralizing antibodies against diverse variants. In contrast, prime-boost vaccination further strengthened and broadened the neutralizing antibody responses against highly divergent SARS-CoV-2 variants. The heterologous administration of Ad5-B.1.617.2 and Ad5-B.1.429 to Ad5-WT-primed mice resulted in superior antibody responses against most VOCs. In particular, the Omicron spike could only stimulate self-matched neutralizing antibodies with infrequent cross-reactivities to other variants used in single-dose vaccination strategies; moreover, with prime-boost regimens, this vaccine elicited an optimal specific neutralizing antibody response to Omicron, and prompted cross-antibody responses against other VOCs that were very similar to those obtained with Ad5-WT booster. Overall, this study delineated the unique characteristics of antibody responses to the SARS-CoV-2 VOC spikes with the single-dose or prime-boost vaccination strategies and provided insight into the vaccine development of next SARS-CoV-2 VOCs., (© 2022. The Author(s).)

Pancreatic microcirculatory dysfunction emerged as a novel mechanism in the development of hypertension. However, the changes of pancreatic microcirculation profiles in hypertension remain unknown. Pancreatic microcirculatory blood distribution pattern and microvascular vasomotion of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs) were determined by laser Doppler. Wavelet transform analysis was performed to convert micro-hemodynamic signals into time-frequency domains, based on which amplitude spectral scalograms were constructed. The amplitudes of characteristic oscillators were compared between SHRs and WKYs. The expression of eNOS was determined by immunohistochemistry, and plasma nitrite/nitrate levels were measured by Griess reaction. Additionally, endothelin-1, malondialdehyde, superoxide dismutase and interleukin-6 were determined by enzyme-linked immunosorbent assay. SHRs exhibited a lower scale blood distribution pattern with decreased average blood perfusion, frequency and amplitude. Wavelet transform spectral analysis revealed significantly reduced amplitudes of endothelial oscillators. Besides reduced expression of eNOS, the blood microcirculatory chemistry complements micro-hemodynamic profiles as demonstrated by an increase in plasma nitrite/nitrate, endothelin-1, malondialdehyde, interleukin-6 and a decrease of superoxide dismutase in SHRs. Here, we described abnormal pancreatic microcirculation profiles in SHRs, including disarranged blood distribution pattern, impaired microvascular vasomotion and reduced amplitudes of endothelial oscillators.

Objectives: Pancreatic microcirculation has an essential role in orchestrating pancreatic homeostasis. Inherent complexity and technological limitation lead to interobserver variability and 1-sided microcirculatory data. Here, we introduce a multimodal device and computer algorithm-based platform for monitoring and visualizing integrated pancreatic microcirculation profiles., Methods: After anesthetizing and exposing pancreas tissue of BALB/c mice, probes of Oxygen to See, Microx TX3, and MoorVMS-LDF2 were positioned at pancreas in situ to capture the pancreatic microcirculatory oxygen (hemoglobin oxygen saturation, relative amount of hemoglobin, and partial oxygen pressure) and microhemodynamic data (microvascular blood perfusion and velocity). To assess and visualize pancreatic microcirculation profiles, raw data of pancreatic microcirculation profiles were processed and transformed using interquartile range and min-max normalization by Python and Apache ECharts., Results: The multimodal device-based platform was established and 3-dimensional microcirculatory modules were constructed. Raw data sets of pancreatic microcirculatory oxygen and microhemodynamic were collected. The outlier of data set was adjusted to the boundary value and raw data set was preprocessed. Normalized pancreatic microcirculation profiles were integrated into the 3-dimensional histogram and scatter modules, respectively. The 3-dimensional modules of pancreatic microcirculation profiles were then generated., Conclusions: We established a multimodal device and computer algorithm-based monitoring platform for visualizing integrated pancreatic microcirculation profiles.

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we find that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protect mice completely against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protects ferrets from wild-type SARS-CoV-2 infection in the upper respiratory tract. This study suggests that the mucosal vaccination may provide a desirable protective efficacy and this delivery mode is worth further investigation in human clinical trials.

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X L inhibitor that selectively and potently induces apoptosis in BCL-X L -dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X L inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp 3 -rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X L . A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program., Competing Interests: The authors declare the following competing financial interest(s): AbbVie and Genentech participated in interpretation of data and review and approval of publication. L.W., G.A.D., A.S.J., Z-F.T., T. M. H., R.R.F., X.S., M.B., A.R.K., X.W., M.D.W., N.D.C., S.S., D.C.P., R.A.J., P.N., M.L.S., S.K.T., Y.X., J.X., H.Z., P.N.L., M.J.M., E.R.B., W.G., P.K., S.W.E., J.D.L., and A.J.S. are employees of AbbVie, Inc. C.H.P. was an employee of AbbVie, Inc at the time of the study. E.C. and W.J.F. are employees of Genentech, Inc. J.A.F., D.D., and D.S. were employees of Genentech, Inc. at the time of the study.

Feynman's path integral approach is to sum over all possible spatiotemporal paths to reproduce the quantum wave function and the corresponding time evolution, which has enormous potential to reveal quantum processes in the classical view. However, the complete characterization of the quantum wave function with infinite paths is a formidable challenge, which greatly limits the application potential, especially in the strong-field physics and attosecond science. Instead of brute-force tracking every path one by one, here we propose a deep-learning-performed strong-field Feynman's formulation with a preclassification scheme that can predict directly the final results only with data of initial conditions, so as to attack unsurmountable tasks by existing strong-field methods and explore new physics. Our results build a bridge between deep learning and strong-field physics through Feynman's path integral, which would boost applications of deep learning to study the ultrafast time-dependent dynamics in strong-field physics and attosecond science and shed new light on the quantum-classical correspondence.

Background: Zika virus (ZIKV) infection may be associated with severe complications and disseminated via both vector-borne and nonvector-borne routes. Adenovirus-vectored vaccines represent a favorable controlling measure for the ZIKV epidemic because they have been shown to be safe, immunogenic, and rapidly generable for other emerging viral infections. Evaluations of 2 previously reported adenovirus-vectored ZIKV vaccines were performed using nonlethal animal models and/or nonepidemic ZIKV strain., Methods: We constructed 2 novel human adenovirus 5 (Ad5)-vectored vaccines containing the ZIKV premembrane-envelope (Ad5-Sig-prM-Env) and envelope (Ad5-Env) proteins, respectively, and evaluated them in multiple nonlethal and lethal animal models using epidemic ZIKV strains., Results: Both vaccines elicited robust humoral and cellular immune responses in immunocompetent BALB/c mice. Dexamethasone-immunosuppressed mice vaccinated with either vaccine demonstrated robust and durable antibody responses and significantly lower blood and tissue viral loads than controls (P < .05). Similar findings were also observed in interferon-α/β receptor-deficient A129 mice. In both of these immunocompromised animal models, Ad5-Sig-prM-Env-vaccinated mice had significantly (P < .05) higher titers of anti-ZIKV-specific neutralizing antibody titers and lower (undetectable) viral loads than Ad5-Env-vaccinated mice. The close correlation between the neutralizing antibody titer and viral load helped to explain the better protective effect of Ad5-Sig-prM-Env than Ad5-Env. Anamnestic response was absent in Ad5-Sig-prM-Env-vaccinated A129 mice., Conclusions: Ad5-Sig-prM-Env provided sterilizing protection against ZIKV infection in mice.

Anthrax is a highly lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis. The major virulence factor of B. anthracis consists of protective antigen (PA), lethal factor (LF) and edema factor (EF). PA binds with LF to form lethal toxin (LT), and PA binds with EF to form edema toxin (ET). Antibiotics is hard to work in advanced anthrax infections, because injuries and deaths of the infected are mainly caused by lethal toxin (LT). Thus, the therapeutic neutralizing antibody is the most effective treatment of anthrax. Currently most of the anthrax toxin antibodies are monoclonal antibodies (MAbs) for PA and US FDA has approved ABTHRAX humanized PA monoclonal antibody for the treatment of inhalational anthrax. Once B. anthracis was artificially reconstructed or PA had mutations within recognized neutralization epitopes, anti-PA MAbs would no longer be effective. Therefore, anti-LF MAbs is an important supplement for anthrax treatment. Most of the anti-LF antibodies are murine or chimeric antibodies. By contrast, fully human MAbs can avoid the high immunogenicity of murine antibodies. First, we used LF to immunize the transgenic mice and used fluorescent cell sorting to get antigen-specific memory B cells from transgenic mice spleen lymphocytes. By single cell PCR method, we quickly found two strains of anti-LF MAbs with binding activity, 1D7 and 2B9. Transiently transfected Expi 293F cells to obtain MAbs protein after purification. Both 1D7 and 2B9 efficiently neutralized LT in vitro, and had good synergistic effect when mixed with anti-PA MAbs. In summary, combining the advantages of transgenic mice, fluorescent cell sorting and single-cell PCR methods, this study shows new ideas and methods for the rapid screening of fully human monoclonal antibodies.

Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 10⁸ infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD₅₀) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax.

Objective: To express human-mouse chimeric antibody against Yersinia pestis F1 capsular antigen (F1 antigen) and analyze its biological activities., Methods: The heavy chain gene of the chimeric antibody was obtained by fusing the variable region gene of the mouse mAb heavy chain with human IgG1 constant region gene. The light chain gene of the chimeric antibody was obtained by fusing the variable region gene of the mouse mAb light chain with the human kappa constant region gene. Both the heavy and light chain genes of the chimeric antibody were further verified by sequencing. The chimeric antibody heavy and light chain genes were inserted into EcoR I/Not I of pcDNA3.1 (+) to construct expression plasmids termed pcDNA3.1-L and pcDNA3.1-H, respectively. Then, two plasmids were mixed and transfected into CHO-S cells. Finally, the stable cell clone secreting chimeric antibody was obtained by G418 selection. The culture supernatants of serum-free medium were collected and the chimeric antibody was purified by MabSelect SuRe affinity chromatography. The purified chimeric antibody was analyzed by SDS-PAGE, Western blotting, ELISA and evaluated in the protective effect in vivo., Results: PCR and sequencing analysis proved that plasmids pcDNA3.1-H and pcDNA3.1-L were correctly constructed. Dot blot showed that a cell line with high-level expression of chimeric antibody was obtained. SDS-PAGE and western blot showed that the chimeric antibody was successfully purified. ELISA showed that the chimeric antibody could specifically bind to F1 antigen. In vivo activity assay showed that 80% BALB/c mice treated with the chimeric antibody survived from 36 MLD virulent Yersinia pestis., Conclusion: The chimeric antibody against F1 antigen with neutralizing activity was successfully expressed in CHO-S cells, which laid a foundation for the preparation of anti-plague passive immunity agents.

Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90alpha, hsp90beta, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.

Objective: Set an objectively scientific foundation for name, diagnosis, therapy and assessment of mutational falsetto., Method: We analyzed the acoustic samples of patients by computer, 15 patients, 12 normal young men, 13 normal young women and 12 normal children were asked to produced comfortable modal vowel/a/ and /i/, sustained 3 seconds. The falsetto /a/ and /i/ were only collected from young men and women. The acoustic parameters were compared between any two groups., Result: Both vowel /a/ and /i/, the fundamental frequency, highest fundamental frequency and lowest fundamental frequency of patients are closed to young women's (P > 0.05). Jitter percent and pitch perturbation quotient is significantly higher than other groups (P < 0.05). Fundamental frequency variation has no significant difference between groups, but the patients mean is higher than others. Shimmer percent and peak-to-peak amplitude variation of patients' vowel /a/ are distinctly greater than other groups. Amplitude perturbation quotient of vowel /a/ has no significance between groups, but the patients' group is higher than others. Shimmer percent, peak-to-peak amplitude variation and amplitude perturbation of vowel /i/ has no significant difference between most groups, but the results of patients are the biggest. Noise to harmonic ratio of falsetto is the lowest among all groups. Voice turbulence index of the patients and falsetto is lower than that of others. Soft phonation index of patients is higher than other groups and near to falsetto, vowel /i/ is more significant than /a/. The children falsetto and the patients have voice break., Conclusion: Mutational "falsetto" is not really falsetto, but rather similar to female's voice. To lower fundamental frequency and improve chest resonance is the key of treatment. Both psychotherapy and voice training are important. We can try to use rigid phonation to treat patients.