Search

To improve awareness of diversity in MD-PhD program applicants, matriculants, and graduates; facilitators and barriers to matriculation and/or completion among minoritized groups; and the effects of research experience programs on admissions processes aimed to increase representation of minoritized groups in MD-PhD programs.The authors conducted a scoping review, searching EMBASE, MEDLINE, PsycINFO, CINAHL, and Web of Science through December 21, 2021, for studies that contained data on the characteristics of MD-PhD learners and initiatives aimed to make the clinician-scientist trainee population more diverse. They excluded studies that had no primary data, were unavailable in English, and were not peer-reviewed.Of 4,369 articles identified, 16 met inclusion criteria. Studies conceptualized diversity inconsistently, including as sex/gender disparities (n = 11), race/ethnicity underrepresentation (n = 9), disability (n = 2), first-generation student (n = 1), visible minority (n = 1), Indigenous population (n = 1), and economic/social disadvantage (n = 1). Potential barriers to entering or continuing in an MD-PhD program among women and underrepresented ethnic minorities included the long program duration and lack of mentorship; potential facilitators included the flexibility of the dual-degree program. Limited data on high school, undergraduate, and postbaccalaureate research experience programs targeting underrepresented minorities suggest that they may help facilitate admission into MD-PhD programs.The findings of this scoping review suggest that the diversity of MD-PhD students has been conceptualized in unitary, inconsistent terms, without addressing how different dimensions of diversity may intersect and impact MD-PhD admissions. Future studies should be explicit and intentional in defining "diversity" as it relates to their research questions, explore the impact of intersectionality, and systematically identify and address causal facilitators and barriers of entry to and completion of MD-PhD programs among minoritized groups.

As a hydrolytic product of collagen, gelatin is a polypeptide of biological origin. Gelatin hydrogels emerge as promising material candidates for traditional dressings due to good biocompatibility and the ability to keep wounds moist. However, it is difficult to simultaneously achieve gelatin hydrogel with robust mechanical property for long-term usage, reliable tissue adhesion, self-healing and antibacterial properties. Herein, we propose a simply synthesized strategy of a multifunctional gelatin hydrogel dressing, which is constructed by conjugating a newly synthesized 2-(4'-aldehydephenyl)-4-(2',3',4'-trihydroxyphenyl)-2,3-phthalazine-1(2H)-one (THPZB) to gelatin with Schiff base and chelating with Fe

Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.

Supplementary Figure from Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy.Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed.In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Supplementary Figure from B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model

Supplementary Data from Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors

Hi, Mom (Nihao, Li Huanying 2021) is the first film directed by Jia Ling, a comedian. An autobiographical movie, it develops a mom–daughter-reuniting visional field in the mode of a time-travelling film. In fantasy scenes set in the 1980s, the film reshapes the “mother–daughter” emotional logic with that of “sisterhood”, using comic effects created by misplaced identities to reveal the tragic crux of the cruel reality of “forever losing maternal love”. “The art of analyzing emotions” is pursued through “interpreting visions”. The protagonist ultimately reconciles with reality not by controlling the vision rationally and subjectively, but by creating a deeper vision—a “true fairy tale”. This is for the purpose of retaining a scene of imagined realization of desire: bidding a fond farewell to mom in the vision, fulfilling a wish in the farewell and reconciling with reality and ego in the visional “mutual reconciliation”.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Supplementary Figure S3

Supplementary Table S2

Purpose:Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts.Results:GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy.Conclusions:Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance.Significance:These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

Supplementary Figure 1. Generation of Enz-resistant prostate cancer cell lines. Supplementary Figure 2. AR directly represses CXCR7 gene expression. Supplementary Figure 3. CXCR7 expression is required for C4-2B Enz-resistant prostate cancer cell survival and invasiveness. Supplementary Figure 4. CXCR7 activates MAPK pathway independently of CXCR4 and CXCL12. Supplementary Figure 5. ARRB2 expression is required for Enz-resistant prostate cancer cell growth and invasion. Supplementary Figure 6. CXCR7 is upregulated in metastatic prostate cancer. Supplementary Figure 7. MEK inhibitor trametinib suppresses Enz-resistant prostate cancer growth in vitro and in vivo. Supplementary Table S1: Oligonucleotides that were utilized in this study.

Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. MAIT cells also sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unknown. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster mainstream virus-specific CD8+T cell responses, and potentiate heterosubtypic antiviral protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency, Toll-like receptor 3 (TLR3) and cell-autonomous type I interferon receptor signaling. Furthermore, the observed phenomenon was manifest in young and old female and male mice, and could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.

Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.

Neutralizing antibodies are known to have a crucial role in protecting against SARS-CoV-2 infection and have been suggested to be a useful correlate of protection for vaccine clinical trials and for population-level surveys. In addition to neutralizing virus directly, antibodies can also engage immune effectors through their Fc domains, including Fc receptor-expressing immune cells and complement. The outcome of these interactions depends on a range of factors, including antibody isotype-Fc receptor combinations, Fc receptor-bearing cell types and antibody post-translational modifications. A growing body of evidence has shown roles for these Fc-dependent antibody effector functions in determining the outcome of SARS-CoV-2 infection. However, measuring these functions is more complicated than assays that measure antibody binding and virus neutralization. Here, we examine recent data illuminating the roles of Fc-dependent antibody effector functions in the context of SARS-CoV-2 infection, and we discuss the implications of these data for the development of next-generation SARS-CoV-2 vaccines and therapeutics.

Antibody recruiting molecules (ARMs) represent an important class of "proximity-inducing" chemical tools with therapeutic potential. ARMs function by simultaneously binding to a hapten-specific serum antibody (Ab) (e.g., anti-dinitrophenyl (DNP)) and a cancer cell surface protein, enforcing their proximity. ARM anticancer efficacy depends on the formation of ARM:Ab complexes on the cancer cell surface, which activate immune cell recognition and elimination of the cancer cell. Problematically, ARM function in human patients may be limited by conditions that drive the dissociation of ARM:Ab complexes, namely, intrinsically low binding affinity and/or low concentrations of anti-hapten antibodies in human serum. To address this potential limitation, we previously developed a covalent ARM (cARM) chemical tool that eliminates the ARM:antibody equilibrium through a covalent linkage. In the current study, we set out to determine to what extent maximizing the stability of ARM:antibody complexes via cARMs enhances target immune recognition. We observe cARMs significantly increase target immune recognition relative to ARMs across a range of therapeutically relevant antibody concentrations. These results demonstrate that ARM therapeutic function can be dramatically enhanced by increasing the kinetic stability of ARM:antibody complexes localized on cancer cells. Our findings suggest that a) high titres/concentrations of target antibody in human serum are not neccessary and b) saturative antibody recruitment to cancer cells not sufficient, to achieve maximal ARM therapeutic function.

Background Nonpharmaceutical interventions such as physical distancing and mandatory masking were adopted in many jurisdictions during the coronavirus disease 2019 pandemic to decrease spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined the effects of these interventions on incidence of healthcare utilization for other infectious diseases. Methods Using a healthcare administrative dataset, we employed an interrupted time series analysis to measure changes in healthcare visits for various infectious diseases across the province of Ontario, Canada, from January 2017 to December 2020. We used a hierarchical clustering algorithm to group diagnoses that demonstrated similar patterns of change through the pandemic months. Results We found that visits for infectious diseases commonly caused by communicable respiratory pathogens (eg, acute bronchitis, acute sinusitis) formed distinct clusters from diagnoses that often originate from pathogens derived from the patient’s own flora (eg, urinary tract infection, cellulitis). Moreover, infectious diagnoses commonly arising from communicable respiratory pathogens (hierarchical cluster 1: highly impacted diagnoses) were significantly decreased, with a rate ratio (RR) of 0.35 (95% confidence interval [CI], .30–.40; P Conclusions Public health measures to curtail the incidence of SARS-CoV-2 were widely effective against other communicable respiratory infectious diseases with similar modes of transmission but had little effect on infectious diseases not strongly dependent on person-to-person transmission.

A comparison of SARS-CoV-2 wild-type and the beta variant virus neutralization capacity between 2 and 3 mRNA vaccine series in nursing home residents, and between nursing home and assisted living residents strongly supports 3rd dose vaccine recommendations, and equivalent polices for nursing homes and assisted living settings. Findings suggest that residents mount a robust humoral response to a 3rd mRNA vaccination, and have greater neuralization capacity compared to a 2 dose series.

SummaryThe conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next generation universal influenza vaccines. Protection provided by hemagglutinin stalk binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level, and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual’s titers of stalk-binding antibodies, and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

Debris laser ranging (DLR) is receiving considerable attention as an accurate and effective method of determining and predicting the orbits of space debris. This paper reports some technologies of DLR, such as the high pulse repetition frequency (PRF) laser pulse, large-aperture telescope, telescope array, multi-static stations receiving signals. DLR with a picosecond laser at the Shanghai Astronomical Observatory is also presented. A few hundred laps of space debris laser-ranging measurements have been made. A double-pulse picosecond laser with an average power of 4.2 W, a PRF of 1 kHz, and a wavelength of 532 nm has been implemented successfully in DLR, it’s the first time that DLR technology has reached a ranging precision at the sub-decimeter level. In addition, the characteristics of the picosecond-pulse-width laser transmission with the advantages of transmission in laser ranging were analyzed. With a mode of the pulse-burst picosecond laser having high average power, the DLR system has tracked small debris with a radar cross-section (RCS) of 0.91 m2 at a ranging distance up to 1726.8 km, corresponding to an RCS of 0.1 m2 at a distance of 1000 km. These works are expected to provide new technologies to further improve the performance of DLR.

According to Newton's law of universal gravitation, the movement of matter and the change in density cause a gravitational variation. Due to the anisotropic distribution of matter, the vertical and the normal directions at a point on the ground are probably inconsistent, which is referred to as the deflection of the vertical (DOV) and is indispensable to astrogeodetic and geophysics research. Two new non‐optical methods, including small network transformation and azimuth‐axis inclination inversion, are proposed to determine the DOV at a very long baseline interferometry (VLBI) telescope at the Urumqi station. A generalized expression of the pointing calibration model considering axis‐related errors is also presented. Therefore, the pointing calibration model and indirect model used for reference point (RP) determination are unified by redefining their coordinate system, angle direction, and axis‐related errors. The DOV given by the small network transformation agrees well with the DOVs determined by the real surveying and other different models. Due to the possible asymmetric coverage of calibrating sources in the north‐south direction in antenna pointing calibration, the north‐south DOV component based on azimuth‐axis inclination inversion differs from the surveyed value. However, the west‐east DOV component fits well in both direction and magnitude. The proposed methods enable the VLBI telescope to sense the direction of the local plumb line by introducing local leveling. We also establish the connections among VLBI delay observation, RP determination, and telescope pointing calibration, which has a benefit to multi‐tech systematic error identification, monitoring, and correction. The research indicates that telescope point calibration can also be taken as a regular technique to monitor systematic error.

BACKGROUND Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. Thus, targeting distinct histone modifier activities would be an effective approach for treating AT/RT. METHODS The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. RESULTS AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. Genes associated with DNA-repair pathway was downregulated upon EZH2 and BRD4 inhibition, and the sensitivity to cisplatin was elevated upon combination of EZH2 and BRD4 inhibitors in vitro. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. CONCLUSION Histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.

Nursing home residents often fail to mount robust responses to vaccinations and recent reports of breakthrough infections, particularly from variants of concern, raise questions about whether vaccination regimens elicit a sufficient humoral immune response or if booster doses are warranted. We examined SARS-CoV-2 antibody levels and neutralizing capacity in nursing home residents 3-5 months after 2 doses of mRNA-1273 or BNT163b2 vaccination as per recommended schedules.Nursing home residents were recruited from eight long-term care homes in Ontario, Canada, between March and July 2021. Antibody levels and neutralization capacity from a previously published convalescent cohort were used as a comparator. Serum SARS-CoV-2 IgA/G/M against spike (S) protein and its receptor-binding domain (RBD) were measured by validated ELISA, with assay cut-off at the mean and 3 standard deviations of a pre-COVID-19 population from the same geographic region. Antibody neutralization was measured against the wild-type strain of SARS-CoV-2 and the beta variant of concern (B.1.351).No neutralizing antibodies were detected in ∼20% of residents to the wild-type virus (30/155; 19%) or beta variant (27/134; 20%). Residents that received BNT163b2 had a ∼4-fold reduction in neutralization to the wild-type strain, and a ∼2-fold reduction in neutralization to the beta variant relative to those who received mRNA-1273.Current mRNA SARS-CoV-2 vaccine regimens may not have equivalent efficacy in nursing home residents. Our findings imply that differences in the humoral immune response may contribute to breakthrough infections, and suggest that consideration of the type of vaccine administered to older adults will have a positive impact on the generation of protective immunity.

Bone-like apatite is a promising coating of poly(ether ether ketone) (PEEK) for bone implantation. Poly(aryl ether nitrile ketone) containing phthalazinone moiety (PPENK) is a novel alternative for its easy synthesis. Here, chitosan/gelatin hybrid hydrogel coating is applied to induce the formation of apatite on the surface of PPENK substrate through biomineralization to improve its biocompatibility and osteogenic property. PPENK possessing allyl groups (PPENK-d) are synthesized and spin-coated on PPENK substrate to impart reactive groups. The hydrogel coating is prepared by the ultraviolet crosslinking of gelatin methacrylate (GelMA) and chitosan methacrylate (CSMA) on PPENK substrate. PPENK-d, GelMA, and CSMA are characterized by 1 H-NMR to confirm the designed structures. The presence of chitosan increases the chelation of calcium ions and thus induces the nucleation of apatite. The microstructural and compositional results reveal that the chitosan-containing hydrogel coating induced apatite coating yields a higher apatite quantity compared to the gelatin hydrogel coating. The apatite coatings on PPENK substrate promote the cytocompatibility and osteogenesis of MC3T3-E1 preosteoblasts in vitro.

SummaryThe emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

Polyoxidometalates (POMs) exhibit a range of biological properties that can be exploited for a variety of therapeutic applications. However, their potential utility as antivirals has been largely overlooked in the ongoing efforts to identify safe, effective and robust therapeutic agents to combat COVID-19. We focus on decavanadate (V10), a paradigmatic member of the POM family, to highlight the utility of electrostatic forces as a means of disrupting molecular processes underlying the SARS-CoV-2 entry into the host cell. While the departure from the traditional lock-and-key approach to the rational drug design relies on less-specific and longer-range interactions, it may enhance the robustness of therapeutic agents by making them less sensitive to the viral mutations. Native mass spectrometry (MS) not only demonstrates the ability of V10 to associate with the receptor-binding domain of the SARS-CoV-2 spike protein, but also provides evidence that this association disrupts the protein binding to its host cell-surface receptor. Furthermore, V10 is also shown to be capable of binding to the polybasic furin cleavage site within the spike protein, which is likely to decrease the effectiveness of the proteolytic processing of the latter (a pre-requisite for the viral fusion with the host cell membrane). Although in vitro studies carried out with SARS-CoV-2 infected cells identify V10 cytotoxicity as a major factor limiting its utility as an antiviral agent, the collected data provide a compelling stimulus for continuing the search for effective, robust and safe therapeutics targeting the novel coronavirus among members of the POM family.

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next-generation universal influenza vaccines. Protection provided by hemagglutinin stalk-binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual's titers of stalk-binding antibodies and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.