Search

Summary: All-optical physiology (AOP) manipulates and reports neuronal activities with light, allowing for interrogation of neuronal functional connections with high spatiotemporal resolution. However, contemporary high-speed AOP platforms are limited to single-depth or discrete multi-plane recordings that are not suitable for studying functional connections among densely packed small neurons, such as neurons in Drosophila brains. Here, we constructed a 3D AOP platform by incorporating single-photon point stimulation and two-photon high-speed volumetric recordings with a tunable acoustic gradient-index (TAG) lens. We demonstrated the platform effectiveness by studying the anterior visual pathway (AVP) of Drosophila. We achieved functional observation of spatiotemporal coding and the strengths of calcium-sensitive connections between anterior optic tubercle (AOTU) sub-compartments and >70 tightly assembled 2-μm bulb (BU) microglomeruli in 3D coordinates with a single trial. Our work aids the establishment of in vivo 3D functional connectomes in neuron-dense brain areas. : Neuroscience; Techniques in Neuroscience; Biological Sciences Research Methodologies; Biological Sciences Tools Subject Areas: Neuroscience, Techniques in Neuroscience, Biological Sciences Research Methodologies, Biological Sciences Tools

AIM: To evaluate the visual outcomes of standard amblyopic treatment add-on training via perceptual learning in refractive amblyopic children and to identify the risk factors for treatment failure. METHODS: Retrospective charts were reviewed in children with refractive amblyopia who received standard treatment and add-on Cambridge Visual Stimulator (CAM) training. The add-on CAM group that was enrolled had worn full-corrected glasses for at least 2mo before training. A control group received only the standard treatment. Treatment success was defined as best-corrected visual acuity (BCVA) ≥20/25. The age, sex, initial BCVA, refractive errors, sessions and duration of training, and final BCVA were recorded. RESULTS: A total of 209 children (129 children in add-on CAM group and 80 children in control group) were enrolled. Seventy-six percent of unilateral and 87% of bilateral amblyopic children achieved treatment success. In children with unilateral or bilateral moderate amblyopia, the duration to reach BCVA ≥20/25 was significantly shorter in add-on CAM group than in control group. Poor initial BCVA (P

Verteporfin (VP) has been used for photodynamic therapy (PDT) for over 20 years, and new applications have brought it back into the spotlight. VP is hydrophobic and requires lipid carriers for clinical delivery as Visudyne. A nanosuspension of VP, termed NanoVP, that requires no carriers is developed, permitting delivery of VP alone in an aqueous solution. NanoVP is produced by solvent–antisolvent precipitation, with dimethyl sulfoxide as the preferable solvent of several screened. The initial formulation has a hydrodynamic diameter of 104 ± 6.0 nm, concentration of 133 ± 10 μm, polydispersity index (Pdi) of 0.12 ± 0.01, and zeta potential of −22.0 ± 0.93 mV. Seeking a concentration >500 μm, a zeta potential

Abstract While surgical resection is a mainstay of cancer treatment, many tumors are unresectable due to stage, location, or comorbidities. Ablative therapies, which cause local destruction of tumors, are effective alternatives to surgical excision in several settings. Ethanol ablation is one such ablative treatment modality in which ethanol is directly injected into tumor nodules. Ethanol, however, tends to leak out of the tumor and into adjacent tissue structures, and its biodistribution is difficult to monitor in vivo. To address these challenges, this study presents a cutting‐edge technology known as Light‐Activatable Sustained‐Exposure Ethanol Injection Technology (LASEIT). LASEIT comprises a three‐part formulation: (1) ethanol, (2) benzoporphyrin derivative, which enables fluorescence‐based tracking of drug distribution and the potential application of photodynamic therapy, and (3) ethyl cellulose, which forms a gel upon injection into tissue to facilitate drug retention. In vitro drug release studies showed that ethyl cellulose slowed the rate of release in LASEIT by 7×. Injections in liver tissues demonstrated a 6× improvement in volume distribution when using LASEIT compared to controls. In vivo experiments in a mouse pancreatic cancer xenograft model showed LASEIT exhibited significantly stronger average radiant efficiency than controls and persisted in tumors for up to 7 days compared to controls, which only persisted for less than 24 h. In summary, this study introduced LASEIT as a novel technology that enabled real‐time fluorescence monitoring of drug distribution both ex vivo and in vivo. Further research exploring the efficacy of LASEIT is strongly warranted.

Abstract One of the strategies towards an effective HIV-1 vaccine is to elicit broadly neutralizing antibody responses that target the high HIV-1 Env diversity. Here, we present an HIV-1 vaccine candidate that consists of cobalt porphyrin-phospholipid (CoPoP) liposomes decorated with repaired and stabilized clade C HIV-1 Env trimers in a prefusion conformation. These particles exhibit high HIV-1 Env trimer decoration, serum stability and bind broadly neutralizing antibodies. Three sequential immunizations of female rabbits with CoPoP liposomes displaying a different clade C HIV-1 gp140 trimer at each dosing generate high HIV-1 Env-specific antibody responses. Additionally, serum neutralization is detectable against 18 of 20 multiclade tier 2 HIV-1 strains. Furthermore, the peak antibody titers induced by CoPoP liposomes can be recalled by subsequent heterologous immunization with Ad26-encoded membrane-bound stabilized Env antigens. Hence, a CoPoP liposome-based HIV-1 vaccine that can generate cross-clade neutralizing antibody immunity could potentially be a component of an efficacious HIV-1 vaccine.

ABSTRACT Epitopes from the Candida cell surface proteins Fba and Met6 are putative vaccine targets for invasive candidiasis. Here, we describe a Candida vaccine approach in which short peptides derived from Fba and Met6 are used in spontaneous nanoliposome antigen particle (SNAP) format. SNAP was enabled by the interaction of cobalt porphyrin phospholipid in liposomes with three histidine residues on the N-terminus of synthetic short peptide immunogens from Fba (F-SNAP), Met6 (M-SNAP), or bivalent Fba and Met6 (FM-SNAP). Liposomes were adjuvanted with synthetic monophosphoryl lipid and QS-21. In mice, immunization with F-SNAP, M-SNAP, or FM-SNAP induced antigen-specific IgG responses and mixed Th1/Th2 immunity. The duplex FM-SNAP vaccine elicited stronger antibody responses against each peptide, even at order-of-magnitude lower peptide dosing than a comparable adjuvanted, conjugate vaccine. Enzyme-linked immunosorbent spot analysis revealed the induction of antigen-specific, cytokine-producing T cells. Compared to F-SNAP or M-SNAP, higher production of TNFα, IL-2, and IFNγ was observed with re-stimulation of splenocytes from bivalent FM-SNAP-immunized mice. When vaccinated BALB/c mice were challenged with Candida auris, analysis of the fungal burden in the kidneys showed that SNAP vaccination protected from disseminated candidiasis. In a lethal fungal exposure model in A/J mice, F-SNAP, M-SNAP, and FM-SNAP vaccination protected mice from candidiasis challenge. Together, these results show that further investigation into the SNAP adjuvant platform is warranted using Fba and Met6 epitopes for a pan-Candida peptide vaccine that provides multifaceted protective immune responses.IMPORTANCEThis study introduces a promising vaccine strategy against invasive candidiasis, a severe fungal infection, by targeting specific peptides on the surface of Candida. Using a novel approach called spontaneous nanoliposome antigen particle (SNAP), we combined peptides from two key Candida proteins, Fba and Met6, into a vaccine. This vaccine induced robust immune responses in mice, including the production of protective antibodies and the activation of immune cells. Importantly, mice vaccinated with SNAP were shielded from disseminated candidiasis in experiments. These findings highlight a potential avenue for developing a broad-spectrum vaccine against Candida infections, which could significantly improve outcomes for patients at risk of these often deadly fungal diseases.

Abstract Background Within the last decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged in the clinic as an effective treatment for numerous malignancies. Preclinical data have demonstrated powerful combination effects of PARPi paired with photodynamic therapy (PDT), which involves light-activation of specialized dyes (photosensitizers) to stimulate cancer cell death through reactive oxygen species generation. Results In this report, the most potent clinical PARP inhibitor, talazoparib, is loaded into the core of a polymeric nanoparticle (NP-Tal), which is interfaced with antibody-photosensitizer conjugates (photoimmunoconjugates, PICs) to form PIC-NP-Tal. In parallel, a new 3D fluorescent coculture model is developed using the parental OVCAR-8-DsRed2 and the chemo-resistant subline, NCI/ADR-RES-EGFP. This model enables quantification of trends in the evolutionary dynamics of acquired chemoresistance in response to various treatment regimes. Results reveal that at a low dosage (0.01 μM), NP-Tal kills the parental cells while sparing the chemo-resistant subline, thereby driving chemoresistance. Next, PIC-NP-Tal and relevant controls are evaluated in the 3D coculture model at multiple irradiation doses to characterize effects on total spheroid ablation and relative changes in parental and subline cell population dynamics. Total spheroid ablation data shows potent combination effects when PIC and NP-Tal are co-administered, but decreased efficacy with the conjugated formulation (PIC-NP-Tal). Analysis of cell population dynamics reveals that PIC, BPD + NP-Tal, PIC + NP-Tal, and PIC-NP-Tal demonstrate selection pressures towards chemoresistance. Conclusions This study provides key insights into manufacturing parameters for PARPi-loaded nanoparticles, as well as the potential role of PDT-based combination therapies in the context of acquired drug resistance.

Abstract Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure‐drug nanoformulation of VP, termed “NanoVP”, eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65–150 nm) and 1500‐fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2‐fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP‐PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5‐aminolevulinic acid (5‐ALA). Moreover, low‐dose NanoVP‐PDT can safely open the blood‐brain barrier, increasing drug accumulation in rat brains by 5.5‐fold compared to 5‐ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM.

Background: Enterotoxigenic Escherichia coli (ETEC) strains cause infectious diarrhea and colonize host intestine epithelia via surface-expressed colonization factors. Colonization factor antigen I (CFA/I), a prevalent ETEC colonization factor, is a vaccine target since antibodies directed to this fimbria can block ETEC adherence and prevent diarrhea. Methods: Two recombinant antigens derived from CFA/I were investigated with a vaccine adjuvant system that displays soluble antigens on the surface of immunogenic liposomes. The first antigen, CfaEB, is a chimeric fusion protein comprising the minor (CfaE) and major (CfaB) subunits of CFA/I. The second, CfaEad, is the adhesin domain of CfaE. Results: Owing to their His-tag, recombinant CfaEB and CfaEad, spontaneously bound upon admixture with nanoliposomes containing cobalt-porphyrin phospholipid (CoPoP), as well as a synthetic monophosphoryl lipid A (PHAD) adjuvant. Intramuscular immunization of mice with sub-microgram doses CfaEB or CfaEad admixed with CoPoP/PHAD liposomes elicited serum IgG and intestinal IgA antibodies. The smaller CfaEad antigen benefitted more from liposome display. Serum and intestine antibodies from mice immunized with liposome-displayed CfaEB or CfaEad recognized native CFA/I fimbria as evidenced by immunofluorescence and hemagglutination inhibition assays using the CFA/I-expressing H10407 ETEC strain. Conclusion: These data show that colonization factor-derived recombinant ETEC antigens exhibit immunogenicity when delivered in immunogenic particle-based formulations.

Abstract To evaluate the potential benefit of HyperArc (HA) fractionated stereotactic radiotherapy (FSRT) for the benign brain lesion. Sixteen patients with a single deep-seated, centrally located benign brain lesion treated by CyberKnife (CK, G4 cone-based model) were enrolled. Treatment plans for HA with two different optimization algorithms (SRS NTO and ALDO) and coplanar RapidArc (RA) were generated for each patient to meet the corresponding treatment plan criteria. These four FSRT treatment plans were divided into two groups—the homogeneous delivery group (HA-SRS NTO and coplanar RA) and the inhomogeneous delivery group (HA-ALDO and cone-based CK)—to compare for dosimetric outcomes. For homogeneous delivery, the brain V5, V12, and V24 and the mean brainstem dose were significantly lower with the HA-SRS NTO plans than with the coplanar RA plans. The conformity index, high and intermediate dose spillage, and gradient radius were significantly better with the HA-SRS NTO plans than with the coplanar RA plans. For inhomogeneous delivery, the HA-ALDO exhibited superior PTV coverage levels to the cone-based CK plans. Almost all the doses delivered to organs at risk and dose distribution metrics were significantly better with the HA-ALDO plans than with the cone-based CK plans. Good dosimetric distribution makes HA an attractive FSRT technique for the treatment of benign brain lesions.

Powdery mildew is a prevalent disease that affects cucumber crops, leading to yield reductions and declines in quality. Bacillus sp. strain Tcb43 culture medium was shown to be capable of inhibiting fungal spore germination in previous reports. In this study, the identification of the Tcb43 strain was updated to Bacillus velezensis by using whole-genome sequencing. The strain exhibited tolerance to a wide range of temperatures (12–40 °C), salinities (7–10%), and pH levels (ranging from 5 to 11). Additionally, Tcb43 demonstrated insensitivity to most tested fungicides. A new fermentation formula, Tcb43FBSO, was developed by adding 0.25% soybean oil to the fermented formula (Tcb43FB). This new formula exhibited a shelf life of up to 12 months with the decrease in bacterial count from 5.35 × 108 to 1.97 × 108 cfu/mL. Greenhouse assays showed that the treatment of potted cucumber plants with a 100-fold dilution (100×) of Tcb43FBSO for four weeks resulted in a significant reduction (64.64%) of cucumber powdery mildew compared to the mock group. In large-scale greenhouse trials, the treatment of cucumber plants with 200× of Tcb43FBSO for 5 weeks effectively suppressed powdery mildew disease, with a control rate that reached 76.6% compared to the mock group. These findings highlight the potential of Tcb43 as a biocontrol agent for managing cucumber powdery mildew and suggest its promising application in agriculture.

Abstract Background The availability of a reliable tumor target for advanced colorectal cancer (CRC) therapeutic approaches is critical since current treatments are limited. Epidermal growth factor-like domain 6 (EGFL6) has been reported to be associated with cancer development. Here, we focused on the role of EGFL6 in CRC progression and its clinical relevance. In addition, an anti-EGFL6 antibody was generated by phage display technology to investigate its potential therapeutic efficacy in CRC. Results EGFL6 expression significantly increased in the colon tissues from CRC patients and mice showing spontaneous tumorigenesis, but not in normal tissue. Under hypoxic condition, EGFL6 expression was enhanced at both protein and transcript levels. Moreover, EGFL6 could promote cancer cell migration invasion, and proliferation of CRC cells via up-regulation of the ERK/ AKT pathway. EGFL6 also regulated cell migration, invasion, proliferation, and self-renewal through EGFR/αvβ3 integrin receptors. Treatment with the anti-EGFL6 antibody EGFL6-E5-IgG showed tumor-inhibition and anti-metastasis abilities in the xenograft and syngeneic mouse models, respectively. Moreover, EGFL6-E5-IgG treatment had no adverse effect on angiogenesis and wound healing Conclusions We demonstrated that EGFL6 plays a role in CRC tumorigenesis and tumor progression, indicating that EGFL6 is a potential therapeutic target worth further investigation.

Abstract Background The Plasmodium falciparum sexual-stage surface proteins Pfs25 and Pfs230 are antigen candidates for a malaria transmission-blocking vaccine (TBV), and have been widely investigated as such. It is not clear whether simultaneously presenting these two antigens in a particulate vaccine would enhance the transmission reducing activity (TRA) of induced antibodies. To assess this, immunization was carried out with liposomes containing synthetic lipid adjuvant monophosphoryl lipid A (MPLA), and cobalt-porphyrin-phospholipid (CoPoP), which rapidly converts recombinant, his-tagged antigens into particles. Methods His-tagged, recombinant Pfs25 and Pfs230C1 were mixed with CoPoP liposomes to form a bivalent vaccine. Antigens were fluorescently labelled to infer duplex particleization serum-stability and binding kinetics using fluorescence resonance energy transfer. Mice and rabbits were immunized with individual or duplexed particleized Pfs25 and Pfs230C1, at fixed total antigen doses. The resulting antibody responses were assessed for magnitude and TRA. Results Pfs230C1 and Pfs25 rapidly bound CoPoP liposomes to form a serum-stable, bivalent particle vaccine. In mice, immunization with 5 ng of total antigen (individual antigen or duplexed) elicited functional antibodies against Pfs25 and Pfs230. Compared to immunization with the individual antigen, Pfs25 antibody production was moderately lower for the bivalent CoPoP vaccine, whereas Pfs230C1 antibody production was not impacted. All antibodies demonstrated at least 92% inhibition in oocyst density at 750 μg/mL purified mouse IgG in the standard membrane feeding assay (SMFA). At lower IgG concentrations, the bivalent vaccine did not improve TRA; antibodies induced by particleized Pfs25 alone showed stronger function in these conditions. In rabbits, immunization with a 20 µg total antigen dose with the duplexed antigens yielded similar antibody production against Pfs25 and Pfs230 compared to immunization with a 20 µg dose of individual antigens. However, no enhanced TRA was observed with duplexing. Conclusions Pfs25, Pfs230 or the duplexed combination can readily be prepared as particulate vaccines by mixing CoPoP liposomes with soluble, recombinant antigens. This approach induces potent transmission-reducing antibodies following immunization in mice and rabbits. Immunization with bivalent, particleized, Pfs230 and Pfs25 did not yield antibodies with superior TRA compared to immunization with particleized Pfs25 as a single antigen. Altogether, duplexing antigens is straightforward and effective using CoPoP liposomes, but is likely to be more useful for targeting distinct parasite life stages.

Abstract Short peptides reflecting major histocompatibility complex (MHC) class I (MHC‐I) epitopes frequently lack sufficient immunogenicity to induce robust antigen (Ag)‐specific CD8+ T cell responses. In the current work, it is demonstrated that position‐scanning peptide libraries themselves can serve as improved immunogens, inducing Ag‐specific CD8+ T cells with greater frequency and function than the wild‐type epitope. The approach involves displaying the entire position‐scanning library onto immunogenic nanoliposomes. Each library contains the MHC‐I epitope with a single randomized position. When a recently identified MHC‐I epitope in the glycoprotein gp70 envelope protein of murine leukemia virus (MuLV) is assessed, only one of the eight positional libraries tested, randomized at amino acid position 5 (Pos5), shows enhanced induction of Ag‐specific CD8+ T cells. A second MHC‐I epitope from gp70 is assessed in the same manner and shows, in contrast, multiple positional libraries (Pos1, Pos3, Pos5, and Pos8) as well as the library mixture give rise to enhanced CD8+ T cell responses. The library mixture Pos1‐3‐5‐8 induces a more diverse epitope‐specific T‐cell repertoire with superior antitumor efficacy compared to an established single mutation mimotope (AH1‐A5). These data show that positional peptide libraries can serve as immunogens for improving CD8+ T‐cell responses against endogenously expressed MHC‐I epitopes.

P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent drug efflux protein commonly associated with multidrug resistance in cancer chemotherapy. In this report, we used a dual-fluorescent co-culture model to study the population dynamics of the drug sensitive human ovarian cancer cell line (OVCAR-8-DsRed2) and its resistant subline that overexpresses P-gp (NCI/ADR-RES-EGFP) during the course of a photodynamic therapy (PDT)-olaparib combination regimen. Without treatment, OVCAR-8-DsRed2 cells grew more rapidly than the NCI/ADR-RES-EGFP cells. Olaparib treatment reduced the total number of cancer cells by 70±4% but selected for the resistant NCI/ADR-RES-EGFP population since olaparib is an efflux substrate for the P-gp pump. This study used the FDA-approved benzoporphyrin derivative (BPD) photosensitizer or its lipidated formulation ((16:0)LysoPC-BPD) to kill OVCAR-8 cells and reduce the likelihood that olaparib-resistant cells would have selective advantage. Three cycles of PDT effectively reduced the total cell number by 66±3%, while stabilizing the population ratio of sensitive and resistant cells at approximately 1:1. The combination of olaparib treatment and PDT enhanced PARP cleavage and deoxyribonucleic acid (DNA) damage, further decreasing the total cancer cell number down to 10±2%. We also showed that the combination of olaparib and (16:0)LysoPC-BPD-based PDT is up to 18-fold more effective in mitigating the selection of resistant NCI/ADR-RES-EGFP cells, compared to using olaparib and BPD-based PDT. These studies suggest that PDT may improve the effectiveness of olaparib, and the use of a lipidated photosensitizer formulation holds promise in overcoming cancer drug resistance.

Breast cancer is the most diagnosed cancer type in women, with it being the second most deadly cancer in terms of total yearly mortality. Due to the prevalence of this disease, better methods are needed for both detection and treatment. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent biomarkers that lend insight into cell and tissue metabolism. As such, we developed an endoscopic device to measure these metabolites in tissue to differentiate between malignant tumors and normal tissue. We performed initial validations in liquid phantoms as well as compared to a previously validated redox imaging system. We also imaged ex vivo tissue samples after modulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and a combination of rotenone and antimycin A. We then imaged the rim and the core of MDA-MB-231 breast cancer tumors, with our results showing that the core of a cancerous lesion has a significantly higher optical redox ratio ([FAD]/([FAD] + [NADH])) than the rim, which agrees with previously published results. The mouse muscle tissues exhibited a significantly lower FAD, higher NADH, and lower redox ratio compared to the tumor core or rim. We also used the endoscope to measure NADH and FAD after photodynamic therapy treatment, a light-activated treatment methodology. Our results found that the NADH signal increases in the malignancy rim and core, while the core of cancers demonstrated a significant increase in the FAD signal.

Bacterial wilt caused by the soil-borne pathogen Ralstonia solanacearum is one of the most devastating diseases in solanaceous plants. No agrochemicals are available to manage bacterial wilt effectively. A Bacillus amyloliquefaciens strain designated PMB01 was recovered from the cabbage rhizosphere and was found to be capable of inhibiting the growth of R. solanacearum. The PMB01 strain was highly resistant to extreme pH, heat, high salt salinity, and various fungicides. In contrast, PMB01 was sensitive to copper-based compounds, streptomycin, and tetracycline. The efficacy of the PMB01 strain in suppressing R. solanacearum and bacterial wilt in tomatoes was significantly improved when the culture medium was supplemented with 1% (w/v) soybean meal. PMB01 was in a 500-liter tank for the pilot production, and the resultant broth could effectively reduce the severity of tomato bacterial wilt in greenhouse trials. The PMB01 fermentation broth was mixed with 10% corn starch and 30% maltodextrin to make a wettable powder (WP). PMB01 could survive in the wettable powder for more than two years without losing its antagonistic activity. In ten field trials, tomato plants treated with 50, 100, or 200-fold dilutions of PMB01 WP reduced bacterial wilt severity by more than 67% compared to the mock (water control) treatment. This work revealed that the effectiveness of the rhizobacterium PMB01 to antagonize R. solanacearum was greatly improved when the culture medium was supplemented with 1% (w/v) soybean meal, indicating that PMB01 is an ideal bio-agent candidate. A durable format suitable for storage was also developed. Similar concepts may be applied to other bio-agent candidates to improve their effectiveness in disease management.

The global pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to efforts in developing effective vaccine approaches. Currently, approved coronavirus disease 2019 (COVID-19) vaccines are administered through an intramuscular (I.M.) route. Here, we show that the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD), when displayed on immunogenic liposomes, can be intranasally (I.N.) administered, resulting in the production of antigen-specific IgA and antigen-specific cellular responses in the lungs. Following I.N. immunization, antigen-presenting cells of the lungs took up liposomes displaying the RBD. K18 human ACE2-transgenic mice that were immunized I.M or I.N with sub-microgram doses of RBD liposomes and that were then challenged with SARS-CoV-2 had a reduced viral load in the early course of infection, with I.M. achieving complete viral clearance. Nevertheless, both vaccine administration routes led to full protection against lethal viral infection, demonstrating the potential for the further exploration and optimization of I.N immunization with liposome-displayed antigen vaccines.

This paper aims to simulate and evaluate the impacts of increases and decreases in oil price on industrial sectors in China. We develop an oil-economy computable general equilibrium (OE-CGE) model with crude oil as an important factor in production. The transmission mechanism of crude oil price swings to various industrial sectors is described in the model. We calibrate parameters in the model parameters using input-output data. In addition, we simulate the rise and fall of oil prices in the model and assess the impact of crude oil prices on various industrial sectors. The results show that crude oil price changes have the greatest impact on the output and consumption of crude oil and gas extraction products sector, crude oil refined coke products, and processed nuclear fuel products sector. The investment of public utilities sector is the most sensitive to changes in crude oil price. When the price of crude oil changes, its investment drops significantly. Crude oil price stability is extremely important for investment and output stability in all sectors.

One of the strategies towards an effective HIV-1 vaccine is to elicit broadly neutralizing antibody responses that target the high HIV-1 Env diversity. Here, we present an HIV-1 vaccine candidate that consists of cobalt porphyrinphospholipid (CoPoP) liposomes decorated with repaired and stabilized clade C HIV-1 Env trimers in a prefusion conformation. These particles exhibit high HIV-1 Env trimer decoration, serum stability and bind broadly neutralizing antibodies. Three sequential immunizations of female rabbits with CoPoP liposomes displaying a different clade C HIV-1 gp140 trimer at each dosing generate high HIV-1 Env-specific antibody responses. Additionally, serum neutralization is detectable against 18 of 20 multiclade tier 2 HIV-1 strains. Furthermore, the peak antibody titers induced by CoPoP liposomes can be recalled by subsequent heterologous immunization with Ad26-encoded membrane-bound stabilized Env antigens. Hence, a CoPoP liposome-based HIV-1 vaccine that can generate cross-clade neutralizing antibody immunity could potentially be a component of an efficacious HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

A novel synthetic pathway to approach 3-(imino)isoindolin-1-ones by the Co-catalyzed cyclization reaction of 2-bromobenzamides with carbodiimides has been developed. This catalytic reaction can tolerate a variety of substituents and provide corresponding products in moderate yields for most cases. According to the literature, the reaction mechanism is proposed through the formation of a five-membered aza-cobalacycle complex, which carries out the following reaction subsequence, including nucleophilic addition and substitution, to furnish the desired structures.

This paper examines a specific mechanism, partner co-signing relationships, through which knowledge sharing in an audit team may influence audit quality. Specifically, we examine whether an engagement partner's co-signing relationships with non-engagement industry specialist partners are associated with audit quality. Using a unique setting in which co-signing relationships for each audit engagement is available, we find that audit quality is higher when the engagement partner for the focal client has cosigning relationships with non-engagement partners who are specialists in the focal client's industry and that the positive association is more likely driven by a learning effect than a consultation effect. Further evidence suggests that attributes of co-signing relationships such as continuity matter and that co-signing relationships with industry specialist partners are more likely to be utilized when engagement partners have limited industry knowledge, clients operate in homogeneous industries, and engagement partners are from large audit firms. Overall, our results suggest that interactions with industry specialist partners facilitate knowledge sharing and hence improve audit quality. [ABSTRACT FROM AUTHOR]