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An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1 with the target cells, and replication. We utilized a previously developed qRT-PCR-based assay to examine the effects of broadly neutralizing antibodies (bNAbs), plasma from vaccine trials, and monoclonal antibodies (mAbs) on virus capture and replication. A panel of bNAbs inhibited primary HIV-1 replication in PBMCs but not virus capture. Plasma from RV144 and RV305 trial vaccinees demonstrated inhibition of virus capture with the HIV-1 subtype prevalent in Thailand. Several RV305 derived V2-specific mAbs inhibited virus replication. One of these RV305 derived V2-specific mAbs inhibited both virus capture and replication, demonstrating that it is possible to elicit antibodies by vaccination that inhibit virus capture and replication. Induction of a combination of such antibodies may be the key to protection from HIV-1 acquisition.
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Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , VIH-1 , Replicación Viral , VIH-1/inmunología , Humanos , Anticuerpos Anti-VIH/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Monoclonales/inmunología , Infecciones por VIH/virología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Anticuerpos ampliamente neutralizantes/inmunologíaRESUMEN
Particulate aluminum salts have long occupied a central place worldwide as inexpensive immunostimulatory adjuvants that enable induction of protective immunity for vaccines. Despite their huge benefits and safety, the particulate structures of aluminum salts require transportation and storage at temperatures between 2 °C and 8 °C, and they all have exquisite sensitivity to damage caused by freezing. Here, we propose to solve the critical freezing vulnerability of particulate aluminum salt adjuvants by introducing soluble aluminum salts as adjuvants. The solubility properties of fresh and frozen aluminum chloride and aluminum triacetate, each buffered optimally with sodium acetate, were demonstrated with visual observations and with UV-vis scattering analyses. Two proteins, A244 gp120 and CRM197, adjuvanted either with soluble aluminum chloride or soluble aluminum triacetate, each buffered by sodium acetate at pH 6.5-7.4, elicited murine immune responses that were equivalent to those obtained with Alhydrogel®, a commercial particulate aluminum hydroxide adjuvant. The discovery of the adjuvanticity of soluble aluminum salts might require the creation of a new adjuvant mechanism for aluminum salts in general. However, soluble aluminum salts might provide a practical substitute for particulate aluminum salts as vaccine adjuvants, thereby avoiding the risk of inactivation of vaccines due to accidental freezing of aluminum salt particles.
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This study investigated whether there are aging-related differences in pupil dilation (pupillometry) while the cognitive load is manipulated using digit- and word-span tasks. A group of 17 younger and 15 cognitively healthy older adults performed digit- and word-span tasks. Each task comprised three levels of cognitive loads with 10 trials for each level. For each task, the recall accuracy and the slope of pupil dilation were calculated and analyzed. The raw signal of measured pupil size was low-pass filtered and interpolated to eliminate blinking artifacts and spike noises. Two-way ANOVA was used for statistical analyses. For the recall accuracy, the significant group differences emerged as the span increases in digit-span (5- vs. 7-digit) and word-span (4- vs. 5-word) tasks, while the group differences were not significant on 3-digit- and 3-word-span tasks with lower cognitive load. In digit-span tasks, there was no aging-related difference in the slope of pupil dilation. However, in word-span tasks, the slope of pupil dilation differed significantly between two groups as cognitive load increased, indicating that older adults presented a higher pupil dilation slope than younger adults especially under the conditions with higher cognitive load. The current study found significant aging effects in the pupil dilations under the more cognitive demanding span tasks when the types of span tasks varied (e.g., digit vs. word). The manipulations successfully elicited differential aging effects, given that the aging effects became most salient under word-span tasks with greater cognitive load especially under the maximum length. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00315-6.
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BACKGROUND: Speech therapy is highly effective for patients with Parkinson's disease (PD) who have speech difficulties; however, its accessibility is limited. Online video-call speech therapy has been explored as an alternative option for PD patients. OBJECTIVES: To evaluate the feasibility and efficacy of video-call speech therapy for PD patients. METHODS: This prospective, comparative study was conducted between July and September 2022. PD patients with speech difficulties were divided into two groups, online speech therapy via video call and in-person therapy at hospital, based on their willingness to visit the hospital frequently. The patients underwent 12 sessions of speech therapy, focusing on respiration and phonation. Acoustic assessments, auditory-perceptual assessment, and voice handicap index (K-VHI10) were evaluated at baseline, post-therapy, and follow-up. RESULTS: Eleven patients were enrolled in the study, though one patient from the online group withdrew. Ten patients completed the therapy (five in each group) without missing a session. The baseline acoustic measurements did not differ between the two groups. After therapy, both group showed an increase in voice intensity and improvement in overall loudness. The post-therapy change from baseline in the acoustic measurements was not significantly different between the two groups. The effect of therapy were maintained in the follow-up evaluation in both groups. The K-VHI10 decreased significantly from baseline to post-therapy and further at follow-up in both groups, with no significant difference between two groups. CONCLUSION: The online speech therapy via video call is feasible in PD patients with speech difficulties and as effective as in-person therapy.
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Enfermedad de Parkinson , Trastornos de la Voz , Humanos , Logopedia , Trastornos de la Voz/etiología , Trastornos de la Voz/terapia , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapia , Estudios Prospectivos , Estudios de Factibilidad , Trastornos del Habla/etiología , Trastornos del Habla/terapiaRESUMEN
This study demonstrates the impact of adjuvant on the development of T follicular helper (Tfh) and B cells, and their influence on antibody responses in mice vaccinated with SARS-CoV-2-spike-ferritin-nanoparticle (SpFN) adjuvanted with either Army Liposome Formulation containing QS-21 (SpFN + ALFQ) or Alhydrogel® (SpFN + AH). SpFN + ALFQ increased the size and frequency of germinal center (GC) B cells in the vaccine-draining lymph nodes and increased the frequency of antigen-specific naive B cells. A single vaccination with SpFN + ALFQ resulted in a higher frequency of IL-21-producing-spike-specific Tfh and GC B cells in the draining lymph nodes and spleen, S-2P protein-specific IgM and IgG antibodies, and elicitation of robust cross-neutralizing antibodies against SARS-CoV-2 variants as early as day 7, which was enhanced by a second vaccination. This was associated with the generation of high titer, high avidity binding antibodies. The third vaccination with SpFN + ALFQ elicited high levels of neutralizing antibodies against the Omicron variant. No cross-neutralizing antibodies against Omicron were induced with SpFN + AH. These findings highlight the importance of ALFQ in orchestrating early induction of antigen-specific Tfh and GC B cell responses and long-lived plasma cells in the bone marrow. The early engagement of S-2P specific naive B cells and high titer IgM antibodies shape the development of long-term neutralization breadth.
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The monoclonal antibodies (MAbs) NCI05 and NCI09, isolated from a vaccinated macaque that was protected from multiple simian immunodeficiency virus (SIV) challenges, both target an overlapping, conformationally dynamic epitope in SIV envelope variable region 2 (V2). Here, we show that NCI05 recognizes a CH59-like coil/helical epitope, whereas NCI09 recognizes a ß-hairpin linear epitope. In vitro, NCI05 and, to a lesser extent, NCI09 mediate the killing of SIV-infected cells in a CD4-dependent manner. Compared to NCI05, NCI09 mediates higher titers of antibody-dependent cellular cytotoxicity (ADCC) to gp120-coated cells, as well as higher levels of trogocytosis, a monocyte function that contributes to immune evasion. We also found that passive administration of NCI05 or NCI09 to macaques did not affect the risk of SIVmac251 acquisition compared to controls, demonstrating that these anti-V2 antibodies alone are not protective. However, NCI05 but not NCI09 mucosal levels strongly correlated with delayed SIVmac251 acquisition, and functional and structural data suggest that NCI05 targets a transient state of the viral spike apex that is partially opened, compared to its prefusion-closed conformation. IMPORTANCE Studies suggest that the protection against SIV/simian-human immunodeficiency virus (SHIV) acquisition afforded by the SIV/HIV V1 deletion-containing envelope immunogens, delivered by the DNA/ALVAC vaccine platform, requires multiple innate and adaptive host responses. Anti-inflammatory macrophages and tolerogenic dendritic cells (DC-10), together with CD14+ efferocytes, are consistently found to correlate with a vaccine-induced decrease in the risk of SIV/SHIV acquisition. Similarly, V2-specific antibody responses mediating ADCC, Th1 and Th2 cells expressing no or low levels of CCR5, and envelope-specific NKp44+ cells producing interleukin 17 (IL-17) also are reproducible correlates of decreased risk of virus acquisition. We focused on the function and the antiviral potential of two monoclonal antibodies (NCI05 and NCI09) isolated from vaccinated animals that differ in antiviral function in vitro and recognize V2 in a linear (NCI09) or coil/helical (NCI05) conformation. We demonstrate that NCI05, but not NCI09, delays SIVmac251 acquisition, highlighting the complexity of antibody responses to V2.
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Anticuerpos Monoclonales , Virus de la Inmunodeficiencia de los Simios , Proteínas Virales , Virus de la Inmunodeficiencia de los Simios/inmunología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Monoclonales/metabolismo , Proteínas Virales/química , Proteínas Virales/inmunología , Epítopos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Estructura Terciaria de Proteína , Modelos Moleculares , Células CHO , Cricetulus , Animales , Macaca/inmunología , Macaca/virología , Anticuerpos Antivirales/sangreRESUMEN
This retrospective study investigated growth outcomes of Kenyan children born to women living with HIV, comparing children who were orphaned maternally, paternally, and totally (both parents deceased) to those who were non-orphaned. We reviewed HIV clinic visits performed in Kenya from January 2011 to August 2016 in children 0 to 4 years of age. Malnutrition was assessed using stunting, underweight status, and wasting (z-scores of ≤-2). Descriptive statistics, Chi-square, t-tests, multivariable logistic regression, and ANCOVA models were performed. Of 15 027 total children in the study population, 3.5% (n = 520) were orphaned maternally, 8.1% (n = 1222) were orphaned paternally, and 2.2% (n = 336) were orphaned totally. Children who were orphans had higher rates of malnutrition compared to non-orphans (P < .001). Children who were orphaned maternally and totally had lower anthropometric mean scores, presented to clinic later, and were more likely to be living with HIV. Children who are orphaned maternally or totally should be targeted in interventional strategies.
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Fisher's linear discriminant analysis is a classical method for classification, yet it is limited to capturing linear features only. Kernel discriminant analysis as an extension is known to successfully alleviate the limitation through a nonlinear feature mapping. We study the geometry of nonlinear embeddings in discriminant analysis with polynomial kernels and Gaussian kernel by identifying the population-level discriminant function that depends on the data distribution and the kernel. In order to obtain the discriminant function, we solve a generalized eigenvalue problem with between-class and within-class covariance operators. The polynomial discriminants are shown to capture the class difference through the population moments explicitly. For approximation of the Gaussian discriminant, we use a particular representation of the Gaussian kernel by utilizing the exponential generating function for Hermite polynomials. We also show that the Gaussian discriminant can be approximated using randomized projections of the data. Our results illuminate how the data distribution and the kernel interact in determination of the nonlinear embedding for discrimination, and provide a guideline for choice of the kernel and its parameters.
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Developing a preventative vaccine for HIV-1 has been a global priority. The elicitation of broadly neutralizing antibodies (bNAbs) against a broad range of HIV-1 envelopes (Envs) from various strains appears to be a critical requirement for an efficacious HIV-1 vaccine. To understand their ability to neutralize HIV-1, it is important to characterize the binding characteristics of bNAbs. Our work is the first to utilize microscale thermophoresis (MST), a rapid, economical, and flexible in-solution temperature gradient method to quantitatively determine the binding affinities of bNAbs and non-neutralizing monoclonal antibodies (mAbs) to HIV-1 recombinant envelope monomer and trimer proteins of different subtypes, pseudoviruses (PVs), infectious molecular clones (IMCs), and cells expressing the trimer. Our results demonstrate that the binding affinities were subtype-dependent. The bNAbs exhibited a higher affinity to IMCs compared to PVs and recombinant proteins. The bNAbs and mAbs bound with high affinity to native-like gp160 trimers expressed on the surface of CEM cells compared to soluble recombinant proteins. Interesting differences were seen with V2-specific mAbs. Although they recognize linear epitopes, one of the antibodies also bound to the Envs on PVs, IMCs, and a recombinant trimer protein, suggesting that the epitope was not occluded. The identification of epitopes on the envelope surface that can bind to high affinity mAbs could be useful for designing HIV-1 vaccines and for down-selecting vaccine candidates that can induce high affinity antibodies to the HIV-1 envelope in their native conformation.
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Vacunas contra el SIDA , Enfermedades Transmisibles , Seropositividad para VIH , VIH-1 , Humanos , Anticuerpos ampliamente neutralizantes , Anticuerpos Monoclonales , Células Clonales , Epítopos , Proteínas Recombinantes , Glicoproteínas , Proteínas gp160 de Envoltorio del VIHRESUMEN
Juvenile hormones prevent molting and metamorphosis in the juvenile stages of insects. There are multiple genes encoding a conserved juvenile hormone binding protein (JHBP) domain in a single insect species. Although some JHBPs have been reported to serve as carriers to release hormones to target tissues, the molecular functions of the other members of the diverse JHBP family of proteins remain unclear. We characterized 16 JHBP genes with conserved JHBP domains in Drosophila melanogaster. Among them, seven JHBP genes were induced by feeding the flies with methyl lucidone, a plant diterpene secondary metabolite (PDSM). Induction was also observed upon feeding the juvenile hormone (JH) analog methoprene. Considering that methyl lucidone and methoprene perform opposite functions in JH-mediated regulation, specifically the heterodimeric binding between a JH receptor (JHR) and steroid receptor coactivator (SRC), the induction of these seven JHBP genes is independent of JH-mediated regulation by the JHR/SRC heterodimer. Tissue-specific gene expression profiling through the FlyAtlas 2 database indicated that some JHBP genes are mainly enriched in insect guts and rectal pads, indicating their possible role during food uptake. Hence, we propose that JHBPs are induced by PDSMs and respond to toxic plant molecules ingested during feeding.
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Monocyte-derived macrophages (MDM) are highly permissive to HIV-1 infection potentially due to the downregulation of innate factors during the differentiation process. The environmental milieu and innate anti-viral factors which are modulated during macrophage differentiation, have been associated with their increased permissiveness to HIV-1 infection. Here, we demonstrate that the Army Liposome Formulation containing MPLA, and QS-21 (ALFQ) activated MDM that are normally permissive to HIV-1 infection to generate a proinflammatory environment and upregulated anti-viral factors notably APOBEC3A. Induction of APOBEC3A by ALFQ decreased permissiveness to HIV-1 infection, while knockdown of APOBEC3A with APOBEC3AsiRNA resulted in a significant loss in the restriction of HIV-1 infectivity. The liposome formulation ALF55, with identical lipid composition but lacking QS-21 had no effect. Furthermore, the capacity of ALFQ to modulate MDM permissiveness to HIV-1 infection was predominantly mediated by large ALFQ liposomes. Our findings highlight a relationship between innate immune activation, proinflammatory milieu, and upregulation of anti-HIV proteins. Induction of these responses can switch the HIV-1 permissive MDM into a more refractory phenotype.
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Infecciones por VIH , VIH-1 , Citidina Desaminasa , Infecciones por VIH/metabolismo , VIH-1/genética , Humanos , Liposomas/metabolismo , Macrófagos/metabolismo , Proteínas , Saponinas , Replicación ViralRESUMEN
Background: COVID-19 patients experience various stressors during the quarantine period and after release from quarantine. However, stressors experienced during each period remain unclear. Methods: A total of 15 mental health experts from the integrated psychological support group for COVID-19participated in this study. Psychological support was provided for the total 932 confirmed COVID-19 patients and their families. Qualitative data were collected using Focus Group Interview (FGI). The participants were divided into two groups and semi-structured questions were used to allow participants to speak their minds. Results: During the quarantine period, difficulties of being diagnosed with COVID-19, concerns about recovery from COVID-19, stress related to quarantine, issues related to the treatment environment, and limited information about COVID-19 and communication were frequently reported. After release from quarantine, the reported main stressors include reinfection or reactivation, concerns about complications, and financial difficulties. Confusion as vectors and victims, stigma and discrimination, and conflicts within a family were observed during both periods. Conclusions: COVID-19 patients suffered various stressors during the quarantine period and after release from quarantine. Moreover, returning to their daily life required timely psychosocial support, intervention, and treatment for COVID-19 infection.
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Adverse pregnancy outcomes (APOs) are associated with an increased risk of chronic diseases, including cardiovascular disease (CVD) and metabolic syndrome (MS), in the future. We designed a large-scale cohort study to evaluate the influence of APOs (preeclampsia, gestational diabetes mellitus (GDM), stillbirth, macrosomia, and low birth weight) on the incidence of chronic diseases, body measurements, and serum biochemistry in the future and investigate whether combinations of APOs had additive effects on chronic diseases. We used health examinee data from the Korean Genome and Epidemiology Study (KoGES-HEXA) and extracted data of parous women (n = 30,174; mean age, 53.02 years) for the analysis. Women with APOs were more frequently diagnosed with chronic diseases and had a family history of chronic diseases compared with women without APOs. Composite APOs were associated with an increased risk of hypertension, diabetes mellitus, hyperlipidemia, angina pectoris, stroke, and MS (adjusted odds ratio: 1.093, 1.379, 1.269, 1.351, 1.414, and 1.104, respectively) after adjustment for family history and social behaviors. Preeclampsia and GDM were associated with an increased risk of some chronic diseases; however, the combination of preeclampsia and GDM did not have an additive effect on the risk. APOs moderately influenced the future development of maternal CVD and metabolic derangements, independent of family history and social behaviors.
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Nucleic acid testing (NAT) is important for the identification and quantification of specific nucleic acid targets, both DNA and RNA, in life sciences and clinical diagnostics. Nucleic acid amplification can be a time-consuming step in NAT using the polymerase chain reaction (PCR) assay. Therefore, this study aimed to develop a simple method to reduce the amplification time while maintaining the PCR system. The three-step process of a general qPCR was reduced to a two-step process. The annealing/extension temperatures were increased to minimize the differences between the denaturation temperature and the annealing/extension temperatures. Subsequently, the time for each of these steps was reduced and, finally, the denaturation temperature was lowered. Taq polymerase was replaced with SD polymerase because it has strand displacement activity and is efficient in amplifying partial dsDNA at lower denaturation temperatures. In the two-step qPCR of genomic DNA using SD polymerase, the final conditions included an initial denaturation at 92 °C for 2 min, and 1 s at each cycling step with a denaturation temperature of 87 °C and an annealing/extension temperature of 72 °C. Amplification of the nucleocapsid (N) gene of SARS-CoV-2 RNA virus was evaluated at a template concentration as low as 10 copies. This method, named SF-qPCR (strand displacement-based fast quantitative polymerase chain reaction), can stably detect less than 10 copies of DNA and RNA within 25-40 min. This new protocol allows for sensitive and rapid detection of important DNA and RNA targets in clinical diagnosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13206-021-00044-x.
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The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.
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INTRODUCTION: The development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the execution of vaccine efficacy testing in the context of evolving biomedical prevention interventions. This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps. METHODS: We conducted a targeted peer-reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors' own experience and engagement with collaborators in HIV vaccine research. DISCUSSION: The HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime-boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates. CONCLUSIONS: HIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. These strategies have yielded novel mosaic antigen constructs now in efficacy testing, produced a diverse pipeline of early-stage immunogens and novel adjuvants, and advanced the field towards a globally effective HIV vaccine.
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Vacunas contra el SIDA , Infecciones por VIH , Adyuvantes Inmunológicos , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH/prevención & control , Humanos , TailandiaRESUMEN
The need for SARS-CoV-2 next-generation vaccines has been highlighted by the rise of variants of concern (VoC) and the long-term threat of other coronaviruses. Here, we designed and characterized four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of prefusion Spike (S), S1 and RBD. These immunogens induced robust S-binding, ACE2-inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2 in mice. A Spike-ferritin nanoparticle (SpFN) vaccine elicited neutralizing titers more than 20-fold higher than convalescent donor serum, following a single immunization, while RBD-Ferritin nanoparticle (RFN) immunogens elicited similar responses after two immunizations. Passive transfer of IgG purified from SpFN- or RFN-immunized mice protected K18-hACE2 transgenic mice from a lethal SARS-CoV-2 virus challenge. Furthermore, SpFN- and RFN-immunization elicited ACE2 blocking activity and neutralizing ID50 antibody titers >2,000 against SARS-CoV-1, along with high magnitude neutralizing titers against major VoC. These results provide design strategies for pan-coronavirus vaccine development. HIGHLIGHTS: Iterative structure-based design of four Spike-domain Ferritin nanoparticle classes of immunogensSpFN-ALFQ and RFN-ALFQ immunization elicits potent neutralizing activity against SARS-CoV-2, variants of concern, and SARS-CoV-1Passively transferred IgG from immunized C57BL/6 mice protects K18-hACE2 mice from lethal SARS-CoV-2 challenge.
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To prevent the spread of HIV-1, a vaccine should elicit antibodies that block viral entry for all cell types. Recently, we have developed a virus capture assay to quantitatively examine early time points of infection. Here we present data on the ability of bNAbs to inhibit capture (1 h) or replication (48 h) of purified primary acute or chronic HIV or infectious molecular clones (IMCs) in human peripheral blood mononuclear cells (PBMCs) as quantified by qRT-PCR. Although bNAbs significantly inhibited HIV-1 replication in PBMCs in a virus subtype and in a PBMC-donor specific manner, they did not inhibit virus capture of primary viruses. In contrast, IMC capture and replication in PBMCs and purified CD4+ T cells were significantly inhibited by bNAbs, thus indicating that unlike IMCs, primary HIV-1 may initially bind to other cell surface molecules, which leads to virus capture even in the presence of bNAbs. Our results demonstrate that the initial interactions and some aspects of infectivity of primary HIV-1 and IMCs are inherently different, which underscores the importance of studying virus transmission using primary viruses in in vitro studies, an issue that could impact HIV-1 vaccine design strategies.
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Zika virus (ZIKV) remains as a public health threat due to the congenital birth defects the virus causes following infection of pregnant women. Congenital microcephaly is among the neurodevelopmental disorders the virus can cause in newborns, and this defect has been associated with ZIKV-mediated cytopathic effects in human neural progenitor cells (hNPCs). In this study, we investigated the cellular changes that occur in hNPCs in response to ZIKV (African and Asian lineages)-induced cytopathic effects. Transmission electron microscopy showed the progress of cell death as well as the formation of numerous vacuoles in the cytoplasm of ZIKV-infected hNPCs. Infection with both African and Asian lineages of ZIKV induced apoptosis, as demonstrated by the increased activation of caspase 3/7, 8, and 9. Increased levels of proinflammatory cytokines and chemokines (IL-6, IL-8, IL-1ß) were also detected in ZIKV-infected hNPCs, while z-VAD-fmk-induced inhibition of cell death suppressed ZIKV-mediated cytokine production in a dose-dependent manner. ZIKV-infected hNPCs also displayed significantly elevated gene expression levels of the pro-apoptotic Bcl2-mediated family, in particular, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, TRAIL signaling led to augmented ZIKV-mediated cell death and the knockdown of TRAIL-mediated signaling adaptor, FADD, resulted in enhanced ZIKV replication. In conclusion, our findings provide cellular insights into the cytopathic effects induced by ZIKV infection of hNPCs.
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Apoptosis/fisiología , Células-Madre Neurales/virología , Factores de Necrosis Tumoral/metabolismo , Infección por el Virus Zika/virología , Virus Zika/patogenicidad , Apoptosis/genética , Humanos , Recién Nacido , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Replicación Viral/fisiología , Virus Zika/genética , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/patologíaRESUMEN
BACKGROUND: Mobile health (mHealth) tools may be useful platforms for dietary monitoring and assessment. OBJECTIVE: This study aims to evaluate the effectiveness of a mobile dietary self-monitoring app for weight loss versus a paper-based diary among adults with a BMI of 23 kg/m2 or above. METHODS: A total of 33 men and 17 women aged 18-39 years participated in a 6-week randomized controlled trial. We randomly assigned participants to one of two groups: (1) a smartphone app group (n=25) or (2) a paper-based diary group (n=25). The smartphone app group recorded foods and dietary supplements that they consumed and received immediate dietary feedback using Well-D, a dietary self-monitoring app developed by our team. The paper-based diary group was instructed to record foods or supplements that they consumed using a self-recorded diary. The primary outcomes were weight, BMI, waist circumference, body fat mass, and skeletal muscle mass. We also examined changes in nutrient intake, including energy, carbohydrate, protein, fat, dietary fiber, vitamins, and minerals, using 3-day 24-hour recalls. Differences in changes between the two groups were analyzed using independent t tests or Wilcoxon Mann-Whitney tests. All of the data were analyzed using intent-to-treat analysis. RESULTS: The mean number of days recorded was 18.5 (SD 14.1) for the app group and 15.5 (SD 10.1) for the paper-based diary group. The differences in changes in weight, BMI, and waist circumference were not significantly different between the app group and paper-based diary group (P=.33, .34, and .70, respectively). Similarly, changes in body fat mass or skeletal muscle mass did not differ between the two groups (P=.71 and .054, respectively). Although energy intake was reduced in both groups, there was no significant difference in changes in energy intake between the two groups (P=.98). CONCLUSIONS: There were no differences in changes in anthropometric measures and nutrient intake between the app group and the paper-based diary group. Both mobile dietary self-monitoring app and paper-based diary may be useful for improving anthropometric measures. TRIAL REGISTRATION: Clinical Research Information Service KCT0003170; https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=11642<ype=&rtype=.