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1.
Cell ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38761800

RESUMO

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.

2.
medRxiv ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38562833

RESUMO

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys. Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations. Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

3.
Rev Sci Instrum ; 95(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38651988

RESUMO

The temporal evolution of the electron cloud at room temperature has been recorded through a resonance circuit by observing the axial oscillation frequency of its center of mass. The electron cloud undergoes radial expansion by interacting with the residual gas molecules, and it is finally lost upon hitting the Penning trap electrodes. It has been confirmed through detailed experimental investigations that the unique temporal pattern of frequency variation is a consequence of the cloud's radial expansion. Consequently, this approach offers a non-destructive means for single-shot detection, enabling continuous monitoring of the electron cloud's radial expansion during the confinement time. This technique offers a significant advantage over its destructive alternatives.

4.
Cell Host Microbe ; 32(5): 693-709.e7, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38670093

RESUMO

A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here, we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knockin mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof of concept and milestone toward development of an HIV-1 vaccine.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Linfócitos B , Anticorpos Anti-HIV , HIV-1 , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/genética , Animais , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , HIV-1/genética , Camundongos , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Humanos , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Anticorpos Amplamente Neutralizantes/imunologia , Mutação , Desenvolvimento de Vacinas , Imunização Secundária , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
5.
Access Microbiol ; 6(2): 000401, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482347

RESUMO

Resistance against antimicrobial agents is dramatically increasing and gradually impacting treatment costs. Using existing drugs would have helped avoid bacterial infections in various circumstances. The primary objectives of this study were to determine the prevalence of pathogens responsible for postsurgical wound infections and their antimicrobial susceptibility and resistance pattern among the patients admitted to Khulna Medical College Hospital, Khulna Bangladesh. This cross-sectional study involved 250 patients suffering from postsurgical wound infection as respondents. The bacterial pathogens were isolated from pus samples obtained from those patients. The isolated bacterial pathogens were identified through several standard biochemical tests, and finally, the culture sensitivity tests of those bacterial isolates were performed. The study was conducted from August 2019 to June 2020. Data regarding the patient's age, gender, occupation, surgery performed, duration of hospital stay, and comorbidity were also documented using standard questionnaires. Five bacterial pathogens were identified with different frequencies, including Pseudomonas aeruginosa (36 %), Escherichia coli (21.2 %), Staphylococcus aureus (8.8 %), Klebsiella spp. (7.2 %) and Proteus spp. (4.8 %). These bacterial pathogens showed sensitivity to ciprofloxacin (75 %), piperacillin-tazobactam (56.7 %) and gentamicin (50 %). Besides, S. aureus showed sensitivity to linezolid and vancomycin and resistance to cefuroxime, ceftazidime and imipenem. Male patients (68.4 %) suffered more from postsurgical wound infection than female patients (31.6 %). Patients aged 31 to 40 years were more severely affected than patients from other age groups. Postsurgical wound infection was vigorously observed in the patients who underwent hand surgery. Intensive occurrence of this infection was found in the patients who stayed in the hospital from 31 to 40 days. Diabetic patients suffered more from postsurgical wound infection compared to the other patients. Throughout the study, ciprofloxacin has been the best performer against E. coli, Klebsiella spp., and Proteus spp., and gentamicin showed better performance against S. aureus. The antibiotic resistance pattern of these bacterial pathogens reflects the worldwide necessity of rational antibiotic management and proper steps to maintain hospital hygiene in Bangladesh.

6.
BMJ Glob Health ; 9(3)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548342

RESUMO

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.


Assuntos
Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Etionamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Genômica , Testes de Sensibilidade Microbiana , Aprendizado de Máquina
7.
Sci Adv ; 10(5): eadj0396, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306419

RESUMO

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 µs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.


Assuntos
HIV-1 , Produtos do Gene env do Vírus da Imunodeficiência Humana , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Anticorpos Anti-HIV , Conformação Molecular , Multimerização Proteica , Conformação Proteica
8.
Int J Biol Macromol ; 264(Pt 1): 130388, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38417756

RESUMO

Among the major Surface Exposed Colonization Proteins (SECPs) of Campylobacter jejuni (C. jejuni), Jejuni lipoprotein A (JlpA) plays a crucial role in host cell adhesion specifically by binding to the N-terminal domain of the human heat shock protein 90α (Hsp90α-NTD). Although the JlpA binding to Hsp90α activates NF-κB and p38 MAP kinase pathways, the underlying mechanism of JlpA association with the cellular receptor remains unclear. To this end, we predicted two potential receptor binding sites within the C-terminal domain of JlpA: one spanning from amino acid residues Q332-A354 and the other from S258-T295; however, the latter exhibited weaker binding. To assess the functional attributes of these predicted sequences, we generated two JlpA mutants (JlpAΔ1: S258-T295; JlpAΔ2: Q332-A354) and assessed the Hsp90α-binding affinity-kinetics by in vitro and ex vivo experiments. Our findings confirmed that the residues Q332-A354 are of greater importance in host cell adhesion with a measurable impact on cellular responses. Further, thermal denaturation by circular dichroism (CD) confirmed that the reduced binding affinity of the JlpAΔ2 to Hsp90α is not associated with protein folding or stability. Together, this study provides a possible framework for determining the molecular function of designing rational inhibitors efficiently targeting JlpA.


Assuntos
Campylobacter jejuni , Lipoproteína(a) , Humanos , Lipoproteína(a)/metabolismo , Campylobacter jejuni/genética , Campylobacter jejuni/metabolismo , Ligantes , Proteínas de Choque Térmico/metabolismo , NF-kappa B/metabolismo
9.
Cell ; 187(1): 79-94.e24, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38181743

RESUMO

The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.


Assuntos
Vacinas contra a AIDS , HIV-1 , Animais , Humanos , Anticorpos Amplamente Neutralizantes , Antígenos CD4 , Moléculas de Adesão Celular , HIV-1/fisiologia , Macaca , Vacinas contra a AIDS/imunologia
10.
Heliyon ; 10(2): e24094, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38293493

RESUMO

Breast cancer, a significant threat to women's health, demands early detection. Automating histopathological image analysis offers a promising solution to enhance efficiency and accuracy in diagnosis. This study addresses the challenge of breast cancer histopathological image classification by leveraging the ResNet architecture, known for its depth and skip connections. In this work, two distinct approaches were pursued, each driven by unique motivations. The first approach aimed to improve the learning process through self-supervised contrastive learning. It utilizes a small subset of the training data for initial model training and progressively expands the training set by incorporating confidently labeled data from the unlabeled pool, ultimately achieving a reliable model with limited training data. The second approach focused on optimizing the architecture by combining ResNet50 and Inception module to get a lightweight and efficient classifier. The dataset utilized in this work comprises histopathological images categorized into benign and malignant classes at varying magnification levels (40X, 100X, 200X, 400X), all originating from the same source image. The results demonstrate state-of-the-art performance, achieving 98% accuracy for images magnified at 40X and 200X, and 94% for 100X and 400X. Notably, the proposed architecture boasts a substantially reduced parameter count of approximately 3.6 million, contrasting with existing leading architectures, which possess parameter sizes at least twice as large.

11.
Mymensingh Med J ; 33(1): 45-48, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38163772

RESUMO

Chronic obstructive pulmonary disease (COPD) remains a major public health problem with relatively high prevalence rates worldwide (5-13%). COPD is a major cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. The purpose of the study was to explore the alteration of serum calcium in patients with COPD. This cross-sectional study was carried out in the Department of Biochemistry, Mymensingh Medical College, Bangladesh from January 2021 to December 2021. Data was collected from Medicine Department of Mymensingh Medical College Hospital, Mymensingh. A total number of 120 subjects participated in this study. Out of them, 60 apparently normal healthy individuals were selected as Group I and another 60 diagnosed COPD patients were selected as Group II. Serum calcium was measured by colorimetric method using the test kit. The results were calculated and analyzed by using statistical package for social science (SPSS), windows package version 21.0. Data were expressed in mean ±SD and statistical significance was done by Student's unpaired 't' test. In this study, the mean ±SD values of serum calcium were 9.21±1.06mg/dl and 8.26±0.95mg/dl in Group I and Group II respectively. The results were highly significant (p<0.001). The result suggested that there was significant relation between COPD and alteration of serum calcium. So, by this study we recommended that routine evaluation of serum calcium is important for prevention of exacerbations, reduction of morbidity and mortality in patients with COPD.


Assuntos
Cálcio , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos Transversais , Estudos de Casos e Controles , Bangladesh/epidemiologia
12.
Int J Biol Macromol ; 257(Pt 1): 128357, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38035970

RESUMO

This study attempted to develop a low-cost and eco-friendly bio-based composite adsorbent that is highly efficient in capturing potential toxic metals. The bio-composite adsorbent was prepared using graphene oxide (GO), carboxymethyl cellulose (CMC) and chitosan (CS); and characterized using FTIR, SEM-EDX and WAXD techniques. Metal-ion concentration in an aqueous solution was measured by ICP-OES. This article reveals that the adsorption of heavy metal ions varied according to the adsorbent quantity, initial metal concentration, pH, and interaction time. The metal ions' adsorption capacity (mg/g) was observed to increase when the interaction time and metal concentration increased. Conversely, metal ions adsorption was decreased with an increase in adsorbent dosages. The effect of pH on metal ions' adsorption was ion-specific. The substantial adsorption by GO/CMC/CS composite for Co2+, CrO42-, Mn2+ and Cd2+, had the respective values of 43.55, 77.70, 57.78, and 91.38 mg/g under acidic conditions. The metal ions experimental data were best fitted with pseudo-second-order (PSO) kinetics, and Freundlich isotherm model (except Co2+). The separation factors (RL) value in the present investigation were found between 0 and 1, meaning that the metal ions adsorption onto GO/CS/CMC composite is favorable. The RL and sorption intensity (1/n) values fitted well to the adsorption isotherm.


Assuntos
Quitosana , Grafite , Poluentes Químicos da Água , Carboximetilcelulose Sódica/química , Adsorção , Quitosana/química , Água/química , Cinética , Poluentes Químicos da Água/análise , Concentração de Íons de Hidrogênio , Íons
13.
J Virol ; 97(12): e0107023, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38019013

RESUMO

IMPORTANCE: Multiple SARS-CoV-2 variants of concern have emerged and caused a significant number of infections and deaths worldwide. These variants of concern contain mutations that might significantly affect antigen-targeting by antibodies. It is therefore important to further understand how antibody binding and neutralization are affected by the mutations in SARS-CoV-2 variants. We highlighted how antibody epitope specificity can influence antibody binding to SARS-CoV-2 spike protein variants and neutralization of SARS-CoV-2 variants. We showed that weakened spike binding and neutralization of Beta (B.1.351) and Omicron (BA.1) variants compared to wildtype are not universal among the panel of antibodies and identified antibodies of a specific binding footprint exhibiting consistent enhancement of spike binding and retained neutralization to Beta variant. These data and analysis can inform how antigen-targeting by antibodies might evolve during a pandemic and prepare for potential future sarbecovirus outbreaks.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , COVID-19 , SARS-CoV-2/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
14.
Gates Open Res ; 7: 107, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38009106

RESUMO

Label-free techniques including Surface Plasmon Resonance (SPR) and Biolayer Interferometry (BLI) are biophysical tools widely used to collect binding kinetics data of bimolecular interactions. To efficiently analyze SPR and BLI binding kinetics data, we have built a new high throughput analysis tool named the TitrationAnalysis. It can be used as a package in the Mathematica scripting environment and ultilize the non-linear curve-fitting module of Mathematica for its core function. This tool can fit the binding time course data and estimate association and dissociation rate constants ( k a and k d respectively) for determining apparent dissociation constant ( K D) values. The high throughput fitting process is automatic, requires minimal knowledge on Mathematica scripting and can be applied to data from multiple label-free platforms. We demonstrate that the TitrationAnalysis is optimal to analyze antibody-antigen binding data acquired on Biacore T200 (SPR), Carterra LSA (SPR imaging) and ForteBio Octet Red384 (BLI) platforms. The k a, k d and K D values derived using TitrationAnalysis very closely matched the results from the commercial analysis software provided specifically for these instruments. Additionally, the TitrationAnalysis tool generates user-directed customizable results output that can be readily used in downstream Data Quality Control associated with Good Clinical Laboratory Practice operations. With the versatility in source of data input source and options of analysis result output, the TitrationAnalysis high throughput analysis tool offers investigators a powerful alternative in biomolecular interaction characterization.

15.
bioRxiv ; 2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-37986885

RESUMO

A vaccine that can achieve protective immunity prior to sexual debut is critical to prevent the estimated 410,000 new HIV infections that occur yearly in adolescents. As children living with HIV can make broadly neutralizing antibody (bnAb) responses in plasma at a faster rate than adults, early childhood is an opportune window for implementation of a multi-dose HIV immunization strategy to elicit protective immunity prior to adolescence. Therefore, the goal of our study was to assess the ability of a B cell lineage-designed HIV envelope SOSIP to induce bnAbs in early life. Infant rhesus macaques (RMs) received either BG505 SOSIP or the germline-targeting BG505 GT1.1 SOSIP (n=5/group) with the 3M-052-SE adjuvant at 0, 6, and 12 weeks of age. All infant RMs were then boosted with the BG505 SOSIP at weeks 26, 52 and 78, mimicking a pediatric immunization schedule of multiple vaccine boosts within the first two years of life. Both immunization strategies induced durable, high magnitude binding antibodies and plasma autologous virus neutralization that primarily targeted the CD4-binding site (CD4bs) or C3/465 epitope. Notably, three BG505 GT1.1-immunized infants exhibited a plasma HIV neutralization signature reflective of VRC01-like CD4bs bnAb precursor development and heterologous virus neutralization. Finally, infant RMs developed precursor bnAb responses at a similar frequency to that of adult RMs receiving a similar immunization strategy. Thus, a multi-dose immunization regimen with bnAb lineage designed SOSIPs is a promising strategy for inducing protective HIV bnAb responses in childhood prior to adolescence when sexual HIV exposure risk begins.

16.
J Neurochem ; 167(4): 505-519, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37818836

RESUMO

NADPH oxidase (Nox), a major source of reactive oxygen species (ROS), is involved in neurodegeneration after injury and disease. Nox is expressed in both neuronal and non-neuronal cells and contributes to an elevated ROS level after injury. Contrary to the well-known damaging effect of Nox-derived ROS in neurodegeneration, recently a physiological role of Nox in nervous system development including neurogenesis, neuronal polarity, and axonal growth has been revealed. Here, we tested a role for neuronal Nox in neurite regeneration following mechanical transection in cultured Aplysia bag cell neurons. Using a novel hydrogen peroxide (H2 O2 )-sensing dye, 5'-(p-borophenyl)-2'-pyridylthiazole pinacol ester (BPPT), we found that H2 O2 levels are elevated in regenerating growth cones following injury. Redistribution of Nox2 and p40phox in the growth cone central domain suggests Nox2 activation after injury. Inhibiting Nox with the pan-Nox inhibitor celastrol reduced neurite regeneration rate. Pharmacological inhibition of Nox is correlated with reduced activation of Src2 tyrosine kinase and F-actin content in the growth cone. Taken together, these findings suggest that Nox-derived ROS regulate neurite regeneration following injury through Src2-mediated regulation of actin organization in Aplysia growth cones.


Assuntos
Aplysia , Neuritos , Animais , Espécies Reativas de Oxigênio , NADPH Oxidases/farmacologia , Neurônios , Neurogênese , Actinas , NADPH Oxidase 4
17.
Curr Opin HIV AIDS ; 18(6): 300-308, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37751363

RESUMO

PURPOSE OF REVIEW: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development. RECENT FINDINGS: New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans. SUMMARY: Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.

18.
bioRxiv ; 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37546738

RESUMO

Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing yet it protected mice and cynomolgus macaques from severe disease. The mechanisms of this non-neutralizing antibody-mediated protection are unknown. Here we show that Fc effector functions mediate non-neutralizing antibody (non-nAb) protection against SARS-CoV-2 MA10 viral challenge in mice. Though non-nAb infusion did not suppress infectious viral titers in the lung as potently as NTD neutralizing antibody (nAb) infusion, disease markers including gross lung discoloration were similar in nAb and non-nAb groups. Fc functional knockout substitutions abolished non-nAb protection and increased viral titers in the nAb group. Finally, Fc enhancement increased non-nAb protection relative to WT, supporting a positive association between Fc functionality and degree of protection in SARS-CoV-2 infection. This study demonstrates that non-nAbs can utilize Fc-mediated mechanisms to lower viral load and prevent lung damage due to coronavirus infection.

19.
J Med Imaging (Bellingham) ; 10(Suppl 2): S22410, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37360323

RESUMO

Purpose: We evaluate texture quantified from ultrasound Nakagami parametric images for non-invasive characterization of breast tumors, as Nakagami images can more faithfully represent intrinsic tumor characteristics than standard B-mode images. Approach: Parametric images were formed using sliding windows applied to ultrasound envelope data. To analyze the trade-off between spatial resolution and stability of estimated Nakagami parameters for texture quantification, two different window sizes were used for image formation: (i) the standard square window with sides equal to three times the pulse length of incident ultrasound, and (ii) a smaller square window with sides equal to exactly the pulse length. Texture was quantified from two different regions of interest (ROIs) consisting of the tumor core and a 5 mm surrounding margin. A total of 186 texture features were analyzed for each ROI, and feature selection was used to identify the most relevant feature sets for breast tumor characterization. Results: Texture quantified from parametric images formed using the two different windows did not outperform each other by a significant margin. However, when the mean pixel value within the tumor region of the parametric images was incorporated with the texture features, texture quantified from the tumor core and surrounding margin of images formed using the standard square window thoroughly outperformed other considerations for breast lesion characterization. The highest performing set of texture and mean value features yielded a significant AUC of 0.94, along with sensitivity of 90.38% and specificity of 89.58%. Conclusions: We establish that texture quantified from ultrasound Nakagami parametric images are diagnostically relevant and may be used to characterize breast lesions effectively.

20.
Nat Commun ; 14(1): 2782, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37188681

RESUMO

Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza has therefore focused on recapitulating the natural affinity maturation process. Here, we determine structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of the broadly neutralizing HIV-1 V3-glycan targeting DH270 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/prevenção & controle , HIV-1/genética , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Polissacarídeos
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