Engineering of pH-dependent antigen binding properties for toxin-targeting IgG1 antibodies using light-chain shuffling.

Immunoglobulin G (IgG) antibodies that bind their cognate antigen in a pH-dependent manner (acid-switched antibodies) can release their bound antigen for degradation in the acidic environment of endosomes, while the IgGs are rescued by the neonatal Fc receptor (FcRn). Thus, such IgGs can neutralize multiple antigens over time and therefore be used at lower doses than their non-pH-responsive counterparts. Here, we show that light-chain shuffling combined with phage display technology can be used to discover IgG1 antibodies with increased pH-dependent antigen binding properties, using the snake venom toxins, myotoxin II and α-cobratoxin, as examples. We reveal differences in how the selected IgG1s engage their antigens and human FcRn and show how these differences translate into distinct cellular handling properties related to their pH-dependent antigen binding phenotypes and Fc-engineering for improved FcRn binding. Our study showcases the complexity of engineering pH-dependent antigen binding IgG1s and demonstrates the effects on cellular antibody-antigen recycling.

Multiple enzymatic activities of a Sir2-HerA system cooperate for anti-phage defense.

In response to the persistent exposure to phage infection, bacteria have evolved diverse antiviral defense mechanisms. In this study, we report a bacterial two-component defense system consisting of a Sir2 NADase and a HerA helicase. Cryo-electron microscopy reveals that Sir2 and HerA assemble into a ∼1 MDa supramolecular octadecamer. Unexpectedly, this complex exhibits various enzymatic activities, including ATPase, NADase, helicase, and nuclease, which work together in a sophisticated manner to fulfill the antiphage function. Therefore, we name this defense system "Nezha" after a divine warrior in Chinese mythology who employs multiple weapons to defeat enemies. Our findings demonstrate that Nezha could sense phage infections, self-activate to arrest cell growth, eliminate phage genomes, and subsequently deactivate to allow for cell recovery. Collectively, Nezha represents a paradigm of sophisticated and multifaceted strategies bacteria use to defend against viral infections.

Assembly-mediated activation of the SIR2-HerA supramolecular complex for anti-phage defense.

SIR2-HerA, a bacterial two-protein anti-phage defense system, induces bacterial death by depleting NAD+ upon phage infection. Biochemical reconstitution of SIR2, HerA, and the SIR2-HerA complex reveals a dynamic assembly process. Unlike other ATPases, HerA can form various oligomers, ranging from dimers to nonamers. When assembled with SIR2, HerA forms a hexamer and converts SIR2 from a nuclease to an NAD+ hydrolase, representing an unexpected regulatory mechanism mediated by protein assembly. Furthermore, high concentrations of ATP can inhibit NAD+ hydrolysis by the SIR2-HerA complex. Cryo-EM structures of the SIR2-HerA complex reveal a giant supramolecular assembly up to 1 MDa, with SIR2 as a dodecamer and HerA as a hexamer, crucial for anti-phage defense. Unexpectedly, the HerA hexamer resembles a spiral staircase and exhibits helicase activities toward dual-forked DNA. Together, we reveal the supramolecular assembly of SIR2-HerA as a unique mechanism for switching enzymatic activities and bolstering anti-phage defense strategies.

The influence of standardized dry ivy leaf extract on the proportion of nasal secretion after post-septoplasty nasal packing removal / A influência do extrato de folha de hera seca na secreção nasal após remoção de tampão nasal pós-septoplastia

Abstract Introduction: After post-septoplasty nasal packing removal, a certain proportion of nasal secretion occurs, leading to local and sometimes systemic infections. Objective: The aim was to determine if standardized dry ivy leaf extract application after nasal packing removal influences the reduction of nasal secretion and diminish the occurrence of local infections. Methods: The study included 70 post-septoplasty patients (divided into two equal groups) whose nasal packing was removed on the third day after the procedure. Group I was treated with standardized dry ivy leaf extract syrup along with regular nasal irrigation for the five days after the nasal packing removal whereas the Group II had only nasal lavage. On the sixth day after nasal packing removal, the quantity of nasal secretion was determined using a visual analog scale and nasal endoscopic examination. Results: The group treated with standardized dry ivy leaf extract syrup had significantly lesser nasal secretion both by subjective patients' assessment (p < 0.001) and by nasal endoscopic examination (p = 0.003). The post-surgical follow up examination on the sixth day after nasal packing removal showed no development of local infection in the Group I, while in the Group II a local infection was evident in five patients (14.29%) and antibiotic therapy was required. Conclusion: The use of the standardized dry ivy leaf extract after nasal packing removal significantly lowers the proportion of nasal secretion.

Resumo Introdução: Após a remoção do tampão nasal pós-septoplastia, ocorre produção de secreção nasal, predispondo infecções locais e, por vezes, sistêmicas. Objetivo: O objetivo foi determinar se a aplicação do extrato padronizado de folhas de hera seca após a remoção do tampão nasal influencia a redução da secreção nasal e diminui a ocorrência de infecções locais. Método: O estudo incluiu 70 pacientes pós-septoplastia (divididos em dois grupos iguais) cujo tampão nasal foi retirado no terceiro dia após o procedimento. O grupo I foi tratado com xarope padronizado de extrato de folha seca de hera juntamente com irrigação nasal regular por cinco dias após a remoção do tamponamento nasal, enquanto ao grupo II foi recomendado apenas lavagem nasal. No sexto dia após a remoção do tampão nasal, a quantidade de secreção nasal foi determinada pela escala EVA (escala visual analógica) e pelo exame endoscópico nasal. Resultados: O grupo tratado com xarope de extrato seco de folhas de hera apresentou secreção nasal significativamente menor tanto pela avaliação subjetiva dos pacientes (p < 0,001) quanto pelo exame endoscópico nasal (p = 0,003). O exame de acompanhamento pós-cirúrgico no sexto dia após a remoção do tampão nasal não mostrou desenvolvimento de infecção local nos pacientes do grupo I, enquanto que no grupo II, cinco apresentaram sinais de infecção local (14,29%) com necessidade de antibioticoterapia. Conclusão: O uso do extrato padronizado de folhas secas de hera após a remoção do tampão nasal reduz significativamente a produção de secreção nasal.

Produção e comercialização de fitoterápicos à base de Hedera helix: avaliação comparativa dos produtos disponíveis no Brasil / Production and marketing of Hedera helix-based phytotherapeutic products: comparative assessment of the products available in Brazil

O mercado brasileiro de fitoterápicos apresenta diversos produtos broncodilatadores e expectorantes produzidos com extratos da espécie hera (Hedera helix L. - Araliaceae), os quais apresentam distintas composições em termos de quantidade de extrato seco e de marcador por ml. Visando contribuir ao entendimento dessas diferenças, realizou-se levantamento da literatura clínica sobre a espécie com foco nos aspectos de concentração de extratos e quantidade de marcadores. Verificou-se existirem mundialmente três diferentes formatos comerciais de extratos de hera, preparados com relação droga-extrato de 3-6:1, 5-7,5:1 e 4-8:1, gerando diferentes teores de marcador por cento. Os dois primeiros formatos estão presentes no mercado brasileiro, apresentam base clínica eficaz e segura, demonstrando que a espécie em questão mostra faixa variável de ação. O estudo multicêntrico de maior evidência clínica foi realizado por Fazio e colaboradores (2009), utilizando produto com concentração de marcadores que somente são fornecidas, no Brasil, pelos fitoterápicos de formulação do tipo 5-7,5:1, enquanto produtos no formato de formulação 3-6:1 apresenta teores abaixo do mínimo utilizado nesse estudo multicêntrico. O perfil de segurança dos vários tipos de produtos à base de Hedera helix é muito bem estabelecido, com mínimas ocorrências de efeitos adversos, basicamente gastrointestinais.

Hemispheric Asymmetry for Encoding Unrelated Word Pairs? A Functional Near-infrared Spectroscopy Study / 航天医学与医学工程

Objective To explore the role of the prefrontal cortex in semantic encoding of unrelated word pairs by using functional near-infrared spectroscopy (fNIRS). Method Forty-eight subjects were presented unrelated pairs of Chinese words under both the nonsemantic and semantic encoding conditions. Under the nonsemantic condition, subjects judged whether the two words had similar orthographic structures; under the semantic condition, they generated a sentence involving the presented word pairs. The changes of regional blood volume associated with the cognitive tasks were measured by using fNIRS equipment which was a continuous optical imager. Result The regions that corresponded to the prefrontal regions showed greater activation under semantic than nonsemantic condition in both left and right hemispheres, although the extent of the activation was larger in the left than right prefrontal regions. This result was consistent with other neuroimaging studies on unrelated word pairs processing, but did not conform to the strict interpretations of the hemispheric encoding/retrieval asymmetry model (HERA). Conclusion This study suggests that material specificity is one of the important factors to influence hemispheric asymmetry in memory encoding. When associations between items are required, right prefrontal regions participate in the encoding processing as well. It also indicates that fNIRS imaging is a viable method of investigating higher level cognitive processing such as memory.