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AbstractPenicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations. Structure–activity relationship studies focusing on the branching of the boron-connecting carbon and quantum mechanical/molecular mechanical simulations showed that reaction barrier free energies are compatible with fast reversible covalent binding and small or missing reaction free energies limit the inhibitory activity of the investigated boronic acid derivatives. Therefore, covalent labelling of the lysine residue of the catalytic dyad was also investigated. Compounds with a carbonyl warhead and an appropriately positioned boronic acid moiety were shown to inhibit and covalently label PBP1b. Reversible covalent labelling of the catalytic lysine by imine formation and the stabilisation of the imine by dative N–B bond is a new strategy for PBP1b inhibition.

Não obstante a importância da antropologia jurídica para a discussão do direito, a disciplina consta em apenas pequena parte das grades curriculares dos cursos, a nível global. Por isso, o objetivo é valer-se de um caso concreto, que facilmente atinja acadêmicos em seus diferentes níveis de formação, para colocar em evidência, de forma exemplificativa, a fundamentalidade da promoção dessa disciplina nos currículos dos futuros operadores do direito. O caso eleito é a Lei brasileira de acesso ao patrimônio genético e aos conhecimentos tradicionais associados (Lei da Biodiversidade). Ao analisar os aspectos considerados como questionáveis da norma, o artigo sublinha o fato de que ela constitui um exemplo concreto do caráter ambivalente do processo de juridicização e, em consequência, da importância da antropologia jurídica para identificá-lo. Como o artigo não apenas discute a importância desta última nos currículos, mas também ele próprio é desenvolvido à luz dela, inicialmente parte-se de como foi o processo que conduziu a que a antropologia contribuísse à discussão do direito. Em segundo lugar, os aspectos controversos da lei são trazidos. Na sequência, dois autores da disciplina são mobilizados: primeiramente, o Professor de antropologia jurídica da Faculdade de Direito da Universidade de São Paulo (USP) Orlando Villas Bôas Filho, sobre o fato de que, não raras vezes - e como exemplificado no caso concreto -, o processo de juridicização pode acabar por atender interesses contrários aos dos povos indígenas. Isto feito, mobiliza-se o autor francês do Laboratório de Antropologia Jurídica de Paris (LAJP) Étienne Le Roy e sua Teoria do Multijuridismo, estabelecendo-se relações entre ela e o caso concreto eleito, em diálogo com intelectuais/líderes indígenas. A metodologia seguida foi a sistêmica e a técnica de pesquisa baseou-se na revisão bibliográfica e interpretação de normas legais e decretos regulamentares. Despite the importance of legal anthropology for the discussion of law, the discipline appears in only a small part of the course curricula, globally. Therefore, the objective is to use a concrete case, which easily reaches academics at their different levels of training, to highlight, in an exemplifying way, the fundamentality of promoting this discipline in the curricula of future legal professionals. The chosen case is the Brazilian Act on access to genetic heritage and associated traditional knowledge (Biodiversity Act). By analysing the aspects considered as questionable of the norm, the article highlights the fact that it constitutes a concrete example of the ambivalent nature of the juridicization process and, consequently, the importance of legal anthropology to identify it. As the article not only discusses the importance of the latter in curricula, but is itself also developed in light of it, it initially starts with how the process was that led anthropology to contribute to the discussion of law. Secondly, the controversial aspects of the Act are brought to the fore. Following this, two authors of the discipline are mobilized: firstly, the Professor of legal anthropology at the Faculty of Law of the University of São Paulo (USP) Orlando Villas Bôas Filho, on the fact that, not infrequently - and as exemplified in the concrete case -, the juridicization process may end up serving interests contrary to those of indigenous peoples. This done, the French author from the Laboratory of Legal Anthropology of Paris (LAJP) Étienne Le Roy and his Theory of Multijuridism are mobilized, establishing relationships between it and the concrete case chosen, in dialogue with indigenous intellectuals/leaders. The methodology followed was systemic and the research technique was based on literature review and interpretation of legal norms and regulatory decrees.

Simple Summary: In the last decade, artificial intelligence and machine learning (AI/ML) have been increasingly explored in the field of intraocular tumors. Retinoblastoma (RB) is the most common eye cancer in childhood. Early detection is crucial for optimizing outcomes in RB. Hence, we aimed to employ AI/ML to develop a potential screening tool for RB and established the feasibility of training an AI model to detect and classify RB from fundus images in an Asian Indian cohort previously. Taking this work ahead, we explored the model's ability to detect and classify RB in a multiracial cohort. Despite unequal frequency distribution between the races, we identified the scope for improvement and retrained the AI model to detect and classify RB. The AI model displayed an accuracy of 97% for detecting RB and 98%, 93%, >99%, 94%, and 93% for grouping tumors into the International Classification of Retinoblastoma groups A to E, respectively. Background: The color variation in fundus images from differences in melanin concentrations across races can affect the accuracy of artificial intelligence and machine learning (AI/ML) models. Hence, we studied the performance of our AI model (with proven efficacy in an Asian-Indian cohort) in a multiracial cohort for detecting and classifying intraocular RB (iRB). Methods: Retrospective observational study. Results: Of 210 eyes, 153 (73%) belonged to White, 37 (18%) to African American, 9 (4%) to Asian, 6 (3%) to Hispanic races, based on the U.S. Office of Management and Budget's Statistical Policy Directive No.15 and 5 (2%) had no reported race. Of the 2473 images in 210 eyes, 427 had no tumor, and 2046 had iRB. After training the AI model based on race, the sensitivity and specificity for detection of RB in 2473 images were 93% and 96%, respectively. The sensitivity and specificity of the AI model were 74% and 100% for group A; 88% and 96% for group B; 88% and 100% for group C; 73% and 98% for group D, and 100% and 92% for group E, respectively. Conclusions: The AI models built on a single race do not work well for other races. When retrained for different races, our model exhibited high sensitivity and specificity in detecting RB and classifying RB. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

β-amyloid (Aβ) peptides form self-organizing fibrils in Alzheimer's disease. The biologically active, toxic Aβ25–35 fragment of the full-length Aβ-peptide forms a stable, oriented filament network on the mica surface with an epitaxial mechanism at the timescale of seconds. While many of the structural and dynamic features of the oriented Aβ25–35 fibrils have been investigated before, the β-strand arrangement of the fibrils and their exact orientation with respect to the mica lattice remained unknown. By using high-resolution atomic force microscopy, here, we show that the Aβ25–35 fibrils are oriented along the long diagonal of the oxygen hexagon of mica. To test the structure and stability of the oriented fibrils further, we carried out molecular dynamics simulations on model β-sheets. The models included the mica surface and a single fibril motif built from β-strands. We show that a sheet with parallel β-strands binds to the mica surface with its positively charged groups, but the C-terminals of the strands orient upward. In contrast, the model with antiparallel strands preserves its parallel orientation with the surface in the molecular dynamics simulation, suggesting that this model describes the first β-sheet layer of the mica-bound Aβ25–35 fibrils well. These results pave the way toward nanotechnological construction and applications for the designed amyloid peptides. [ABSTRACT FROM AUTHOR]

The authors consider that the organic animal breeding – as one of the methods with a significant influence on the human nutrition – is the necessary consequence of the 21st century. They present the way of establishing the organic breeding by some Hungarian and Central-European animal farms. They show some examples for the period of transformation into eco farms. The results cover the objective, personal, animal breed and feeding relations. Results of changing and operation: raw materials and products with some of their advantages are shown, just as some examples for protection of origin and food safety. Suggestions for marketing and cooperation, as well as for development are finally given, with special regard to rural development (employment, direct marketing) and to the importance of environmental protection with regard to eco / alternative animal breeding.

The role of hydrophobic and polar interactions in providing thermodynamic stability to folded proteins has been intensively studied, but the relative contribution of these interactions to the mechanical stability is less explored. We used steered molecular dynamics simulations with constant-velocity pulling to generate force-extension curves of selected protein domains and monitor hydrophobic surface unravelling upon extension. Hydrophobic contribution was found to vary between one fifth and one third of the total force while the rest of the contribution is attributed primarily to hydrogen bonds. Moreover, hydrophobic force peaks were shifted towards larger protein extensions with respect to the force peaks attributed to hydrogen bonds. The higher importance of hydrogen bonds compared to hydrophobic interactions in providing mechanical resistance is in contrast with the relative importance of the hydrophobic interactions in providing thermodynamic stability of proteins. The different contributions of these interactions to the mechanical stability are explained by the steeper free energy dependence of hydrogen bonds compared to hydrophobic interactions on the relative positions of interacting atoms. Comparative analyses for several protein domains revealed that the variation of hydrophobic forces is modest, while the contribution of hydrogen bonds to the force peaks becomes increasingly important for mechanically resistant protein domains.

Among women aged 27–45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27–45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27–45 years versus women and men aged 16–26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27–45 years. Efficacy of qHPV vaccine in men aged 27–45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27–45 years versus 16–26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27–45 years of age, and vaccine efficacy was inferred in men 27–45 years of age based on the serological results.

The ubiquitin–proteasome system is responsible for the degradation of proteins and plays a critical role in key cellular processes. While the constitutive proteasome (cPS) is expressed in all eukaryotic cells, the immunoproteasome (iPS) is primarily induced during disease processes, and its inhibition is beneficial in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Oxathiazolones were reported to selectively inhibit iPS over cPS, and the inhibitory activity of several oxathiazolones against iPS was experimentally determined. However, the detailed mechanism of the chemical reaction leading to irreversible iPS inhibition and the key selectivity drivers are unknown, and separate characterization of the noncovalent and covalent inhibition steps is not available for several compounds. Here, we investigate the chemical reaction between oxathiazolones and the Thr1 residue of iPS by quantum mechanics/molecular mechanics (QM/MM) simulations to establish a plausible reaction mechanism and to determine the rate-determining step of covalent complex formation. The modelled binding mode and reaction mechanism are in line with the selective inhibition of iPS versus cPS by oxathiazolones. The kinact value of several ligands was estimated by constructing the potential of mean force of the rate-determining step by QM/MM simulations coupled with umbrella sampling. The equilibrium constant Ki of the noncovalent complex formation was evaluated by classical force field-based thermodynamic integration. The calculated Ki and kinact values made it possible to analyse the contribution of the noncovalent and covalent steps to the overall inhibitory activity. Compounds with similar intrinsic reactivities exhibit varying selectivities for iPS versus cPS owing to subtle differences in the binding modes that slightly affect Ki, the noncovalent affinity, and importantly alter kinact, the covalent reactivity of the bound compounds. A detailed understanding of the inhibitory mechanism of oxathiazolones is useful in designing iPS selective inhibitors with improved drug-like properties.

Resumo Atualmente a membra amniótica (MA) tem obtido importância devido à comprovada capacidade de reduzir inflamação, auxiliar a cicatrização e epitelização, possuindo propriedades antimicrobianas e antivirais, além de baixa imunogenicidade. As indicações de seu uso na oftalmologia têm aumentado muito nas duas últimas décadas. Objetivo: Descrever a estrutura básica e as propriedades biológicas da MA em relação aos componentes da sua matriz extracelular e fatores de crescimento, as consequências de diferentes técnicas empregadas na sua preservação e esterilização, métodos para remoção do epitélio e a comparação dos custos dos diferentes meios de conservação atualmente empregados. Métodos: Pesquisa nas bases de dados do Portal da Biblioteca Virtual em Saúde (BVS), Pubmed, Cochrane, Scielo e Lilacs com as palavras-chave: membrana amniótica, transplante, reconstrução da córnea, doenças da conjuntiva. Resultados: A literatura é vasta na descrição dos efeitos de diversos agentes e técnicas na preparação da MA, dentre elas sua preservação, esterilização e desepitelização. A membrana desnuda tem sido a escolha para a reconstrução da superfície ocular, pois facilita a cicatrização. Em relação aos agentes conservantes, o glicerol é o meio mais utilizado mundialmente pelo baixo custo e facilidade de manuseio. Conclusão: A comparação das diversas técnicas nos guia na elaboração de protocolos de preparo da MA para uso oftalmológico. A membrana desnuda facilita a cicatrização em relação a com células epiteliais. O glicerol é o meio de conservação mais utilizado pelo baixo custo e facilidade de manuseio.

RESUMO Objetivo: Identificar se há mudança refracional significativa após realização de capsulotomia posterior com laser Nd:YAG em olhos pseudofácicos. Métodos: Estudo retrospectivo com análise de prontuários de pacientes atendidos em um hospital com diagnóstico de opacificação de cápsula posterior do cristalino tratada com capsulotomia posterior com laser Nd:YAG no período de outubro de 2019 a março de 2021. A comparação entre a refração antes e após o procedimento foi realizada calculando-se o equivalente esférico. Também foi avaliada a mudança da acuidade visual, aferida por LogMAR. Resultados: Foram analisados 90 prontuários, totalizando 140 olhos, de pacientes submetidos à capsulotomia posterior com laser Nd:YAG. O equivalente esférico médio pré-procedimento foi de -0,07±0,89D, mínimo de -3,0D e máximo de +2,5D, mediana (intervalo interquartil) de 0,0D (-0,50D a +0,375D). A média pós-procedimento foi de -0,18±0,86D, mínimo de -3,5D e máximo de +2,25D, mediana (intervalo interquartil) de -0,125D (-0,50D a 0,0D). com p

Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the N-methylated heterocycles and to compare the two generations of heterocyclic electrophiles.

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)