Chemical modification of proteins - challenges and trends at the start of the 2020s.

Ribosomally expressed proteins perform multiple, versatile, and specialized tasks throughout Nature. In modern times, chemically modified proteins, including improved hormones, enzymes, and antibody-drug-conjugates have become available and have found advanced industrial and pharmaceutical applications. Chemical modification of proteins is used to introduce new functionalities, improve stability or drugability. Undertaking chemical reactions with proteins without compromising their native function is still a core challenge as proteins are large conformation dependent multifunctional molecules. Methods for functionalization ideally should be chemo-selective, site-selective, and undertaken under biocompatible conditions in aqueous buffer to prevent denaturation of the protein. Here the present challenges in the field are discussed and methods for modification of the 20 encoded amino acids as well as the N-/C-termini and protein backbone are presented. For each amino acid, common and traditional modification methods are presented first, followed by more recent ones.

Carbon dioxide enhances sulphur-selective conjugate addition reactions.

Sulphur-selective conjugate addition reactions play a central role in synthetic chemistry and chemical biology. A general tool for conjugate addition reactions should provide high selectivity in the presence of competing nucleophilic functional groups, namely nitrogen nucleophiles. We report CO2-mediated chemoselective S-Michael addition reactions where CO2 can reversibly control the reaction pHs, thus providing practical reaction conditions. The increased chemoselectivity for sulphur-alkylation products was ascribed to CO2 as a temporary and traceless protecting group for nitrogen nucleophiles, while CO2 efficiently provide higher conversion and selectivity sulphur nucleophiles on peptides and human serum albumin (HSA) with various electrophiles. This method offers simple reaction conditions for cysteine modification reactions when high chemoselectivity is required.

Tuning Peptide Structure and Function through Fluorobenzene Stapling.

Cyclic peptides are promising next-generation therapeutics with improved biological stability and activity. A catalyst-free stapling method for cysteine-containing peptides has been developed that enables fine-tuning of the macrocycle by using the appropriate regioisomers of fluorobenzene linkers. Stapling was performed on the unprotected linear peptide or, more conveniently, directly on-resin after peptide synthesis. NMR spectroscopy and circular dichroism studies demonstrate that the type of stapling can tune the secondary structures of the peptides. The method was applied to a set of potential agonists for melanocortin receptors, generating a library of macrocyclic potent ligands with ortho, meta or para relationships between the thioethers. Their small but significant differences in potency and efficacy demonstrate how the method allows facile fine-tuning of macrocyclic peptides towards biological targets from the same linear precursor.

Canine and Feline Cutaneous Mast Cell Tumor: A Comprehensive Review of Treatments and Outcomes.

Mast cell tumor (MCT) or mastocytoma is one of the most frequent malignant cutaneous tumors in the dog, and the second most frequent in the cat. Several mast cell tumor therapeutic approaches have been proposed in the past years for dogs and cats, resulting in very distinct outcomes. The current comprehensive literature review presents a critical approach to the scientific information published about the MCTs treatments and the subsequent prognosis and survival times, in dogs and in cats diagnosed with MCTs. A systematic review of the literature following the Cochrane principles and methodology was performed. The authors resorted to MEDLINE, Scopus, Google Scholar and Web of Science databases to select the 133 publications with evidence-based treatments for MCTs in companion animals. Results of the review suggest that the recommended treatment, prognosis and survival times for dogs and cats with MCTs depends at all times on the clinical staging, histological grade and location of the tumor.

Dihydroquinazolinones via A3 -Type Reactions of N-Carbamoyliminium Ions.

A variant of the A3 coupling reaction was developed utilizing in situ generated N-carbamoyliminium ions. The tandem INCIC/A3 -coupling sequence provided a facile one-pot synthesis of dihydroquinazolinone derivatives. The scope of the reaction was demonstrated in solution as well as on solid support. The reaction was further combined with peptide synthesis, SN Ar reactions, CuAAC triazole formation or bromination, providing additional opportunities for further diversification of the dihydroquinazolinone scaffolds.

Percutaneous vertebroplasty: a new animal model.

BACKGROUND CONTEXT: Percutaneous vertebroplasty (PVP) is a minimally invasive surgical procedure and is frequently performed in humans who need surgical treatment of vertebral fractures. PVP involves cement injection into the vertebral body, thereby providing rapid and significant pain relief. PURPOSE: The testing of novel biomaterials depends on suitable animal models. The aim of this study was to develop a reproducible and safe model of PVP in sheep. STUDY DESIGN: This study used ex vivo and in vivo large animal model study (Merino sheep). METHODS: Ex vivo vertebroplasty was performed through a bilateral modified parapedicular access in 24 ovine lumbar hemivertebrae, divided into four groups (n=6). Cerament (Bone Support, Lund, Sweden) was the control material. In the experimental group, a novel composite was tested-Spine-Ghost-which consisted of an alpha-calcium sulfate matrix enriched with micrometric particles of mesoporous bioactive glass. All vertebrae were assessed by micro-computed tomography (micro-CT) and underwent mechanical testing. For the in vivo study, 16 sheep were randomly allocated into control and experimental groups (n=8), and underwent PVP using the same bone cements. All vertebrae were assessed postmortem by micro-CT, histology, and reverse transcription-polymerase chain reaction (rt-PCR). This work has been supported by the European Commission under the 7th Framework Programme for collaborative projects (600,000-650,000 USD). RESULTS: In the ex vivo model, the average defect volume was 1,275.46±219.29 mm3. Adequate defect filling with cement was observed. No mechanical failure was observed under loads which were higher than physiological. In the in vivo study, cardiorespiratory distress was observed in two animals, and one sheep presented mild neurologic deficits in the hind limbs before recovering. CONCLUSIONS: The model of PVP is considered suitable for preclinical in vivo studies, mimicking clinical application. All sheep recovered and completed a 6-month implantation period. There was no evidence of cement leakage into the vertebral foramen in the postmortem examination.

Hydrogen-bond promoted nucleophilic fluorination: concept, mechanism and applications in positron emission tomography.

Due to the tremendous interest in carbon-fluorine bond-forming reactions, research efforts in this area have been dedicated to the development of facile processes to synthesize small fluorine-containing organic molecules. Among others, PET (Positron Emission Tomography) is one of the most important applications of fluorine chemistry. Recognizing the specific requirements of PET processes, some groups have focused on fluorination reactions using alkali metal fluorides, particularly through SN2-type reactions. However, a common "misconception" about the role of protic solvents and hydrogen bonding interactions in this class of reactions has hampered the employment of these excellent promoters. Herein, we would like to review recent discoveries in this context, showing straightforward nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents. Simultaneous dual activation of reacting partners by intermolecular hydrogen bonding and the enhancement of the "effective fluoride nucleophilicity", which is Nature's biocatalytic approach with the fluorinase enzyme, are the key to this unprecedentedly successful nucleophilic fluorination.

Diastereodivergent de-epimerization in catalytic asymmetric allylic alkylation.

Diastereomers made to order: In an unprecedented ligand-controlled process a racemic mixture of four stereoisomers can be converted with high selectivity into each one of the diastereomers of the product, at will (see scheme). The mechanism of this deracemization of epimers, that is, a de-epimerization, was also studied.

Catalytic asymmetric diastereodivergent deracemization.

Your wish is my command: Deracemization is a powerful strategy wherein a racemate is converted into a 100 % yield of a single enantiopure product. A new concept in catalytic deracemization is presented, in which a racemate with n stereogenic elements can be selectively converted into each one of 2(m) (m = number of chiral centers of the product) different enantiopure products, by simple tuning of the reaction conditions.

A concise access to 3-substituted 2-pyrones.

The development of a modular synthesis of 3-substituted-2-pyrones is described. The attainment of this strategy hinges on a new electrophilic pyrone derivative which can be readily prepared on a multigram scale and which performs very competently in metal-catalyzed cross-coupling reactions with a variety of nucleophiles.

Perfil clínico-epidemiológico da fibrilação atrial espontânea em cães / Clinical-epidemiological profile of spontaneous atrial fibrilation in dogs

Fundamentos: A fibrilação atrial (FA) é considerada a arritmia sustentada mais importante em medicina veterinária, estando usualmente associada à doença cardíaca estrutural, com manifestações clínicas de insuficiência cardíaca avançada. São poucos os trabalhos epidemiológicos na literatura internacional e raros os relatos no Brasil. Estudos comparativos sobre FA espontânea entre espécies têm sido raramente publicados. Objetivos: Conhecer o perfil-epidemiológico de uma coorte de cães portadores de FA espontânea, bem como comparar com o observado em seres humanos. Métodos: Estudo retrospectivo com os dados dos registros de 108 cães com fibrilação atrial diagnosticada através do eletrocardiograma, no período entre janeiro de 1999 e janeiro de 2006 e os resultados comparados com o disposto na literatura relacionados com FA em cães e em humanos. Os dados coletados incluíram raça, sexo, idade, peso e freqüência cardíaca. Resultados: A investigação identificou que os animais pertenciam a 21 raças pura e a mestiços de várias raças, de ambos os sexos, com peso variando entre 5,5kg e 68kg. Todos os animais apresentavam sinais de insuficiência cardíaca estágios C ou D (NYHA), sendo identifdicados através de ecocardiograma e radiografia de tórax três grupos de cardiopatias: cardiopatia dilatada (49 por cento), endocardiose valvar mitral (36 por cento) e o terceiro grupo (15 por cento) incluiu outras causas, congênitas e adquiridas...

Aspectos da informatizaçäo da sociedade brasileira: trabalho, saúde e controle social: o caso do setor bancário / Aspects of the informatization of the Brazilian society: work, health and social control: the case of the bank section

Propoe uma reflexäo sobre o impacto da informática, hoje um dos principais fenômenos de mudança social, na sociedade brasileira. Essa abordagem se justifica pela importância e visibilidade mundial do fenômeno. Para isso tomou-se como exemplo a penetraçäo dos terminais de computadores do sistema bancário. Faz-se primeiramente uma descriçäo do processo que resultou na configuraçäo do sistema financeiro tal como ele se apresenta hoje no Brasil. Em seguida procedeu-se a discussäo sobre as máquinas industriais mas também de informaçäo, isto é, eletrônicas. Neste ponto procurou-se rastrear o caminho que trouxe a sociedade a um controle social sempre mais rigoroso, através da utilizaçäo do tempo e a relaçäo que esse processo manteve e continua mantendo com a criaçäo de aparelhos e de maquinaria sobretudo eletrônica. Em terceiro lugar abriu-se espaço para que emergissem os atores sociais envolvidos nessa dinâmica. Foram entäo estudados aspectos como a transformaçoes das ocupaçoes, a desqualificaçäo profissional, a transformaçäo dos ambientes de trabalho e outros, a luz dos elementos do tema da burocracia. No quarto ítem foram abordados especificamente os aspectos da saúde dos trabalhadores que operam máquinas eletrônicas, entendendo-se a saúde como uma questäo social. Essa leitura foi feita privilegiando-se o conceito de alienaçäo. (CPG)

Notas sobre as contradiçöes do processo de informatizaçäo social / Notes on the contradictions og the social informatization process

Os processos automáticos que se väo implantando em praticamente todos os países do mundo neste final de século provocam impactos em áreas sociais, assim como sobre uma série de valores culturais. Neste artigo procura-se fazer um balanço geral dessas modificaçöes