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Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology.
After the first seed concept introduced in the 18th century, different disciplines have attributed different names to dual-functional molecules depending on their application, including bioconjugates, bifunctional compounds, multitargeting molecules, chimeras, hybrids, engineered compounds. However, these engineered constructs share a general structure: a first component that targets a specific cell and a second component that exerts the pharmacological activity. A stable or cleavable linker connects the two modules of a chimera. Herein, we discuss the recent advances in the rapidly expanding field of chimeric molecules leveraging chemical biology concepts. This Perspective is focused on bifunctional compounds in which one component is a lead compound or a drug. In detail, we discuss chemical features of chimeric molecules and their use for targeted delivery and for target engagement studies
Oltre l'apartheid. Rimarginare le cicatrici di una città ferita
Apartheid, literally "separation", "partition" was the policy of racial segregation established after World War II by the white ethnic government of South Africa. The city, in an attempt to be distilled through an image, has often been compared to a living organism, with its heart, lungs, skeleton and tissues. In this organic metaphor, South African history has left the scars of ime visible, suggestive and with a great socioeconomic impact on the organism of Cape Town. This paper aims to deepen the relationship between the city, its memory, and its future in a delicate context such as the post-Apartheid, in order to open the debate to how the designer can intervene by repairing the urban fabric, preserving the memory and celebrating it through a project intervention that gives back to the community not only a physical asset, but also the opportunity to rebuild a fragmented community
Impact of Pre-Analytical Time on the Recovery of Pathogens from Blood Cultures: Results from a Large Retrospective Survey
Prompt identification of bloodstream pathogens is essential for optimal management of patients. Significant changes in analytical methods have improved the turnaround time for laboratory diagnosis. Less attention has been paid to the time elapsing from blood collection to incubation and to its potential effect on recovery of pathogens. We evaluated the performance of blood cultures collected under typical hospital conditions in relation to the length of their pre-analytical time. We carried out a large retrospective study including 50,955 blood cultures collected, over a 30-month period, from 7,035 adult septic patients. Cultures were accepted by the laboratory only during opening time (Mon-Fri: 8am\ub14pm; Sat: 8am\ub12pm). Samples collected outside laboratory hours were stored at room temperature at clinical wards. All cultures were processed by automated culture systems. Day and time of blood collection and of culture incubation were known for all samples. A maximum pre-analytical interval of 2 hours is recommended by guidelines. When the laboratory
was open, 57% of cultures were processed within 2 h. When the laboratory was closed, 4.9% of cultures were processed within 2 h (P<0.001). Samples collected when the laboratory was closed showed pre-analytical times significantly longer than those collected when laboratory was open (median time: 13 h and 1 h, respectively, P<0.001). The prevalence
of positive cultures was significantly lower for samples collected when the laboratory was closed compared to open (11% vs 13%, P<0.001). The probability of a positive result decreased of 16% when the laboratory was closed (OR:0.84; 95%CI:0.80\ub10.89, P<0.001). Further, each hour elapsed from blood collection to incubation resulted associated with a
decrease of 0.3% (OR:0.997; 95%CI:0.994\ub10.999, P<0.001) in the probability of a positive result. Delayed insertions of cultures into automated systems was associated with lower detection rates, with potentially important consequences for patients. In each hospital setting the logistic factors able to shorten pre-analytical time should be carefully investigated and specifically targeted
Trapping at the Solid−Gas Interface: Selective Adsorption of Naphthalene by Montmorillonite Intercalated with a Fe(III)− Phenanthroline Complex
In this study, stable hybrid materials (Mt−Fe(III)Phen),
made by the μ-oxo Fe(III)−phenanthroline complex [(OH2)3(Phen)-
FeOFe(Phen)(OH2)3]4+ (Fe(III)Phen) intercalated in different amounts
into montmorillonite (Mt), were used as a trap for immobilizing gaseous
benzene and naphthalene and their mono chloro-derivatives at 25 and 50
°C. The entrapping process was studied through elemental analysis, magic
angle spinning NMR spectroscopy, thermal analysis, and evolved gas mass
spectrometry. Naphthalene and 1-chloronaphthalene were found to be
immobilized in large amount at both temperatures. Molecular modeling
allowed designing of the structure of the interlayer in the presence of the
immobilized aromatic molecules. Adsorption is affected by the amount of
the Fe complex hosted in the interlayer of the entrapping hybrid materials.
On the contrary, under the same conditions, benzene and chlorobenzene
were not adsorbed. Thermal desorption of naphthalenes was obtained
under mild conditions, and immobilization was found to be reversible at least for 20 adsorption/desorption cyclesThe authors are thankful to the University of Modena and
Reggio Emilia for FAR 2016 funding program (PAsTIME
Project, grant number: FAR2016DIPBORSARI), for the
Visiting Professor program, and for the facilities provided by
the Centro Interdipartimentale Grandi Strumenti, to MIUR for
funding program FFABR 2017, to the Computational Centre
of University of Granada and CINECA of Bologna for the
high-performance computing service, and to the Andalusian
project RMN1897 and the Spanish projects FIS2013-48444-
C2-2-P and FIS2016-77692-C2-2-P for financial support
Resultados de la implementación de los cuidados integrados pos-parada cardiorrespiratoria en un hospital universitario
Objetivos: identificar os cuidados pós-parada cardiorrespiratória (PCR) realizados e relacioná-los com o estado neurológico e a sobrevida nas primeiras 24 horas, na alta, após seis meses e um ano. Método: estudo retrospectivo, analítico e quantitativo, realizado no Serviço de Emergência de um hospital universitário em São Paulo. Foram incluídos 88 prontuários de pacientes atendidos em PCR, que apresentaram retorno da circulação espontânea sustentado por mais de 20 minutos e identificados os cuidados pós-PCR realizados nas primeiras 24 horas, como também a relação com a sobrevida e estado neurológico. Resultados: os cuidados pós-PCR realizados com maior frequência foram a obtenção de uma via área avançada e passagem de sonda vesical de demora. Para os pacientes que tiveram manutenção de boa respiração e circulação, controle da temperatura e transferência para unidade de terapia intensiva, a sobrevida foi maior nas primeiras 24 horas, após seis meses e um ano da alta. O bom estado neurológico em seis meses e um ano após a alta associou-se a não utilização de drogas vasoativas e à investigação das causas da PCR. Conclusão: a identificação das boas práticas em relação aos cuidados pós-PCR pode auxiliar na diminuição da mortalidade destes indivíduos e na melhora da sua qualidade de vida.Objetivos: identificar los cuidados pos-parada cardiorrespiratoria (PCR) realizados y relacionarlos con el estado neurológico y la sobrevida en las primeras 24 horas en el alta, después de seis meses y un año. Método: estudio retrospectivo, analítico y cuantitativo, realizado en el Servicio de Emergencia, de un hospital universitario en São Paulo. Fueron incluidos 88 prontuarios de pacientes atendidos en PCR, que presentaron retorno de la circulación espontánea sustentado por más de 20 minutos e identificados los cuidados pos-PCR realizados en las primeras 24 horas y la relación con la sobrevida y estado neurológico. Resultados: los cuidados pos-PCR realizados con mayor frecuencia fueron la obtención de una vía área avanzada y pasaje de sonda vesical de demora. Los pacientes que tuvieron mantenimiento de buena respiración y circulación, control de la temperatura y transferencia para unidad de terapia intensiva a sobrevida fue mayor en las primeras 24 horas, después de seis meses y un año del alta. El buen estado neurológico en seis meses y un año después del alta se asoció a la no utilización de drogas vasoactivas y la investigación de las causas de la PCR. Conclusión: la identificación de las buenas prácticas en relación a los cuidados pos-PCR puede auxiliar en la disminución de la mortalidad de estos individuos y en la mejoría de su calidad de vida.Objectives: to identify the care measures performed after cardiorespiratory arrest (CRA) and to relate them to the neurological status and survival at four moments: within the first 24 hours, at the discharge, six months after discharge, and one year after discharge. Method: retrospective, analytical and quantitative study performed at the Emergency Department of a university hospital in São Paulo. Eighty-eight medical records of CRA patients who had a return of spontaneous circulation sustained for more than 20 minutes were included and the post-CRA care measures performed in the first 24 hours were identified, as well as its relationship with survival and neurological status. Results: the most frequent post-CRA care measures were use of advanced airway access techniques and indwelling bladder catheterization. Patients who had maintained good breathing and circulation, temperature control and who were transferred to intensive care unit had a better survival in the first 24 hours, after six months and one year after discharge. Good neurological status at six months and one year after discharge was associated with non-use of vasoactive drugs and investigation of the causes of the CRA. Conclusion: the identification of good practices in post-CRA care may help to reduce the mortality of these individuals and to improve their quality of life
Chemical trapping of gaseous H2S at high and low partial pressures by an iron complex immobilized inside the montmorillonite interlayer
A stable hybrid material (Mt-Fe(III)Phen) formed by intercalation of the μ-oxo Fe(III)-phenanthroline complex
[(OH2)3(Phen)FeOFe(Phen)(OH2)3]4+ (Fe(III)Phen) in montmorillonite (Mt) is able to immobilize H2S in gaseous
phase with high efficiency even at extremely low pressures. DR UV–vis and I.R. spectroscopies, elemental analysis,
X-ray powder diffraction, thermal analysis coupled with evolved gas mass spectrometry, and X-ray absorption
spectroscopy show that the material has high adsorption capacity, performs fast H2S trapping and is long-lasting.
Moreover, even extremely low levels of H2S can be removed easily and quickly from gaseous phase using a suitable
amount of the trapping material. The immobilization mechanism likely involves a redox reaction between
iron (III) and one S2− ion, followed by the binding of a second S2− ion to the metal centre. The process takes
place at room temperature, is reversible for several cycles, and does not require pre-treatment of neither gaseous
H2S nor the adsorbent material. Therefore, this modified montmorillonite is a promising material to get rid of
H2S in processes of environmental interest and to obtain gaseous (and gasifiable) high quality hydrocarbons in
fuels refineries
Interlayer-Confined Cu(II) Complex as an Efficient and Long-Lasting Catalyst for Oxidation of H2S on Montmorillonite
Removal of highly toxic H2S for pollution control and operational safety is a pressing need. For this purpose, a montmorillonite intercalated with Cu(II)-phenanthroline complex [Cu[(Phen)(H2O)2]2+ (Mt-CuPhen) was prepared to capture gaseous H2S under mild conditions. This hybrid material was simple to obtain and demonstrated an outstanding ability to entrap H2S at room temperature, retaining high efficiency for a very long time (up to 36.8 g of S/100 g Mt-CuPhen after 3 months of exposure). Sorbent and H2S uptake were investigated by elemental analysis, X-ray powder diffraction measurements, diffuse reflectance (DR) UV–Vis and infrared spectroscopy, thermal analysis and evolved gas mass spectrometry, scanning electron microscopy equipped with energy-dispersive X-ray spectrometer, and X-ray absorption spectroscopy. The H2S capture was studied over time and a mechanism of action was proposed. The entrapping involves a catalytic mechanism in which [Cu[(Phen)(H2O)2]2+ acts as catalyst for H2S oxidation to S0 by atmospheric oxygen. The low cost and the long-lasting performance for H2S removal render Mt-CuPhen an extremely appealing trap for H2S removal and a promising material for many technological applications
Pre-amyloid oligomers budding:a metastatic mechanism of proteotoxicity
The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology
The Copper Chemical Garden as a Low Cost and Efficient Material for Breaking Down Air Pollution by Gaseous Ammonia
Chemical garden (CG) from copper(II) sulfate, nitrate and chloride (CG CuSO, CG Cu(NO), CG CuCl) were grown, and characterized from the structural and compositional point of view by using scanning electron microscopy, X-ray powder diffraction, elemental analysis, thermogravimetric analysis coupled with mass spectrometry, and DR (diffuse reflectance) UV-Vis-NIR spectroscopy. The main crystalline phases, controlled by the anion of the starting salt, were brochantite and kobyashevite for CG CuSO, gerhardtite, rouaite and anthonyite for CG Cu(NO), and atacamite for CG CuCl. The materials were then exposed to ammonia vapors to test the effectiveness of their entrapping property. All materials proved to be very efficient and rapid in the uptake of ammonia, which invariably results in the formation of a Cu(II)/NH complex. However, after a few tens of minutes, CG Cu(NO) and CG CuCl release water and get wet, thereby resulting unsuitable for applications. Only CG CuSO remains dry for at least 25 hours. This makes it a valid candidate for building devices for trapping ammonia, and possibly other gases capable of interacting with Cu(II). The entrapment of ammonia by this material was also characterized by H and Si MAS-NMR XAS spectroscopies.The authors would like to acknowledge the contribution of the European Cooperation in Science and Technology (COST Action, grant number CA17120) supported by the EU Framework Programme Horizon 2020. This research is also under the contribution of progetti di rilevante interesse nazionale (PRIN2017)(it) “Mineral Reactivity, a Key to Understand Large-Scale Processes: from Rock Forming Environments to Solid Waste Recovering/Lithification”, grant number 2017 L83S77
Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants
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