Synthesis of axially chiral heterobiaryl alkynes via dynamic kinetic asymmetric alkynylation

The dynamic kinetic Pd0 -catalyzed alkynylation of racemic heterobiaryl sulfonates was used for the asymmetric synthesis of axially chiral heterobiaryl alkynes with a broad scope. The use of Pd(OAc)2/ (S)-QUINAP as the precatalyst provides products in excellent yields and enantioselectivities under mild conditions (DMSO, 40 8C). Semireduction, 1,3-dipolar cycladdition or N-oxidation served to illustrate the synthetic potential of the methodology

在非虚构绘本书籍和教科书中阅读和学习的情感过程

The consideration of the emotional processes of learning is a growing didactic line, as well as the edition of nonfiction illustrated books for children and young readers. The “new nonfiction” shows a hybridisation of genres, textual structures and semantic codes. Its careful format, interactive resources and abundant illustrations add aesthetic and playful components to reading and learning, while still offering rigorous content. These characteristics distinguish them from informative books and, above all, from textbooks. To what extent do they also add important emotional components to the cognitive processes of learning, usually prioritized? Which of its features create and reinforce “opportunities for learning”? Using the criteria of the Orbis Pictus Award Committee, we analysed a nonfiction illustrated book about ancient Egypt and contrasted it with the didactic unit of a 1st ESO book on the same subject. The results show that the organization, design and style of the nonfiction work make information attractive, stimulate the attitude of inquiry, creativity and play, reinforce the construction of meaning through recursive reading and fuse the cognitive and emotional components of reading and learning, far from the mere assimilation of informative content. In conclusion, the nonfiction work turns learning into a vivid experience, as compared to the more expository and cold approach of the textbook.La consideración de los procesos emocionales del aprendizaje constituye una línea didáctica en auge, al igual que la edición de libros ilustrados de no-ficción para lectores infantiles o juveniles. La “nueva no-ficción” muestra una hibridación de géneros, estructuras textuales y códigos semánticos. Su cuidado formato, recursos interactivos y abundantes ilustraciones añaden componentes estéticos y lúdicos a la lectura y al aprendizaje, sin dejar de ofrecer contenidos rigurosos. Estas características distinguen a los libros ilustrados de no-ficción de los libros informativos y, sobre todo, de los libros de texto. ¿En qué medida añaden también importantes componentes emocionales a los procesos cognitivos del aprendizaje, habitualmente priorizados? ¿Cuáles de sus características crean “oportunidades para el aprendizaje” y lo refuerzan? Utilizando los criterios del Orbis Pictus Award Committee, analizamos un libro ilustrado de no-ficción sobre el antiguo Egipto y lo contrastamos con la unidad didáctica de un libro de 1.º de Educación Secundaria Obligatoria (ESO) sobre el mismo tema. Los resultados muestran que la organización, diseño y estilo de la obra de no-ficción hacen atractiva la información, estimulan la actitud de indagación, la creatividad y el juego, refuerzan la construcción del sentido mediante la lectura recursiva y fusionan los componentes cognitivos y emocionales de la lectura y del aprendizaje, lejos de la mera asimilación de contenidos informativos. En conclusión, la obra de no-ficción convierte el aprendizaje en una experiencia vívida, frente al enfoque más expositivo y frío del libro de texto.Рассмотрение эмоциональных процессов обучения является растущим дидактическим направлением, как и публикация иллюстрированных нехудожественных книг для детей и юных читателей. Новый non-fiction демонстрирует гибридизацию жанров, текстовых структур и семантических кодов. Их аккуратный формат, интерактивные ресурсы и обилие иллюстраций добавляют эстетические и игровые компоненты к чтению и обучению, но при этом предлагают строгое содержание. Эти особенности отличают нехудожественные книги с картинками от информационных книг и, прежде всего, от учебников. В какой степени они также добавляют к когнитивным процессам обучения важные эмоциональные компоненты, которые обычно ставятся на первое место? Какие из их особенностей создают “возможности для обучения” и усиливают обучение? Используя критерии комитета премии Orbis Pictus, мы проанализировали нехудожественную книгу с иллюстрациями о Древнем Египте и сравнили ее с учебным блоком учебника обязательной средней школы по той же теме. Результаты показывают, что организация, дизайн и стиль нехудожественной литературы делают информацию привлекательной, стимулируют отношение к поиску, творчеству и игре, усиливают построение смысла через рекурсивное чтение и объединяют когнитивные и эмоциональные компоненты чтения и обучения, далекие от простого усвоения содержания информации. В заключение следует отметить, что нон-фикшн превращает обучение в яркий опыт, в отличие от более экспозиционного и холодного подхода учебника.对学习的情感过程的考虑以及为儿童或年轻读者出版的非虚构类绘本书籍构成了一条正在兴起的教学路线。 “新型非虚构”展示了体裁、文本结构和语义代码的混合。其精心的格式、互动资源和丰富的插图在提供严谨的内容的同时，也为阅读和学习增添了审美和趣味性。这些特征将非虚构绘本类书籍与信息书籍区分开来，尤其是与教科书区分开来。他们在多大程度上为学习的认知过程添加了通常会优先考虑的重要的情感成分？它的哪些特征创造了“学习机会”并对其进行加强？ 我们使用 Orbis Pictus Award Committee的标准，分析了一本关于古埃及的非虚构绘本类书籍，并将其与中学一年级 (ESO) 同一主题教学单元的教科书进行对比。 结果表明，非虚构作品的组织、设计和风格使信息具有吸引力，激发了探究、创造力和游戏的态度，通过递归阅读加强了意义的构建，融合了学习和阅读中的认知和情感成分，而不仅仅是对信息内容的同化。 总而言之，非虚构作品让学习成为一种生动的体验，而不是教科书更多的说明性和冷冰冰的方法

Novel genes and sex differences in COVID-19 severity.

post-print1561 K

Vaccine breakthrough infections with SARS-CoV-2 Alpha mirror mutations in Delta Plus, Iota, and Omicron.

Replication of SARS-CoV-2 in the human population is defined by distributions of mutants that are present at different frequencies within the infected host and can be detected by ultra-deep sequencing techniques. In this study, we examined the SARS-CoV-2 mutant spectra of amplicons from the spike-coding (S-coding) region of 5 nasopharyngeal isolates derived from patients with vaccine breakthrough. Interestingly, all patients became infected with the Alpha variant, but amino acid substitutions that correspond to the Delta Plus, Iota, and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from patients with vaccine breakthrough revealed a rich reservoir of mutant types and may also identify tolerated substitutions that can be represented in epidemiologically dominant variants.post-print656 K

SARS-CoV-2 Point Mutation and Deletion Spectra and Their Association with Different Disease Outcomes

Mutant spectra of RNA viruses are important to understand viral pathogenesis and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultradeep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)- coding regions of 30 nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low-frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype, and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three-dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19. IMPORTANCE The study shows that mutant spectra of SARS-CoV-2 from diagnostic samples differ in point mutation abundance and complexity and that significantly larger values were observed in virus from patients who developed mild COVID-19 symptoms. Mutant spectrum complexity is not a uniform trait among isolates. The nature and location of low-frequency amino acid substitutions present in mutant spectra anticipate great potential for phenotypic diversification of SARS-CoV-2.post-print3280 K

Androgen receptor polyQ alleles and COVID-19 severity in men: A replication study.

Background Ample evidence indicates a sex-related difference in severity of COVID-19, with less favorable outcomes observed in men. Genetic factors have been proposed as candidates to explain this difference. The polyglutamine (polyQ) polymorphism in the androgen receptor gene has been recently described as a genetic biomarker of COVID-19 severity. Objective To test the association between the androgen receptor polyQ polymorphism and COVID-19 severity in a large cohort of COVID-19 male patients. Materials and methods This study included 1136 male patients infected with SARS-CoV-2 as confirmed by positive PCR. Patients were retrospectively and prospectively enrolled from March to November 2020. Patients were classified according to their severity into three categories: oligosymptomatic, hospitalized and severe patients requiring ventilatory support. The number of CAG repeats (polyQ polymorphism) at the androgen receptor was obtained by PCR and patients were classified as either short (<23 repeats) or long (≥23 repeats) allele carriers. The association between polyQ alleles (short or long) and COVID-19 severity was assessed by Chi-squared (Chi2) and logistic regression analysis. Results The mean number of polyQ CAG repeats was 22 (±3). Patients were classified as oligosymptomatic (15.5%), hospitalized (63.2%), and severe patients (21.3%) requiring substantial respiratory support. PolyQ alleles distribution did not show significant differences between severity classes in our cohort (Chi2 test p > 0.05). Similar results were observed after adjusting by known risk factors such as age, comorbidities, and ethnicity (multivariate logistic regression analysis). Discussion Androgen sensitivity may be a critical factor in COVID-19 disease severity. However, we did not find an association between the polyQ polymorphism and the COVID-19 severity. Additional studies are needed to clarify the mechanism underlying the association between androgens and COVID-19 outcome. Conclusions The results obtained in our study do not support the role of this polymorphism as biomarker of COVID-19 severity.post-print253 K

Análogos fluorescentes de fármacos lipídicos con actividad antiparasitaria y antineoplásica. Diseño, síntesis y aplicaciones

Tesis leída en la Facultad de Ciencias Químicas en octubre de 2009.La emisión de fluorescencia en fase condensada es un proceso de origen electrónico, lo que ha retrasado históricamente su comprensión, a pesar de que las primeras observaciones del fenómeno se realizaron en Sevilla ya en el siglo XVI.1 Hoy en día se sabe que las molécula excitadas electrónicamente por absorción fotónica permanecen nanosegundos en dicho estado excitado, un tiempo que es ~ 106 veces mayor que el requerido para la excitación. En la mayoría de los casos, la molécula pierde este exceso de energía electrónica a través de procesos no radiantes. Sin embargo, para un número reducido de compuestos la probabilidad de la emisión es mayor que la de los procesos no radiantes y, por tanto, se produce emisión de fluorescencia. Como era de esperar, se ha dedicado un gran esfuerzo investigador a lo largo de casi un siglo para determinar los factores electrónicos y estructurales que optimizan las propiedades emisivas de una molécula; sin embargo, todavía hoy el diseño de nuevos grupos fluorescentes (fluoróforos) se lleva a cabo de forma semi-empírica. En contraste, el desarrollo de las técnicas instrumentales para la excitación y detección de fluorescencia ha progresado considerablemente.Peer reviewe

Dynamic Kinetic Resolution of Hetero biaryl Ketones by Zinc- Catalyzed Asymmetr ic Hydrosil ylation

Adiastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile hetero- biaryl ketones is described. The DKR proceeds by zinc- catalyze dhydrosilylation of the carbonyl group ,thus leading to secondary alcohols bearing axial and central chirality .The strategy relies on the labilization of the stereogenic axis that takes place thanks to aLewis acid–base interaction between anitrogen atom in the heterocycle and the ketone carbonyl group .The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocata- lysts.Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P, CTQ2016-76908-C2-2-P, contract RYC-2013-12585)European FEDER FundsJunta de Andalucía (Grant 2012/FQM 10787)European Union - Marie Skłodowska-Curie (COFUND—Grant Agreement n 8 8 291780