Total synthesis of [-]-anominine via target-directed organocatalysis: an asymmetric approach to the wieland-miescher ketone and analogues

[spa] La tesis doctoral consta de dos bloques principales. El primero es un estudio metodológico donde se estudia la preparación enantioselectiva de derivados de la cetona de Wieland-Miescher que posteriormente se empleará en el segundo bloque que es la síntesis total del diterpenoide fúngico anominina. En el estudio metodológico se implementó un catalizador que promoviese la reacción aldólica de forma estereoselectiva, tanto inter- como intramolecular. El estudio se centró en la reacción aldólica intramolecular de cetonas (anelación de Robinson) obteniendo distintos derivados de la cetona de Wieland-Miescher sustituidos en la posición 8a (metilo, alilo, dimetilalilo, bencilo, propargilo, homoalilo, isohexilo, isohexenilo y hasta 11 ejemplos). La metodología desarrollada evita el uso de disolventes, tanto en la reacción como en su purificación, consiguiendo así un protocolo más barato económicamente y que respeta el medio ambiente. Se probaron distintos catalizadores ya conocidos para esta transformación siendo el mejor N-tosyl-(Sa)-binam-L-prolinamida. Los rendimientos químicos y ópticos obtenidos (hasta 93% rendimiento y 97% ee con 2.5 mol% de catalizador) son notablemente superiores a los descritos anteriormente en la literatura y, teniendo en cuenta que la cetona de Wieland-Miescher es un precursor muy importante para la síntesis de terpenos y esteroides (como por ejemplo el agente antitumoral taxol), hace que esta mejora suponga un avance metodológico importante. El segundo bloque corresponde a la primera síntesis estereoselectiva del diterpenoide anominina, aislado del esclerocio del hongo Aspergillus nomius. Dicho producto natural presenta actividades insecticidas del orden de los piretroides comerciales frente a la especie Helicoverpa zea, una de las plagas más importantes en EUA en términos de pérdidas económicas. En esta parte de la tesis se utilizó la metodología desarrollada en el primer bloque para preparar estereoselectivamente el biciclo precursor de la síntesis. Una vez fijado el primer centro estereogénico se utilizó su inducción asimétrica para instalar los sucesivos estereocentros. Así, las reacciones claves para la síntesis son: la adición conjugada de metilcuprato para generar estereoselectivamente el segundo centro cuaternario; una transposición 2,3-sigmatrópica de selenóxido; una hidrogenación quimioselectiva; una oxidación alílica mediada por microondas; una adición conjugada de indol catalizada por tetracloruro de zirconio y una reacción quimioselectiva de metátesis de alquenos. Además, otros aspectos interesantes de la ruta sintética son el acoplamiento de reacciones consecutivas evitando purificaciones por cromatografía en columna, cosa que reduce los costes así como los tiempos de manipulación experimental. Finalmente, decir que la metodología desarrollada no sólo sirve para la preparación de dicho terpeno sino que supone también una ruta sintética hacia la familia de productos naturales aislados de hongos Aspergillus

Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer

Non-Perturbative Effects on a Fractional D3-Brane

In this note we study the N=1 abelian gauge theory on the world volume of a single fractional D3-brane. In the limit where gravitational interactions are not completely decoupled we find that a superpotential and a fermionic bilinear condensate are generated by a D-brane instanton effect. A related situation arises for an isolated cycle invariant under an orientifold projection, even in the absence of any gauge theory brane. Moreover, in presence of supersymmetry breaking background fluxes, such instanton configurations induce new couplings in the 4-dimensional effective action, including non-perturbative contributions to the cosmological constant and non-supersymmetric mass terms.Comment: 18 pages, v3: refs adde

Identification of non-canonical Wnt receptors required for Wnt-3a-induced early differentiation of human neural stem cells

Wnt proteins preferentially activate either β-catenin-dependent or β-cateninindependent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a β-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a. Silencing of ROR2 increased neuronal differentiation, as measured by expression of the genes DCX, NEUROD1 and NGN1, suggesting ROR2 signals normally prevent differentiation. Silencing of the other Wnt receptors singly did not affect Wnt-3ainduced neuronal differentiation. However, pair-wise silencing of ROR1 and FZD4 or FZD5 and of LRP6 and FZD4 or FZD5 inhibited neuronal differentiation, as detected by reductions in the expression of neuronal genes and immunocytochemical detection of DCX and NEUROD1 and DCX. Ectopic expression of these receptors in HEK 293 cells increased ATF2-dependent transcription. In addition, ROR1 co-immunoprecipitated with FZD4 and LRP6 in transfected HEK 293 cells and colocalized with FZD4 and with LRP6 at the cell surface of transfected L cells. Wnt-3a did not appear to affect these interactions but did alter the interactions between LRP6 and FZD4/5. Together, these observations highlight roles for ROR1, LRP6, FZD4 and FZD5 in neural stem cell differentiation and provide support for a model in which dynamic interactions among these receptors mediate Wnt-3a activation of ATF2 signaling

The Standard Model quiver in de Sitter string compactifications

We argue that the Standard Model quiver can be embedded into compact Calabi-Yau geometries through orientifolded D3-branes at del Pezzo singularities dPn with n ≥ 5 in a framework including moduli stabilisation. To illustrate our approach, we explicitly construct a local dP5 model via a combination of Higgsing and orientifolding. This procedure reduces the original dP5 quiver gauge theory to the Left-Right symmetric model with three families of quarks and leptons as well as a Higgs sector to further break the symmetries to the Standard Model gauge group. We embed this local model in a globally consistent Calabi-Yau flux compactification with tadpole and Freed-Witten anomaly cancellations. The model features closed string moduli stabilisation with a de Sitter minimum from T-branes, supersymmetry broken by the Kähler moduli, and the MSSM as the low energy spectrum. We further discuss phenomenological and cosmological implications of this construction

Prevalence of post-traumatic stress disorder (PTSD) in university students during the COVID-19 pandemic: a meta-analysis attending SDG 3 and 4 of the 2030 agenda

Background: Most universities around the world have been heavily affected by the COVID-19 pandemic, as declared by the World Health Organization (WHO) in March 2020. Many students were isolated at home and underwent a forced transition from face-to-face learning to e-learning, at least in the first few months. The subsequent months and years were typically characterised by a slow return to normal learning under COVID-19 protocols and restrictions. A potential consequence of the lockdowns, social restrictions and changes to learning is the development of PTSD (post-traumatic stress disorder) in university students, affecting their health and well-being (SDG3) and quality of education (SDG4). Materials and Methods: Medline was searched through PubMed for studies on the prevalence of PTSD in university students from 1 December 2019 to 31 December 2021. The pooled prevalence of PTSD was calculated with random-effects models. Results: A total of six studies were included, across which the prevalence of PTSD among university students was 23%. Meta-regression showed that the prevalence of PTSD was significantly higher with older age, but independent of the percentage of women in a study or its methodological quality. Conclusions: Our results suggest that students suffer from PTSD at a moderate rate. Measures are needed to address the mental health issues of university students that have arisen during COVID-19 all around the world. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

A natural renormalizable model of metastable SUSY breaking

We propose a model of metastable dynamical supersymmetry breaking in which all scales are generated dynamically. Our construction is a simple variant of the Intriligator-Seiberg-Shih model, with quark masses induced by renormalizable couplings to an auxiliary supersymmetric QCD sector. Since all scales arise from dimensional transmutation, the model has no fundamental dimensionful parameters. It also does not rely on higher-dimensional operators.Comment: 9 pages; v2: typos correcte

Four-modulus "Swiss Cheese" chiral models

We study the 'Large Volume Scenario' on explicit, new, compact, four-modulus Calabi-Yau manifolds. We pay special attention to the chirality problem pointed out by Blumenhagen, Moster and Plauschinn. Namely, we thoroughly analyze the possibility of generating neutral, non-perturbative superpotentials from Euclidean D3-branes in the presence of chirally intersecting D7-branes. We find that taking proper account of the Freed-Witten anomaly on non-spin cycles and of the Kaehler cone conditions imposes severe constraints on the models. Nevertheless, we are able to create setups where the constraints are solved, and up to three moduli are stabilized.Comment: 40 pages, 10 figures, clarifying comments added, minor mistakes correcte

D-brane Instantons as Gauge Instantons in Orientifolds of Chiral Quiver Theories

Systems of D3-branes at orientifold singularities can receive non-perturbative D-brane instanton corrections, inducing field theory operators in the 4d effective theory. In certain non-chiral examples, these systems have been realized as the infrared endpoint of a Seiberg duality cascade, in which the D-brane instanton effects arise from strong gauge theory dynamics. We present the first UV duality cascade completion of chiral D3-brane theories, in which the D-brane instantons arise from gauge theory dynamics. Chiral examples are interesting because the instanton fermion zero mode sector is topologically protected, and therefore lead to more robust setups. As an application of our results, we provide a UV completion of certain D-brane orientifold systems recently claimed to produce conformal field theories with conformal invariance broken only by D-brane instantons.Comment: 50 pages, 32 figures. v2: version published in JHEP with references adde