152 research outputs found
Conformational analysis of a TADDOL-based phosphoramidite P,N ligand in a palladium(II) η3-Ï-allyl complex
Highlights Two lowest energy conformers differ in allyl conformation, conformer with exo allyl having lower energy. Lowest energy conformer has âchairâ conformation of 7-membered ring and âedge-on/face-on/face-on/edge-onâ array of pH groups. Next lowest energy conformer with exo allyl has alternating âedge-on/face-onâ arrangement and âtwistâ 7-membered ring. Changes in âchair/twistâ conformations with different substrates is possible due to 2.4âŻkcal/mol energy difference. These results explain stereochemical outcome of the reaction, and will guide design of new catalysts. Abstract The most stable conformations of a TADDOL-based phosphoramidite P,N ligand coordinated to a palladium(II) η3-Ï-allyl fragment have been investigated using molecular mechanical and quantum mechanical calculations. The conformational analysis initially generated 53 unique structures within 5âŻkcal/mol and subsequent geometry optimization narrowed the number of low-energy conformers down to 13. The two lowest energy conformers differ mainly in the conformation of the allyl group. The conformer with an endo allyl group has a slightly higher relative energy than the conformer with an exo allyl group. Comparison of the main geometric parameters around the Pd(II) metal center in the two lowest energy conformers with the available X-ray single crystal structures of Pd(II) η3-Ï-allyl complexes of P,N ligands shows a good agreement in both the bond lengths and angles. The lowest energy structure has a âchairâ conformation of the seven-membered phospha-dioxa-cycloheptane ring and âedge-on/face-on/face-on/edge-onâ arrangement of the phenyl rings. The next lowest energy conformer with an exo allyl group has a âtwistâ conformation of the seven-membered ring and alternating âedge-onâ and âface-onâ arrangement of the phenyl rings as anticipated from the Knowles âedge-on/face-onâ concept. The results of this study support published hypotheses regarding the origin of the chiral induction in the enantioselective Pd(0) catalyzed intramolecular allylic alkylation reaction by the repulsive interactions between one of the phenyl groups in the seven-membered ring in the lowest energy conformer of the ligand with the substrate. As such, the results of this research can be used to guide the synthesis of new and improved variants of this important catalyst family
Ortho-Fluoro Effect on the CâC Bond Activation of Benzonitrile Using Zerovalent Nickel
The effect of fluoro substitution on the CâC bond activation of aromatic nitriles has been studied by reacting a variety of fluorinated benzonitriles with the nickel(0) fragment [Ni(dippe)] and by locating the reaction intermediates and transition-state structures on the potential energy surface by using density functional theory calculations with the [Ni(dmpe)] fragment (dippe = 1,2-bis(diisopropylphosphino)ethane, dmpe = 1,2-bis(dimethylphosphino)ethane). As in the previous reports, the reaction of fluorinated benzonitriles with the [Ni(dippe)] fragment initially formed an η2-nitrile complex, which then converted to the CâCN bond activation product. Thermodynamic parameters for the equilibrium between these complexes have been determined experimentally in both a polar (tetrahydrofuran) and a nonpolar (toluene) solvent for 3-fluoro- and 4-fluorobenzonitrile. The stability of the CâC bond activation products is shown to be strongly dependent on the number of ortho-F substituents (â6.6 kcal/mol per o-F) and only slightly dependent on the number of meta-F substituents (â1.8 kcal/mol per m-F)
Investigation on the Synthesis, Application and Structural Features of Heteroaryl 1,2-Diketones
A set of unsymmetrical heteroaryl 1,2-diketones were synthesized by a heteroarylation/oxidation sequence with up to 65% isolated yields. Palladium catalyst XPhos Pd G4 and SeO2 were the key reagents used in this methodology, and microwave irradiation was utilized to facilitate an efficient and ecofriendly process. The application of heteroaryl 1,2-diketones is demonstrated through the synthesis of an unsymmetrical 2-phenyl-3-(pyridin-3-yl)quinoxaline (5a) from 1-phenyl-2-(pyridin-3-yl)ethane-1,2-dione (4a). The lowest energy conformations of 4a and 5a were located using Density Functional Theory (DFT) at the M06-2X/def2-TZVP level of theory. Two lowest energy conformations of 4a differ with respect to the position of the N atom in the pyridyl ring and 0.27 kcal/mol energy difference between them corresponds to 60.4 and 39.6% at 50 °C in toluene. Four lowest energy conformations for 5a have the energy differences of 0.01, 0.03 and 0.07 kcal/mol that corresponds to 26.0, 25.7, 24.9 and 23.4%, respectively. A comparison of 4a and 5a to the less hindered analogs (oxalyl chloride and oxalic acid) is used to investigate the structural features and bonding using Natural Bond Orbital (NBO) analysis
Ex Vivo Drug Testing in Patient-derived Papillary Renal Cancer Cells Reveals EGFR and the BCL2 Family as Therapeutic Targets
BACKGROUND
Immune checkpoint inhibitors and antiangiogenic agents are used for first-line treatment of advanced papillary renal cell carcinoma (pRCC) but pRCC response rates to these therapies are low.
OBJECTIVE
To generate and characterise a functional ex vivo model to identify novel treatment options in advanced pRCC.
DESIGN, SETTING, AND PARTICIPANTS
We established patient-derived cell cultures (PDCs) from seven pRCC samples from patients and characterised them via genomic analysis and drug profiling.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Comprehensive molecular characterisation in terms of copy number analysis and whole-exome sequencing confirmed the concordance of pRCC PDCs with the original tumours. We evaluated their sensitivity to novel drugs by generating drug scores for each PDC.
RESULTS AND LIMITATIONS
PDCs confirmed pRCC-specific copy number variations such as gains in chromosomes 7, 16, and 17. Whole-exome sequencing revealed that PDCs retained mutations in pRCC-specific driver genes. We performed drug screening with 526 novel and oncological compounds. Whereas exposure to conventional drugs showed low efficacy, the results highlighted EGFR and BCL2 family inhibition as the most effective targets in our pRCC PDCs.
CONCLUSIONS
High-throughput drug testing on newly established pRCC PDCs revealed that inhibition of EGFR and BCL2 family members could be a therapeutic strategy in pRCC.
PATIENT SUMMARY
We used a new approach to generate patient-derived cells from a specific type of kidney cancer. We showed that these cells have the same genetic background as the original tumour and can be used as models to study novel treatment options for this type of kidney cancer
Investigation on the Synthesis, Application and Structural Features of Heteroaryl 1,2-Diketones
A set of unsymmetrical heteroaryl 1,2-diketones were synthesized by a heteroarylation/oxidation sequence with up to 65% isolated yields. Palladium catalyst XPhos Pd G4 and SeO2 were the key reagents used in this methodology, and microwave irradiation was utilized to facilitate an efficient and ecofriendly process. The application of heteroaryl 1,2-diketones is demonstrated through the synthesis of an unsymmetrical 2-phenyl-3-(pyridin-3-yl)quinoxaline (5a) from 1-phenyl-2-(pyridin-3-yl)ethane-1,2-dione (4a). The lowest energy conformations of 4a and 5a were located using Density Functional Theory (DFT) at the M06-2X/def2-TZVP level of theory. Two lowest energy conformations of 4a differ with respect to the position of the N atom in the pyridyl ring and 0.27 kcal/mol energy difference between them corresponds to 60.4 and 39.6% at 50 °C in toluene. Four lowest energy conformations for 5a have the energy differences of 0.01, 0.03 and 0.07 kcal/mol that corresponds to 26.0, 25.7, 24.9 and 23.4%, respectively. A comparison of 4a and 5a to the less hindered analogs (oxalyl chloride and oxalic acid) is used to investigate the structural features and bonding using Natural Bond Orbital (NBO) analysis
Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development
Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.
Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46, XY DSD. Additional cases with 46, XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-beta (ER-beta) was performed in an 8-week-old human male embryo.
Results: We identified a homozygous ESR2 variant, c.541_543del p. (Asn181del), located in the highly conserved DNA-binding domain of ER-beta, in an individual with syndromic 46, XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-beta, were found in unrelated, nonsyndromic 46, XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-beta immunostaining was positive in the developing intestine and eyes.
Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46, XY DSD
Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe
Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to â„ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of â„ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of â„ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by ana
Urban and rural differences in frequency of fruit, vegetable, and soft drink consumption among 6â9âyearâold children from 19 countries from the WHO European region
In order to address the paucity of evidence on the association between childhood eating habits and urbanization, this cross-sectional study describes urbanârural differences in frequency of fruit, vegetable, and soft drink consumption in 123,100 children aged 6â9 years from 19 countries participating in the fourth round (2015-2017) of the WHO European Childhood Obesity Surveillance Initiative (COSI). Children's parents/caregivers completed food-frequency questionnaires. A multivariate multilevel logistic regression analysis was performed and revealed wide variability among countries and within macroregions for all indicators. The percentage of children attending rural schools ranged from 3% in Turkey to 70% in Turkmenistan. The prevalence of less healthy eating habits was high, with between 30â80% and 30â90% children not eating fruit or vegetables daily, respectively, and up to 45% consuming soft drinks on >3 days a week. For less than one third of the countries, children attending rural schools had higher odds (OR-range: 1.1â2.1) for not eating fruit or vegetables daily or consuming soft drinks >3 days a week compared to children attending urban schools. For the remainder of the countries no significant associations were observed. Both population-based interventions and policy strategies are necessary to improve access to healthy foods and increase healthy eating behaviors among children.The authors gratefully acknowledge support from a grant from the
Russian Government in the context of the WHO European Office for
the Prevention and Control of NCDs.
Data collection in the countries was made possible through
funding from Albania: WHO through the Joint Programme on
Children, Food Security and Nutrition âReducing Malnutrition in
Children,â funded by the Millennium Development Goals Achievement Fund, and the Institute of Public Health; Austria: Federal Ministry of Social Affairs, Health, Care and Consumer Protection, Republic
of Austria; Bulgaria: Ministry of Health, National Center of Public
Health and Analyses, WHO Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and WHO
Regional Office for Europe; Ministry of Health of the Czech Republic,
grant nr. AZV MZÄR 17-31670 A and MZÄRâRVO EĂ 00023761;
Denmark: Danish Ministry of Health; Estonia: Ministry of Social
Affairs, Ministry of Education and Research (IUT 42-2), WHO Country
Office, and National Institute for Health Development; Georgia:
WHO; Ireland: Health Service Executive; Italy: Ministry of Health and
Italian National Institute of Health; Kazakhstan: Ministry of Health of
the Republic of Kazakhstan and WHO Country Office; Kyrgyzstan:
World Health Organization; Latvia: Ministry of Health, Centre for
Disease Prevention and Control; Lithuania: Science Foundation of
Lithuanian University of Health Sciences and Lithuanian Science
Council and WHO; Malta: Ministry of Health; Montenegro: WHO and
Institute of Public Health of Montenegro; North Macedonia: COSI in
North Macedonia is funded by the Government of North Macedonia
through National Annual Program of Public Health and implemented
by the Institute of Public Health and Centers of Public Health in the
country. WHO country office provides support for training and data
management; Norway: Ministry of Health and Norwegian Institute of
Public Health; Poland: National Health Programme, Ministry of
Health; Portugal: Ministry of Health Institutions, the National Institute
of Health, Directorate General of Health, Regional Health Directorates and the kind technical support from the Center for Studies and
Research on Social Dynamics and Health (CEIDSS); Romania: Ministry
of Health; Serbia: This study was supported by the World Health
Organization (Ref. File 2015-540940); Slovakia: Biennial Collaborative
Agreement between WHO Regional Office for Europe and Ministry
of Health SR; Spain: Spanish Agency for Food Safety and Nutrition
(AESAN); Tajikistan: WHO Country Office in Tajikistan and Ministry
of Health and Social Protection; Turkmenistan: WHO Country Office
in Turkmenistan and Ministry of Health; Turkey: Turkish Ministry of
Health and World Bank.info:eu-repo/semantics/publishedVersio
Echinoderms from the Museum of Zoology from the Universidad de Costa Rica
El Museo de ZoologĂa de la Universidad de Costa Rica (MZUCR) se funda en 1966 y alberga la colecciĂłn de organismos vertebrados e invertebrados mĂĄs completa de Costa Rica. El MZUCR cuenta actualmente con 24 colec-ciones que contienen mĂĄs de cinco millones de especĂme-nes, y mĂĄs de 13 000 especies identificadas. Las primeras colecciones datan 1960 e incluyen peces, reptiles, anfibios, poliquetos, crustĂĄceos y equinodermos. Para este Ășltimo grupo, el MZUCR posee un total de 157 especies, en 1 173 lotes y 4 316 ejemplares. Estas 157 especies representan el 54% del total de especies de equinodermos que posee Costa Rica (293 especies). El resto de especies estĂĄn repar-tidas en las siguientes instituciones: Academia de la Cien-cias de California (CAS) (4.8%), Instituto OceanogrĂĄfico Scripps (SIO) (5.2%), en la ColecciĂłn Nacional de equino-dermos âDra. Ma. Elena Casoâ de la Universidad Nacional AutĂłnoma de MĂ©xico (ICML-UNAM) (12.7%), Museo de ZoologĂa Comparada de Harvard (MZC) (19.2%), y en el Museo Nacional de Historia Natural del Instituto Smithso-niano (USNM) (35.1%). Es posible que haya material de Costa Rica en el Museo de Historia Natural de Dinamarca (NCD) y en el Museo de Historia Natural de los Ăngeles (LACM), sin embargo, no hubo acceso a dichas coleccio-nes. A su vez hay 9.6% de especies que no aparecen en ningĂșn museo, pero estĂĄn reportadas en la literatura. Con base en esta revisiĂłn de colecciones se actualizĂł el listado taxonĂłmico de equinodermos para Costa Rica que consta de 293 especies, 152 gĂ©neros, 75 familias, 30 Ăłrdenes y cinco clases. La costa PacĂfica de Costa Rica posee 153 especies, seguida por la isla del Coco con 134 y la costa Caribe con 65. Holothuria resultĂł ser el gĂ©nero mĂĄs rico con 25 especies.The Museum of Zoology, Universidad de Costa Rica (MZUCR) was founded in 1966 and houses the most complete collection of vertebrates and invertebrates in Costa Rica. The MZUCR currently has 24 collections containing more than five million specimens, and more than 13 000 species. The earliest collections date back to 1960 and include fishes, reptiles, amphibians, polychaetes, crustaceans and echinoderms. For the latter group, the MZUCR has a total of 157 species, in 1 173 lots and 4 316 specimens. These 157 species represent 54% of the total species of echino-derms from Costa Rica. The remaining species are distributed in the following institutions: California Academy of Sciences (CAS) (4.8%), Scripps Oceanographic Institute (SIO) (5.2%), National Echinoderm Collection âDr. Ma. Elena Casoâ from the National Autonomous University of Mexico (ICML-UNAM) (12.7%), the National Museum of Natural History, Smithsonian Institute (USNM) (35.1%), and the Harvard Museum of Comparative Zoology (19.2%). There may be material from Costa Rica in the Natural History Museum of Denmark (NCD) and the Natural History Museum of Los Angeles (LACM), however, there was no access to such collections. There are 9.6% that do not appear in museums, but are reported in the literature. Based on this revision, the taxonomic list of echinoderms for Costa Rica is updated to 293 species, 152 genera, 75 families, 30 orders and 5 classes. The Pacific coast of Costa Rica has 153 species, followed by the Isla del Coco with 134 and the Caribbean coast with 65. Holothuria is the most diverse genus with 25 species.UCR::VicerrectorĂa de Docencia::Ciencias BĂĄsicas::Facultad de Ciencias::Escuela de BiologĂaUCR::VicerrectorĂa de InvestigaciĂłn::Unidades de InvestigaciĂłn::Ciencias BĂĄsicas::Centro de InvestigaciĂłn en Ciencias del Mar y LimnologĂa (CIMAR)UCR::VicerrectorĂa de InvestigaciĂłn::Unidades de InvestigaciĂłn::Artes y Letras::Museo de la Universidad de Costa Ric
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