Facile modular synthesis of jasmonoyl-l-isoleucine analogs possessing a pyrazolidin-3-one core.

A short and flexible route to pyrazolidin-3-one analogs of the phytohormone (+)-7-iso-jasmonoyl-l-isoleucine is presented. The compounds were assembled from four basic building blocks, namely a pyrazolidin-3-one core, alkyl chain, linker and amino ester or acid. The efficacy of this approach was demonstrated in the synthesis of 11 analogs with variations in all parts of the molecule.

Biological activities of 4H-thiochromen-4-one 1,1-dioxide derivatives against tropical disease parasites: A target-based drug design approach.

A promising strategy for developing novel therapies against tropical diseases, including malaria, leishmaniasis, and trypanosomiasis, is to detect biological targets such as trypanothione reductase, a vital parasite enzyme that regulates oxidative stress. This enzyme is highly selective and conserved in the Trypanosotidae family and has an ortholog in the Plasmodium genus. Previous studies have established that an isosteric replacement of naphthoquinone's carbonyl group with a sulfone group leads to compounds with high bioactivity and selectivity (half-maximal inhibitory concentration = 3 μM against intracellular amastigotes of , selectivity index = 153 over monocytes U-937).

Emotional and physical experiences of people with neovascular age-related macular degeneration during the injection process in Germany: a qualitative study.

Objectives: In order to better understand the continued barriers to the provision of vascular endothelial inhibitor therapy, this study aims to investigate patients' experiences with neovascular age-related macular degeneration (nvAMD) in Germany during the injection process and how they deal with it.

Design And Participants: This analysis is part of the qualitative arm of a wider mixed-methods study. We recruited participants all over Germany via ophthalmologists, eye clinics, general practitioners, care bases and support groups between June 2018 and December 2020 and selected a subsample of study participants with nvAMD who were either undergoing or had previously undergone vascular endothelial growth factor inhibitor therapy.

Presenting scientifically-derived illness experiences online - Evaluation of the use of the DIPEx Germany website.

Objective: To evaluate the real-time usage of krankheitserfahrungen.de, a website providing scientifically collected and analyzed experiences of persons with various chronic illnesses.

Methods: Web analytics of website use of www.

Learning-by-doing: the importance of experiential knowledge sharing for meeting the information needs of people with colorectal cancer in Germany-a qualitative study.

Objective: The aim of this article is to understand how, when and why the topics of information and information needs arise when people diagnosed with colorectal cancer (CRC) narrate their illness experiences.

Methods: Guided by principles of grounded theory, a qualitative interview study was conducted that collected a wide variety of illness experiences with CRC in Germany using maximum variation sampling. Sampling criteria included place of residence, age at interview, age at diagnosis, treatment, disease course and sociodemographic factors such as varying family backgrounds and professions.

An Artificial Cofactor Catalyzing the Baylis-Hillman Reaction with Designed Streptavidin as Protein Host*.

An artificial cofactor based on an organocatalyst embedded in a protein has been used to conduct the Baylis-Hillman reaction in a buffered system. As protein host, we chose streptavidin, as it can be easily crystallized and thereby supports the design process. The protein host around the cofactor was rationally designed on the basis of high-resolution crystal structures obtained after each variation of the amino acid sequence.

Fumarase Deficiency: A Case With a New Pathogenic Mutation and a Review of the Literature.

Fumarase deficiency (FD) is a rare and severe autosomal disorder, caused by inactivity of the enzyme fumarase, due to biallelic mutations of the fumarase hydratase () gene. Several pathogenic mutations have been published. The article describes an infant with failure to thrive, microcephaly, axial hypotonia, and developmental retardation with increased excretion of fumarate, no activity of fumarase and a homozygous mutation of the gene, which was until recently only known as a variant of unknown significance.

Connecting one's own illness story to the illness experiences of others on a website-An evaluation study using the think aloud method.

Objective: It is well described how telling one's illness story can help to cope with illness, but little is known about the processes of reception of other people's stories. This study aimed to analyse patients' reception processes of other patients' experiences while using a website (www.krankheitserfahrungen.

Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease.

The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular "Inside-Out" Approach.

Bisquinolizidine alkaloids are characterized by a chiral bispidine core (3,7-diazabicyclo[3.3.1]nonane) to which combinations of an α,N-fused 2-pyridone, an endo- or exo-α,N-annulated piperidin(on)e, and an exo-allyl substituent are attached.

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects.

Background: Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects.

Methods: In this study, we describe a mutation in the MYH7 gene, c. 5754C > G; p.

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

Purpose: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.

Design: Case series.

Participants: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.

[Patient experiences and patient centeredness : The website project DIPEx Germany].

Patient centeredness is a central concept in the treatment and rehabilitation of persons with chronic illness in Germany. There are various concepts of and approaches to patient centeredness, most of them developed from the perspective of health care research and the institutions. In terms of participation requirements, there has been a lack of understanding of the patient's perspective and experiences so far.

Diagnostic exome sequencing in 266 Dutch patients with visual impairment.

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity.

Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS.

Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing.

Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by the formation of numerous kidney cysts, is caused by PKD1 or PKD2 mutations and affects 0.1% of the population. Although recent clinical studies indicate that reduction of cAMP levels slows progression of PKD, this finding has not led to an established safe and effective therapy for patients, indicating the need to find new therapeutic targets.

Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry.

The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria.

Deletion of the entire interferon-γ receptor 1 gene causing complete deficiency in three related patients.

Purpose: Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene.

Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors.

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous α-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5 mC) hydroxylases.

[Maturity-onset diabetes of the young].

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes mellitus, estimated to account for approximately 1-4% of patients with diabetes. The predicted prevalence is, therefore, 20,000 patients in The Netherlands. Unfortunately less than 5% of these patients are confirmed by molecular genetic analysis.

The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions.

The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines.

LRP5 variants may contribute to ADPKD.

Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD).

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease.

In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury.