A Practical Catalytic Reductive Amination of Carboxylic Acids

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced

Childbirth experience questionnaire 2 – Icelandic translation and validation

Funding Information: We would like to thank the women who took time to participate in the study. Furthermore, we would like to acknowledge Dr. Anna Dencker for the permission to translate the CEQ and useful advice regarding the translation and validation process. The study received financial support from The Icelandic Centre for Research and the Memorial Fund of Midwife Björg Magnúsdóttir and Farmer Magnús Jónasson. Publisher Copyright: © 2023 The Authors Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.Objective: The aim of this study was to translate the Childbirth Experience Questionnaire (CEQ2) to Icelandic and assess its psychometric characteristics. Methods: The CEQ2 was translated to Icelandic using forward-to-back translation and tested for face-validity (n = 10). Then data was collected in an online survey to test validation in terms of reliability and construct validity (n = 1125). Reliability was assessed by calculating Cronbach's alpha for the total scale and subscales. Cronbach's alpha > 0.7 was regarded as satisfactory. Construct validity was measured using known-groups validation with data collected on women's birth outcomes known to be associated with more positive birth experiences. A comparison was made of CEQ2 subscale scores and total CEQ2 score for country of origin, social complications, parity, pregnancy complications, birthplace, mode of birth, maternal autonomy and decision making (MADM), and mothers on respect index (MORi). Mann Whitney U and Kruskal Wallis H tests were used to compare scale scores between the groups. Principal components analysis with varimax rotation was chosen to determine whether the Icelandic version of the CEQ had similar psychometric properties as the original version. Results: The face validity and internal consistency reliability (Cronbach's alpha > 0.85 for the total scale and all subscales) of the Icelandic version of CEQ2 was good. Our findings indicate that two of the items in the 'own capacity' domain were not sufficiently related to other items of the scale to warrant inclusion. Conclusions: The Icelandic CEQ2 is a valid and reliable measure of childbirth experience but further work is needed to determine the optimal number of items and domains of the Icelandic CEQ2.Peer reviewe

Gaining insight from future mothers : A survey of attitudes and perspectives of childbirth

Funding Information: We thank Dr. Caroline Stretton (AUT University, School of Public Health & Interdisciplinary Studies) and Dr. Jean Rankin (University of the West of Scotland, School of Health and Life Sciences) for their contribution to this article in its early inception. Not applicable. Publisher Copyright: © 2022Objective: To determine whether participant characteristics and/or birth preferences of future mothers are associated with a fear of birth. Design: A cross-sectional survey was used to determine if fear of birth could be profiled in specific participant characteristics and birth choices. Setting: Urban New Zealand university. Participants: A convenience sample of women (final n = 339) who were 20 (‘severe’) for depression on DASS-21 scale (n=11, mean CFPP=44.8, SE=1.7, p < 0.0001) were all positively associated with CFPP. Post-hoc analyses revealed that mean CFPP was higher for those that perceived birth technologies as easier, safer, necessary, and required. Conclusions: Women born outside of New Zealand and/or suffering ‘severe’ depression were more likely to have a fear of birth. Fear of birth was associated with the participants choices towards medicalised childbirth. Familiarising women with the provision of maternity care in New Zealand and identifying mental health status early could reduce fear of birth and possibly support the vaginal birth intentions of future parents.Peer reviewe

A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease

The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action. © 2020 by the authors

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

A cross-country survey of attitudes toward childbirth technologies and interventions among university students

Problem & Aim: Cultural beliefs that equate birth technology with progress, safety and convenience contribute to widespread acceptance of childbirth technology and interventions. Little is known about attitudes towards childbirth technology and interventions among the next generation of maternity care users and whether attitudes vary by country, age, gender, childbirth fear, and other factors. Methods: Data were collected via online survey in eight countries. Students who had never had children, and who planned to have at least one child were eligible to participate. Findings: The majority of participants (n= 4569) were women (79.3%), and the median age was 22 years. More than half of students agreed that birth technology makes birth easier (55.8 %), protects babies from harm (49.1 %) and that women have a right to choose a medically non-indicated cesarean (50.8 %).Respondents who had greater acceptance of childbirth technology and interventions were from countries with higher national caesarean birth rates, reported higher levels of childbirth fear, and were more likely to report that visual media or school-based education shaped their attitudes toward birth. Positive attitudes toward childbirth technology and interventions were also associated with less confidence in knowledge of birth, and more common among younger and male respondents. Discussion/Conclusion: Educational strategies to teach university students about pregnancy and birth in ways that does not frighten them and promotes critical reflection about childbirth technology are needed. This is especially true in countries with high rates of interventions that reciprocally shape culture norms, attitudes, and expectations

Catalyzing Transcriptomics Research in Cardiovascular Disease : The CardioRNA COST Action CA17129

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu)

A novel treatment of cystic fibrosis acting on-target:cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment

Dynamic Imaging of CD8+ T Cells and Dendritic Cells during Infection with Toxoplasma gondii

To better understand the initiation of CD8+ T cell responses during infection, the primary response to the intracellular parasite Toxoplasma gondii was characterized using 2-photon microscopy combined with an experimental system that allowed visualization of dendritic cells (DCs) and parasite specific CD8+ T cells. Infection with T. gondii induced localization of both these populations to the sub-capsular/interfollicular region of the draining lymph node and DCs were required for the expansion of the T cells. Consistent with current models, in the presence of cognate antigen, the average velocity of CD8+ T cells decreased. Unexpectedly, infection also resulted in modulation of the behavior of non-parasite specific T cells. This TCR-independent process correlated with the re-modeling of the lymph node micro-architecture and changes in expression of CCL21 and CCL3. Infection also resulted in sustained interactions between the DCs and CD8+ T cells that were visualized only in the presence of cognate antigen and were limited to an early phase in the response. Infected DCs were rare within the lymph node during this time frame; however, DCs presenting the cognate antigen were detected. Together, these data provide novel insights into the earliest interaction between DCs and CD8+ T cells and suggest that cross presentation by bystander DCs rather than infected DCs is an important route of antigen presentation during toxoplasmosis

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis