A theoretical study on the mechanism of the base-promoted decomposition of N-chloro,N-methylethanolamine

The first step of the base-promoted decomposition of N-chloro,N-methylethanolamine in aqueous solution (CH3N(Cl)CH2CH2OH + HO- →imine + Cl- + H2O (+ CH2O)→amine + aldehyde) is investigated at the MP2/6-31++G(d,p) computing level. Solvation is included by using both a microsolvated model, in which two explicit water molecules simulate the specific solvent effects, and a hybrid cluster-continuum model, by applying a polarized continuum on the previous results, to account for the bulk effect of the solvent. Four alternative pathways (bimolecular fragmentation, Hofmann, Zaitsev and intramolecular eliminations) are possible for the rate-limiting step of this base-promoted decomposition. These reactive processes are bimolecular asynchronous concerted reactions. The common feature of the four pathways is the proton transfer to HO- being more advanced than all other molecular events, whereas imine formation is delayed. Non-reactive cyclic arrangements involving one of the explicit water molecules are found at transition structures of Hofmann and Zaitsev eliminations, such water molecule acting both as H+ donor and acceptor. Although MP2 calculations misjudge the absolute activation Gibbs free energy values, this computational level adequately predicts the enhancement in the decomposition rate due to the presence of the -OH grou

Decoupling of optoelectronic properties from morphological changes in sodium treated kesterite thin film solar cells

Sodium is typically used during the synthesis of kesterite thin films to enhance the performance of solar cells. As sodium tends to affect grain growth and morphology, it is difficult to analyse solely the electronic effects of sodium as dopant. To decouple the structural and electronic effects from each other, two processes were designed in this work to successfully incorporate sodium into a vacuum-processed Cu2ZnSnSe4absorber without changing the morphology. A thin layer of NaF is deposited before precursor deposition (Pre-NaF) or after absorber synthesis to undergo a post deposition treatment (NaF-PDT). While composition and distribution of matrix elements remain unchanged, the sodium concentration is increased upon sodium treatment up to 140 ppm as measured by inductively coupled plasma mass spectrometry. X-ray photoelectron spectroscopy showed that the surface composition was not altered. Within its detection limit, sodium was not present at the absorber surface. For a Pre-NaF sample measured with atom probe tomography a sodium concentration of 30 ppm was measured in a grain, suggesting that sodium might segregate at grain boundaries. The additional sodium content in the film leads to an increased acceptor concentration, which results in improved open-circuit voltage and fill factor.Financial support from the Swiss National Science Foundation (SNF) in the network of the Indo-Swiss Joint Research Programme (ISJRP) [IZLIZ2_157140/1] is gratefully acknowledged. T. Schwarz is grateful for the support of the German Research Foundation (DFG) [Contract GA 2450/1-1]. R. Caballero acknowledges financial support from Spanish MINECO within the Ramón y Cajal program [RYC-2011-08521], MINECO project WINCOST [ENE2016-80788-C5-2-R] and from Spanish Ministry of Education, Culture and Sport within the José Castillejo program [CAS 15/00070

The BIDIAP index: a clinical, analytical and ultrasonographic score for the diagnosis of acute appendicitis in children

Background: Pediatric acute appendicitis (PAA) continues to be a diagnostic challenge today. The diagnostic performance of classical indices is only moderate, especially in pediatric population. This study aimed to define a clinical, radiological and analytical index for the diagnosis of PAA. Materials and methods: This prospective study included 151 patients divided into two groups: (1) 53 patients with non-surgical abdominal pain (NSAP) and (2) 98 patients with a confirmed PAA. Sociodemographic and clinical characteristics were compared between groups using the Mann-Whitney U test and the Fisher exact test. To identify the predictors of PAA, we performed a multivariable logistic regression using a forward stepwise analysis and we assigned multiples of integer values to the selected variables. The diagnostic performance of the index was assessed by calculating the area under the receiver operating characteristic curve. Intra-cohort calibration was assessed with the Hosmer-Lemeshow test. Results: We developed the BIDIAP index (BIomarkers for the DIagnosis of Appendicitis in Pediatrics), which included three variables that independently predicted higher odds of PAA: appendiceal caliber (≥ 6.9 mm), systemic immune-inflammation index (≥ 890) and peritoneal irritation, which scored 4, 3 and 2 points, respectively. Mean (SD) score of the participants was 2.38 (2.06) in group 1 and 7.89 (1.50) in group 2. The area under the ROC was 0.97 (95% CI 0.95-0.99). The cut-off point was established at 4 points, resulting in a sensitivity of 98.98% and a specificity of 77.78%. Conclusions: The BIDIAP index has an exceptional diagnostic performance in PAA. The importance of these results lies in its novelty and in the simplicity of the index. Although external validation will be necessary, initial results look promising

Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing

We thank C. Mirth, C. Ribeiro and A. Jacinto for their comments and suggestions; I. Miguel-Aliaga, A. Jacinto, P. Leopold, P. Domingos, C. Mirth, R. Teodoro, M. Dominguez, M.L. Vasconcelos, J.C. Yin and M. O'Connor, for reagents. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. A.M.G., F.H., A.M., A.R.M.D. and T.K. are supported by the FCT, under the FCT Investigator Programme and FCT fellowships SFRH/BPD/94112/2013, PD/BD/52421/2013, SFRH/BD/94931/2013 and SFRH/BPD/74313/2010, respectively. A.G. is supported by the CONICET and UNS, and Y.A.V. holds a CONICET fellowship. The work in the laboratory of A.M.G. is funded by the CEDOC and the European Commission FP7 (PCIG13-GA-2013-618847). A.G. thanks N.P. Rotstein and L.E. Politi for providing funds and space to develop a part of this project in their lab.How different organs in the body sense growth perturbations in distant tissues to coordinate their size during development is poorly understood. Here we mutate an invertebrate orphan relaxin receptor gene, the Drosophila Leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), and find body asymmetries similar to those found in insulin-like peptide 8 (dilp8) mutants, which fail to coordinate growth with developmental timing. Indeed, mutation or RNA intereference (RNAi) against Lgr3 suppresses the delay in pupariation induced by imaginal disc growth perturbation or ectopic Dilp8 expression. By tagging endogenous Lgr3 and performing cell type-specific RNAi, we map this Lgr3 activity to a new subset of CNS neurons, four of which are a pair of bilateral pars intercerebralis Lgr3-positive (PIL) neurons that respond specifically to ectopic Dilp8 by increasing cAMP-dependent signalling. Our work sheds new light on the function and evolution of relaxin receptors and reveals a novel neuroendocrine circuit responsive to growth aberrations.publishersversionpublishe

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.Y.-H.O. received fellowships from Alborada Scholar-ship (University of Cambridge), Trinity-Henry Barlow Scholarship (Universityof Cambridge), and R.O.C. Government Scholarship to Study Abroad (GSSA). A.G.G. received fellowships from the Ramon Areces Foundationand the LaCaixa Foundation. C.K. was supported by Marie Curie Career Inte-gration (H2020-MSCA-IF-2015-70841). S.M.-F. was supported by Red TerCel (ISCIII-Spanish Cell Therapy Network). V.A. is supported by grants from theSpanish Ministerio de Economıa,Industria y Competitividad (MEIC) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER, ‘‘Una manerade hacer Europa’’) (SAF2016-79490-R), the Instituto de Salud Carlos III (AC16/00091 and AC17/00067), the Fundacio Marato TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014–52). TheCNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCIU), and the Pro CNIC Foundation,and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work wassupported by core support grants from the Wellcome Trust and the MRC to theCambridge Stem Cell Institute, MEIC (SAF-2011-30308), Ramon y Cajal Program Grant (RYC-2009-04703), ConSEPOC-Comunidad de Madrid (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-64765 and MarieCurie Career Integration grant FP7-PEOPLE-2011-RG-294096), and a Programme Foundation Award from Cancer Research UK to S.M.-F., who wasalso supported in part by an International Early Career Scientist grant fromthe Howard Hughes Medical Institute.S

Diagnostic performance of serum pentraxin-3 in pediatric acute appendicitis: a prospective diagnostic validation study

Introduction Pediatric acute appendicitis (PAA) is a pathology with a high rate of diagnostic error. The search for new diagnostic tools is justified by the high morbidity and healthcare costs associated with diagnostic error. Methods We designed a prospective study to validate serum pentraxin-3 (PTX3) as a diagnostic tool in PAA. Participants were divided into three groups: (1) patients with no underlying pathology (2) patients with non-surgical abdominal pain and (3) patients with a confirmed diagnosis of PAA. For further analyses, patients in group 3 were divided into complicated or uncomplicated PAA. Quantitative variables were expressed as medians and interquartile ranges and categorical variables as percentages. Quantitative variables were compared using the Kruskal–Wallis test and the Mann–Whitney U test. Diagnostic performance was evaluated with ROC curves. Results This study included 215 patients divided into group 1 (n : 63), group 2 (n : 53) and group 3 (n : 99). Median serum PTX3 values were 2.54 (1.70–2.95) ng/mL, 3.29 (2.19–7.64) ng/mL and 8.94 (6.16–14.05) in groups 1, 2 and 3, respectively (p : 0.001). Patients with complicated PAA showed significantly higher values than patients with uncomplicated PAA (p = 0.04). The AUC (group 2 vs. 3) was 0.77 (95/100 CI 0.69–0.85) and the best cut-off point was at 7.28 ng/mL, with a sensitivity of 61.3/100 and a specificity of 73.1/100. The AUC (complicated vs. uncomplicated PAA) was 0.65 (95/100 CI 0.54–0.77) and the best cut-off point was 12.33 ng/mL, with a sensitivity of 51.72/100 and a specificity of 72.73/100. Conclusions The diagnostic ability of serum PTX3 in PAA is only moderate and therefore it cannot be considered a definitive diagnostic test. The discriminatory ability of PTX3 between complicated and uncomplicated PAA is poor. These findings, which contrast with those reported to date, should be validated with future properly designed prospective studies

Pathological Features in Paediatric Patients with TK2 Deficiency

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1-49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated