Stable Biological Production in the Eastern Equatorial Pacific Across the Plio-Pleistocene Transition (∼3.35–2.0 Ma)

Upwelling within the Eastern Equatorial Pacific (EEP) Ocean is a key factor for the Earth's climate because it supports >10% of the present-day biological production. The dynamics of upwelling in the EEP across the Plio-Pleistocene transition—an interval particularly relevant for understanding near-future warming due to Anthropocene-like atmospheric carbon-dioxide levels—have been intensively studied for the region east of the East Pacific Rise. In contrast, changes of the equatorial upwelling regime in the open Pacific Ocean west of this oceanographic barrier have received markedly less attention. We therefore provide new proxy records from Ocean Drilling Program Site 849 located within the EEP open-ocean upwelling regime. Our target interval (∼3.35–2.0 Ma) covers the Plio-Pleistocene transition characterized by the intensification of Northern Hemisphere Glaciation (iNHG). We use benthic δ18O values to generate a new, high-resolution age model for Site 849, and sand-accumulation rates together with benthic δ13C values to evaluate net export production. Although showing temporary substantial glacial-interglacial variations, our records indicate stability in net export production on secular timescales across the iNHG. We suggest the following processes to have controlled the long-term evolution of primary productivity at Site 849. First, nutrient export from the high latitudes to the EEP; second, a successive shoaling of the Pacific nutricline during the studied interval; and third, a simultaneous reduction in dust-borne iron input.publishedVersio

Crystallization behavior of iron- and boron-containing nepheline (Na2 O●Al2 O3 ●2SiO2 ) based model high-level nuclear waste glasses

This study focuses on understanding the relationship between iron redox, composition, and heat‐treatment atmosphere in nepheline‐based model high‐level nuclear waste glasses. Glasses in the Na2O–Al2O3–B2O3–Fe2O3–SiO2 system with varying Al2O3/Fe2O3 and Na2O/Fe2O3 ratios have been synthesized by melt‐quench technique and studied for their crystallization behavior in different heating atmospheres—air, inert (N2), and reducing (96%N2–4%H2). The compositional dependence of iron redox chemistry in glasses and the impact of heating environment and crystallization on iron coordination in glass‐ceramics have been investigated by Mössbauer spectroscopy and vibrating sample magnetometry. While iron coordination in glasses and glass‐ceramics changed as a function of glass chemistry, the heating atmosphere during crystallization exhibited minimal effect on iron redox. The change in heating atmosphere did not affect the phase assemblage but did affect the microstructural evolution. While glass‐ceramics produced as a result of heat treatment in air and N2 atmospheres developed a golden/brown colored iron‐rich layer on their surface, those produced in a reducing atmosphere did not exhibit any such phenomenon. Furthermore, while this iron‐rich layer was observed in glass‐ceramics with varying Al2O3/Fe2O3 ratio, it was absent from glass‐ceramics with varying Na2O/Fe2O3 ratio. An explanation of these results has been provided on the basis of kinetics of diffusion of oxygen and network modifiers in the glasses under different thermodynamic conditions. The plausible implications of the formation of iron‐rich layer on the surface of glass‐ceramics on the chemical durability of high‐level nuclear waste glasses have been discussed

Control of the Electroporation Efficiency of Nanosecond Pulses by Swinging the Electric Field Vector Direction

Reversing the pulse polarity, i.e., changing the electric field direction by 180°, inhibits electroporation and electrostimulation by nanosecond electric pulses (nsEPs). This feature, known as “bipolar cancellation,” enables selective remote targeting with nsEPs and reduces the neuromuscular side effects of ablation therapies. We analyzed the biophysical mechanisms and measured how cancellation weakens and is replaced by facilitation when nsEPs are applied from different directions at angles from 0 to 180°. Monolayers of endothelial cells were electroporated by a train of five pulses (600 ns) or five paired pulses (600 + 600 ns) applied at 1 Hz or 833 kHz. Reversing the electric field in the pairs (180° direction change) caused 2-fold (1 Hz) or 20-fold (833 kHz) weaker electroporation than the train of single nsEPs. Reducing the angle between pulse directions in the pairs weakened cancellation and replaced it with facilitation at angles \u3c160° (1 Hz) and \u3c130° (833 kHz). Facilitation plateaued at about three-fold stronger electroporation compared to single pulses at 90–100° angle for both nsEP frequencies. The profound dependence of the efficiency on the angle enables novel protocols for highly selective focal electroporation at one electrode in a three-electrode array while avoiding effects at the other electrodes. Nanosecond-resolution imaging of cell membrane potential was used to link the selectivity to charging kinetics by co- and counter-directional nsEPs

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen

Health-related quality of life in patients with cleft palate : validity and reliability of the VPI effects on life outcomes (VELO) questionnaire translated to Dutch

BACKGROUND : Disease-specific health-related quality of life (HRQOL) questionnaires provide the clinician with important information regarding the impact of the disease on functioning and well-being. For patients with velopharyngeal insufficiency (VPI), the VPI Effects on Life Outcomes (VELO) questionnaire was developed and validated in English by Skirko et al. (2012). However, a valid and reliable Dutch translation of this questionnaire is not available yet. METHODS : The English questionnaire was translated to Dutch following a forward-backward translation procedure. A linguistic validation and the evaluation of the internal consistency (Cronbach's α) of this Dutch version were performed based on the responses of 39 parents of patients with cleft (lip and) palate (mean age: 6.8 years) (parent report) and the responses of 14 patients older than 8 years (mean age: 9.5 years) (child report). Additionally, the concurrent validity was assessed by comparing the scores on the parent report to those on the pediatric voice handicap index. Furthermore, the validity of the parent proxy assessment and the relationship between age and responses on the VELO questionnaire were investigated. Based on the responses of an age and gender matched control group without cleft palate, the discriminant validity was evaluated. RESULTS : The parent report was easy to complete for all parents. Nine of the fourteen (64%) patients were able to complete the child report independently. The median scores on the parent report and the child report were 82.7 and 95.1 respectively. The patient group had a significantly worse perception of HRQOL compared to the control group (p < 0.001; p = 0.029). There were no significant differences between the responses of the parent and their child's (p = 0.345). A significant positive correlation was found between the score on the parent report and the age of the patients (p = 0.001). Furthermore, a significant negative correlation was found between the parent report and the P-VHI (p < 0.001). Cronbach's α was 0.955 and 0.817 for the parent report and the child report respectively. CONCLUSION : The Dutch VELO questionnaire is a valid, reliable and user-friendly tool that provides important information about HRQOL in patients with cleft (lip and) palate.The first author (L.B.) was funded by a PhD grant of the Research Foundation Flanders (1S01216N).http://www.elsevier.com/locate/ijporl2018-07-30Speech-Language Pathology and Audiolog

Consensus and Different Perspectives on Treatment of Supracondylar Fractures of the Humerus in Children

Background: Although closed reduction and percutaneous pinning is accepted as the treatment of choice for displaced supracondylar fracture of the humerus, there are some debates on the pinning techniques, period of immobilization, elbow range of motion (ROM) exercise, and perceptions on the restoration of elbow ROM. This study was to investigate the consensus and different perspectives on the treatment of supracondylar fractures of the humerus in children. Methods: A questionnaire was designed for this study, which included the choice of pinning technique, methods of elbow motion, and perception on the restoration of elbow ROM. Seventy-six orthopedic surgeons agreed to participate in the study and survey was performed by a direct interview manner in the annual meetings of Korean Pediatric Orthopedic Association and Korean Society for Surgery of the Hand. There were 17 pediatric orthopedic surgeons, 48 hand surgeons, and 11 general orthopedic surgeons. Results: Ninety-six percent of the orthopedic surgeons agreed that closed reduction and percutaneous pinning was the treatment of choice for the displaced supracondylar fracture of the humerus in children. They showed significant difference in the choice of pin entry (lateral vs. crossed pinning, p = 0.017) between the three groups of orthopedic surgeons, but no significant difference was found in the number of pins, all favoring 2 pins over 3 pins. Most of the orthopedic surgeons used a removable splint during the ROM exercise period. Hand surgeons and general orthopedic surgeons tended to be more concerned about elbow stiffness after supracondylar fracture than pediatric orthopedic surgeons, and favored gentle passive ROM exercise as elbow motion. Pediatric orthopedic surgeons most frequently adopted active ROM exercise as the elbow motion method. Pediatric orthopedic surgeons and general orthopedic surgeons acknowledged that the patient&apos;s age was the most contributing factor to the restoration of elbow motion, whereas hand surgeons acknowledged the amount of injury to be the most contributing factor. Conclusions: More investigation and communication will be needed to reach a consensus in treating pediatric supracondylar fractures of the humerus between the different subspecialties of orthopedic surgeons, which can minimize malpractice and avoid medicolegal issues. © 2012 by The Korean Orthopaedic Association.Y

Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum

Axenfeld–Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld–Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. USP9X and JAG1 explained three families each. USP9X was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy–Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with FOXC1-ARS. Anterior segment anomalies are not currently associated with USP9X, yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in CDK13, BCOR, and an X chromosome deletion encompassing HCCS and AMELX (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for PITX2/FOXC1 sequencing and copy number analysis, with attention to the described genes/regions

Rosmarinic acid, major phenolic constituent of Greek sage herbal tea, modulates rat intestinal SGLT1 levels with effects on blood glucose

Scope: Previous results suggested that the effects of Salvia fruticosa tea (SFT) drinking on glucose regulation might be at the intestinal level. Here we aim to characterize the effects of SFT treatment and of its main phenolic constituent – rosmarinic acid (RA) – on the levels and localization of the intestinal Na+/glucose cotransporter-1 (SGLT1), the facilitative glucose transporter 2 and glucagon-like peptide-1 (GLP-1). Methods and results: Two models of SGLT1 induction in rats were used: through diabetes induction with streptozotocin (STZ) and through dietary carbohydrate manipulation. Drinking water was replaced with SFT or RA and blood parameters, liver glycogen and the levels of different proteins in enterocytes quantified. Two weeks of SFT treatment stabilized fasting blood glucose levels in STZ-diabetic animals. The increase in SGLT1 localized to the enterocyte brush-border membrane (BBM) induced by STZ treatment was significantly abrogated by treatment with SFT, without significant changes in total cellular transporter protein levels. No effects were observed on glucose transporter 2, Na+/K+-ATPase or glucagon-like peptide-1 levels by SFT. Additionally, SFT and RA for 4 days significantly inhibited the carbohydrate-induced adaptive increase of SGLT1 in BBM. Conclusion: SFT and RA modulate the trafficking of SGLT1 to the BBM and may contribute to the control of plasma glucose.We thank NANTA, Fábrica de Moagem do Marco S.A., Portugal, for offering the Soybean meal 47.5 (LC diet). M. F. A. was supported by the Foundation for Science and Technology, Portugal, through the grant SFRH/BD/12527/2003. This work was supported by the Foundation for Science and Technology, Portugal, through the research grant POCI/AGR/62040/2004

A standard of care for individuals with PIK3CA ‐related disorders: an international expert consensus statement

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge

Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS