Exploring the relationship between cleft type and speech outcome in 4-to-6-year-olds with non-syndromic cleft palate using different measures: A preliminary report.

Cleft type affects speech outcomes, but exact relationships remain unclear as outcome measures vary. The primary aim was to investigate the relationship between cleft type and speech outcome using different measures in 4-to-6-year-olds with non-syndromic clefts. Secondary aims were to explore the relationships between (i) speech measures used; and (ii) parent perception of speech intelligibility and listener familiarity. Twenty-two pre-schoolers with clefts, plus one parent for each child, were recruited through a hospital outpatient clinic. Children with cleft lip and palate (CLP; n = 11) and those with cleft palate only (CP; n = 11), matched on age and time of palate repair, were compared on Percentage Consonants Correct (PCC), clinician-reported speech intelligibility, and parent rating on the Intelligibility-in-Context Scale (ICS). Children with CLP had significantly lower PCC scores than children with CP (p = .020), but had no significant differences in their clinician- or parent-reported speech intelligibility. Clinician-reported speech intelligibility correlated significantly with both PCC (τ = .594, p < 0.01) and ICS (τ = .424, p = 0.009). No significant correlation was found between PCC and ICS (τ =.197, p = 0.113). Overall, parents rated their child's intelligibility higher for familiar compared to unfamiliar communication partners (τ = 2.325, p = 0.001, r = .76). Cleft type is crucial for intervention planning when objective measures are employed. Speech outcomes should be evaluated at impairment, activity, and participation levels, and by different communication partners, to comprehensively evaluate communicative effectiveness.

Enhanced hybrid photocatalytic dry reforming using a phosphated Ni-CeO2 nanorod heterostructure.

Operating the dry reforming reaction photocatalytically presents an opportunity to produce commodity chemicals from two greenhouse gases, carbon dioxide and methane, however, the top-performing photocatalysts presented in the academic literature invariably rely on the use of precious metals. In this work, we demonstrate enhanced photocatalytic dry reforming performance through surface basicity modulation of a Ni-CeO2 photocatalyst by selectively phosphating the surface of the CeO2 nanorod support. An optimum phosphate content is observed, which leads to little photoactivity loss and carbon deposition over a 50-hour reaction period. The enhanced activity is attributed to the Lewis basic properties of the PO43- groups which improve CO2 adsorption and facilitate the formation of small nickel metal clusters on the support surface, as well as the mechanical stability of CePO4. A hybrid photochemical-photothermal reaction mechanism is demonstrated by analyzing the wavelength-dependent photocatalytic activities. The activities, turnover numbers, quantum efficiencies, and energy efficiencies are shown to be on par with other dry-reforming photocatalysts that use noble metals, representing a step forward in understanding how to stabilize ignoble nickel-based dry reforming photocatalysts. The challenges associated with comparing the performance of photocatalysts reported in the academic literature are also commented on.

Recurrences and bleeding during extended treatment of patients with venous thromboembolism: results of the international, prospective, observational WHITE study.

BACKGROUND: Little data are available on real-life long-term treatments after a venous thromboembolism (VTE), and on recurrent VTE or bleeds events during treatments. METHODS: We investigated the complications occurring during follow-up (FU) in VTE patients who had received the treatment decisions given by the clinical centers, active in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, Tunisia), which participated in the international, prospective, observational WHITE study. RESULTS: FU information was collected in 1004 patients, recruited by 62 clinical centers (17 centers did not participate in FU collection). Extended treatments were proposed to 811 patients: direct oral anticoagulants (DOACs) (475), sulodexide (202), antiplatelet agents (73), vitamin K antagonists (VKAs) (45), low molecular weight heparin (LMWH) (16). All specific treatments were stopped in the remaining 193 patients. Patients who during FU used treatments different than those prescribed by the local investigators (263) or for other causes (26) were excluded from analysis. 50 primary events occurred throughout 1044 years FU in 715 patients, 4.8 incidence (×100 patient-years) [3.8 for recurrences, and 0.96 for bleeding (major or clinically relevant)]. Primary event incidence differed according to treatments (LMWH=33.3, antiplatelets =7.6, VKAs = 6.1, DOACs = 4.7, sulodexide = 4.2, all treatment stopped = 2.5), and differed across the involved countries. CONCLUSIONS: DOACs were the most used drugs for extended treatments. Overall, the rate of primary events during FU was low. The investigators identified patients at low risk of recurrence and high bleeding risk. Sulodexide use for secondary prevention deserves further studies.

Spatiotemporal mapping of gene expression landscapes and developmental trajectories during zebrafish embryogenesis.

A major challenge in understanding vertebrate embryogenesis is the lack of topographical transcriptomic information that can help correlate microenvironmental cues within the hierarchy of cell-fate decisions. Here, we employed Stereo-seq to profile 91 zebrafish embryo sections covering six critical time points during the first 24 h of development, obtaining a total of 152,977 spots at a resolution of 10 × 10 × 15 µm3 (close to cellular size) with spatial coordinates. Meanwhile, we identified spatial modules and co-varying genes for specific tissue organizations. By performing the integrated analysis of the Stereo-seq and scRNA-seq data from each time point, we reconstructed the spatially resolved developmental trajectories of cell-fate transitions and molecular changes during zebrafish embryogenesis. We further investigated the spatial distribution of ligand-receptor pairs and identified potentially important interactions during zebrafish embryo development. Our study constitutes a fundamental reference for further studies aiming to understand vertebrate development.

Influence of clinical presentation, site, and extent of venous thrombosis on decision about duration of anticoagulation: Data from the international, prospective, observational WHITE study.

BACKGROUND: Low attention has generally been dedicated to the influence of clinical presentation, extent of venous thrombosis and presence of residual vein obstruction (RVO) on the decision about the duration of secondary prophylaxis after a first venous thromboembolism (VTE). AIM: This study aimed at investigating the role of the mentioned VTE characteristics on the therapeutic decision using the information collected in the international, prospective, observational WHITE study. RESULTS: 1240 patients were recruited by 79 clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). 35 patients had as index event a pulmonary embolism (PE) without a deep vein thrombosis (DVT), and all continued anticoagulation. We focused on the 1205 subjects with DVT. The treatment decision differed among countries; altogether, more than 85% of patients with proximal (with or without distal) DVT continued a prophylactic treatment with anticoagulants, or antithrombotics; 34% of patients with isolated distal DVT stopped treatment, and more than 85% of patients with a PE associated to a DVT continued treatment. At multivariable analysis, the presence of proximal DVT, signs of post-thrombotic syndrome (PTS), residual vein obstruction (RVO), maintenance <180 days and concomitant diseases was associated with increased probability to continue secondary prophylaxis. CONCLUSION: The presentation as proximal DVT (with or without PE) or isolated PE influenced the treating physicians' decision in favor of extension of secondary prophylaxis, together with the presence of concomitant diseases and local conditions which may increase the risk of post-thrombotic syndrome.

Unprovoked or provoked venous thromboembolism: not the prevalent criterion to decide on anticoagulation extension in clinical practice of various countries-the prospective, international, observational WHITE study.

The decision on treatment after a first venous thromboembolism (VTE) to prevent recurrences may be influenced by many factors. The prospective, observational, WHITE study aimed to analyze how this issue was tackled in every-day clinical practice in various countries, which have sensibly different socio-economic conditions and healthcare systems. Doctors active in 79 Internal or Vascular clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia) enrolled VTE patients after the maintenance treatment phase. The present report analyzed information, collected in the central database, regarding the baseline characteristics, index events, type and duration of anticoagulant therapy and decision on post-maintenance treatment. From April 2018 to December 2020, 1240 patients were enrolled, 58% with an unprovoked index event. Direct oral anticoagulants (DOACs) were used in > 85% of all cases in China, Poland, Portugal, Russia and Czechia, in 52% in Slovakia and in no patient in Tunisia. The maintenance anticoagulation lasted in average approximately 6 months. Altogether, anticoagulation was stopped in 20%, extended in about 50%, regardless of whether the event was unprovoked or provoked and shifted to antithrombotics (mainly sulodexide or aspirin) in the remaining patients. In conclusion, some differences in VTE patient management were found between countries. The provoked/unprovoked nature of the index event, instead, was not the prevalent criterion to drive the decision on extension of anticoagulation, without large variations between countries. DOACs were the most widely used anticoagulant drugs, whereas > 25% of patients received antithrombotic drugs instead of anticoagulants as extended treatment.

Solar Urea: Towards a Sustainable Fertilizer Industry.

Urea, an agricultural fertilizer, nourishes humanity. The century-old Bosch-Meiser process provides the world's urea. It is multi-step, consumes enormous amounts of non-renewable energy, and has a large CO2 footprint. Thus, developing an eco-friendly synthesis for urea is a priority. Herein we report a single-step Pd/LTA-3A catalyzed synthesis of urea from CO2 and NH3 under ambient conditions powered solely by solar energy. Pd nanoparticles serve the dual function of catalyzing the dissociation of NH3 and providing the photothermal driving force for urea formation, while the absorption capacity of LTA-3A removes by-product H2 O to shift the equilibrium towards urea production. The solar urea conversion rate from NH3 and CO2 is 87 µmol g-1 h-1 . This advance represents a first step towards the use of solar energy in urea production. It provides insights into green fertilizer production, and inspires the vision of sustainable, modular plants for distributed production of urea on farms.

Anticoagulation Duration After First Venous Thromboembolism: Real-Life Data From the International, Observational WHITE Study.

BACKGROUND: International guidelines recommend at least three months anticoagulation in all patients after acute venous thromboembolism (VTE) and suggest those with unprovoked events be considered for indefinite anticoagulation if the risk of recurrence is high and the risk of bleeding during treatment non-high. Other authors have recently argued against using a dichotomy unprovoked/provoked events to decide on anticoagulation duration and suggest instead using overall risk factors present in each patient as the basis for deciding. AIM: This sub-analysis of the WHITE study aimed at assessing the reasons for the treatment decisions taken by doctors in different countries. RESULTS: 1240 patients were recruited in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). Anticoagulation was extended in 51.7% and 49.3% of patients with unprovoked or provoked events (n.s.); stopped in 15.4% versus 28.9% (P < .0001), and changed to antithrombotic drugs (sulodexide or aspirin) in 32.9% versus 21.8% (P < .0001). In the 430 subjects with isolated distal deep vein thrombosis (IDDVT) anticoagulation was stopped in 34.4%, continued in 37.0% (mainly those with post-thrombotic syndrome [PTS]) and switched to antithrombotics in the balance. High risk of recurrence was the most prevalent reason (>83% of cases) given to continue anticoagulation, regardless of nature and site of the index events, followed by risk of bleeding and presence of PTS signs. CONCLUSION: On average, attending physicians estimated the risk of recurrence in real life conditions, and the consequent therapeutic decision, using all the information available, not limiting to the location or nature of the index event.

Corrigendum to "Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy".

[This corrects the article DOI: 10.1155/2019/2936962.].

Chromatin accessibility landscapes of immune cells in rheumatoid arthritis nominate monocytes in disease pathogenesis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that involves a variety of cell types. However, how the epigenetic dysregulations of peripheral immune cells contribute to the pathogenesis of RA still remains largely unclear. RESULTS: Here, we analysed the genome-wide active DNA regulatory elements of four major immune cells, namely monocytes, B cells, CD4+ T cells and CD8+ T cells, in peripheral blood of RA patients, osteoarthritis (OA) patients and healthy donors using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq). We found a strong RA-associated chromatin dysregulation signature in monocytes, but no other examined cell types. Moreover, we found that serum C-reactive protein (CRP) can induce the RA-associated chromatin dysregulation in monocytes via in vitro experiments. And the extent of this dysregulation was regulated through the transcription factor FRA2. CONCLUSIONS: Together, our study revealed a CRP-induced pathogenic chromatin dysregulation signature in monocytes from RA patients and predicted the responsible signalling pathway as potential therapeutic targets for the disease.

Development of double-positive thymocytes at single-cell resolution.

BACKGROUND: T cells generated from thymopoiesis are essential for the immune system, and recent single-cell studies have contributed to our understanding of the development of thymocytes at the genetic and epigenetic levels. However, the development of double-positive (DP) T cells, which comprise the majority of thymocytes, has not been well investigated. METHODS: We applied single-cell sequencing to mouse thymocytes and analyzed the transcriptome data using Seurat. By applying unsupervised clustering, we defined thymocyte subtypes and validated DP cell subtypes by flow cytometry. We classified the cell cycle phases of each cell according to expression of cell cycle phase-specific genes. For immune synapse detection, we used immunofluorescent staining and ImageStream-based flow cytometry. We studied and integrated human thymocyte data to verify the conservation of our findings and also performed cross-species comparisons to examine species-specific gene regulation. RESULTS: We classified blast, rearrangement, and selection subtypes of DP thymocytes and used the surface markers CD2 and Ly6d to identify these subtypes by flow cytometry. Based on this new classification, we found that the proliferation of blast DP cells is quite different from that of double-positive cells and other cell types, which tend to exit the cell cycle after a single round. At the DP cell selection stage, we observed that CD8-associated immune synapses formed between thymocytes, indicating that CD8sp selection occurred among thymocytes themselves. Moreover, cross-species comparison revealed species-specific transcription factors (TFs) that contribute to the transcriptional differences of thymocytes from humans and mice. CONCLUSIONS: Our study classified DP thymocyte subtypes of different developmental stages and provided new insight into the development of DP thymocytes at single-cell resolution, furthering our knowledge of the fundamental immunological process of thymopoiesis.

CYP46A1-dependent and independent effects of efavirenz treatment.

Cholesterol excess in the brain is mainly disposed via cholesterol 24-hydroxylation catalysed by cytochrome P450 46A1, a CNS-specific enzyme. Cytochrome P450 46A1 is emerging as a promising therapeutic target for various brain diseases with both enzyme activation and inhibition having therapeutic potential. The rate of cholesterol 24-hydroxylation determines the rate of brain cholesterol turnover and the rate of sterol flux through the plasma membranes. The latter was shown to affect membrane properties and thereby membrane proteins and membrane-dependent processes. Previously we found that treatment of 5XFAD mice, an Alzheimer's disease model, with a small dose of anti-HIV drug efavirenz allosterically activated cytochrome P450 46A1 in the brain and mitigated several disease manifestations. Herein, we generated Cyp46a1-/- 5XFAD mice and treated them, along with 5XFAD animals, with efavirenz to ascertain cytochrome P450 46A1-dependent and independent drug effects. Efavirenz-treated versus control Cyp46a1-/- 5XFAD and 5XFAD mice were compared for the brain sterol and steroid hormone content, amyloid ß burden, protein and mRNA expression as well as synaptic ultrastructure. We found that the cytochrome P450 46A1-dependent efavirenz effects included changes in the levels of brain sterols, steroid hormones, and such proteins as glial fibrillary acidic protein, Iba1, Munc13-1, post-synaptic density-95, gephyrin, synaptophysin and synapsin-1. Changes in the expression of genes involved in neuroprotection, neurogenesis, synaptic function, inflammation, oxidative stress and apoptosis were also cytochrome P450 46A1-dependent. The total amyloid ß load was the same in all groups of animals, except lack of cytochrome P450 46A1 decreased the production of the amyloid ß40 species independent of treatment. In contrast, altered transcription of genes from cholinergic, monoaminergic, and peptidergic neurotransmission, steroid sulfation and production as well as vitamin D3 activation was the main CYP46A1-independent efavirenz effect. Collectively, the data obtained reveal that CYP46A1 controls cholesterol availability for the production of steroid hormones in the brain and the levels of biologically active neurosteroids. In addition, cytochrome P450 46A1 activity also seems to affect the levels of post-synaptic density-95, the main postsynaptic density protein, possibly by altering the calcium/calmodulin-dependent protein kinase II inhibitor 1 expression and activity of glycogen synthase kinase 3ß. Even at a small dose, efavirenz likely acts as a transcriptional regulator, yet this regulation may not necessarily lead to functional effects. This study further confirmed that cytochrome P450 46A1 is a key enzyme for cholesterol homeostasis in the brain and that the therapeutic efavirenz effects on 5XFAD mice are likely realized via cytochrome P450 46A1 activation.

Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes.

Cytochrome P450 46A1 encoded by CYP46A1 catalyzes cholesterol 24-hydroxylation and is a CNS-specific enzyme that controls cholesterol removal and turnover in the brain. Accumulating data suggest that increases in cytochrome P450 46A1 activity in mouse models of common neurodegenerative diseases affect various, apparently unlinked biological processes and pathways. Yet, the underlying reason for these multiple enzyme activity effects is currently unknown. Herein, we tested the hypothesis that cytochrome P450 46A1-mediated sterol flux alters physico-chemical properties of the plasma membranes and thereby membrane-dependent events. We used 9-month old 5XFAD mice (an Alzheimer's disease model) treated for 6 months with the anti-HIV drug efavirenz. These animals have previously been shown to have improved behavioral performance, increased cytochrome P450 46A1 activity in the brain, and increased sterol flux through the plasma membranes. We further examined 9-month old Cyp46a1 -/- mice, which have previously been observed to have cognitive deficits and decreased sterol flux through brain membranes. Synaptosomal fractions from the brain of efavirenz-treated 5XFAD mice had essentially unchanged cholesterol levels as compared to control 5XFAD mice. However with efavirenz treatment in these mice, there were changes in the membrane properties (increased cholesterol accessibility, ordering, osmotic resistance, and thickness) as well as total glutamate content and ability to release glutamate in response to mild stimulation. Similarly, the cholesterol content in synaptosomal fractions from the brain of Cyp46a1 -/- mice was essentially the same as in wild type mice but knockout of Cyp46a1 was associated with changes in membrane properties and glutamate content and its exocytotic release. Changes in Cyp46a1 -/- mice were in the opposite direction to those observed in efavirenz-treated vs control 5XFAD mice. Incubation of synaptosomal fractions with the inhibitors of glycogen synthase kinase 3, cyclin-dependent kinase 5, protein phosphatase 1/2A or calcineurin, and protein phosphatase 2B revealed that increased sterol flux in efavirenz-treated vs control 5XFAD mice affected the ability of all four enzymes to modulate glutamate release. In contrast, in Cyp46a1 -/- vs wild type mice, decreased sterol flux altered the ability of only cyclin-dependent kinase 5 and protein phosphatase 2B to regulate the glutamate release. Collectively, our results support cytochrome P450 46A1-mediated sterol flux as an important contributor to the fundamental properties of the membranes, protein phosphorylation, and synaptic transmission Also, our data provide an explanation of how one enzyme, cytochrome P450 46A1, can affect multiple pathways and processes and serve as a common potential target for several neurodegenerative disorders.

Anchoring BaII to Pd/Hy WO3-x Nanowires Promotes a Photocatalytic Reverse Water-Gas Shift Reaction.

Surface deposition of BaII on Pd/Hy WO3-x nanowires was developed by using a solution-phase atomic layer deposition process. The procedure involves the generation of Brønsted surface OH sites by H2 spillover on Pd/WO3 , which can then hydrolytically condense with Ba(OEt)2 to produce surface BaII . At just 0.2 at % Ba, CO production by the light-assisted activity of the reverse water-gas shift (RWGS) reaction was observed to increase by about 300 %. In situ DRIFTS studies suggested enhanced CO2 capturing capabilities of a Ba-decorated surface. This study further exemplifies the importance of surface chemistry in optimizing materials for catalysis.

Hybrid Photo- and Thermal Catalyst System for Continuous CO2 Reduction.

Heterogeneous thermal catalytic processes are vital for industrial production of fuels, fertilizers, and other chemicals necessary for sustaining human life. However, these processes are highly energy-intensive, requiring a vast consumption of fossil fuels. An emerging class of heterogeneous catalysts that are thermally driven but also exhibit a photochemically enhanced rate can potentially reduce process energy intensity by partially substituting conventional heat (where fossil fuels are needed) with solar energy. Such catalyst systems have yet to be practically utilized. Here, we demonstrate a compact electrically heated photo- and thermal annular reactor module to reduce CO2 to CO, via the reverse water gas shift reaction. A first-principles-based design approach was taken in developing a SiO2 on an Al photo- and thermal catalyst system for the model photo- and thermal indium oxide hydroxide (In2O3-x(OH)y) catalysts. A 5-fold light enhancement in the CO production rate and over 70 h of stable CO production were achieved. This represents the highest light enhancement effect reported for this model photocatalyst to date. The reactor presented herein allows continuous operation and a significant reduction of 31% in heater power consumption when provided with an additional 2 suns of irradiation, demonstrating the strong photo- and thermal-harvesting performances of the catalyst system developed in this work.

APEC: an accesson-based method for single-cell chromatin accessibility analysis.

The development of sequencing technologies has promoted the survey of genome-wide chromatin accessibility at single-cell resolution. However, comprehensive analysis of single-cell epigenomic profiles remains a challenge. Here, we introduce an accessibility pattern-based epigenomic clustering (APEC) method, which classifies each cell by groups of accessible regions with synergistic signal patterns termed "accessons". This python-based package greatly improves the accuracy of unsupervised single-cell clustering for many public datasets. It also predicts gene expression, identifies enriched motifs, discovers super-enhancers, and projects pseudotime trajectories. APEC is available at https://github.com/QuKunLab/APEC.

Chromatin accessibility analysis reveals regulatory dynamics of developing human retina and hiPSC-derived retinal organoids.

Retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs) provide potential opportunities for studying human retinal development and disorders; however, to what extent ROs recapitulate the epigenetic features of human retinal development is unknown. In this study, we systematically profiled chromatin accessibility and transcriptional dynamics over long-term human retinal and RO development. Our results showed that ROs recapitulated the human retinogenesis to a great extent, but divergent chromatin features were also discovered. We further reconstructed the transcriptional regulatory network governing human and RO retinogenesis in vivo. Notably, NFIB and THRA were identified as regulators in human retinal development. The chromatin modifications between developing human and mouse retina were also cross-analyzed. Notably, we revealed an enriched bivalent modification of H3K4me3 and H3K27me3 in human but not in murine retinogenesis, suggesting a more dedicated epigenetic regulation on human genome.

Landscape and Dynamics of the Transcriptional Regulatory Network During Natural Killer Cell Differentiation.

Natural killer (NK) cells are essential in controlling cancer and infection. However, little is known about the dynamics of the transcriptional regulatory machinery during NK cell differentiation. In this study, we applied the assay of transposase accessible chromatin with sequencing (ATAC-seq) technique in a home-developed in vitro NK cell differentiation system. Analysis of ATAC-seq data illustrated two distinct transcription factor (TF) clusters that dynamically regulate NK cell differentiation. Moreover, two TFs from the second cluster, FOS-like 2 (FOSL2) and early growth response 2 (EGR2), were identified as novel essential TFs that control NK cell maturation and function. Knocking down either of these two TFs significantly impacted NK cell differentiation. Finally, we constructed a genome-wide transcriptional regulatory network that provides a better understanding of the regulatory dynamics during NK cell differentiation.

Cu Atoms on Nanowire Pd/HyWO3-x Bronzes Enhance the Solar Reverse Water Gas Shift Reaction.

Nanowire hydrogen bronzes of WO3 nanowires decorated with Pd (Pd/HyWO3-x) were previously demonstrated to effectively capture broadband radiation across the ultraviolet to near-infrared wavelength range and catalyze the reverse water gas shift reaction (RWGS). Herein, we report a synthetic strategy to enhance the performance of this class of photocatalysts by conformally coating Cu atoms onto the surface of Pd/HyWO3-x by anchoring Cu(I)OtBu to the Brønsted acidic protons of the bronze. The resulting materials are characterized by a suite of analytical methods, including electron microscopy and X-ray absorption spectroscopy. In addition, in situ diffuse reflectance infrared Fourier transform spectroscopy demonstrated that for the light-driven RWGS reaction, as little as 0.2 at. % Cu facilitates the formation of surface carboxylate species from CO2, resulting in a 300-500% enhancement in the rate of CO production. This metal anchoring method enables atom precise modification of the surfaces of metal oxide nanomaterials for catalytic applications, circumventing the need for complex and expensive atomic layer deposition processes.