Miracle-dz/UniFAR-FTUs huggingface dataset:
Combined L-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.

Newborn pigs with chronic hypoxia-induced pulmonary hypertension (PH) have evidence of eNOS uncoupling. In this model, we showed that therapies that promote eNOS coupling, either tetrahydrobiopterin (BH4), a NOS co-factor, or L-citrulline, a NO-L-arginine precursor, inhibit PH. We wanted to determine whether co-treatment with L-citrulline and a BH4 compound, Sapropterin Dihydrochloride, improves NO signaling and chronic hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with L-citrulline or BH4, or were co-treated with L-citrulline and BH4, from day 3 through 10 of hypoxia. Catheters were placed for hemodynamic measurements and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared to the untreated hypoxic group, PVR was lower in hypoxic piglets co-treated with L-citrulline and BH4 and in those treated with L-citrulline alone, but not for those treated solely with BH4. NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets co-treated with L-citrulline and BH4 than in piglets treated with either alone. Co-treatment with L-citrulline and BH4 more effectively improves NO signaling and inhibits chronic hypoxia-induced PH than either treatment alone. Combination therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.
Three-dimensional digital mapping of ecosystems: a new era in spatial ecology

Ecological processes occur over multiple spatial, temporal and thematic scales in three-dimensional (3D) ecosystems. Characterizing and monitoring change in 3D structure at multiple scales is challenging within the practical constraints of conventional ecological tools. Remote sensing from satellites and crewed aircraft has revolutionized broad-scale spatial ecology, but fine-scale patterns and processes operating at sub-metre resolution have remained understudied over continuous extents. We introduce two high-resolution remote sensing tools for rapid and accurate 3D mapping in ecology—terrestrial laser scanning and structure-from-motion photogrammetry. These technologies are likely to become standard sampling tools for mapping and monitoring 3D ecosystem structure across currently under-sampled scales. We present practical guidance in the use of the tools and address barriers to widespread adoption, including testing the accuracy of structure-from-motion models for ecologists. We aim to highlight a new era in spatial ecology that uses high-resolution remote sensing to interrogate 3D digital ecosystems.
Effects of Bisphenol A on Foxl2 gene expression and DNA damage in adult viviparous fish Goodea atripinnis

ABSTRACT Bisphenol A (BPA) is an emerging pollutant of global concern. Viviparous fish Goodea atripinnis is endemic to the Central Mexican Plateau where BPA was detected; however, few studies examined the influence of this chemical on native viviparous fish. The effects of BPA (sublethal dose) were determined on DNA integrity and Foxl2 expression in G. atripinnis gonads, and interactions of BPA with FOXL2 protein. Genotoxicity analysis revealed that % comets, at 14 and 28 days and comet tail length (at 14 days) were significantly higher in exposed compared to controls. In general, the % DNA tail was not markedly higher in BPA-treated fish; however, tail moment related to tail length exhibited significant increases in DNA damage. RT-qPCR assays showed Foxl2 overexpression after 14 and 28 days of exposure in females; while in males, Foxl2 was overexpressed after 28 days. In silico analysis demonstrated that BPA interacted with seven residues located in FOXL2 homeodomain. In summary, sublethal BPA doses induced DNA damage and changes in Foxl2 expression in gonadal cells of G. atripinnis, which may adversely affect reproduction in BPA-exposed wild populations. Foxl2 overexpression and BPA-FOXL2 interaction suggested alterations in processes involving Foxl2. Viviparous fish may thus serve as potential non-conventional models for assessing pollutants effects.
Use of Micellar Liquid Chromatography to Determine Mebendazole in Dairy Products and Breeding Waste from Bovine Animals

Mebendazole is an anthelmintic drug used in cattle production. However, residues may occur in produced food and in excretions, jeopardizing population health. A method based on micellar liquid chromatography (MLC) was developed to determine mebendazole in dairy products (milk, cheese, butter, and curd) and nitrogenous waste (urine and dung) from bovine animals. Sample treatment was expedited to simple dilution or solid-to-liquid extraction, followed by filtration and direct injection of the obtained solution. The analyte was resolved from matrix compounds in less than 8 min, using a C18 column and a mobile phase made up of 0.15 M sodium dodecyl sulfate (SDS)–6% 1-pentanol phosphate buffered at pH 7, and running at 1 mL/min under isocratic mode. Detection was performed by absorbance at 292 nm. The procedure was validated according to the guidelines of the EU Commission Decision 2002/657/EC in terms of: specificity, method calibration range (from the limit of quantification to 25–50 ppm), sensitivity (limit of detection 0.1–0.2 ppm; limit of quantification, 0.3–0.6 ppm), trueness (92.5–102.3%), precision (<7.5%, expressed at RSD), robustness, and stability. The method is reliable, sensitive, easy-to-handle, eco-friendly, safe, inexpensive, and provides a high sample-throughput. Therefore, it is useful for routine analysis as a screening or quantification method in a laboratory for drug-residue control.
Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation

DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.
The C-terminal domain of feline and bovine SAMHD1 proteins has a crucial role in lentiviral restriction

SAM and HD domain-containing protein 1 (SAMHD1) is a host factor that restricts reverse transcription of lentiviruses such as HIV in myeloid cells and resting T cells through its dNTP triphosphohydrolase (dNTPase) activity. Lentiviruses counteract this restriction by expressing the accessory protein Vpx or Vpr, which targets SAMHD1 for proteasomal degradation. SAMHD1 is conserved among mammals, and the feline and bovine SAMHD1 proteins (fSAM and bSAM) restrict lentiviruses by reducing cellular dNTP concentrations. However, the functional regions of fSAM and bSAM that are required for their biological functions are not well-characterized. Here, to establish alternative models to investigate SAMHD1 in vivo, we studied the restriction profile of fSAM and bSAM against different primate lentiviruses. We found that both fSAM and bSAM strongly restrict primate lentiviruses and that Vpx induces the proteasomal degradation of both fSAM and bSAM. Further investigation identified one and five amino acid sites in the C-terminal domain (CTD) of fSAM and bSAM, respectively, that are required for Vpx-mediated degradation. We also found that the CTD of bSAM is directly involved in mediating bSAM's antiviral activity by regulating dNTPase activity, whereas the CTD of fSAM is not. Our results suggest that the CTDs of fSAM and bSAM have important roles in their antiviral functions. These findings advance our understanding of the mechanism of fSAM- and bSAM-mediated viral restriction and might inform strategies for improving HIV animal models.
Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors

In this study, a drug discovery programme that sought to identify novel dual bacterial topoisomerase II inhibitors (NBTIs) led to the selection of six optimized compounds. In enzymatic assays, the molecules showed equivalent dual-targeting activity against the DNA gyrase and topoisomerase IV enzymes of Staphylococcus aureus and Escherichia coli. Consistently, the compounds demonstrated potent activity in susceptibility tests against various Gram-positive and Gram-negative reference species, including ciprofloxacin-resistant strains. The activity of the compounds against clinical multidrug-resistant isolates of S. aureus, Clostridium difficile, Acinetobacter baumannii, Neisseria gonorrhoeae, E. coli and vancomycin-resistant Enterococcus spp. was also confirmed. Two compounds (1 and 2) were tested in time-kill and post-antibiotic effect (PAE) assays. Compound 1 was bactericidal against all tested reference strains and showed higher activity than ciprofloxacin, and compound 2 showed a prolonged PAE, even against the ciprofloxacin-resistant S. aureus BAA-1720 strain. Spontaneous development of resistance to both compounds was selected for in S. aureus at frequencies comparable to those obtained for quinolones and other NBTIs. S. aureus BAA-1720 mutants resistant to compounds 1 and 2 had single point mutations in gyrA or gyrB outside of the quinolone resistance-determining region (QRDR), confirming the distinct site of action of these NBTIs compared to that of quinolones. Overall, the very good antibacterial activity of the compounds and their optimizable in vitro safety and physicochemical profile may have relevant implications for the development of new broad-spectrum antibiotics.
Pain Management in Infants, Children, Adolescents, and Individuals with Special Health Care Needs

This statement provides dentists and stakeholders with current best practices for pediatric pain management. Infants, children, adolescents, and individuals with special health care needs may experience pain resulting from dental/orofacial injury, infection, and dental procedures. Dental pain is an inflammatory condition that can be categorized as somatic (i.e., periodontal, alveolar, mucosal) or visceral (i.e., pulpal). Dental professionals should consider pain assessment for all patients. Inadequate pain management may lead to significant physical and psychological consequences for patients. Perioperative pain management approaches include pre-emptive pain management (e.g., anesthetics), use of local anesthesia during general anesthesia for postoperative pain control, nonpharmacological anxiolytic interventions (e.g., providing a calm environment, emotional support), distraction and imagery (e.g., counting, video games), and pharmacological pain control agents including non-opioid analgesics (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen) and opioid analgesics. Acetaminophen and nonsteroidal anti-inflammatory medications are first line pharmacologic therapies for pain management. Use of opioids for pediatric dental patients should be rare, and steps to mitigate opioid misuse are discussed. This document was developed
Grasping Force Control of Multi-Fingered Robotic Hands through Tactile Sensing for Object Stabilization

Grasping force control is important for multi-fingered robotic hands to stabilize the grasped object. Humans are able to adjust their grasping force and react quickly to instabilities through tactile sensing. However, grasping force control through tactile sensing with robotic hands is still relatively unexplored. In this paper, we make use of tactile sensing for multi-fingered robot hands to adjust the grasping force to stabilize unknown objects without prior knowledge of their shape or physical properties. In particular, an online detection module based on Deep Neural Network (DNN) is designed to detect contact events and object material simultaneously from tactile data. In addition, a force estimation method based on Gaussian Mixture Model (GMM) is proposed to compute the contact information (i.e., contact force and contact location) from tactile data. According to the results of tactile sensing, an object stabilization controller is then employed for a robotic hand to adjust the contact configuration for object stabilization. The spatio-temporal property of tactile data is exploited during tactile sensing. Finally, the effectiveness of the proposed framework is evaluated in a real-world experiment with a five-fingered Shadow Dexterous Hand equipped with BioTac sensors.
Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Despite the consensus around the clinical potential of the α-emitting radionuclide astatine-211 (211At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing 211At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of 211At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with 211At depend on custom systems for recovering 211At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of 211At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between 211At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing 211At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with 211At.
Integrating Suitable Linkage of Covalent Organic Frameworks into Covalently Bridged Inorganic/Organic Hybrids toward Efficient Photocatalysis.

Covalent organic frameworks (COFs) are excellent platforms with tailored functionalities in photocatalysis. There are still challenges in increasing photochemical performance of COFs. Therefore, we designed and prepared a series of COFs for photocatalytic hydrogen generation. Varying different ratios of β-ketoenamine to imine moieties in the linkages could differ the ordered structure, visible light harvesting and bandgap. Overall β-ketoenamine linked-COFs exhibited much better photocatalytic activity than those COFs having both β-ketoenamine and imine moieties on account of non-quenched excited-state and more favorable HOMO level in photoinduced oxidation reaction from the former. Specifically, after in situ growth of β-ketoenamine linked COFs onto NH2-Ti3C2Tx (Tx = -O and -OH) MXene via covalent connection, the hetero-hybrid showed an obvious improvement in photocatalytic H2 evolution because of strong covalent coupling, electrical conductivity and efficient charge transfer. This integrated linkage evolution and covalent hybridization approach advances the development of COF-based photocatalysts.
The impact of the field width on VMAT plan quality and the assessment of half field method

Abstract Purpose The goal of this work is to investigate the field width dependence of the volumetric modulated arc therapy (VMAT) plan quality and to propose a half field method to irradiate large volumes effectively with VMAT. Materials and methods We compared four different VMAT methods; namely three full field (3ff), four full field (4ff), three half field (3hf), four half field (4hf). To evaluate the impact of the field width on VMAT plan quality, 12 different size PTVs were created in the virtual phantom and treatment plans generated for each PTV were compared. The effectiveness of our half field method was tested using computed tomography (CT) data of 10 nasopharyngeal carcinoma patients. Results In the virtual phantom study, organs at risk (OAR) mean dose, the maximum point dose, and Homogeneity Index (HI) were found to be field width dependent. Conformation Number (CN) was not significantly affected. In the clinical study, 4hf plans obtained statistically significant dose reduction at brainstem (P < 0.001), right parotid (P = 0.034), oral cavity (P < 0.001), larynx (P = 0.003), cochlea (P = 0.017), lips (P = 0.024), and Body‐PTV (P = 0.04) compared to 4ff plans. Conclusion Our results indicate that VMAT plan quality is dependent on the field width. Half field VMAT method, with the help of reduced field width, shows a clear advantage for the irradiation of large size targets compared to traditionally used full field VMAT plans.
Long-term Effect of Intraocular Lens vs Contact Lens Correction on Visual Acuity After Cataract Surgery During Infancy: A Randomized Clinical Trial.

Importance Although intraocular lenses (IOLs) are often implanted in children, little is known whether primary IOL implantation or aphakia and contact lens correction results in better long-term visual outcomes after unilateral cataract surgery during infancy. Objective To compare long-term visual outcomes with contact lens vs IOL correction following unilateral cataract surgery during infancy. Design, Setting, and Participants This multicenter randomized clinical trial enrolled 114 infants with a unilateral congenital cataract who underwent cataract surgery with or without primary IOL implantation between 1 and 6 months of age. Data on long-term visual outcomes were collected when the children were age 10.5 years (July 14, 2015, to July 12, 2019) and analyzed from March 30 through August 6, 2019. Interventions Intraocular lens implantation at the time of cataract surgery. Main Outcomes and Measures Best-corrected visual acuity using the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) testing protocol. Analysis was performed on an intention-to-treat basis. Results Best-corrected visual acuity was measured at age 10.5 years for 110 of the 114 patients (96%) enrolled as infants. The participants included 58 girls (53%) and 52 boys (47%). Overall, 27 of the children (25%) had good (logMAR 0.30 [Snellen equivalent, 20/40] or better) visual acuity in the treated eye (12 [22%] in the IOL group and 15 [27%] in the aphakia group), but 50 children (44%) had a visual acuity of logMAR 1.00 (Snellen equivalent, 20/200) or worse (25 [44%] in the IOL group and 25 [44%] in the aphakia group). The median logMAR acuity in the treated eye was similar in children randomized to receive an IOL at the time of cataract extraction (0.89; interquartile range [IQR], 0.33-1.43 [Snellen equivalent, 20/159]) and those who remained aphakic (0.86; IQR, 0.30-1.46 [Snellen equivalent, 20/145]) (IQR, 0.30-1.46; P = .82). Although the overall difference in median visual acuity between the 2 groups was small, the estimate was imprecise (99% CI for the difference in medians was -0.54 to 0.47). Conclusions and Relevance As in previous phases of the study, visual acuity outcomes were highly variable with only 27 children (25%) achieving excellent visual acuity in their treated eye and 50 children (44%) having poor vision in the treated eye. Implanting an IOL at the time of cataract extraction was neither beneficial nor detrimental to the visual outcome. Trial Registration ClinicalTrials.gov Identifier: NCT00212134.
Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.
Effects of Birthing Room Design on Maternal and Neonate Outcomes: A Systematic Review

Aim: To summarize, categorize, and describe published research on how birthing room design influences maternal and neonate physical and emotional outcomes. Background: The physical healthcare environment has significant effects on health and well-being. Research indicates that birthing environments can impact women during labor and birth. However, summaries of the effects of different environments around birth are scarce. Methods: We conducted a systematic review, searching 10 databases in 2016 and 2017 for published research from their inception dates, on how birthing room design influences maternal and neonate physical and emotional outcomes, using a protocol agreed a priori. The quality of selected studies was assessed, and data were extracted independently by pairs of authors and described in a narrative analysis. Results: In total, 3,373 records were identified and screened by title and abstract; 2,063 were excluded and the full text of 278 assessed for analysis. Another 241 were excluded, leaving 15 articles presenting qualitative and quantitative data from six different countries on four continents. The results of the analysis reveal four prominent physical themes in birthing rooms that positively influence on maternal and neonate physical and emotional outcomes: (1) means of distraction, comfort, and relaxation; (2) raising the birthing room temperature; (3) features of familiarity; and (4) diminishing a technocratic environment. Conclusions: The evidence on how birthing environments affect outcomes of labor and birth is incomplete. There is a crucial need for more research in this field.