bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare diseases of ectoderm: Translating discovery to therapy
Authors: Wright John Timothy , Abbott Becky M. , Salois Maddison N. , Gugger Jessica A. , Parraga Shirley P. , Swanson Amanda K. , Fete Mary , Koster Maranke I. 
Published: December 2022

AbstractHeritable conditions known as ectodermal dysplasias are rare and can be associated with marked morbidity, mortality, and a reduced quality of life. The diagnosis and care of individuals affected by one of the many ectodermal dysplasias presents myriad challenges due to their rarity and the diverse phenotypes. These conditions are caused by abnormalities in multiple genes and signaling pathways that are essential for the development and function of ectodermal derivatives. During a 2021 international conference focused on translating discovery to therapy, researchers and clinicians gathered with the goal of advancing the diagnosis and treatment of conditions affecting ectodermal tissues with an emphasis on skin, hair, tooth, and eye phenotypes. Conference participants presented a variety of promising treatment strategies including gene or protein replacement, gene editing, cell therapy, and the identification of druggable targets. Further, barriers that negatively influence the current development of novel therapeutics were identified. These barriers include a lack of accurate prevalence data for rare conditions, absence of an inclusive patient registry with deep phenotyping data, and insufficient animal models and cell lines. Overcoming these barriers will need to be prioritized in order to facilitate the development of novel treatments for genetic disorders of the ectoderm.
New prospectives on treatment opportunities in RASopathies
Authors: Gelb Bruce D. , Yohe Marielle E. , Wolf Cordula , Andelfinger Gregor 
Published: December 2022

AbstractThe RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen‐activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state‐of‐the‐art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK‐associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.
Two‐Dimensional Polymer Networks Locking on Inorganic Nanoparticles
Authors: Tao Xingfu , Li Yang , Yu Linxiuzi , Zhang Yinshu , Han Chenglong , Yang Yang , Qian Hujun , Lu Zhongyuan , Liu Kun 
Published: December 2022

AbstractTwo‐dimensional polymers (2DPs), single‐layer networks of covalently linked monomers, show perspectives as membranes and in electronics. However, 2D polymerization of monomers in orthogonal directions limited the formation of 2DPs on nanoparticles (NPs) with high surface curvatures. Here we propose a high‐curvature 2D polymerization to form a single‐layer 2DP network as a non‐contacting ligand on the surface of NPs for their stabilization and functionalization. The high‐curvature 2D polymerization of amphiphilic Gemini monomers was conducted in situ on surfaces of NPs with various sizes, shapes, and materials, forming highly cross‐linked 2DPs. Selective etching of core–shell NPs led to 2DPs as a non‐contact ligand of yolk‐shell structures with excellent shape retention and high NP‐surface accessibility. In addition, by copolymerization, the 2DP ligands can covalently link to other functional molecules. This work promotes the development of 2DPs on NPs for their functional modification.
A Widely Distributed Biosynthetic Cassette Is Responsible for Diverse Plant Side Chain Cross‐Linked Cyclopeptides**
Authors: Lima Stella T. , Ampolini Brigitte G. , Underwood Ethan B. , Graf Tyler N. , Earp Cody E. , Khedi Imani C. , Pasquale Michael A. , Chekan Jonathan R. 
Published: December 2022

AbstractCyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome‐mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP peptide cyclase containing gene clusters. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. Reconstitution of the enzyme activity for the BURP found in the biosynthesis of arabipeptin A validates the activity of the newly discovered split BURP peptide cyclases. These results expand our understanding of the biosynthetic pathways responsible for diverse cyclic plant peptides and suggest that these side chain cross‐link modifications are widely distributed in eudicots.
Protoglobin‐Catalyzed Formation of cis‐Trifluoromethyl‐Substituted Cyclopropanes by Carbene Transfer
Authors: Schaus Lucas , Das Anuvab , Knight Anders M. , Jimenez‐Osés Gonzalo , Houk K. N. , Garcia‐Borràs Marc , Arnold Frances H. , Huang Xiongyi 
Published: December 2022

AbstractTrifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans‐CF3‐CPAs, stereoselective production of corresponding cis‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis of cis‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery.
Chloroacetamide‐Modified Nucleotide and RNA for Bioconjugations and Cross‐Linking with RNA‐Binding Proteins
Authors: Brunderová Mária , Krömer Matouš , Vlková Marta , Hocek Michal 
Published: December 2022

AbstractReactive RNA probes are useful for studying and identifying RNA‐binding proteins. To that end, we designed and synthesized chloroacetamide‐linked 7‐deaza‐ATP which was a good substrate for T7 RNA polymerase in in vitro transcription assay to synthesize reactive RNA probes bearing one or several reactive modifications. Modified RNA probes reacted with thiol‐containing molecules as well as with cysteine‐ or histidine‐containing peptides to form stable covalent products. They also reacted selectively with RNA‐binding proteins to form cross‐linked conjugates in high conversions thanks to proximity effect. Our modified nucleotide and RNA probes are promising tools for applications in RNA (bio)conjugations or RNA proteomics.
Photochemical Processes of Superbase Generation in Xanthone Carboxylic Salts
Authors: Ley Christian , Siedel Antoine , Bertaux Tony , Croutxé‐Barghorn Céline , Allonas Xavier 
Published: December 2022

AbstractPhotobase generators are species that allow the photocatalysis of various reactions, such as thiol‐Michael, thiol‐isocyanate, and ring‐opening polymerization reactions. However, existing compounds have complex syntheses and low quantum yields. To overcome these problems, photobase generators based on the photodecarboxylation reaction were developed. We synthesized and studied the photochemistry and photophysics of two xanthone photobase, their carboxylic acid precursors, and their photoproducts to understand the photobase generation mechanism. We determined accurate quantum yields of triplet states and photobase generation. The effect of the intermediate radical preceding the base release was demonstrated. We characterized the photophysics of the photobase by femtosecond spectroscopy and showed that the photodecarboxylation process occurred from the second excited triplet state with a rate constant of 2.2×109 s−1.
Super‐Resolution Tension PAINT Imaging with a Molecular Beacon
Authors: Kim Seong Ho , Li Isaac T. S. 
Published: December 2022

AbstractDNA‐PAINT enabled super‐resolution imaging through the transient binding of fluorescently‐labelled single‐stranded DNA (ssDNA) imagers to target ssDNA. However, its performance is constrained by imager background fluorescence, resulting in relatively long image acquisition and potential artifacts. We designed a molecular beacon (MB) as the PAINT imager. Unbound MB in solution reduces the background fluorescence due to its natively quenched state. They are fluorogenic upon binding to target DNA to create individual fluorescence events. We demonstrate that MB‐PAINT provides localization precision similar to traditional linear imager DNA‐PAINT. We also show that MB‐PAINT is ideally suited for fast super‐resolution imaging of molecular tension probes in living cells, eliminating the potential of artifacts from free‐diffusing imagers in traditional DNA‐PAINT at the cell‐substrate interface.
Association of Circulating Antibody‐Secreting Cell Maturity With Disease Features in Primary Sjögren's Syndrome
Authors: Steinmetz Tobit D. , Verstappen Gwenny M. , Schulz Sebastian R. , de Wolff Liseth , Wilbrink Rick , Visser Annie , Terpstra Janneke , Bootsma Hendrika , Kroese Frans G. M. 
Published: December 2022

ObjectiveB cell hyperactivity plays an important role in primary Sjögren's syndrome (SS). We undertook this study to better understand the B cell effector branch, namely antibody‐secreting cells (ASCs) in primary SS, and to examine the quantity, maturity, and inflammatory properties of ASCs in primary SS patients.MethodsCirculating ASCs, defined as CD3–CD14–CD27+CD38++ cells, from 21 primary SS patients and 10 healthy controls were assessed using spectral flow cytometry. Expression levels of relevant ASC markers relating to maturity, survival, and inflammatory status were analyzed using a t‐distributed stochastic neighbor embedding approach. Correlation of ASC properties with primary SS disease parameters was assessed.ResultsASCs were more abundant in peripheral blood from primary SS patients than from healthy controls (mean ± SD 3.1 ± 5.1 cells/μl versus 1.1 ± 1.0 cells/μl, respectively; P = 0.048) and displayed a more mature phenotype (mean ± SD CD19– ASCs 0.37 ± 1.21 cells/μl versus 0.06 ± 0.11 cells/μl, respectively; P = 0.005). An inflammatory CXCR3+ phenotype of ASCs correlated positively with our newly developed ASC maturity index (r = 0.568, P = 0.007) but correlated negatively with antiinflammatory interleukin‐10 expression (r = –0.769, P < 0.001). ASCs with a higher maturity index also demonstrated higher levels of the pro‐survival protein myeloid cell leukemia 1 (r = 0.567, P = 0.007). Frequency and/or maturity of ASCs correlated with several primary SS disease parameters, such as antinuclear antibody and anti‐La/SSB titers, salivary gland focus scores, and ocular staining scores.ConclusionQuantity and maturity of ASCs in primary SS patients are increased and correlate with disease parameters. A higher maturity index of ASCs marks a pro‐survival and proinflammatory phenotype. Altogether, B cell hyperactivity in primary SS extends to the peripheral ASC compartment, raising potential for ASCs as future biomarkers or targets for primary SS treatment.image
Multidimensional motor performance in children with autism mostly remains stable with age and predicts social communication delay, language delay, functional delay, and repetitive behavior severity after accounting for intellectual disability or cognitive delay: A SPARK dataset analysis
Authors: Bhat Anjana 
Published: December 2022

AbstractWhen motor difficulties continue into adolescence/adulthood, they could negatively impact an individual with autism spectrum disorder (ASD)'s daily living skills, physical fitness, as well as physical and mental health/well‐being. Few studies have examined motor difficulties in children with ASD as a function of sex or age; however, greater cognitive challenges are associated with worse general motor performance. Based on the Developmental Coordination Disorder‐Questionnaire (DCD‐Q) data from the SPARK study sample, 87%–88% children with ASD were at‐risk for a general motor impairment that persisted until 15 years and was related to their core and co‐occurring difficulties. Bhat et al. confirmed motor difficulties in children with ASD on multiple motor dimensions that predicted core and co‐occurring conditions after accounting for age and sex. However, presence of intellectual disability (ID) or cognitive delay was not controlled in the previous analysis. Additionally, the effects of age, sex, and cognitive ability on multidimensional motor difficulties of the SPARK sample have not been discussed before. Therefore, this analysis examines the effects of age, sex, and cognitive ability (presence of ID or level of cognitive delay) on the motor performance of children from the SPARK sample using the DCD‐Q. Except fine motor skills, multiple motor domains did not change with age in children with ASD. Females without ID improved their fine motor scores with age, and performed better compared to males without ID. Children with ASD and ID had greater motor difficulties across multiple motor domains than those without ID. Even after controlling for age, sex, and presence of ID/cognitive delay; motor performance was predictive of social communication skills, repetitive behavior severity, as well as language and functional delays. Gross motor skills contributed more than fine motor and general motor competence skills in predicting social communication delay. However, fine motor and general motor competence skills contributed more than gross motor skills in predicting repetitive behavior severity and language delay. Both, fine and gross motor skills predicted functional delay. In light of consistent findings on motor difficulties in children with ASD, adding motor issues as a specifier within the ASD definition could provide a clear clinical route for movement clinicians to address motor difficulties of individuals with ASD.
Behavioral and neuroinflammatory changes caused by glyphosate: Base herbicide in mice offspring
Authors: de Castro Vieira Carneiro Carla Larissa , Chaves Edna Maria Camelo , Neves Kelly Rose Tavares , Braga Marcus Davis Machado , Assreuy Ana Maria Sampaio , de Moraes Maria Elisabete Amaral , Aragão Gislei Frota 
Published: December 2022

AbstractBackgroundGlyphosate is a pesticide considered of low toxicity, but scientific evidences show it can be harmful to health. This study aimed to evaluate the toxicity in mice offspring exposed to glyphosate‐based herbicide (GBH) during the intrauterine period.MethodsFemale matrices received glyphosate 0.3 mg/kg daily per oral throughout the gestational period, which was variable between 18 and 22 days. From the 25th until the 28th days post‐birth, mice offspring were subjected to behavioral tests, and the prefrontal cortex was processed for immunohistochemical analysis.ResultsTwo significant behavioral changes were observed: anxiety in the GLIF0.3 group, increase in the behavior burying marbles in the marble‐burying test and hyperactivity, expressed by the significant increase of the crossing number in the open field test. The increased microglia, TNF‐alpha, and astrocyte expression were also observed in the prefrontal cortex of offspring treated with GLIF0.3.ConclusionExposure to GBH during mice intrauterine development induces hyperactive and anxious behavior, evidencing neuroinflammation.
Identification and characterization of the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes by LC–Orbitrap–MS/MS combined with diagnostic fragment ions and accurate mass measurements
Authors: Hu Aizhen , Liu Qingwang , Ouyang Jing 
Published: December 2022

AbstractMoscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra‐high‐performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC–Orbitrap–MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC–Orbitrap–MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.
Surgical repair of an obstructed mixed‐type total anomalous pulmonary venous connection
Authors: Shammout Reem , Alkhadraa Doaa , Alkadi Sidra , Al‐Dairy Alwaleed 
Published: December 2022

AbstractTotal anomalous pulmonary venous connection is a rare congenital anomaly and has four anatomical subtypes of which the mixed type represents diagnostic and therapeutic challenge. When associated with obstruction, however, urgent surgical repair is needed. Herein, we present a rare case of obstructed mixed type total anomalous pulmonary venous connection with successful surgical repair.
Managing soil acidity vs. soil Ca:Mg ratio: What is more important for crop productivity?
Authors: Leiva Soto Andrea , Culman Steve W , Herms Catherine , Sprunger Christine , Doohan Douglas 
Published: December 2022

AbstractSoil balancing (SB), or base cation saturation ratio (BCSR), is a soil management approach that strives to maintain specific soil calcium (Ca) and magnesium (Mg) levels to improve soil health, decrease pest problems, have better crops, and increase crop yield. To achieve ideal levels of Ca to Mg, BCSR practitioners apply gypsum (calcium sulfate) and high‐calcium lime (Hi‐Cal lime) amendments, with the former increasing Ca base saturation and the later increasing both Ca base saturation and soil pH. We hypothesized that positive benefits ascribed by BCSR practitioners are due to increasing soil pH, rather than increasing Ca levels, both of which occur after lime application. Thus, we conducted successive applications of gypsum or epsom (magnesium sulfate) with and without Hi‐Cal or dolomitic lime, to either increase or lower soil Ca:Mg ratio and pH in an Ohio‐based experiment over 6 yr and evaluated soil and yield responses in a corn (Zea mays L.)–soybean (Glycine max L.)–small grain rotation. Repeated applications of gypsum with and without Hi‐Cal lime significantly increased soil Ca:Mg ratio and repeated applications of epsom with and without dolomitic lime significantly decreased the soil Ca:Mg ratio. Crop yield was not affected by soil Ca:Mg ratio for any crop in any year. However, over the 6 yr of the study, corn yields were positively related to increases in soil pH. We conclude that balancing soil Ca and Mg levels did not impact corn or soybean yields but managing soil acidity remains a fundamental tool to improve crop yields.
Cysteine‐Selective Modification of Peptides and Proteins via Desulfurative C−C Bond Formation
Authors: Griffiths Rhys C. , Smith Frances R. , Li Diyuan , Wyatt Jasmine , Rogers David M. , Long Jed E. , Cusin Lola M. L. , Tighe Patrick J. , Layfield Robert , Hirst Jonathan D. , Müller Manuel M. , Mitchell Nicholas J. 
Published: December 2022

AbstractThe site‐selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp3)−C(sp3) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible‐light‐mediated reaction is described that enables the site‐selective modification of peptides and proteins via desulfurative C(sp3)−C(sp3) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM‐mimic is successfully integrated into a recombinantly expressed histone.
Enantioselective Desymmetrization Triggered by Iminium‐Enamine Activation: Access to Complex Cyclohepta[b]indoles
Authors: Magham Lakshmi Revati , Thopate Satish B. , Samad Abdus , Chegondi Rambabu 
Published: December 2022

AbstractThe expeditious construction of complex molecules having multiple stereocentres is highly desirable in organic chemistry. In the present communication, we report the development of an organocatalytic asymmetric desymmetrization of prochiral enal‐tethered cyclohexadienones via the C3‐selective Friedel−Crafts alkylation of indoles triggered by LUMO‐lowering iminium activation/HOMO‐raising enamine activation. The reaction provides access to bicyclic enones, which further undergo acid‐mediated intramolecular annulation from C2‐position to afford highly strained cyclohepta[b]indoles with five contiguous stereocentres and three new C−C bonds in excellent enantioselectivity and diastereoselectivity.
Specific Signal Enhancement on an RNA‐Protein Interface by Dynamic Nuclear Polarization
Authors: Aladin Victoria , Sreemantula Arun K. , Biedenbänder Thomas , Marchanka Alexander , Corzilius Björn 
Published: December 2022

AbstractSensitivity and specificity are both crucial for the efficient solid‐state NMR structure determination of large biomolecules. We present an approach that features both advantages by site‐specific enhancement of NMR spectroscopic signals from the protein‐RNA binding site within a ribonucleoprotein (RNP) by dynamic nuclear polarization (DNP). This approach uses modern biochemical techniques for sparse isotope labeling and exploits the molecular dynamics of 13C‐labeled methyl groups exclusively present in the protein. These dynamics drive heteronuclear cross relaxation and thus allow specific hyperpolarization transfer across the biomolecular complex's interface. For the example of the L7Ae protein in complex with a 26mer guide RNA minimal construct from the box C/D complex in archaea, we demonstrate that a single methyl‐nucleotide contact is responsible for most of the polarization transfer to the RNA, and that this specific transfer can be used to boost both NMR spectral sensitivity and specificity by DNP.