bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients
Authors: Schroeder Christopher , Faust Ulrike , Krauße Luisa , Liebmann Alexandra , Abele Michael , Demidov German , Schütz Leon , Kelemen Olga , Pohle Alexandra , Gauß Silja , Sturm Marc , Roggia Cristiana , Streiter Monika , Buchert Rebecca , Armenau-Ebinger Sorin , Nann Dominik , Beschorner Rudi , Handgretinger Rupert , Ebinger Martin , Lang Peter , Holzer Ursula , Skokowa Julia , Ossowski Stephan , Haack Tobias B. , Mau-Holzmann Ulrike A. , Dufke Andreas , Riess Olaf , Brecht Ines B. 
Published: July 2023

AbstractThe prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.
Structural and functional fine mapping of cysteines in mammalian glutaredoxin reveal their differential oxidation susceptibility
Authors: Corteselli Elizabeth M. , Sharafi Mona , Hondal Robert , MacPherson Maximilian , White Sheryl , Lam Ying-Wai , Gold Clarissa , Manuel Allison M. , van der Vliet Albert , Schneebeli Severin T. , Anathy Vikas , Li Jianing , Janssen-Heininger Yvonne M. W. 
Published: July 2023

AbstractProtein-S-glutathionylation is a post-translational modification involving the conjugation of glutathione to protein thiols, which can modulate the activity and structure of key cellular proteins. Glutaredoxins (GLRX) are oxidoreductases that regulate this process by performing deglutathionylation. However, GLRX has five cysteines that are potentially vulnerable to oxidative modification, which is associated with GLRX aggregation and loss of activity. To date, GLRX cysteines that are oxidatively modified and their relative susceptibilities remain unknown. We utilized molecular modeling approaches, activity assays using recombinant GLRX, coupled with site-directed mutagenesis of each cysteine both individually and in combination to address the oxidizibility of GLRX cysteines. These approaches reveal that C8 and C83 are targets for S-glutathionylation and oxidation by hydrogen peroxide in vitro. In silico modeling and experimental validation confirm a prominent role of C8 for dimer formation and aggregation. Lastly, combinatorial mutation of C8, C26, and C83 results in increased activity of GLRX and resistance to oxidative inactivation and aggregation. Results from these integrated computational and experimental studies provide insights into the relative oxidizability of GLRX’s cysteines and have implications for the use of GLRX as a therapeutic in settings of dysregulated protein glutathionylation.
Macrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery
Authors: Diao Yanyan , Liu Dandan , Ge Huan , Zhang Rongrong , Jiang Kexin , Bao Runhui , Zhu Xiaoqian , Bi Hongjie , Liao Wenjie , Chen Ziqi , Zhang Kai , Wang Rui , Zhu Lili , Zhao Zhenjiang , Hu Qiaoyu , Li Honglin 
Published: July 2023

AbstractInterest in macrocycles as potential therapeutic agents has increased rapidly. Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds, which can contribute to the improvement of the biological activity and physicochemical properties of these molecules. In this study, we propose a computational macrocyclization method based on Transformer architecture (which we name Macformer). Leveraging deep learning, Macformer explores the vast chemical space of macrocyclic analogues of a given acyclic molecule by adding diverse linkers compatible with the acyclic molecule. Macformer can efficiently learn the implicit relationships between acyclic and macrocyclic structures represented as SMILES strings and generate plenty of macrocycles with chemical diversity and structural novelty. In data augmentation scenarios using both internal ChEMBL and external ZINC test datasets, Macformer display excellent performance and generalisability. We showcase the utility of Macformer when combined with molecular docking simulations and wet lab based experimental validation, by applying it to the prospective design of macrocyclic JAK2 inhibitors.
Stiefel-Whitney topological charges in a three-dimensional acoustic nodal-line crystal
Authors: Xue Haoran , Chen Z. Y. , Cheng Zheyu , Dai J. X. , Long Yang , Zhao Y. X. , Zhang Baile 
Published: July 2023

AbstractBand topology of materials describes the extent Bloch wavefunctions are twisted in momentum space. Such descriptions rely on a set of topological invariants, generally referred to as topological charges, which form a characteristic class in the mathematical structure of fiber bundles associated with the Bloch wavefunctions. For example, the celebrated Chern number and its variants belong to the Chern class, characterizing topological charges for complex Bloch wavefunctions. Nevertheless, under the space-time inversion symmetry, Bloch wavefunctions can be purely real in the entire momentum space; consequently, their topological classification does not fall into the Chern class, but requires another characteristic class known as the Stiefel-Whitney class. Here, in a three-dimensional acoustic crystal, we demonstrate a topological nodal-line semimetal that is characterized by a doublet of topological charges, the first and second Stiefel-Whitney numbers, simultaneously. Such a doubly charged nodal line gives rise to a doubled bulk-boundary correspondence—while the first Stiefel-Whitney number induces ordinary drumhead states of the nodal line, the second Stiefel-Whitney number supports hinge Fermi arc states at odd inversion-related pairs of hinges. These results experimentally validate the two Stiefel-Whitney topological charges and demonstrate their unique bulk-boundary correspondence in a physical system.
Identification of biological components for sialolith formation organized in circular multi-layers
Authors: Sodnom-Ish Buyanbileg , Eo Mi Young , Cho Yun Ju , Seo Mi Hyun , Yang Hyeong-Cheol , Kim Min-Keun , Myoung Hoon , Lee Suk Keun , Kim Soung Min 
Published: July 2023

AbstractAccording to the previous studies of sialolithiasis reported so far, this study is aimed to identify the biological components of sialolith, which show different ultrastructures and chemical compositions from other stones, cholelith and urolith. Twenty-two specimens obtained from 20 patients were examined histologically, and analyzed with micro-CT, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM). All sialoliths (n = 22) observed in this study showed a central nidus, which was filled with organoid matrix admixed with exosome vesicles, loose calcium apatite crystals, and many bacteria. The micro-CT and SEM observation clearly defined a single or multiple central nidus(es) encircled by highly calcified compact zone. The circular compact zone showed a band-like calcification, about 1–3 mm in thickness, and usually located between the central nidus and the peripheral multilayer zone. But some sialoliths (n = 5) showed severe erosion of compact zone by expanding multilayered zone depending on the level of calcification and inflammation in sialolith. By observing TEM images, many exosome vesicles and degraded cytoplasmic organelles were found in the central nidus, and some epithelial cells were also found in the calcified matrix of peripheral multilayer zone. Particularly, EDS analysis indicated the highest Ca/P ratio in the intermediate compact zone (1.77), and followed by the central nidus area (1.39) and the peripheral multilayer zone (0.87). Taken together, these data suggest that the central nidus containing many inflammatory exosomes and degraded cytoplasmic organelles has a potential to induce a band-like calcification of compact zone, and followed by the additional multilayer deposition of exfoliated salivary epithelial cells as well as salivary materials. Thereby, the calcium apatite-based sialolith is gradually growing in its volume size, and eventually obstructs the salivary flow and provides a site for the bacterial infection.
Volumetric capnography and return of spontaneous circulation in an experimental model of pediatric asphyxial cardiac arrest
Authors: de la Mata Navazo Sara , Manrique Gema , Fernández Sarah Nicole , Pérez Gema , Butragueño‑Laiseca Laura , García Miriam , Slöcker María , González Rafael , Herrera Laura , Mencía Santiago , del Castillo Jimena , Solana María José , Sanz Débora , Cieza Raquel , López Jorge , Rodríguez Martínez Alicia , Santiago María José , Urbano Javier , López‑Herce Jesús 
Published: July 2023

AbstractA secondary analysis of a randomized study was performed to study the relationship between volumetric capnography (VCAP) and arterial CO2 partial pressure (PCO2) during cardiopulmonary resuscitation (CPR) and to analyze the ability of these parameters to predict the return of spontaneous circulation (ROSC) in a pediatric animal model of asphyxial cardiac arrest (CA). Asphyxial CA was induced by sedation, muscle relaxation and extubation. CPR was started 2 min after CA occurred. Airway management was performed with early endotracheal intubation or bag-mask ventilation, according to randomization group. CPR was continued until ROSC or 24 min of resuscitation. End-tidal carbon
dioxide (EtCO2), CO2 production (VCO2), and EtCO2/VCO2/kg ratio were continuously recorded.
Seventy-nine piglets were included, 26 (32.9%) of whom achieved ROSC. EtCO2 was the best predictor of ROSC (AUC 0.72, p < 0.01 and optimal cutoff point of 21.6 mmHg). No statistical differences were obtained regarding VCO2, VCO2/kg and EtCO2/VCO2/kg ratios. VCO2 and VCO2/kg showed an inverse correlation with PCO2, with a higher correlation coefficient as resuscitation progressed. EtCO2 also had an inverse correlation with PCO2 from minute 18 to 24 of resuscitation. Our findings suggest that EtCO2 is the best VCAP-derived parameter for predicting ROSC. EtCO2 and VCO2 showed an inverse correlation with PCO2. Therefore, these parameters are not adequate to measure ventilation during CPR.
Binomial-discrete Erlang-truncated exponential mixture and its application in cancer disease
Authors: El-Alosey Alaa R. , Eledum Hussein 
Published: July 2023

AbstractAmong diseases, cancer exhibits the fastest global spread, presenting a substantial challenge for patients, their families, and the communities they belong to. This paper is devoted to modeling such a disease as a special case. A newly proposed distribution called the binomial-discrete Erlang-truncated exponential (BDETE) is introduced. The BDETE is a mixture of binomial distribution with the number of trials (parameter $$n$$
n
) taken after a discrete Erlang-truncated exponential distribution. A comprehensive mathematical treatment of the proposed distribution and expressions of its density, cumulative distribution function, survival function, failure rate function, Quantile function, moment generating function, Shannon entropy, order statistics, and stress-strength reliability, are provided. The distribution's parameters are estimated using the maximum likelihood method. Two real-world lifetime count data sets from the cancer disease, both of which are right-skewed and over-dispersed, are fitted using the proposed BDETE distribution to evaluate its efficacy and viability. We expect the findings to become standard works in probability theory and its related fields.
Homology judgements of pre-evolutionary naturalists explained by general human shape matching abilities
Authors: Stegmann Ulrich E. , Schmidt Filipp 
Published: July 2023

AbstractMany biological homologies were discovered before Darwin and without agreed criteria. Paradigmatic examples include the phylogenetic homology of mammalian forelimb bones and the serial homology of floral organs in waterlilies. It is generally assumed that perceiving similarities intuitively was the first step towards establishing morphological homologies. However, this assumption has never been tested. We hypothesize that pre-evolutionary naturalists relied on the well-established ability of humans to find visual correspondences between differently shaped objects. By using images of homologous organs and applying an experimental paradigm from cognitive psychology, we found that (1) na﻿ïve participants utilised this ability when identifying “corresponding” locations. In addition, (2) these locations were statistically indistinguishable from the locations that pre-evolutionary naturalists and contemporary experts considered homologous. Furthermore, (3) presenting na﻿ïve participants with images of intermediate organs influenced their correspondence judgements. This influence was in line with historical reports according to which intermediate organs facilitated the pre-evolutionary recognition of homologies.
PermaNet Dual, a new deltamethrin-chlorfenapyr mixture net, shows improved efficacy against pyrethroid-resistant Anopheles gambiae sensu lato in southern Benin
Authors: Syme Thomas , N’dombidjé Boris , Gbegbo Martial , Todjinou Damien , Ariori Victoria , De Vos Patricia , Pigeon Olivier , Ngufor Corine 
Published: July 2023

AbstractPyrethroid-chlorfenapyr nets have demonstrated improved entomological and epidemiological impact in trials across Africa. This is driving increased demand for this novel net class in malaria-endemic countries. PermaNet Dual is a new deltamethrin-chlorfenapyr net developed by Vestergaard Sàrl to provide more options to malaria control programmes. We performed an experimental hut trial to evaluate the efficacy of PermaNet Dual against wild, free-flying pyrethroid-resistant Anopheles gambiae sensu lato in Covè, Benin. PermaNet Dual induced superior levels of mosquito mortality compared to a pyrethroid-only net and a pyrethroid-piperonyl butoxide net both when unwashed (77% with PermaNet Dual vs. 23% with PermaNet 2.0 and 56% with PermaNet 3.0, p < 0.001) and after 20 standardised washes (75% with PermaNet Dual vs. 14% with PermaNet 2.0 and 30% with PermaNet 3.0, p < 0.001). Using a provisional non-inferiority margin defined by the World Health Organisation, PermaNet Dual was also non-inferior to a pyrethroid-chlorfenapyr net that has demonstrated improved public health value (Interceptor G2), for vector mortality (79% vs. 76%, OR = 0.878, 95% CIs 0.719–1.073) but not for blood-feeding protection (35% vs. 26%, OR = 1.424, 95% CIs 1.177–1.723). PermaNet Dual presents an additional option of this highly effective net class for improved control of malaria transmitted by pyrethroid-resistant mosquitoes.
Investigations towards incorporation of Eu3+ and Cm3+ during ZrO2 crystallization in aqueous solution
Authors: Opitz Lucas , Hübner René , Shams Aldin Azzam Salim , Gilson Sara E. , Finkeldei Sarah C. , Huittinen Nina 
Published: July 2023

AbstractNuclear energy provides a widely applied carbon-reduced energy source. Following operation, the spent nuclear fuel (SNF), containing a mixture of radiotoxic elements such as transuranics, needs to be safely disposed of. Safe storage of SNF in a deep geological repository (DGR) relies on multiple engineered and natural retention barriers to prevent environmental contamination. In this context, zirconia (ZrO2) formed on the SNF rod cladding, could be employed as an engineered barrier for immobilization of radionuclides via structural incorporation. This study investigates the incorporation of Eu3+ and Cm3+, representatives for trivalent transuranics, into zirconia by co-precipitation and crystallization in aqueous solution at 80 °C. Complementary structural and microstructural characterization has been carried out by powder X-ray diffraction (PXRD), spectrum imaging analysis based on energy-dispersive X-ray spectroscopy in scanning transmission electron microscopy mode (STEM-EDXS), and luminescence spectroscopy. The results reveal the association of the dopants with the zirconia particles and elucidate the presence of distinct bulk and superficially incorporated species. Hydrothermal aging for up to 460 days in alkaline media points to great stability of these incorporated species after initial crystallization, with no indication of phase segregation or release of Eu3+ and Cm3+ over time. These results suggest that zirconia would be a suitable technical retention barrier for mobilized trivalent actinides in a DGR.
Simulations of magnetization reversal in FM/AFM bilayers with THz frequency pulses
Authors: Hirst Joel , Ruta Sergiu , Jackson Jerome , Ostler Thomas 
Published: July 2023

AbstractIt is widely known that antiferromagnets (AFMs) display a high frequency response in the terahertz (THz) range, which opens up the possibility for ultrafast control of their magnetization for next generation data storage and processing applications. However, because the magnetization of the different sublattices cancel, their state is notoriously difficult to read. One way to overcome this is to couple AFMs to ferromagnets—whose state is trivially read via magneto-resistance sensors. Here we present conditions, using theoretical modelling, that it is possible to switch the magnetization of an AFM/FM bilayer using THz frequency pulses with moderate field amplitude and short durations, achievable in experiments. Consistent switching is observed in the phase diagrams for an order of magnitude increase in the interface coupling and a tripling in the thickness of the FM layer. We demonstrate a range of reversal paths that arise due to the combination of precession in the materials and the THz-induced fields. Our analysis demonstrates that the AFM drives the switching and results in a much higher frequency dynamics in the FM due to the exchange coupling at the interface. The switching is shown to be robust over a broad range of temperatures relevant for device applications.
Adjuvant effects of combination monophosphoryl lipid A and poly I:C on antigen-specific immune responses and protective efficacy of influenza vaccines
Authors: Le Chau Thuy Tien , Ahn So Yeon , Ho Thi Len , Lee Jueun , Lee Dong-Ha , Hwang Hye Suk , Kang Sang-Moo , Ko Eun-Ju 
Published: July 2023

AbstractToll-like receptor (TLR) agonists improve vaccine immunogenicity and efficacy, but they are currently unlicensed as adjuvants in influenza vaccines. This study aimed to investigate whether a combination of monophosphoryl lipid A (MPL, a TLR4 agonist) and polyriboinosinic polyribocytidylic acid (poly I:C, a TLR3 agonist) can enhance the protective efficacy of an inactivated A/Puerto Rico/8/1934 (A/PR8) H1N1 influenza vaccine against homologous influenza infection and minimize illness outcomes. Results showed that combination MPL and poly I:C adjuvanted influenza vaccination increased the production of antigen-specific antibodies, decreased the levels of cytokines and cellular infiltrates at the infection sites, and induced significant memory T and B cell responses in mice. The results of this study suggest that the combination of MPL and poly I:C can be developed into a possible adjuvant for enhancing the efficacy of influenza vaccines.
Mid-lumbar (L3) epidural stimulation effects on bladder and external urethral sphincter in non-injured and chronically transected urethane-anesthetized rats
Authors: Medina-Aguiñaga Daniel , Hoey Robert F. , Wilkins Natasha L. , Ugiliweneza Beatrice , Fell Jason , Harkema Susan J. , Hubscher Charles H. 
Published: July 2023

AbstractRecent pre-clinical and clinical spinal cord epidural stimulation (scES) experiments specifically targeting the thoracolumbar and lumbosacral circuitries mediating lower urinary tract (LUT) function have shown improvements in storage, detrusor pressure, and emptying. With the existence of a lumbar spinal coordinating center in rats that is involved with external urethral sphincter (EUS) functionality during micturition, the mid-lumbar spinal cord (specifically L3) was targeted in the current study with scES to determine if the EUS and thus the void pattern could be modulated, using both intact and chronic complete spinal cord injured female rats under urethane anesthesia. L3 scES at select frequencies and intensities of stimulation produced a reduction in void volumes and EUS burst duration in intact rats. After chronic transection, three different subgroups of LUT dysfunction were identified and the response to L3 scES promoted different cystometry outcomes, including changes in EUS bursting. The current findings suggest that scES at the L3 level can generate functional neuromodulation of both the urinary bladder and the EUS in intact and SCI rats to enhance voiding in a variety of clinical scenarios.
Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases
Authors: Kägi Jan , Sloan Willough , Schimpf Johannes , Nasiri Hamid R. , Lashley Dana , Friedrich Thorsten 
Published: July 2023

AbstractBacterial energy metabolism has become a promising target for next-generation tuberculosis chemotherapy. One strategy to hamper ATP production is to inhibit the respiratory oxidases. The respiratory chain of Mycobacterium tuberculosis comprises a cytochrome bcc:aa3 and a cytochrome bd ubiquinol oxidase that require a combined approach to block their activity. A quinazoline-type compound called ND-011992 has previously been reported to ineffectively inhibit bd oxidases, but to act bactericidal in combination with inhibitors of cytochrome bcc:aa3 oxidase. Due to the structural similarity of ND-011992 to quinazoline-type inhibitors of respiratory complex I, we suspected that this compound is also capable of blocking other respiratory chain complexes. Here, we synthesized ND-011992 and a bromine derivative to study their effect on the respiratory chain complexes of Escherichia coli. And indeed, ND-011992 was found to inhibit respiratory complex I and bo3 oxidase in addition to bd-I and bd-II oxidases. The IC50 values are all in the low micromolar range, with inhibition of complex I providing the lowest value with an IC50 of 0.12 µM. Thus, ND-011992 acts on both, quinone reductases and quinol oxidases and could be very well suited to regulate the activity of the entire respiratory chain.