bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the limits of graph neural networks for the early diagnosis of Alzheimer’s disease
Authors: Hernández-Lorenzo Laura , Hoffmann Markus , Scheibling Evelyn , List Markus , Matías-Guiu Jordi A. , Ayala Jose L. 
Published: October 2022

AbstractAlzheimer's disease (AD) is a neurodegenerative disease whose molecular mechanisms are activated several years before cognitive symptoms appear. Genotype-based prediction of the phenotype is thus a key challenge for the early diagnosis of AD. Machine learning techniques that have been proposed to address this challenge do not consider known biological interactions between the genes used as input features, thus neglecting important information about the disease mechanisms at play. To mitigate this, we first extracted AD subnetworks from several protein–protein interaction (PPI) databases and labeled these with genotype information (number of missense variants) to make them patient-specific. Next, we trained Graph Neural Networks (GNNs) on the patient-specific networks for phenotype prediction. We tested different PPI databases and compared the performance of the GNN models to baseline models using classical machine learning techniques, as well as randomized networks and input datasets. The overall results showed that GNNs could not outperform a baseline predictor only using the APOE gene, suggesting that missense variants are not sufficient to explain disease risk beyond the APOE status. Nevertheless, our results show that GNNs outperformed other machine learning techniques and that protein–protein interactions lead to superior results compared to randomized networks. These findings highlight that gene interactions are a valuable source of information in predicting disease status.
An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections
Authors: Meir Ohad , Zaknoon Fadia , Mor Amram 
Published: October 2022

AbstractScarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer’s adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer’s potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer’s de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion.
In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia
Authors: Alsagaby Suliman A. , Iqbal Danish , Ahmad Iqrar , Patel Harun , Mir Shabir Ahmad , Madkhali Yahya Awaji , Oyouni Atif Abdulwahab A. , Hawsawi Yousef M. , Alhumaydhi Fahad A. , Alshehri Bader , Alturaiki Wael , Alanazi Bader , Mir Manzoor Ahmad , Al Abdulmonem Waleed 
Published: October 2022

AbstractChronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded byCSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression ofCSNK2A1was associated with early need for therapy (n = 130,p < 0.0001) and short overall survival (OS; n = 107,p = 0.005). Consistently, bioinformatics analyses showedCSNK2A1to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichmentpvalue = 1 × 10–16) that associated with early need for therapy (n = 130,p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: − 10.9 to − 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 107 M−1to 3.77 × 108 M−1) compared with the native ligand (ΔG: − 10.8, Kd: 8.3 × 107 M−−1). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression ofCSNK2A1was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy.
Preferential looking studies of trustworthiness detection confound structural and expressive cues to facial trustworthiness
Authors: Eggleston Adam , Tsantani Maria , Over Harriet , Cook Richard 
Published: October 2022

AbstractOn encountering a stranger, we spontaneously attribute to them character traits (e.g., trustworthiness, intelligence) based on their facial appearance. Participants can base impressions on structural face cues—the stable aspects of facial appearance that support identity recognition–or expression cues, such as the presence of a smile. It has been reported that 6- to 8-month-old infants attend to faces that adults judge to be trustworthy in preference to faces judged untrustworthy. These results are striking because the face stimuli employed were ostensibly emotion neutral. Consequently, these preferential looking effects have been taken as evidence for innate sensitivity to structural face cues to trustworthiness. However, scrutiny of the emotion rating procedure used with adults suggests that the face stimuli employed may have been judged emotion neutral only when interleaved with more obvious examples of facial affect. This means that the faces may vary in emotional expression when compared to each other. Here, we report new evidence obtained from adult raters that the stimuli used in these studies confound trustworthiness and untrustworthiness with the presence of happiness and anger, respectively. These findings suggest that the preferential looking effects described in infants are compatible with a preference for positive facial affect and may not reflect early sensitivity to structural face cues to trustworthiness.
Accuracy of cone-beam computed tomography, digital mammography and digital breast tomosynthesis for microcalcifications and margins to microcalcifications in breast specimens
Authors: Neubauer Claudia , Yilmaz Jannina Samantha , Bronsert Peter , Pichotka Martin , Bamberg Fabian , Windfuhr-Blum Marisa , Erbes Thalia , Neubauer Jakob 
Published: October 2022

AbstractAccurate determination of resection margins in breast specimens is important as complete removal of malignancy is a prerequisite for patients’ outcome. Mammography (DM) as 2D-technique provides only limited value in margin assessment. Therefore, we investigated whether cone-beam computed tomography (CBCT) or digital breast tomosynthesis (DBT) has incremental value in assessing margins to microcalcifications. Three independent readers investigated breast specimens for presence of microcalcifications and the smallest distance to margins. Histopathology served as gold standard. Microcalcifications were detected in 15 out of 21 included specimens (71%). Pooled sensitivity for DM, DBT and CBCT for microcalcifications compared to preoperative DM was 0.98 (CI 0.94–0.99), 0.83 (CI 0.73–0.94) and 0.94 (CI 0.87–0.99), pooled specificity was 0.99 (CI 0.99–0.99), 0.73 (CI 0.51–0.96) and 0.60 (CI 0.35–0.85). Mean measurement error for margin determination for DM, DBT and CBCT was 10 mm, 14 mm and 6 mm (p = 0.002) with significant difference between CBCT and the other devices (p < 0.03). Mean reading time required by the readers to analyze DM, DBT and CBCT, was 36, 43 and 54 s (p < 0.001). Although DM allows reliable detection of microcalcifications, measurement of resection margin was significantly more accurate with CBCT. Thus, a combination of methods or improved CBCT might provide a more accurate determination of disease-free margins in breast specimens.
Spontaneous symmetry breaking propulsion of chemically coated magnetic microparticles
Authors: Rogowski Louis William , Kim Min Jun 
Published: October 2022

AbstractChemically coated micro/nanoparticles are often used in medicine to enhance drug delivery and increase drug up-take into specific areas of the body. Using a recently discovered spontaneous symmetry breaking propulsion mechanism, we demonstrate that chemically coated microparticles can swim through mucus solution under precise navigation and that certain functionalizations can dynamically change propulsion behavior. For this investigation biotin, Bitotin-PEG3-amine, and biotin chitosan were chemically functionalized onto the surfaces of magnetic microparticles using an avidin–biotin complex. These chemicals were chosen because they are used prolifically in drug delivery applications, with PEG and chitosan having well known mucoadhesive effects. Coated microparticles were then suspended in mucus synthesized from porcine stomach mucins and propelled using rotating magnetic fields. The relationship between different chemical coatings, microparticle velocity, and controllability were thoroughly explored and discussed. Results indicate that the biotinylated surface coatings altered the propulsion behavior of microparticles, with performance differences interlinked to both magnetic field properties and localized mucus properties. Precisely controlled drug carrying microparticles are envisioned to help supplant traditional drug delivery methods and enhance existing medical techniques utilizing micro/nanoparticles.
Hypothesis-driven dragging of transcriptomic data to analyze proven targeted pathways in Rhinella arenarum larvae exposed to organophosphorus pesticides
Authors: Pires Natalia S. , Lascano Cecilia I. , Ousset Julia , Ceschin Danilo G. , Venturino Andrés 
Published: October 2022

AbstractTranscriptional analysis of the network of transcription regulators and target pathways in exposed organisms may be a hard task when their genome remains unknown. The development of hundreds of qPCR assays, including primer design and normalization of the results with the appropriate housekeeping genes, seems an unreachable task. Alternatively, we took advantage of a whole transcriptome study onRhinella arenarumlarvae exposed to the organophosphorus pesticides azinphos-methyl and chlorpyrifos to evaluate the transcriptional effects on a priori selected groups of genes. This approach allowed us to evaluate the effects on hypothesis-selected pathways such as target esterases, detoxifying enzymes, polyamine metabolism and signaling, and regulatory pathways modulating them. We could then compare the responses at the transcriptional level with previously described effects at the enzymatic or metabolic levels to obtain global insight into toxicity–response mechanisms. The effects of both pesticides on the transcript levels of these pathways could be considered moderate, while chlorpyrifos-induced responses were more potent and earlier than those elicited by azinphos-methyl. Finally, we inferred a prevailing downregulation effect of pesticides on signaling pathways and transcription factor transcripts encoding products that modulate/control the polyamine and antioxidant response pathways. We also tested and selected potential housekeeping genes based on those reported for other species. These results allow us to conduct future confirmatory studies on pesticide modulation of gene expression in toad larvae.
Cell sorting microbeads as novel contrast agent for magnetic resonance imaging
Authors: Khurana Aman , Marti Francesc , Powell David K. , Brandon J. Anthony , Dugan Adam , Gedaly Roberto , Chapelin Fanny 
Published: October 2022

AbstractThe success of several cell-based therapies and prevalent use of magnetic resonance imaging (MRI) in the clinic has fueled the development of contrast agents for specific cell tracking applications. Safe and efficient labeling of non-phagocytic cell types such as T cells nonetheless remains challenging. We developed a one-stop shop approach where the T cell sorting agent also labels the cells which can subsequently be depicted using non-invasive MRI. We compared the MR signal effects of magnetic-assisted cell sorting microbeads (CD25) to the current preclinical gold standard, ferumoxytol. We investigated in vitro labeling efficiency of regulatory T cells (Tregs) with MRI and histopathologic confirmation. Thereafter, Tregs and T cells were labeled with CD25 microbeads in vitro and delivered via intravenous injection. Liver MRIs pre- and 24 h post-injection were performed to determine in vivo tracking feasibility. We show that CD25 microbeads exhibit T2 signal decay properties similar to other iron oxide contrast agents. CD25 microbeads are readily internalized by Tregs and can be detected by non-invasive MRI with dose dependent T2 signal suppression. Systemically injected labeled Tregs can be detected in the liver 24 h post-injection, contrary to T cell control. Our CD25 microbead-based labeling method is an effective tool for Treg tagging, yielding detectable MR signal change in cell phantoms and in vivo. This novel cellular tracking method will be key in tracking the fate of Tregs in inflammatory pathologies and solid organ transplantation.
Disease stages and therapeutic hypotheses in two decades of neurodegenerative disease clinical trials
Authors: Mortberg Meredith A. , Vallabh Sonia M. , Minikel Eric Vallabh 
Published: October 2022

AbstractNeurodegenerative disease is increasingly prevalent and remains without disease-modifying therapies. Engaging the right target, at the right disease stage, could be an important determinant of success. We annotated targets and eligibility criteria for 3238 neurodegenerative disease trials registered at ClinicalTrials.gov from 2000 to 2020. Trials became more selective as the mean number of inclusion and exclusion criteria increased and eligible score ranges shrank. Despite a shift towards less impaired participants, only 2.7% of trials included pre-symptomatic individuals; these were depleted for drug trials and enriched for behavioral interventions. Sixteen novel, genetically supported therapeutic hypotheses tested in drug trials represent a small, non-increasing fraction of trials, and the mean lag from genetic association to first trial was 13 years. Though often linked to disease initiation, not progression, these targets were tested mostly at symptomatic disease stages. The potential for disease modification through early intervention against root molecular causes of disease remains largely unexplored.
Serum kisspeptin and proopiomelanocortin in cystic fibrosis: a single study
Authors: Galiniak Sabina , Podgórski Rafał , Rachel Marta , Mazur Artur 
Published: October 2022

AbstractThe determination of hormonal biomarkers is of increasing interest in many diseases, including cystic fibrosis (CF). Hormones that have not been estimated and described so far in CF include kisspeptin (KISS) and proopiomelanocortin (POMC), which are involved in the regulation of many processes, including appetite and fertility. Therefore, the aim of our study was to estimate the level of KISS and POMC in sera from CF patients and to determine the correlation between these hormones and clinical parameters. For this purpose, we estimated the levels of KISS and POMC in 38 CF patients and 16 healthy participants with enzyme-linked immunosorbent assay. We found significantly reduced levels of KISS and POMC in people with CF compared to healthy subjects (1.76 ± 0.46 vs. 2.27 ± 0.56 ng/mL, p < 0.05 and 6.25 ± 4.36 vs. 14.74 ± 6.24 ng/mL, p < 0.001, respectively). Furthermore, the level of both hormones was negatively correlated with age. The hormones studied did not correlate with the results of spirometry and each other. Thus, decreased KISS and POMC levels may be associated with lower body weight and delayed puberty in patients with CF.
GC/MS profiling of essential oils from Bontia daphnoides L., chemometric discrimination, isolation of dehydroepingaione and evaluation of antiviral activity
Authors: Thabet Amany A. , Moghannem Saad , Ayoub Iriny M. , Youssef Fadia S. , Al Sayed Eman , Singab Abdel Nasser B. 
Published: October 2022

AbstractBontia daphnoidesL. has been utilized in traditional medicine for treatment of herpes, cough and colds. The aim of this study was to analyze the volatile constituents of this plant by GC/MS (Gas Chromatography coupled to Mass Spectrometry) and to assess their antiviral activity. A total of 64 compounds were identified where dehydroepingaione represented 83.60, 72.36, 58.78 and 34.18% in the leaves, stems, flowers and fruits, respectively. Principal component and hierarchical cluster analysis revealed the discrimination of the organs as the leaves and stems were distributed in the same cluster in contrast to the flowers and fruits. Furthermore, the antiviral activity was assessed where the oils of leaves and stems exhibited potent antiviral activity displaying IC50of 11.98, 12.62 µg/ml against HSV-1 and 13.34, 14.50 µg/ml against CoxB4, respectively. Dehydroepingaione was isolated from then-hexane fraction of the leaves and showed activity against HSV-1 and CoxB with IC50of 24.46 and 25.32 µg/ml, respectively. Molecular modelling studies illustrated that the major compounds showed good affinity towards HSV type-1 thymidine kinase. Therefore, it can be concluded that the oils fromB. daphnoideshave promising antiviral activity that may be attributed to the major oxygenated sesquiterpenes.
Biosensors based on novel nonlinear delta-function photonic crystals comprising weak nonlinearities
Authors: Mehaney Ahmed , Abadla Mazen M. , Elsayed Hussein A. 
Published: October 2022

AbstractIn this research, we propose a novel nonlinear delta-function photonic crystal for detecting sodium iodide (NaI) solution of different concentrations. The suggested structure comprises 50 delta stacks of GaP in an aqueous solution of NaI. These stacks are considered to have weak defocusing nonlinearity in the order of 10−6 (V/m)−2. Due to nonlinearity of the design, a defect-like resonance is formed within the photonic band gap. Thus, the detection of NaI with different concentrations can be easily investigated without the inclusion of a defect through the photonic crystal structure. The effects of both the linear part of the refractive index of GaP layers and nonlinear coefficient on the transmittance value are thoroughly discussed. The numerical findings investigate that the resonant peak begins to split at some critical nonlinearity. In our proposed structure, splitting occurs at about − 12 × 10−6 (V/m)−2. In this regard, the suggested sensor provides a high sensitivity of 409.7 nm/RIU and a wonderful detection limit of 0.0008.
Automated classification of estrous stage in rodents using deep learning
Authors: Wolcott Nora S. , Sit Kevin K. , Raimondi Gianna , Hodges Travis , Shansky Rebecca M. , Galea Liisa A. M. , Ostroff Linnaea E. , Goard Michael J. 
Published: October 2022

AbstractThe rodent estrous cycle modulates a range of biological functions, from gene expression to behavior. The cycle is typically divided into four stages, each characterized by distinct hormone concentration profiles. Given the difficulty of repeatedly sampling plasma steroid hormones from rodents, the primary method for classifying estrous stage is by identifying vaginal epithelial cell types. However, manual classification of epithelial cell samples is time-intensive and variable, even amongst expert investigators. Here, we use a deep learning approach to achieve classification accuracy at expert level. Due to the heterogeneity and breadth of our input dataset, our deep learning approach (“EstrousNet”) is highly generalizable across rodent species, stains, and subjects. The EstrousNet algorithm exploits the temporal dimension of the hormonal cycle by fitting classifications to an archetypal cycle, highlighting possible misclassifications and flagging anestrus phases (e.g., pseudopregnancy). EstrousNet allows for rapid estrous cycle staging, improving the ability of investigators to consider endocrine state in their rodent studies.
Picomolar fluorescent probes for compound affinity determination to carbonic anhydrase IX expressed in live cancer cells
Authors: Matulienė Jurgita , Žvinys Gediminas , Petrauskas Vytautas , Kvietkauskaitė Agnė , Zakšauskas Audrius , Shubin Kirill , Zubrienė Asta , Baranauskienė Lina , Kačenauskaitė Lina , Kopanchuk Sergei , Veiksina Santa , Paketurytė-Latvė Vaida , Smirnovienė Joana , Juozapaitienė Vaida , Mickevičiūtė Aurelija , Michailovienė Vilma , Jachno Jelena , Stravinskienė Dovilė , Sližienė Aistė , Petrošiūtė Agnė , Becker Holger M. , Kazokaitė-Adomaitienė Justina , Yaromina Ala , Čapkauskaitė Edita , Rinken Ago , Dudutienė Virginija , Dubois Ludwig J , Matulis Daumantas 
Published: October 2022

AbstractNumerous human cancers, especially hypoxic solid tumors, express carbonic anhydrase IX (CAIX), a transmembrane protein with its catalytic domain located in the extracellular space. CAIX acidifies the tumor microenvironment, promotes metastases and invasiveness, and is therefore considered a promising anticancer target. We have designed a series of high affinity and high selectivity fluorescein-labeled compounds targeting CAIX to visualize and quantify CAIX expression in cancer cells. The competitive binding model enabled the determination of common CA inhibitors’ dissociation constants for CAIX expressed in exponentially growing cancer cells. All tested sulfonamide compounds bound the proliferating cells with similar affinity as to recombinantly purified CAIX. The probes are applicable for the design of selective drug-like compounds for CAIX and the competition strategy could be applied to other drug targets.