bluuebunny/crossref_metadata_2025 huggingface dataset:
Priming conditions shape breadth of neutralizing antibody responses to sarbecoviruses
Authors: Jia Janice Zhirong , Tan Chee Wah , Cheng Samuel M. S. , Gu Haogao , Yeoh Aileen Ying Yan , Mok Chris Ka Pun , Wang Yanqun , Zhao Jincun , Leung Nancy H. L. , Cowling Benjamin J. , Poon Leo L. M. , Hui David S. C. , Wang Linfa , Peiris Malik , Valkenburg Sophie A.
Published: October 2022

Vaccines that are broadly cross-protective against current and future SARS-CoV-2 variants of concern (VoC) or across the sarbecoviruses subgenus remain a priority for public health. Virus neutralization is the best available correlate of protection. To define the magnitude and breadth of cross-neutralization in individuals with different exposure to SARS-CoV-2 infection and vaccination, we here use a multiplex surrogate neutralization assay based on virus spike receptor binding domains of multiple SARS-CoV-2 VoC, as well as related bat and pangolin viruses. We include sera from cohorts of individuals vaccinated with two or three doses of mRNA (BNT162b2) or inactivated SARS-CoV-2 (Coronavac or Sinopharm) vaccines with or without a history of previous SARS-CoV-2 or SARS-CoV-1 infection. SARS-CoV-2 or SARS-CoV-1 infection followed by BNT162b2 vaccine, Omicron BA.2 breakthrough infection following BNT162b2 vaccine or a third dose of BNT162b2 following two doses of BNT162b2 or Coronavac elicit the highest and broadest neutralization across VoCs. For both breadth and magnitude of neutralization across all sarbecoviruses, those infected with SARS-CoV-1 immunized with BNT162b2 outperform all other combinations of infection and/or vaccination. These data may inform vaccine design strategies for generating broadly neutralizing antibodies to SARS-CoV-2 variants or across the sarbecovirus subgenus.
Population genomics of Puccinia graminis f.sp. tritici highlights the role of admixture in the origin of virulent wheat rust races
Authors: Guo Yuanwen , Betzen Bliss , Salcedo Andres , He Fei , Bowden Robert L. , Fellers John P. , Jordan Katherine W. , Akhunova Alina , Rouse Mathew N. , Szabo Les J. , Akhunov Eduard
Published: October 2022

Puccinia graminis f.sp. tritici (Pgt) causes stem rust disease in wheat that can result in severe yield losses. The factors driving the evolution of its virulence and adaptation remain poorly characterized. We utilize long-read sequencing to develop a haplotype-resolved genome assembly of a U.S. isolate of Pgt. Using Pgt haplotypes as a reference, we characterize the structural variants (SVs) and single nucleotide polymorphisms in a diverse panel of isolates. SVs impact the repertoire of predicted effectors, secreted proteins involved in host-pathogen interaction, and show evidence of purifying selection. By analyzing global and local genomic ancestry we demonstrate that the origin of 8 out of 12 Pgt clades is linked with either somatic hybridization or sexual recombination between the diverged donor populations. Our study shows that SVs and admixture events appear to play an important role in broadening Pgt virulence and the origin of highly virulent races, creating a resource for studying the evolution of Pgt virulence and preventing future epidemic outbreaks.
Personalized risk predictor for acute cellular rejection in lung transplant using soluble CD31
Authors: Tran-Dinh Alexy , Laurent Quentin , Even Guillaume , Tanaka Sébastien , Lortat-Jacob Brice , Castier Yves , Mal Hervé , Messika Jonathan , Mordant Pierre , Nicoletti Antonino , Montravers Philippe , Caligiuri Giuseppina , Morilla Ian
Published: October 2022

We evaluated the contribution of artificial intelligence in predicting the risk of acute cellular rejection (ACR) using early plasma levels of soluble CD31 (sCD31) in combination with recipient haematosis, which was measured by the ratio of arterial oxygen partial pressure to fractional oxygen inspired (PaO2/FiO2) and respiratory SOFA (Sequential Organ Failure Assessment) within 3 days of lung transplantation (LTx). CD31 is expressed on endothelial cells, leukocytes and platelets and acts as a “peace-maker” at the blood/vessel interface. Upon nonspecific activation, CD31 can be cleaved, released, and detected in the plasma (sCD31). The study included 40 lung transplant recipients, seven (17.5%) of whom experienced ACR. We modelled the plasma levels of sCD31 as a nonlinear dependent variable of the PaO2/FiO2 and respiratory SOFA over time using multivariate and multimodal models. A deep convolutional network classified the time series models of each individual associated with the risk of ACR to each individual in the cohort.
Vitamin D status in chimpanzees in human care: a Europe wide study
Authors: Moittié Sophie , Jarvis Rachel , Bandelow Stephan , Byrne Sarah , Dobbs Phillipa , Grant Melissa , Reeves Christopher , White Kate , Liptovszky Mátyás , Baiker Kerstin
Published: October 2022

While vitamin D deficiency is a public health concern in humans, comparatively little is known about vitamin D levels in non-human primates. Vitamin D plays a crucial role in overall health and its deficiency is associated with a range of disorders, including cardiovascular disease, which is a leading cause of death in great apes. Serum samples (n = 245) from chimpanzees (Pan troglodytes) housed at 32 European zoos were measured for 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and total 25-hydroxyvitamin D (25-OHD) using liquid chromatography and tandem mass spectrometry. Of these samples, 33.1% indicated inadequate vitamin D status, using the human reference interval (25-OHD < 50 nmol/L). The season of the year, health status of the animal, and the provision of daily outdoor access had a significant effect on vitamin D status. This is the first large-scale study on vitamin D status of non-human great apes in human care. Inadequate 25-OHD serum concentrations are widespread in the chimpanzee population in Europe and could be a risk factor for the development of idiopathic myocardial fibrosis, a major cause of mortality in this species, as well as other diseases. A review of husbandry and nutrition practices is recommended to ensure optimal vitamin D supply for these endangered animals.
Hybrid photon–phonon blockade
Authors: Abo Shilan , Chimczak Grzegorz , Kowalewska-Kudłaszyk Anna , Peřina Jan , Chhajlany Ravindra , Miranowicz Adam
Published: October 2022

We describe a novel type of blockade in a hybrid mode generated by linear coupling of photonic and phononic modes. We refer to this effect as hybrid photon–phonon blockade and show how it can be generated and detected in a driven nonlinear optomechanical superconducting system. Thus, we study boson-number correlations in the photon, phonon, and hybrid modes in linearly coupled microwave and mechanical resonators with a superconducting qubit inserted in one of them. We find such system parameters for which we observe eight types of different combinations of either blockade or tunnelling effects (defined via the sub- and super-Poissonian statistics, respectively) for photons, phonons, and hybrid bosons. In particular, we find that the hybrid photon–phonon blockade can be generated by mixing the photonic and phononic modes which do not exhibit blockade.
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

Alzheimer'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

Scarcity 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

Chronic 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

On 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

Accurate 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

Chemically 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

Transcriptional 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

The 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

Neurodegenerative 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

The 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

Bontia 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

In 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

The 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

Numerous 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.
Influence of Potamogeton crispus harvesting on phosphorus composition of Lake Yimeng
Authors: Wang Lizhi , Wu Xiyuan , Song Hongli , An Juan , Dong Bin , Wu Yuanzhi , Wang Yun , Li Bao , Liu Qianjin , Yu Wanni
Published: October 2022

Harvesting is an important method used to control the overproduction of Potamogeton crispus in lakes. A three-year comparative field study was performed in a eutrophic lake (harvested area) and its connected lake (non-harvested area) to determine the effects of harvesting on the phosphorus (P) composition and environmental factors in the water and sediment. Results revealed that harvesting significantly reduced the dissolved total P and dissolved organic P (DOP) and increased the alkaline phosphatase activity and particulate P (PP) in the water. No significant differences were detected in the water total P (TP), soluble reactive P, chlorophyll-a, pH, and dissolved oxygen between the harvested and non-harvested areas. Sediment TP and organic P (OP) were significantly reduced in the harvested area. Harvesting changed the P composition in the water. In the non-harvested area, P was mainly formed by DOP (40%) in the water body, while in the harvested area, PP was the main water component (47%). Harvesting increased the proportion of inorganic P (IP) in the sediment and decreased the proportion of OP. In the water, the IP to TP ratio in the non-harvested and harvested areas were 58.26% and 63.51%, respectively. Our results showed that harvesting changed the P composition in the water and sediment. In the harvesting of submerged vegetation, our results can serve as a reference for the management of vegetation-rich lakes.
U(1) dynamics in neuronal activities
Authors: Lin Chia-Ying , Chen Ping-Han , Lin Hsiu-Hau , Huang Wen-Min
Published: October 2022

Neurons convert external stimuli into action potentials, or spikes, and encode the contained information into the biological nervous system. Despite the complexity of neurons and the synaptic interactions in between, rate models are often adapted to describe neural encoding with modest success. However, it is not clear whether the firing rate, the reciprocal of the time interval between spikes, is sufficient to capture the essential features for the neuronal dynamics. Going beyond the usual relaxation dynamics in Ginzburg-Landau theory for statistical systems, we propose that neural activities can be captured by the U(1) dynamics, integrating the action potential and the “phase” of the neuron together. The gain function of the Hodgkin-Huxley neuron and the corresponding dynamical phase transitions can be described within the U(1) neuron framework. In addition, the phase dependence of the synaptic interactions is illustrated and the mapping to the Kinouchi-Copelli neuron is established. It suggests that the U(1) neuron is the minimal model for single-neuron activities and serves as the building block of the neuronal network for information processing.
Phase separation in mullite-composition glass
Authors: Wilke Stephen K. , Benmore Chris J. , Ilavsky Jan , Youngman Randall E. , Rezikyan Aram , Carson Michael P. , Menon Vrishank , Weber Richard
Published: October 2022

Aluminosilicates (AS) are ubiquitous in ceramics, geology, and planetary science, and their glassy forms underpin vital technologies used in displays, waveguides, and lasers. In spite of this, the nonequilibrium behavior of the prototypical AS compound, mullite (40SiO2-60Al2O3, or AS60), is not well understood. By deeply supercooling mullite-composition liquid via aerodynamic levitation, we observe metastable liquid–liquid unmixing that yields a transparent two-phase glass, comprising a nanoscale mixture of AS7 and AS62. Extrapolations from X-ray scattering measurements show the AS7 phase is similar to vitreous SiO2 with a few Al species substituted for Si. The AS62 phase is built from a highly polymerized network of 4-, 5-, and 6-coordinated AlOx polyhedra. Polymerization of the AS62 network and the composite morphology provide essential mechanisms for toughening the glass.
Directed evolution for soluble and active periplasmic expression of bovine enterokinase in Escherichia coli
Authors: Lee Weiluo , Pradhan Subhas , Zhang Cheng , Venanzi Niccolo A. E. , Li Weina , Goldrick Stephen , Dalby Paul A.
Published: October 2022

Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of affinity-purification tags from high-value biopharmaceuticals. However, recombinant expression in Escherichia coli produces insoluble inclusion bodies, requiring solubilisation, refolding, and autocatalytic activation to recover functional enzyme. Error-prone PCR and DNA shuffling of the EKL gene, T7 promoter, lac operon, ribosome binding site, and pelB leader sequence, yielded 321 unique variants after screening ~ 6500 colonies. The best variants had > 11,000-fold increased total activity in lysates, producing soluble enzyme that no longer needed refolding. Further characterisation identified the factors that improved total activity from an inactive and insoluble starting point. Stability was a major factor, whereby melting temperatures > 48.4 °C enabled good expression at 37 °C. Variants generally did not alter catalytic efficiency as measured by kcat/Km, which improved for only one variant. Codon optimisation improved the total activity in lysates produced at 37 °C. However, non-optimised codons and expression at 30 °C gave the highest activity through improved protein quality, with increased kcat and Tm values. The 321 variants were statistically analysed and mapped to protein structure. Mutations detrimental to total activity and stability clustered around the active site. By contrast, variants with increased total activity tended to combine stabilising mutations that did not disrupt the active site.
Prediction of decreased estimated glomerular filtration rate using liver fibrosis markers: a renal biopsy-based study
Authors: Mima Akira
Published: October 2022

Non-alcoholic fatty liver disease is the most common chronic liver disease and is associated with chronic kidney disease. The fibrosis-4 index and non-alcoholic fatty liver disease score are widely used as non-invasive diagnostic methods for non-alcoholic fatty liver disease. However, the relationship between these markers and specific renal histopathologies in chronic kidney disease remain unclear. This study included 179 patients aged between 16 and 80 years who underwent renal biopsy. We examined the association between the fibrosis-4 index or non-alcoholic fatty liver disease score and change in estimated glomerular filtration rate 12 months after kidney biopsy for each renal histopathology. Renal histopathologies were determined by renal biopsy. Our results showed that there was a significant negative correlation between the fibrosis-4 index and estimated glomerular filtration rate. In nephrosclerosis, the non-alcoholic fatty liver disease score and estimated glomerular filtration rate tended to have a negative correlation, albeit without significance. In IgA nephropathy, both the fibrosis-4 index and non-alcoholic fatty liver disease score were significantly negatively correlated with estimated glomerular filtration rate. Furthermore, the fibrosis-4 index was not associated with urinary protein-to-creatinine ratio or renal function markers such as urinary b2 microglobulin and urinary N-acetyl-d-glucosamine. Our kidney biopsy-based study showed that the liver fibrosis markers fibrosis-4 index and non-alcoholic fatty liver disease score were negatively correlated with the estimated glomerular filtration rate in nephrosclerosis and IgA nephropathy.
The effects of sugar in drinking water on Streptococcus pyogenes colonisation in a murine nasopharyngeal infection model
Authors: Hashimi Farina Nor , Bennett Julie , Baker Michael G. , Moreland Nicole J. , Merry Troy L. , Loh Jacelyn M. S.
Published: October 2022

The number of sugar-sweetened beverages consumed per day has been associated with an increased risk of acute rheumatic fever, an autoimmune disease triggered by superficial Streptococcus pyogenes infection. To explore if there could be a biological basis for this association, we used a mouse model of S. pyogenes nasopharyngeal colonisation combined with a dietary intervention. We observed an increased bacterial load in the nasopharynx of mice receiving sucrose drinking water post-infection, suggesting that high sucrose intake promotes S. pyogenes growth and/or survival. This provides new insight into the potential biological basis behind the association seen in humans.
Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing's syndrome: comparison of CAR with findings in dexamethasone suppression test
Authors: Iwamoto Yuichiro , Tatsumi Fuminori , Itoh Takashi , Sasaki Taku , Mori Shigehito , Sugisaki Toshitomo , Nakao Erina , Ohnishi Mana , Kusano Takashi , Takenouchi Haruka , Iwamoto Hideyuki , Sanada Junpei , Fushimi Yoshiro , Katakura Yukino , Kimura Tomohiko , Shimoda Masashi , Nakanishi Shuhei , Kaku Kohei , Mune Tomoatsu , Kaneto Hideaki
Published: October 2022

Cushing's syndrome and subclinical Cushing's syndrome (SCS) are conditions of increased cortisol secretion from the adrenal glands. Cushing's syndrome includes adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (Cushing's disease) and ACTH-independent Cushing's syndrome (AICS). The purpose of this study was to investigate the diagnostic potential of the cortisol / adrenocorticotropic hormone (ACTH) ratio (CAR) for diagnosis of Cushing's syndrome or SCS in adult subjects. This was a single-center, retrospective, observational study. This study enrolled 44 subjects with SCS, 14 AICS, 10 CD, and 248 non-Cushing's syndrome subjects who had undergone a 1 mg dexamethasone suppression test (1 mg DST). Definition of SCS was as follows: no physical signs characteristic of Cushing syndrome and cortisol was ≥ 83 nmol/L in 1 mg DST. The diagnostic potential of CAR for diagnosis of Cushing's syndrome was evaluated by comparing the correlation between CAR and after-load cortisol level in 1 mg DST. As the results, there was a strong positive correlation between CAR and after-load cortisol level in subjects with AICS (r = 0.800, p < 0.005). CAR was 10,040 ± 4170 nmol/pmol in subjects with NCS, 17,535 ± 10,246 nmol/pmol in SCS, 101,221 ± 18,009 nmol/pmol in AICS, and 4324 ± 2051 nmol/pmol in CD, all of which were significantly higher compared to those with AICS (p < 0.0005). The cutoff values of CAR for screening at our institution were 11,849.6 nmol/pmol for AICS (AUC 0.935, p < 0.005, sensitivity 92.3%, specificity 83.5%) and 7006.1 nmol/pmol for CD (AUC 0.714, p < 0.05, sensitivity 100.0%, specificity 46.8%). There was a positive correlation between CAR and adrenal adenoma diameter in subjects with AICS (r = 0.508, p < 0.05), but there was no correlation between tumor diameter and CAR in subjects with SCS and CD. In conclusion, high CAR indicates increased cortisol secretion from the adrenal glands. Since CAR is a simple indicator that can be easily evaluated by general practitioners as well as endocrinologists, we think CAR would be useful for the early detection of Cushing's syndrome.
Pharmacological effects of caffeine on ventilation in adult zebrafish under free-swimming conditions
Authors: Harada Yuki , Soh Zu , Wakitani Shin , Yoshida Masayuki , Tsuji Toshio
Published: October 2022

The zebrafish is widely used as a model in biological studies. In particular, the heart rate and cortisol levels of zebrafish are commonly measured to elucidate the pharmacological effects of chemical substances. Meanwhile, although ventilation is also an important physiological index reflecting emotion-like states, few studies have evaluated the effects of chemicals on ventilation in adult zebrafish. In this study, we assessed whether it is possible to evaluate the pharmacological effects elicited by caffeine in adult zebrafish under free-swimming conditions. We measured the ventilation in adult zebrafish exposed to multiple concentrations of caffeine under restraint and free-swimming conditions and evaluated the pharmacological effects of caffeine using linear mixed model analysis. In addition, results of electrocardiogram analysis and swimming speeds were compared with those in previous reports to ensure that an appropriate dose of caffeine was administered. Under restraint conditions, caffeine significantly decreased heart rate and increased ventilation in a concentration-dependent manner. Under free-swimming conditions, the ventilation rate significantly increased with increasing caffeine concentration. These results indicate that the pharmacological effects elicited by chemicals on ventilation can be evaluated in free-swimming zebrafish.
SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas
Authors: Zhu Eliot Y. , Riordan Jesse D. , Vanneste Marion , Henry Michael D. , Stipp Christopher S. , Dupuy Adam J.
Published: October 2022

Rare gain-of-function mutations inRAC1drive drug resistance to targeted BRAF inhibition in cutaneous melanoma. Here, we show that wildtype RAC1 is a critical driver of growth and drug resistance, but only in a subset of melanomas with elevated markers of de-differentiation. Similarly, SRC inhibition also selectively sensitized de-differentiated melanomas to BRAF inhibition. One possible mechanism may be the suppression of the de-differentiated state, as SRC and RAC1 maintained markers of de-differentiation in human melanoma cells. The functional differences between melanoma subtypes suggest that the clinical management of cutaneous melanoma can be enhanced by the knowledge of differentiation status. To simplify the task of classification, we developed a binary classification strategy based on a small set of ten genes. Using this gene set, we reliably determined the differentiation status previously defined by hundreds of genes. Overall, our study informs strategies that enhance the precision of BRAFi by discovering unique vulnerabilities of the de-differentiated cutaneous melanoma subtype and creating a practical method to resolve differentiation status.
Deep learning-assisted co-registration of full-spectral autofluorescence lifetime microscopic images with H&E-stained histology images
Authors: Wang Qiang , Fernandes Susan , Williams Gareth O. S. , Finlayson Neil , Akram Ahsan R. , Dhaliwal Kevin , Hopgood James R. , Vallejo Marta
Published: October 2022

Autofluorescence lifetime images reveal unique characteristics of endogenous fluorescence in biological samples. Comprehensive understanding and clinical diagnosis rely on co-registration with the gold standard, histology images, which is extremely challenging due to the difference of both images. Here, we show an unsupervised image-to-image translation network that significantly improves the success of the co-registration using a conventional optimisation-based regression network, applicable to autofluorescence lifetime images at different emission wavelengths. A preliminary blind comparison by experienced researchers shows the superiority of our method on co-registration. The results also indicate that the approach is applicable to various image formats, like fluorescence in-tensity images. With the registration, stitching outcomes illustrate the distinct differences of the spectral lifetime across an unstained tissue, enabling macro-level rapid visual identification of lung cancer and cellular-level characterisation of cell variants and common types. The approach could be effortlessly extended to lifetime images beyond this range and other staining technologies.
Selecting a single powdered activated carbon against multiple threats: taste & odour and benzene
Authors: Lompe Kim Maren , Solliec Morgan , Rivas Maria , Peldszus Sigrid , Barbeau Benoit
Published: October 2022

MIB and geosmin removal performance by 11 supplier-recommended powdered activated carbons varied by factor 3 to 4. Well performing carbons also effectively removed benzene traces.
Walnut protein hydrolysates ameliorate alcohol-induced cognitive impairment (AICI) by alleviating oxidative stress and inflammation in the brain and improving hippocampal synaptic plasticity in Sprague–Dawley rats
Authors: Xu Defeng , Zhao Mouming
Published: October 2022

Walnut protein hydrolysate (WPH) ameliorates Alcohol-induced cognitive impairment (AICI) via alleviating oxidative stress and inflammation in brain tissue and improving the hippocampal synaptic plasticity.
Effects of pectins on colorectal cancer: targeting hallmarks as a support for future clinical trials
Authors: Donadio Janaina L. S. , Prado Samira Bernardino Ramos do , Rogero Marcelo M. , Fabi João Paulo
Published: October 2022

The intake of dietary fibers has been associated with a reduction in the risk of colorectal cancer.
Facile preparation of graphene@polyaniline nanofiber network/oxidized carbon cloth composites for high-performance flexible solid-state supercapacitors
Authors: Wang Shaohua , Li Yuying , Xu Qiang , Fu Qiuping , Guo Xinli , Zheng Yanmei , Zhang Weijie , Cao Zhen , Li Ruiting , Ren Jingxuan
Published: October 2022

A rGO@PANI-NFN/OCC composite was prepared by a facile impregnation method. The constructed supercapacitors exhibit excellent mechanical and energy storage performance, showing a great potential for flexible energy storage device applications.
Self-catalyzed synthesis of a nano-capsule and its application as a heterogeneous RCMP catalyst and nano-reactor
Authors: Oh Xin Yi , Sakar Jit , Cham Ning , Er Gerald Tze Kwang , Pan Houwen Matthew , Goto Atsushi
Published: October 2022

A nano-capsule synthesized via self-catalyzed RCMP and its use as a heterogeneous catalyst and a nano-reactor of RCMP to generate a multi-elemental particle.
The in vitro fermentation of compound oral liquid by human colonic microbiota altered the abundance of probiotics and short-chain fatty acid production
Authors: Xiao Ruiming , Chen Hongzhang , Han Hongbei , Luo Guangjuan , Lin Ying
Published: October 2022

The crushing pretreatment before extraction facilitated the nutrients to dissolve in compound oral liquid and enhanced the prebiotic effects for promoting the abundance of probiotics and short-chain fatty acid synthesis.