bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying progress in research topics across nations
Authors: Asatani Kimitaka , Oki Sumihiro , Momma Takuya , Sakata Ichiro
Published: March 2023

A scientist’s choice of research topic affects the impact of their work and future career. While the disparity between nations in scientific information, funding, and facilities has decreased, scientists on the cutting edge of their fields are not evenly distributed across nations. Here, we quantify relative progress in research topics of a nation from the time-series comparison of reference lists from papers, using 71 million published papers from Scopus. We discover a steady leading-following relationship in research topics between Western nations or Asian city-states and others. Furthermore, we find that a nation’s share of information-rich scientists in co-authorship networks correlates highly with that nation’s progress in research topics. These results indicate that scientists’ relationships continue to dominate scientific evolution in the age of open access to information and explain the failure or success of nations’ investments in science.
Image analysis of cutaneous melanoma histology: a systematic review and meta-analysis
Authors: Clarke Emily L. , Wade Ryckie G. , Magee Derek , Newton-Bishop Julia , Treanor Darren
Published: March 2023

The current subjective histopathological assessment of cutaneous melanoma is challenging. The application of image analysis algorithms to histological images may facilitate improvements in workflow and prognostication. To date, several individual algorithms applied to melanoma histological images have been reported with variations in approach and reported accuracies. Histological digital images can be created using a camera mounted on a light microscope, or through whole slide image (WSI) generation using a whole slide scanner. Before any such tool could be integrated into clinical workflow, the accuracy of the technology should be carefully evaluated and summarised. Therefore, the objective of this review was to evaluate the accuracy of existing image analysis algorithms applied to digital histological images of cutaneous melanoma.
Database searching of PubMed and Embase from inception to 11th March 2022 was conducted alongside citation checking and examining reports from organisations. All studies reporting accuracy of any image analysis applied to histological images of cutaneous melanoma, were included. The reference standard was any histological assessment of haematoxylin and eosin-stained slides and/or immunohistochemical staining. Citations were independently deduplicated and screened by two review authors and disagreements were resolved through discussion. The data was extracted concerning study demographics; type of image analysis; type of reference standard; conditions included and test statistics to construct 2 × 2 tables. Data was extracted in accordance with our protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Diagnostic Test Accuracy (PRISMA-DTA) Statement. A bivariate random-effects meta-analysis was used to estimate summary sensitivities and specificities with 95% confidence intervals (CI). Assessment of methodological quality was conducted using a tailored version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The primary outcome was the pooled sensitivity and specificity of image analysis applied to cutaneous melanoma histological images. Sixteen studies were included in the systematic review, representing 4,888 specimens. Six studies were included in the meta-analysis. The mean sensitivity and specificity of automated image analysis algorithms applied to melanoma histological images was 90% (CI 82%, 95%) and 92% (CI 79%, 97%), respectively. Based on limited and heterogeneous data, image analysis appears to offer high accuracy when applied to histological images of cutaneous melanoma. However, given the early exploratory nature of these studies, further development work is necessary to improve their performance.
Comparison of hepatic responses to glucose perturbation between healthy and obese mice based on the edge type of network structures
Authors: Ito Yuki , Uda Shinsuke , Kokaji Toshiya , Hirayama Akiyoshi , Soga Tomoyoshi , Suzuki Yutaka , Kuroda Shinya , Kubota Hiroyuki
Published: March 2023

Interactions between various molecular species in biological phenomena give rise to numerous networks. The investigation of these networks, including their statistical and biochemical interactions, supports a deeper understanding of biological phenomena. The clustering of nodes associated with molecular species and enrichment analysis is frequently applied to examine the biological significance of such network structures. However, these methods focus on delineating the function of a node. As such, in-depth investigations of the edges, which are the connections between the nodes, are rarely explored. In the current study, we aimed to investigate the functions of the edges rather than the nodes. To accomplish this, for each network, we categorized the edges and defined the edge type based on their biological annotations. Subsequently, we used the edge type to compare the network structures of the metabolome and transcriptome in the livers of healthy (wild-type) and obese (ob/ob) mice following oral glucose administration (OGTT). The findings demonstrate that the edge type can facilitate the characterization of the state of a network structure, thereby reducing the information available through datasets containing the OGTT response in the metabolome and transcriptome.
Market efficiency of cryptocurrency: evidence from the Bitcoin market
Authors: Yi Eojin , Yang Biao , Jeong Minhyuk , Sohn Sungbin , Ahn Kwangwon
Published: March 2023

This study examines whether the Bitcoin market satisfies the (weak-form) efficient market hypothesis using a quantum harmonic oscillator, which provides the state-specific probability density functions that capture the superimposed Gaussian and non-Gaussian states of the log return distribution. Contrasting the mixed evidence from a variance ratio test, the high probability allocated to the ground state suggests a near-efficient Bitcoin market. Findings imply that as Bitcoin evolves into an efficient market, speculators might encounter difficulty in exploiting profitable trading strategies. Furthermore, when policymakers initiate tight regulations to control the market, they should closely monitor market efficiency as an index of price distortion.
Clinical variations of polypoidal choroidal vasculopathy: A cohort study from Japan and the USA
Authors: Fukuyama Hisashi , BouGhanem Ghazi , Moir John , Skondra Dimitra , Gomi Fumi , Fawzi Amani A.
Published: March 2023

We describe the clinical characteristics of treatment-naïve polypoidal choroidal vasculopathy (PCV) in three tertiary clinic settings in 2 cities (Chicago in the USA and Nishinomiya in Japan). This cohort study was a retrospective, multicenter, consecutive case series. A total of 126 patients with treatment-naïve PCV—46 in Chicago and 80 in Nishinomiya—were identified. The proportion of PCV in patients with neovascular age-related macular degeneration was lower in Chicago (10.8% vs. 36.9%). Patients in Chicago had a significantly higher prevalence of soft drusen (50.0% vs 25.0%, p = 0.006) and intra-retinal cyst (37.0% vs 15.0%, p = 0.008), and a significantly lower prevalence of pachyvessels (41.3% vs 62.5%, p = 0.03). At baseline, presenting vision for patients in Chicago was worse than in Nishinomiya (mean log MAR: 0.609 vs. 0.312, p < 0.001). Ninety-five eyes were followed for more than one year. The Nishinomiya group received a higher rate of combination therapy (61.0%) compared to the Chicago group (5.3%). Vision and central foveal thickness at month 12 were significantly improved from baseline in both Chicago (p = 0.009 and p = 0.01) and Nishinomiya groups (both p < 0.001). Our study highlights interesting differences in the proportion of PCV, clinical findings and treatment responses of PCV, that need to be further evaluated in larger, epidemiologic cohorts.
The maternal brain is more flexible and responsive at rest: effective connectivity of the parental caregiving network in postpartum mothers
Authors: Orchard Edwina R. , Voigt Katharina , Chopra Sidhant , Thapa Tribikram , Ward Phillip G. D. , Egan Gary F. , Jamadar Sharna D.
Published: March 2023

The field of neuroscience has largely overlooked the impact of motherhood on brain function outside the context of responses to infant stimuli. Here, we apply spectral dynamic causal modelling (spDCM) to resting-state fMRI data to investigate differences in brain function between a group of 40 first-time mothers at 1-year postpartum and 39 age- and education-matched women who have never been pregnant. Using spDCM, we investigate the directionality (top–down vs. bottom–up) and valence (inhibition vs excitation) of functional connections between six key left hemisphere brain regions implicated in motherhood: the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, posterior cingulate cortex, parahippocampal gyrus, amygdala, and nucleus accumbens. We show a selective modulation of inhibitory pathways related to differences between (1) mothers and non-mothers, (2) the interactions between group and cognitive performance and (3) group and social cognition, and (4) differences related to maternal caregiving behaviour. Across analyses, we show consistent disinhibition between cognitive and affective regions suggesting more efficient, flexible, and responsive behaviour, subserving cognitive performance, social cognition, and maternal caregiving. Together our results support the interpretation of these key regions as constituting a parental caregiving network. The nucleus accumbens and the parahippocampal gyrus emerging as ‘hub’ regions of this network, highlighting the global importance of the affective limbic network for maternal caregiving, social cognition, and cognitive performance in the postpartum period.
Eye-movement indices of arousal predict ADHD and comorbid externalizing symptoms over a 2-year period
Authors: Kleberg Johan Lundin , Frick Matilda A. , Brocki Karin C.
Published: March 2023

Attention-deficit/hyperactivity disorder (ADHD) follows a variable course across childhood. Disrupted arousal has been hypothesized to underlie core symptoms as well as comorbid internalizing and externalizing conditions. The current study examined eye-movement and pupil-dilation metrics indexing arousal as longitudinal predictors of ADHD, externalizing, and internalizing symptoms over a 2-year period. Participants aged 8–13 years (N = 54, 30% with a diagnosis of ADHD) completed a modified version of the gap-overlap task including arousal-inducing auditory warning signals. Parents rated symptoms at the time of testing and at 2 years follow-up. Phasic alerting (reaction-time reduction after alerting cues) is an index of arousal. Here, larger phasic alerting effects predicted higher ADHD-symptom levels 2 years later. Blunted pupil-dilation responses predicted externalizing symptoms at T2, controlling for ADHD and externalizing at T1. Our results support the theory that ADHD is associated with altered arousal. Blunted arousal reactivity may be a longitudinal risk factor for externalizing problems in children with ADHD symptoms.
Optimizing human α-galactosidase for treatment of Fabry disease
Authors: Hallows William C. , Skvorak Kristen , Agard Nick , Kruse Nikki , Zhang Xiyun , Zhu Yu , Botham Rachel C. , Chng Chinping , Shukla Charu , Lao Jessica , Miller Mathew , Sero Antoinette , Viduya Judy , Ismaili Moulay Hicham Alaoui , McCluskie Kerryn , Schiffmann Raphael , Silverman Adam P. , Shen Jin-Song , Huisman Gjalt W.
Published: March 2023

Fabry disease is caused by a deficiency of α-galactosidase A (GLA) leading to the lysosomal accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids. Fabry patients experience significant damage to the heart, kidney, and blood vessels that can be fatal. Here we apply directed evolution to generate more stable GLA variants as potential next generation treatments for Fabry disease. GLAv05 and GLAv09 were identified after screening more than 12,000 GLA variants through 8 rounds of directed evolution. Both GLAv05 and GLAv09 exhibit increased stability at both lysosomal and blood pH, stability to serum, and elevated enzyme activity in treated Fabry fibroblasts (19-fold) and GLA–/–podocytes (10-fold). GLAv05 and GLAv09 show improved pharmacokinetics in mouse and non-human primates. In a Fabry mouse model, the optimized variants showed prolonged half-lives in serum and relevant tissues, and a decrease of accumulated Gb3 in heart and kidney. To explore the possibility of diminishing the immunogenic potential of rhGLA, amino acid residues in sequences predicted to bind MHC II were targeted in late rounds of GLAv09 directed evolution. An MHC II-associated peptide proteomics assay confirmed a reduction in displayed peptides for GLAv09. Collectively, our findings highlight the promise of using directed evolution to generate enzyme variants for more effective treatment of lysosomal storage diseases.
The perspectives of UK personnel towards current killing practices for laboratory rodents
Authors: Clarkson Jasmine M. , Leach Matthew C. , McKeegan Dorothy E. F. , Martin Jessica E.
Published: March 2023

Rodents are the predominant species used for scientific research and must be humanely killed upon completion of the work. In the UK this is regulated by Schedule 1 of the Animals Scientific Procedures Act 1986, which lists permitted methodologies considered capable of humane killing, including overdose of an anaesthetic, exposure to carbon dioxide (CO2) gas, dislocation of the neck and concussion of the brain by striking the cranium. Although all are permitted, operator motivations behind method selection and individual operator preference remain unknown. The views of 219 laboratory animal personnel on institutional availability and use of Schedule 1 killing methods for laboratory rodents were obtained. Only 10% of participants reported that all four methods were available at their institution with 57.5% of respondents preferring cervical dislocation. For CO2, only 18.6% of participants reported using the recommended flow rate, while 45.5% did not know the flow rate employed. We highlight the urgent requirement for the development of quality-controlled training programmes, to improve knowledge and confidence in the selection and application of killing methods. We advocate for continuous review of killing practices to ensure best practice is reflected in legislation and achieve optimal protection of the welfare of laboratory rodents during killing.
Identification and gene expression analysis of serine proteases and their homologs in the Asian corn borer Ostrinia furnacalis
Authors: Yang Lei , Xu Xiaoli , wei Wei , Chen Xiaoyun , Peng Cheng , Wang Xiaofu , Xu Junfeng
Published: March 2023

Serine proteases (SPs) and their homologs (SPHs) are among the best-characterized gene families. They are involved in several physiological processes, including digestion, embryonic development and immunity. In the current study, a total of 177 SPs-related genes were characterized in the genome of Ostrinia furnacalis. The activation site of SPs/SPHs and enzyme specificity of SPs were identified, and the findings showed that most of the SPs analyzed possessed trypsin substrate specificity. Several SPs/SPHs with similar simple gene structures had tandem repeat-like distributions on the scaffold, indicated that gene expansion has occurred in this large family. Furthermore, we constructed 30 RNA sequencing libraries including four with developmental stage and four middle larval stage tissues to study the transcript levels of these genes. Differentially upregulated and downregulated genes were obtained via data analysis. More than one-quarter of the genes were specifically identified as highly expressed in the midgut in compared to the other three tissues evaluated. In the current study, the domain structure, gene location and phylogenetic relationship of genes in O. furnacalis were explored. Orthologous comparisons of SPs/SPHs between model insects and O. furnacalis indicated their possible functions. This information provides a basis for understanding the functional roles of this large family.
Evaluation of a point-of-care haemozoin assay (Gazelle device) for rapid detection of Plasmodium knowlesi malaria
Authors: Tan Angelica F. , Thota Priyaleela , Sakam Sitti Saimah Binti , Lew Yao Long , Rajahram Giri S. , William Timothy , Barber Bridget E. , Kho Steven , Anstey Nicholas M. , Bell David , Grigg Matthew J.
Published: March 2023

Plasmodium knowlesi is the major cause of zoonotic malaria in Southeast Asia. Rapid and accurate diagnosis enables effective clinical management. A novel malaria diagnostic tool, Gazelle (Hemex Health, USA) detects haemozoin, a by-product of haem metabolism found in all Plasmodium infections. A pilot phase refined the Gazelle haemozoin identification algorithm, with the algorithm then tested against reference PCR in a larger cohort of patients with P. knowlesi mono-infections and febrile malaria-negative controls. Limit-of-detection analysis was conducted on a subset of P. knowlesi samples serially diluted with non-infected whole blood. The pilot phase of 40 P. knowlesi samples demonstrated 92.5% test sensitivity. P. knowlesi-infected patients (n = 203) and febrile controls (n = 44) were subsequently enrolled. Sensitivity and specificity of the Gazelle against reference PCR were 94.6% (95% CI 90.5–97.3%) and 100% (95% CI 92.0–100%) respectively. Positive and negative predictive values were 100% and 98.8%, respectively. In those tested before antimalarial treatment (n = 143), test sensitivity was 96.5% (95% CI 92.0–98.9%). Sensitivity for samples with ≤ 200 parasites/µL (n = 26) was 84.6% (95% CI 65.1–95.6%), with the lowest parasitaemia detected at 18/µL. Limit-of-detection (n = 20) was 33 parasites/µL (95% CI 16–65%). The Gazelle device has the potential for rapid, sensitive detection of P. knowlesi infections in endemic areas.
Water cycle changes in reanalyses: a complementary framework
Authors: Vargas Godoy Mijael Rodrigo , Markonis Yannis
Published: March 2023

Climate reanalyses complement traditional surface-based measurements and offer unprecedented coverage over previously inaccessible or unmonitored regions. Even though these have improved the quantification of the global water cycle, their varying performances and uncertainties limit their applicability. Herein, we discuss how a framework encompassing precipitation, evaporation, their difference, and their sum could further constrain uncertainty by unveiling discrepancies otherwise overlooked. Ahead, we physically define precipitation plus evaporation to describe the global water cycle fluxes in four reanalysis data sets (20CR v3, ERA-20C, ERA5, and NCEP1). Among them, we observe four different responses to the temperature increase between 1950–2010, with ERA5 showing the best agreement with the water cycle acceleration hypothesis. Our results show that implementing the framework proposed can improve the evaluation of reanalyses’ performance and enhance our understanding of the water cycle changes on a global scale.
Satureja khuzistanica Jamzad essential oil and pure carvacrol attenuate TBI-induced inflammation and apoptosis via NF-κB and caspase-3 regulation in the male rat brain
Authors: Abbasloo Elham , Amiresmaili Sedigheh , Shirazpour Sara , Khaksari Mohammad , Kobeissy Firas , Thomas Theresa Currier
Published: March 2023

Traumatic brain injury (TBI) causes progressive dysfunction that induces biochemical and metabolic changes that lead to cell death. Nevertheless, there is no definitive FDA-approved therapy for TBI treatment. Our previous immunohistochemical results indicated that the cost-effective natural Iranian medicine, Satureja khuzistanica Jamzad essential oil (SKEO), which consists of 94.16% carvacrol (CAR), has beneficial effects such as reducing neuronal death and inflammatory markers, as well as activating astrocytes and improving neurological outcomes. However, the molecular mechanisms of these neuroprotective effects have not yet been elucidated. This study investigated the possible mechanisms involved in the anti-inflammatory and anti-apoptotic properties of SKEO and CAR after TBI induction. Eighty-four male Wistar rats were randomly divided into six groups: Sham, TBI, TBI + Vehicle, TBI + CAR (100 and 200 mg/kg), and TBI + SKEO (200 mg/kg) groups. After establishing the “Marmarou” weight drop model, diffuse TBI was induced in the rat brain. Thirty minutes after TBI induction, SKEO & CAR were intraperitoneally injected. One day after TBI, injured rats exhibited significant brain edema, neurobehavioral dysfunctions, and neuronal apoptosis. Western blot results revealed upregulation of the levels of cleaved caspase-3, NFκB p65, and Bax/Bcl-2 ratio, which was attenuated by CAR and SKEO (200 mg/kg). Furthermore, the ELISA results showed that CAR treatment markedly prevents the overproduction of the brain pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Moreover, the neuron-specific enolase (NSE) immunohistochemistry results revealed the protective effect of CAR and SKEO on post-TBI neuronal death. The current study revealed that the possible neuroprotective mechanisms of SKEO and CAR might be related to (at least in part) modulating NF-κB regulated inflammation and caspase-3 protein expression. It also suggested that CAR exerts more potent protective effects than SKEO against TBI. Nevertheless, the administration of SKEO and CAR may express a novel therapeutic approach to ameliorate TBI-related secondary phase neuropathological outcomes.
Precise control of liposome size using characteristic time depends on solvent type and membrane properties
Authors: Choi Sunghak , Kang Bongsu , Yang Eunhye , Kim Keesung , Kwak Moon Kyu , Chang Pahn-Shick , Jung Ho-Sup
Published: March 2023

Controlling the sizes of liposomes is critical in drug delivery systems because it directly influences their cellular uptake, transportation, and accumulation behavior. Although hydrodynamic focusing has frequently been employed when synthesizing nano-sized liposomes, little is known regarding how flow characteristics determine liposome formation. Here, various sizes of homogeneous liposomes (50–400 nm) were prepared according to flow rate ratios in two solvents, ethanol, and isopropyl alcohol (IPA). Relatively small liposomes formed in ethanol due to its low viscosity and high diffusivity, whereas larger, more poly-dispersed liposomes formed when using IPA as a solvent. This difference was investigated via numerical simulations using the characteristic time factor to predict the liposome size; this approach was also used to examine the flow characteristics inside the microfluidic channel. In case of the liposomes, the membrane rigidity also has a critical role in determining their size. The increased viscosity and packing density of the membrane by addition of cholesterol confirmed by fluorescence anisotropy and polarity lead to increase in liposome size (40–530 nm). However, the interposition of short-chain lipids de-aligned the bilayer membrane, leading to its degradation; this decreased the liposome size. Adding short-chain lipids linearly decreased the liposome size (130–230 nm), but at a shallower gradient than that of cholesterol. This analytical study expands the understanding of microfluidic environment in the liposome synthesis by offering design parameters and their relation to the size of liposomes.
Heat shock protein A2 is a novel extracellular vesicle-associated protein
Authors: Sojka Damian Robert , Abramowicz Agata , Adamiec-Organiściok Małgorzata , Karnas Elżbieta , Mielańczyk Łukasz , Kania Daria , Blamek Sławomir , Telka Ewa , Scieglinska Dorota
Published: March 2023

70-kDa Heat Shock Proteins (HSPA/HSP70) are chaperones playing a central role in the proteostasis control mechanisms. Their basal expression can be highly elevated as an adaptive response to environmental and pathophysiological stress conditions. HSPA2, one of poorly characterised chaperones of the HSPA/HSP70 family, has recently emerged as epithelial cells differentiation-related factor. It is also commonly expressed in cancer cells, where its functional significance remains unclear. Previously, we have found that proteotoxic stress provokes a decrease in HSPA2 levels in cancer cells. In the present study we found that proteasome inhibition-related loss of HSPA2 from cancer cells neither is related to a block in the gene transcription nor does it relate to increased autophagy-mediated disposals of the protein. Proteotoxic stress stimulated extracellular release of HSPA2 in extracellular vesicles (EVs). Interestingly, EVs containing HSPA2 are also released by non-stressed cancer and normal cells. In human urinary EVs levels of HSPA2 were correlated with the levels of TSG101, one of the main EVs markers. We conclude that HSPA2 may constitute basic components of EVs. Nevertheless, its specific role in EVs and cell-to-cell communication requires further investigation.
Development of the multi-directional ablation process using the femtosecond laser to create a pattern on the lateral side of a 3D microstructure
Authors: Ha Cheol Woo , Son Yong
Published: March 2023

Two-photon stereolithography (TPS) is widely used for the fabrication of various three–dimensional (3D) structures with sub-micron fabrication resolution in a single fabrication process. However, TPS is unsuitable for microstructures with fine-hole patterns. The laser ablation process can be easily drilled, or made holes in various materials. However, in the case of laser ablation, the focal plane of the laser is fixed, which is limited to the processing plane. In this study, a multidirectional ablation process is studied to apply laser ablation to various processing planes of a 3D microstructure fabricated by the TPS process. A 3D hybrid fabrication process with the advantages of both TPS and laser ablation is expected to improve the fabrication efficiency. The 3D hybrid process is proposed based on a single laser source. The microstructure is fabricated using TPS, and the multi-directional ablation process creates a hole in the lateral side of the 3D microstructure. To develop the multidirectional ablation process, the reflecting mirror system should be designed to adaptably rotate the laser focal plane and guide the laser path for the target process plane. Through various examples, we demonstrate the ability of the multi-directional ablation process with various examples.
Relative contributions of internal variability and external forcing to the inter-decadal transition of climate patterns in East Asia
Authors: Huang Fang , Xu Zhongfeng , Guo Weidong , Feng Jinming , Chen Liang , Zheng Hui , Fu Congbin
Published: March 2023

The annual precipitation in North China and South China shows a dipole pattern with a clear inter-decadal transition around the late 1970s. However, the relative contribution of internal variability and external forcing to this inter-decadal transition is still unclear. Here, we separate internal variability from the externally forced climate response through a set of dynamical downscaling simulations with lateral boundary conditions derived from reanalysis data and a large ensemble mean of the CMIP5 historical simulations. We find that internal variability accounts for about 65 and 55% of the inter-decadal transition of the annual precipitation in South and North China, respectively. By contrast, external forcing accounts for about 70% of the warming trend in eastern China over the second half of the 20th century. This study highlights the differential response of regional precipitation and air temperature to internal variability and external forcing over eastern China on an inter-decadal timescale.
Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data
Authors: Zack Travis , Losert Kurt P. , Maisel Samantha M. , Wild Jennifer , Yaqubie Amin , Herman Michael , Knox Jennifer J. , Mayer Robert J. , Venook Alan P. , Butte Atul , O’Neill Allison F. , Abou-Alfa Ghassan K. , Gordan John D.
Published: March 2023

The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.
Weakly supervised deep learning to predict recurrence in low-grade endometrial cancer from multiplexed immunofluorescence images
Authors: Jiménez-Sánchez Daniel , López-Janeiro Álvaro , Villalba-Esparza María , Ariz Mikel , Kadioglu Ece , Masetto Ivan , Goubert Virginie , Lozano Maria D. , Melero Ignacio , Hardisson David , Ortiz-de-Solórzano Carlos , de Andrea Carlos E.
Published: March 2023

Predicting recurrence in low-grade, early-stage endometrial cancer (EC) is both challenging and clinically relevant. We present a weakly-supervised deep learning framework, NaroNet, that can learn, without manual expert annotation, the complex tumor-immune interrelations at three levels: local phenotypes, cellular neighborhoods, and tissue areas. It uses multiplexed immunofluorescence for the simultaneous visualization and quantification of CD68 + macrophages, CD8 + T cells, FOXP3 + regulatory T cells, PD-L1/PD-1 protein expression, and tumor cells. We used 489 tumor cores from 250 patients to train a multilevel deep-learning model to predict tumor recurrence. Using a tenfold cross-validation strategy, our model achieved an area under the curve of 0.90 with a 95% confidence interval of 0.83–0.95. Our model predictions resulted in concordance for 96,8% of cases (κ = 0.88). This method could accurately assess the risk of recurrence in EC, outperforming current prognostic factors, including molecular subtyping.
Common multi-day rhythms in smartphone behavior
Authors: Ceolini Enea , Ghosh Arko
Published: March 2023

The idea that abnormal human activities follow multi-day rhythms is found in ancient beliefs on the moon to modern clinical observations in epilepsy and mood disorders. To explore multi-day rhythms in healthy human behavior our analysis includes over 300 million smartphone touchscreen interactions logging up to 2 years of day-to-day activities (N401 subjects). At the level of each individual, we find a complex expression of multi-day rhythms where the rhythms occur scattered across diverse smartphone behaviors. With non-negative matrix factorization, we extract the scattered rhythms to reveal periods ranging from 7 to 52 days – cutting across age and gender. The rhythms are likely free-running – instead of being ubiquitously driven by the moon – as they did not show broad population-level synchronization even though the sampled population lived in northern Europe. We propose that multi-day rhythms are a common trait, but their consequences are uniquely experienced in day-to-day behavior.
Comparative analysis of transferrin and IgG N-glycosylation in two human populations
Authors: Trbojević-Akmačić Irena , Vučković Frano , Pribić Tea , Vilaj Marija , Černigoj Urh , Vidič Jana , Šimunović Jelena , Kępka Agnieszka , Kolčić Ivana , Klarić Lucija , Novokmet Mislav , Pučić-Baković Maja , Rapp Erdmann , Štrancar Aleš , Polašek Ozren , Wilson James F. , Lauc Gordan
Published: March 2023

Human plasma transferrin (Tf) N-glycosylation has been mostly studied as a marker for congenital disorders of glycosylation, alcohol abuse, and hepatocellular carcinoma. However, inter-individual variability of Tf N-glycosylation is not known, mainly due to technical limitations of Tf isolation in large-scale studies. Here, we present a highly specific robust high-throughput approach for Tf purification from human blood plasma and detailed characterization of Tf N-glycosylation on the level of released glycans by ultra-high-performance liquid chromatography based on hydrophilic interactions and fluorescence detection (HILIC-UHPLC-FLD), exoglycosidase sequencing, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). We perform a large-scale comparative study of Tf and immunoglobulin G (IgG) N-glycosylation analysis in two human populations and demonstrate that Tf N-glycosylation is associated with age and sex, along with multiple biochemical and physiological traits. Observed association patterns differ compared to the IgG N-glycome corroborating tissue-specific N-glycosylation and specific N-glycans’ role in their distinct physiological functions.
A naturally occurring mini-alanyl-tRNA synthetase
Authors: Antika Titi Rindi , Chrestella Dea Jolie , Tseng Yi-Kuan , Yeh Yi-Hung , Hsiao Chwan-Deng , Wang Chien-Chia
Published: March 2023

Alanyl-tRNA synthetase (AlaRS) retains a conserved prototype structure throughout its biology, consisting of catalytic, tRNA-recognition, editing, and C-Ala domains. The catalytic and tRNA-recognition domains catalyze aminoacylation, the editing domain hydrolyzes mischarged tRNAAla, and C-Ala―the major tRNA-binding module―targets the elbow of the L-shaped tRNAAla. Interestingly, a mini-AlaRS lacking the editing and C-Ala domains is recovered from the Tupanvirus of the amoeba Acanthamoeba castellanii. Here we show that Tupanvirus AlaRS (TuAlaRS) is phylogenetically related to its host’s AlaRS. Despite lacking the conserved amino acid residues responsible for recognition of the identity element of tRNAAla (G3:U70), TuAlaRS still specifically recognized G3:U70-containing tRNAAla. In addition, despite lacking C-Ala, TuAlaRS robustly binds and charges microAla (an RNA substrate corresponding to the acceptor stem of tRNAAla) as well as tRNAAla, indicating that TuAlaRS exclusively targets the acceptor stem. Moreover, this mini-AlaRS could functionally substitute for yeast AlaRS in vivo. This study suggests that TuAlaRS has developed a new tRNA-binding mode to compensate for the loss of C-Ala.
Frequency chirped Fourier-Transform spectroscopy
Authors: Markmann Sergej , Franckié Martin , Bertrand Mathieu , Shahmohammadi Mehran , Forrer Andres , Jouy Pierre , Beck Mattias , Faist Jérôme , Scalari Giacomo
Published: March 2023

Fast (sub-second) spectroscopy with high spectral resolution is of vital importance for revealing quantum chemistry kinetics of complex chemical and biological reactions. Fourier transform (FT) spectrometers can achieve high spectral resolution and operate at hundreds of ms time scales in rapid-scan mode. However, the linear translation of a scanning mirror imposes stringent time-resolution limitations to these systems, which makes simultaneous high spectral and temporal resolution very difficult. Here, we demonstrate an FT spectrometer whose operational principle is based on continuous rotational motion of the scanning mirror, effectively decoupling the spectral resolution from the temporal one. Furthermore, we show that such rotational FT spectrometer can perform Mid-IR dual-comb spectroscopy with a single comb source, since the Doppler-shifted version of the comb serves as the second comb. In our realization, we combine the advantages of dual-comb and FT spectroscopy using a single quantum cascade laser frequency comb emitting at 8.2 μm as a light source. Our technique does not require any diffractive or dispersive optical elements and hence preserve the Jacquinot’s-, Fellgett’s-, and Connes’-advantages of FT spectrometers. By integrating mulitple broadband sources, such system could pave the way for applications where high speed, large optical bandwidth, and high spectral resolution are desired.
A gradual change is more likely to have caused the Mid-Pleistocene Transition than an abrupt event
Authors: Legrain Etienne , Parrenin Frédéric , Capron Emilie
Published: March 2023

The Mid-Pleistocene Transition (~1.2–0.8 million years) corresponds to a time interval when high-amplitude ~100,000 years glacial–interglacial cycles replaced the more subdued ~40,000 years glacial–interglacial cycles. Whether it was triggered by physical processes affecting the climate system at a specific time interval or more gradually over the course of the Pleistocene, is still an open question. Here we use an original approach based on conceptual modelling to identify the temporal structure of the Mid-Pleistocene Transition controlling factors. By comparing our new simulations of global ice volume changes with existing paleo-reconstructions over the past 2 million years, we find that it is more relevant to simulate the Mid-Pleistocene Transition with a gradual-rather-than-abrupt change in the climate system. Our results support the hypothesis that a progressive decrease in atmospheric carbon dioxide concentrations throughout the Pleistocene played a key role in triggering this major climatic transition.
Single-dye NIR-II chemiluminescence system for H2O2 imaging
Authors: Chang Zong , Liu Chenchen , Guo Like , Shu Bingxin , Liang Huageng , Ding Jie , Zhang Xiaoping , Sun Qinchao
Published: March 2023

We present the first efficient single-dye NIR-II chemiluminescence system with the longest emission maximum around 1000 nm, for which a novel electron transfer mechanism was proposed rather than the generally considered LUMODOD–HOMODye model.
Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway
Authors: Hu Shan , Liu Beilei , Yang Manqi , Mao Shuai , Ju Hao , Liu Zheyu , Huang Min , Wu Gang
Published: March 2023

Carnosic acid protects against doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome activity, which is related to the upregulation of the Nrf2/HO-1 transcription pathway.
Identification of fluorescently-barcoded nanoparticles using machine learning
Authors: Ortiz-Perez Ana , Izquierdo-Lozano Cristina , Meijers Rens , Grisoni Francesca , Albertazzi Lorenzo
Published: March 2023

We introduce a machine-learning-assisted workflow to write, read, and classify dye-loaded PLGA–PEG nanoparticles at a single-particle level.
Polymorphism mediated by electric fields: a first principles study on organic/inorganic interfaces
Authors: Cartus Johannes J. , Jeindl Andreas , Werkovits Anna , Hörmann Lukas , Hofmann Oliver T.
Published: March 2023

This work investigates how external electric fields can manipulate interface polymorphism. We find it has strong impact and that it can be used to alter p-T phase diagrams.
Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification
Authors: Ahangarpour Marzieh , Kavianinia Iman , Brimble Margaret A.
Published: March 2023

Cysteine-selective thia-Michael addition provides opportunities in chemistry, biology, and medicine.
Reproducible 2D Ti3C2Tx for perovskite-based photovoltaic device
Authors: Shen Qingchao , Chen Chaoran , Long Jiao , Wang Saili
Published: March 2023

This study highlights the recycling of HF for reproducible 2D MXenes. Equally important, dimethyl sulfoxide was employed to promote the exfoliation of multilayer Ti3C2Tx MXene into Ti3C2Tx nanosheets in aqueous solution.
Multimodal high-resolution nano-DESI MSI and immunofluorescence imaging reveal molecular signatures of skeletal muscle fiber types
Authors: Unsihuay Daisy , Hu Hang , Qiu Jiamin , Latorre-Palomino Alessandra , Yang Manxi , Yue Feng , Yin Ruichuan , Kuang Shihuan , Laskin Julia
Published: March 2023

A multimodal approach that integrates IF and high resolution nano-DESI MSI using image registration and segmentation tools to characterize the chemical composition of skeletal fibers.
Photoelectrochemical water oxidation by a MOF/semiconductor composite
Authors: Gibbons Bradley , Cairnie Daniel R. , Thomas Benjamin , Yang Xiaozhou , Ilic Stefan , Morris Amanda J.
Published: March 2023

Herein, we report the development of a MOF-semiconductor composite film active for water oxidation at a thermodynamic underpotential.
Structure-guided semi-rational design of an imine reductase for enantio-complementary synthesis of pyrrolidinamine
Authors: Zhang Jun , Ma Yaqing , Zhu Fangfang , Bao Jinping , Wu Qiaqing , Gao Shu-Shan , Cui Chengsen
Published: March 2023

In this study, engineered imine reductases (IREDs) of IRED M5, originally fromActinoalloteichus hymeniacidonis, were obtained through structure-guided semi-rational design.
Multifunctional antibiotics-free hydrogel dressings with self-regulated nitric oxide-releasing kinetics for improving open wound healing
Authors: Liu Yuan , Tan Lu , Huang Yan , Chen Maohua , Li Menghuan , Cai Kaiyong , Luo Zhong , Hu Yan
Published: March 2023

In this study, an antibiotics-free hydrogel with self-regulated nitric oxide release kinetics was developed, which could eliminate bacteria in early stages of wound healing while facilitating wound closure at later stages.
A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy
Authors: Yang Ting , Zhang Xianfen , Yang Xing , Li Ying , Xiang Jingjing , Xiang Chunbai , Liu Zhongke , Hai Luo , Huang Saipeng , Zhou Lihua , Liang Ruijing , Gong Ping
Published: March 2023

Self-assembled carrier-free nanoparticles based on a prodrug enhance tumor chemotherapy through mitochondrial targeting, redox-activated drug release, and apoptotic pathway activation.
Healthy diets for sustainable food systems: a narrative review
Authors: Arrieta Ezequiel M. , Aguiar Sebastián
Published: March 2023

Healthy and sustainable diets should be put at the center of food systems planning if we want to feed the growing population while making a sustainable use of natural resources and to protect biodiversity.
Alkali metal doped ruthenium dioxide nanosheets with lattice distortion as highly active oxygen evolution electrocatalysts in acidic media
Authors: Tang Hai , Kong Ming , Cao Wenwen , Ma Wenguang , Ding Jianjun , Shi Chuanxin , Yang Xiaodong , Shen Qi , Sun Yiqiang
Published: March 2023

Developing economic and acid-compatible oxygen evolution electrocatalysts is vital for their practical application in proton exchange membrane water electrolyzers, which has drawn worldwide attention.
Self-assembly of s-indacene-tetrone on Cu(111): molecular trapping and patterning of Cu adatoms
Authors: Kalashnyk Nataliya , Denawi Adam Hassan , Dumur Frédéric , Gigmes Didier , Bouju Xavier , Clair Sylvain
Published: March 2023

The supramolecular self-assembly of indacene-tetrone on the Cu(111) surface exhibits a variety of well-ordered phases stabilized by different bonding types depending on the annealing temperature.
Nanoscale temperature sensing of electronic devices with calibrated scanning thermal microscopy
Authors: Swoboda Timm , Wainstein Nicolás , Deshmukh Sanchit , Köroğlu Çağıl , Gao Xing , Lanza Mario , Hilgenkamp Hans , Pop Eric , Yalon Eilam , Muñoz Rojo Miguel
Published: March 2023

Nanoscale thermal sensing of devices with calibrated scanning thermal microscopy. The calibration allows converting the electrical response of thermo-resistive probes into temperature and considers variable probe-sample thermal exchange processes.
Relay Zn(ii)- and Au(i)-catalyzed aziridination/cyclization/ring expansion sequence to form 3-benzazepine derivatives
Authors: Tanpure Sudhakar Dattatray , Kardile Rahul Dadabhau , Liu Rai-Shung
Published: March 2023

The synthesis of 3H-benzo[d]azepine-2-carboxylates from 2-alkynylphenyl aldimines and α-diazo esters using Zn(ii) and Au(i) catalysts is described.
Exploiting butyrylcholinesterase inhibitors through a combined 3-D pharmacophore modeling, QSAR, molecular docking, and molecular dynamics investigation
Authors: Kumar Sunil , Manoharan Amritha , J Jayalakshmi , Abdelgawad Mohamed A. , Mahdi Wael A. , Alshehri Sultan , Ghoneim Mohammed M. , Pappachen Leena K. , Zachariah Subin Mary , Aneesh T. P. , Mathew Bijo
Published: March 2023

Alzheimer's disease (AD), a neurodegenerative condition associated with ageing, can occur.
Theoretical and experimental comparison of the performance of gold, titanium, and platinum nanodiscs as contrast agents for photoacoustic imaging
Authors: Wi Jung-Sub , Kim Jiwoong , Kim Myeong Yun , Choi Seongwook , Jung Hae Jue , Kim Chulhong , Na Hee-Kyung
Published: March 2023

Nanodiscs with different materials but the same shape and size were synthesized, and their performance as photoacoustic imaging contrast agents was compared both theoretically and experimentally.
Ionic modification of graphene nanosheets to improve anti-corrosive properties of organosilicon composite coatings
Authors: Yao Kai , Zhu Hongxia , Wang Yulu , Luo Rong , Jin Liqiang , Xie Lefu , Tian Zhigang
Published: March 2023

Silicone modified graphene oxide (M-GO) was readily and visually prepared. The M-GO-reinforced silicone composite coating exhibited obvious improvements in thermal stability, mechanical properties, especially anticorrosion.
Retraction: New synthesis of 2-aroylbenzothiazoles via metal-free domino transformations of anilines, acetophenones, and elemental sulfur
Authors: Huynh Tien V. , Doan Khang V. , Luong Ngoc T. K. , Nguyen Duyen T. P. , Doan Son H. , Nguyen Tung T. , Phan Nam T. S.
Published: March 2023

Retraction of ‘New synthesis of 2-aroylbenzothiazoles via metal-free domino transformations of anilines, acetophenones, and elemental sulfur’ by Tien V. Huynh et al., RSC Adv., 2020, 10, 18423–18433, https://doi.org/10.1039/D0RA01750G.
Synthesis of [68Ga]Ga-PSMA-11 using the iMiDEV™ microfluidic platform
Authors: Ovdiichuk Olga , Béen Quentin , Tanguy Laurent , Collet Charlotte
Published: March 2023

Implementation of [68Ga]Ga-PSMA-11 production into the microfluidic synthesizer iMiDEV™, a proof-of-concept study opening access to the microfluidic production of various [68Ga]Ga-radiopharmaceuticals.
Double FIT hybridization probes – towards enhancing brightness, turn-on and specificity of RNA detection
Authors: Schöllkopf Sophie , Knoll Andrea , Homer Amal , Seitz Oliver
Published: March 2023

Efficient fluorogenic hybridization probes combine high brightness and specificity of fluorescence signaling with large turn-on of fluorescence.
Crystal growth, transport behavior and X-ray detection of non-perovskite-phase NH4Pb2Br5
Authors: Li Ning , Zhang Chaofan , Chen Zheyin , Liu Xin , Zhang Bin-Bin
Published: March 2023

Centimeter-sized “125” non-perovskite-phase NH4Pb2Br5 crystals with high quality exhibit high and anisotropic resistivity, transport properties and a potential application as X-ray detectors with good X-ray sensitivity and a low detection limit.
Out-of-plane deformability and its coupling with electrostatics in biomembranes
Authors: Wilke Natalia , Alvares Dayane S.
Published: March 2023

Cell membranes are quasi-bidimensional soft systems formed by multipoles in an ordered array that can be polarized in an electric field. Consequently, electrostatic potentials emerge inside membranes, and membranes respond to external electric fields. From a mechanical perspective, membranes can be easily compressed–expanded, laterally deformed, and curved. Bending is particularly easy, and this kind of deformation translates to changes in the relative positions of the negative and positive charges, leading to strain gradient-induced polarization. Conversely, an external electric field gradient will exert a bending stress that translates to mechanical membrane deformation. These phenomena are described through membrane flexoelectricity. Here, we describe this property in lipid bilayers and cell membranes and summarize the studies in the field with emphasis on the effects promoted by membrane asymmetry.