bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex dimorphism controls dysbindin-related cognitive dysfunctions in mice and humans with the contribution of COMT
Authors: Geraci Federica , Passiatore Roberta , Penzel Nora , Laudani Samuele , Bertolino Alessandro , Blasi Giuseppe , Graziano Adriana C. E. , Kikidis Gianluca C. , Mazza Ciro , Parihar Madhur , Rampino Antonio , Sportelli Leonardo , Trevisan Nicolò , Drago Filippo , Papaleo Francesco , Sambataro Fabio , Pergola Giulio , Leggio Gian Marco
Published: March 2024

Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (pBonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = −3.21; pFDR = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (pFDR = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (pBonferroni = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia.
Chronometric TMS-fMRI of personalized left dorsolateral prefrontal target reveals state-dependency of subgenual anterior cingulate cortex effects
Authors: Grosshagauer Sarah , Woletz Michael , Vasileiadi Maria , Linhardt David , Nohava Lena , Schuler Anna-Lisa , Windischberger Christian , Williams Nolan , Tik Martin
Published: March 2024

Transcranial magnetic stimulation (TMS) applied to a left dorsolateral prefrontal cortex (DLPFC) area with a specific connectivity profile to the subgenual anterior cingulate cortex (sgACC) has emerged as a highly effective non-invasive treatment option for depression. However, antidepressant outcomes demonstrate significant variability among therapy plans and individuals. One overlooked contributing factor is the individual brain state at the time of treatment. In this study we used interleaved TMS-fMRI to investigate the influence of brain state on acute TMS effects, both locally and remotely. TMS was performed during rest and during different phases of cognitive task processing. Twenty healthy participants were included in this study. In the first session, imaging data for TMS targeting were acquired, allowing for identification of individualized targets in the left DLPFC based on highest anti-correlation with the sgACC. The second session involved chronometric interleaved TMS-fMRI measurements, with 10 Hz triplets of TMS administered during rest and at distinct timings during an N-back task. Consistent with prior findings, interleaved TMS-fMRI revealed significant BOLD activation changes in the targeted network. The precise timing of TMS relative to the cognitive states during the task demonstrated distinct BOLD response in clinically relevant brain regions, including the sgACC. Employing a standardized timing approach for TMS using a task revealed more consistent modulation of the sgACC at the group level compared to stimulation during rest. In conclusion, our findings strongly suggest that acute local and remote effects of TMS are influenced by brain state during stimulation. This study establishes a basis for considering brain state as a significant factor in designing treatment protocols, possibly improving TMS treatment outcomes.
Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia
Authors: Shibukawa Shuhei , Kan Hirohito , Honda Shiori , Wada Masataka , Tarumi Ryosuke , Tsugawa Sakiko , Tobari Yui , Maikusa Norihide , Mimura Masaru , Uchida Hiroyuki , Nakamura Yuko , Nakajima Shinichiro , Noda Yoshihiro , Koike Shinsuke
Published: March 2024

Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues’ magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility–volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group’s nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.
Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study
Authors: Ho Ming-Fen , Zhang Cheng , Moon Irene , Tuncturk Mustafa , Coombes Brandon J. , Biernacka Joanna , Skime Michelle , Oesterle Tyler S. , Karpyak Victor M. , Li Hu , Weinshilboum Richard
Published: March 2024

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as “molecular probes” to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.
Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents
Authors: Yin Bangmin , Cai Yuping , Teng Teng , Wang Xiaolin , Liu Xueer , Li Xuemei , Wang Jie , Wu Hongyan , He Yuqian , Ren Fandong , Kou Tianzhang , Zhu Zheng-Jiang , Zhou Xinyu
Published: March 2024

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.
Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells
Authors: Jiao Jia-zheng , Zhang Yang , Zhang Wen-juan , He Min-di , Meng Meng , Liu Tao , Ma Qin-long , Xu Ya , Gao Peng , Chen Chun-hai , Zhang Lei , Pi Hui-feng , Deng Ping , Wu Yong-zhong , Zhou Zhou , Yu Zheng-ping , Deng You-cai , Lu Yong-hui
Published: March 2024

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.
Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway
Authors: Zhang Xingxing , Li Haolong , Wang Yuliang , Zhao Hui , Wang Zhu , Chan Franky Leung
Published: March 2024

Dysregulated activation of Wnt/β-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/β-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (β-catenin) and activation of β-catenin to mediate the activation of Wnt/β-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.
Intracortical recordings reveal vision-to-action cortical gradients driving human exogenous attention
Authors: Seidel Malkinson Tal , Bayle Dimitri J. , Kaufmann Brigitte C. , Liu Jianghao , Bourgeois Alexia , Lehongre Katia , Fernandez-Vidal Sara , Navarro Vincent , Lambrecq Virginie , Adam Claude , Margulies Daniel S. , Sitt Jacobo D. , Bartolomeo Paolo
Published: March 2024

Exogenous attention, the process that makes external salient stimuli pop-out of a visual scene, is essential for survival. How attention-capturing events modulate human brain processing remains unclear. Here we show how the psychological construct of exogenous attention gradually emerges over large-scale gradients in the human cortex, by analyzing activity from 1,403 intracortical contacts implanted in 28 individuals, while they performed an exogenous attention task. The timing, location and task-relevance of attentional events defined a spatiotemporal gradient of three neural clusters, which mapped onto cortical gradients and presented a hierarchy of timescales. Visual attributes modulated neural activity at one end of the gradient, while at the other end it reflected the upcoming response timing, with attentional effects occurring at the intersection of visual and response signals. These findings challenge multi-step models of attention, and suggest that frontoparietal networks, which process sequential stimuli as separate events sharing the same location, drive exogenous attention phenomena such as inhibition of return.
The level of protein in the maternal murine diet modulates the facial appearance of the offspring via mTORC1 signaling
Authors: Xie Meng , Kaiser Markéta , Gershtein Yaakov , Schnyder Daniela , Deviatiiarov Ruslan , Gazizova Guzel , Shagimardanova Elena , Zikmund Tomáš , Kerckhofs Greet , Ivashkin Evgeny , Batkovskyte Dominyka , Newton Phillip T. , Andersson Olov , Fried Kaj , Gusev Oleg , Zeberg Hugo , Kaiser Jozef , Adameyko Igor , Chagin Andrei S.
Published: March 2024

The development of craniofacial skeletal structures is fascinatingly complex and elucidation of the underlying mechanisms will not only provide novel scientific insights, but also help develop more effective clinical approaches to the treatment and/or prevention of the numerous congenital craniofacial malformations. To this end, we performed a genome-wide analysis of RNA transcription from non-coding regulatory elements by CAGE-sequencing of the facial mesenchyme of human embryos and cross-checked the active enhancers thus identified against genes, identified by GWAS for the normal range human facial appearance. Among the identified active cis-enhancers, several belonged to the components of the PI3/AKT/mTORC1/autophagy pathway. To assess the functional role of this pathway, we manipulated it both genetically and pharmacologically in mice and zebrafish. These experiments revealed that mTORC1 signaling modulates craniofacial shaping at the stage of skeletal mesenchymal condensations, with subsequent fine-tuning during clonal intercalation. This ability of mTORC1 pathway to modulate facial shaping, along with its evolutionary conservation and ability to sense external stimuli, in particular dietary amino acids, indicate that the mTORC1 pathway may play a role in facial phenotypic plasticity. Indeed, the level of protein in the diet of pregnant female mice influenced the activity of mTORC1 in fetal craniofacial structures and altered the size of skeletogenic clones, thus exerting an impact on the local geometry and craniofacial shaping. Overall, our findings indicate that the mTORC1 signaling pathway is involved in the effect of environmental conditions on the shaping of craniofacial structures.
Topological minibands and interaction driven quantum anomalous Hall state in topological insulator based moiré heterostructures
Authors: Yang Kaijie , Xu Zian , Feng Yanjie , Schindler Frank , Xu Yuanfeng , Bi Zhen , Bernevig B. Andrei , Tang Peizhe , Liu Chao-Xing
Published: March 2024

The presence of topological flat minibands in moiré materials provides an opportunity to explore the interplay between topology and correlation. In this work, we study moiré minibands in topological insulator films with two hybridized surface states under a moiré superlattice potential created by two-dimensional insulating materials. We show the lowest conduction (highest valence) Kramers’ pair of minibands can be $${{\mathbb{Z}}}_{2}$$

Z

2

non-trivial when the minima (maxima) of moiré potential approximately form a hexagonal lattice with six-fold rotation symmetry. Coulomb interaction can drive the non-trivial Kramers’ minibands into the quantum anomalous Hall state when they are half-filled, which is further stabilized by applying external gate voltages to break inversion. We propose the monolayer Sb2 on top of Sb2Te3 films as a candidate based on first principles calculations. Our work demonstrates the topological insulator based moiré heterostructure as a potential platform for studying interacting topological phases.
An analysis of the accuracy of retrospective birth location recall using sibling data
Authors: von Hinke Stephanie , Vitt Nicolai
Published: March 2024

Many surveys ask participants to retrospectively record their location of birth. This paper examines the accuracy of such data in the UK Biobank using a sample of full siblings. Comparison of reported birth locations for siblings with different age gaps allows us to estimate the probabilities of household moves and of misreported birth locations. Our first contribution is to show that there are inaccuracies in retrospective birth location data, showing a sizeable probability of misreporting, with 28% of birth coordinates, 16% of local districts and 6% of counties of birth being incorrectly reported. Our second contribution is to show that such error can lead to substantial attenuation bias when investigating the impacts of location-based exposures, especially when there is little spatial correlation and limited time variation in the exposure variable. Sibling fixed effect models are shown to be particularly vulnerable to the attenuation bias. Our third contribution is to highlight possible solutions to the attenuation bias and sensitivity analyses to the reporting error.
Treeline displacement may affect lake dissolved organic matter processing at high latitudes and altitudes
Authors: Catalán Núria , Rofner Carina , Verpoorter Charles , Pérez María Teresa , Dittmar Thorsten , Tranvik Lars , Sommaruga Ruben , Peter Hannes
Published: March 2024

Climate change induced shifts in treeline position, both towards higher altitudes and latitudes induce changes in soil organic matter. Eventually, soil organic matter is transported to alpine and subarctic lakes with yet unknown consequences for dissolved organic matter (DOM) diversity and processing. Here, we experimentally investigate the consequences of treeline shifts by amending subarctic and temperate alpine lake water with soil-derived DOM from above and below the treeline. We use ultra-high resolution mass spectrometry (FT-ICR MS) to track molecular DOM diversity (i.e., chemodiversity), estimate DOM decay and measure bacterial growth efficiency. In both lakes, soil-derived DOM from below the treeline increases lake DOM chemodiversity mainly through the enrichment with polyphenolic and highly unsaturated compounds. These compositional changes are associated with reductions in bulk and compound-level DOM reactivity and reduced bacterial growth efficiency. Our results suggest that treeline advancement has the potential to enrich a large number of lake ecosystems with less biodegradable DOM, affecting bacterial community function and potentially altering the biogeochemical cycling of carbon in lakes at high latitudes and altitudes.
Realization of sextuple polarization states and interstate switching in antiferroelectric CuInP2S6
Authors: Li Tao , Wu Yongyi , Yu Guoliang , Li Shengxian , Ren Yifeng , Liu Yadong , Liu Jiarui , Feng Hao , Deng Yu , Chen Mingxing , Zhang Zhenyu , Min Tai
Published: March 2024

Realization of higher-order multistates with mutual interstate switching in ferroelectric materials is a perpetual drive for high-density storage devices and beyond-Moore technologies. Here we demonstrate experimentally that antiferroelectric van der Waals CuInP2S6 films can be controllably stabilized into double, quadruple, and sextuple polarization states, and a system harboring polarization order of six is also reversibly tunable into order of four or two. Furthermore, for a given polarization order, mutual interstate switching can be achieved via moderate electric field modulation. First-principles studies of CuInP2S6 multilayers help to reveal that the double, quadruple, and sextuple states are attributable to the existence of respective single, double, and triple ferroelectric domains with antiferroelectric interdomain coupling and Cu ion migration. These findings offer appealing platforms for developing multistate ferroelectric devices, while the underlining mechanism is transformative to other non-volatile material systems.
Macroevolutionary dynamics of gene family gain and loss along multicellular eukaryotic lineages
Authors: Domazet-Lošo Mirjana , Široki Tin , Šimičević Korina , Domazet-Lošo Tomislav
Published: March 2024

The gain and loss of genes fluctuate over evolutionary time in major eukaryotic clades. However, the full profile of these macroevolutionary trajectories is still missing. To give a more inclusive view on the changes in genome complexity across the tree of life, here we recovered the evolutionary dynamics of gene family gain and loss ranging from the ancestor of cellular organisms to 352 eukaryotic species. We show that in all considered lineages the gene family content follows a common evolutionary pattern, where the number of gene families reaches the highest value at a major evolutionary and ecological transition, and then gradually decreases towards extant organisms. This supports theoretical predictions and suggests that the genome complexity is often decoupled from commonly perceived organismal complexity. We conclude that simplification by gene family loss is a dominant force in Phanerozoic genomes of various lineages, probably underpinned by intense ecological specializations and functional outsourcing.
Silk fibroin hydrogel adhesive enables sealed-tight reconstruction of meniscus tears
Authors: Pan Xihao , Li Rui , Li Wenyue , Sun Wei , Yan Yiyang , Xiang Xiaochen , Fang Jinghua , Liao Youguo , Xie Chang , Wang Xiaozhao , Cai Youzhi , Yao Xudong , Ouyang Hongwei
Published: March 2024

Despite orientationally variant tears of the meniscus, suture repair is the current clinical gold treatment. However, inaccessible tears in company with re-tears susceptibility remain unresolved. To extend meniscal repair tools from the perspective of adhesion and regeneration, we design a dual functional biologic-released bioadhesive (S-PIL10) comprised of methacrylated silk fibroin crosslinked with phenylboronic acid-ionic liquid loading with growth factor TGF-β1, which integrates chemo-mechanical restoration with inner meniscal regeneration. Supramolecular interactions of β-sheets and hydrogen bonds richened by phenylboronic acid-ionic liquid (PIL) result in enhanced wet adhesion, swelling resistance, and anti-fatigue capabilities, compared to neat silk fibroin gel. Besides, elimination of reactive oxygen species (ROS) by S-PIL10 further fortifies localized meniscus tear repair by affecting inflammatory microenvironment with dynamic borate ester bonds, and S-PIL10 continuously releases TGF-β1 for cell recruitment and bridging of defect edge. In vivo rabbit models functionally evidence the seamless and dense reconstruction of torn meniscus, verifying that the concept of meniscus adhesive is feasible and providing a promising revolutionary strategy for preclinical research to repair meniscus tears.
A novel capitate bone Ilizarov external fixator for treating Kienböck’s disease: an anatomical and biomechanical study
Authors: Xiang Feifan , Fan Wei , Tan Xiaoqi , Liu Jinhui , Gu Hao , Yang Yunkang
Published: March 2024

This study aims to measure anatomical data of the capitate bone, develop an external fixator for treating late-stage osteonecrosis of lunate through Ilizarov technique, and evaluate its biomechanical performance. We selected eight wrist joint specimens to measure various parameters of the capitate bone, including its length, the distance from the junction of capitate head and body to the proximal end, as well as the width of its proximal head and distal body. Additionally, we measured these same indicators in 107 patients who had undergone wrist X-ray examination. Based on our measurements, we categorized the capitate bone into two groups and designed two types of capitate bone Ilizarov external fixator (CIEF) for it. Then, we compared it with the orthofix external fixator (OEF) through dynamic fatigue biomechanical experiments and pull-out resistance experiments. The results of the measurement revealed two categories of general patterns in the capitate bone. The first type maintains a consistent longitudinal axis between the proximal and distal ends. The second type is characterized by its proximal end being close to the radial side and its distal end being close to the ulnar side. In the dynamic tensile fatigue test, CIEF-A and CIEF-B had smaller maximum displacement values compared to the OEF (P < 0.05). In the anti-pull-out experiment, both CIEF-A and CIEF-B exhibited higher maximum pull-out force than the OEF (P < 0.05). CIFE is a treatment for advanced osteonecrosis of the lunate bone. It is specifically designed to align with the anatomical characteristics of the capitate bone, providing excellent biomechanical properties and a simple clinical procedure. However, additional clinical experiments are needed to confirm its effectiveness in the future.
Cardiac magnetic resonance patterns of left ventricular remodeling in patients with severe aortic stenosis referred to surgical aortic valve replacement
Authors: Reis Santos Rita , Abecasis João , Maltês Sérgio , Lopes Pedro , Oliveira Luís , Freitas Pedro , Ferreira António , Ribeiras Regina , Andrade Maria João , Sousa Uva Miguel , Neves José Pedro , Gil Victor , Cardim Nuno
Published: March 2024

Left ventricular (LV) hypertrophy is a common finding in patients with severe aortic stenosis (AS). Cardiac magnetic resonance (CMR) is the gold-standard technique to evaluate LV remodeling. Our aim was to assess the prevalence and describe the patterns of LV adaptation in AS patients before and after surgical aortic valve replacement (AVR). Prospective study of 130 consecutive patients (71y [IQR 68–77y], 48% men) with severe AS, referred for surgical AVR. Patterns of LV remodeling were assessed by CMR. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling. At baseline CMR study: mean LV indexed mass: 81.8 ± 26.7 g/m2; mean end-diastolic LV indexed volume: 85.7 ± 23.1 mL/m2 and median geometric remodeling ratio: 0.96 g/mL [IQR 0.82–1.08 g/mL]. LV hypertrophy occurred in 49% of subjects (concentric 44%; eccentric 5%). Both normal LV structure and concentric remodeling had a prevalence of 25% among the cohort; one patient had an adverse remodeling pattern. Asymmetric LV wall thickening was present in 55% of the patients, with predominant septal involvement. AVR was performed in 119 patients. At 3–6 months after AVR, LV remodeling changed to: normal ventricular geometry in 60%, concentric remodeling in 27%, concentric hypertrophy in 10%, eccentric hypertrophy in 3% and adverse remodeling (one patient). Indexes of AS severity, LV systolic and diastolic function and NT-proBNP were significantly different among the distinct patterns of remodeling. Several distinct patterns of LV remodelling beyond concentric hypertrophy occur in patients with classical severe AS. Asymmetric hypertrophy is a common finding and LV response after AVR is diverse.
Comparing deep learning and pathologist quantification of cell-level PD-L1 expression in non-small cell lung cancer whole-slide images
Authors: van Eekelen Leander , Spronck Joey , Looijen-Salamon Monika , Vos Shoko , Munari Enrico , Girolami Ilaria , Eccher Albino , Acs Balazs , Boyaci Ceren , de Souza Gabriel Silva , Demirel-Andishmand Muradije , Meesters Luca Dulce , Zegers Daan , van der Woude Lieke , Theelen Willemijn , van den Heuvel Michel , Grünberg Katrien , van Ginneken Bram , van der Laak Jeroen , Ciompi Francesco
Published: March 2024

Programmed death-ligand 1 (PD-L1) expression is currently used in the clinic to assess eligibility for immune-checkpoint inhibitors via the tumor proportion score (TPS), but its efficacy is limited by high interobserver variability. Multiple papers have presented systems for the automatic quantification of TPS, but none report on the task of determining cell-level PD-L1 expression and often reserve their evaluation to a single PD-L1 monoclonal antibody or clinical center. In this paper, we report on a deep learning algorithm for detecting PD-L1 negative and positive tumor cells at a cellular level and evaluate it on a cell-level reference standard established by six readers on a multi-centric, multi PD-L1 assay dataset. This reference standard also provides for the first time a benchmark for computer vision algorithms. In addition, in line with other papers, we also evaluate our algorithm at slide-level by measuring the agreement between the algorithm and six pathologists on TPS quantification. We find a moderately low interobserver agreement at cell-level level (mean reader-reader F1 score = 0.68) which our algorithm sits slightly under (mean reader-AI F1 score = 0.55), especially for cases from the clinical center not included in the training set. Despite this, we find good AI-pathologist agreement on quantifying TPS compared to the interobserver agreement (mean reader-reader Cohen’s kappa = 0.54, 95% CI 0.26–0.81, mean reader-AI kappa = 0.49, 95% CI 0.27—0.72). In conclusion, our deep learning algorithm demonstrates promise in detecting PD-L1 expression at a cellular level and exhibits favorable agreement with pathologists in quantifying the tumor proportion score (TPS). We publicly release our models for use via the Grand-Challenge platform.
Art therapy masks reflect emotional changes in military personnel with PTSS
Authors: Estrada Gonzalez V. , Meletaki V. , Walker M. , Payano Sosa J. , Stamper A. , Srikanchana R. , King J. L. , Scott K. , Cardillo E. R. , Rhodes C. Sours , Christensen A. P. , Darda K. M. , Workman C. I. , Chatterjee A.
Published: March 2024

Among disabling post-traumatic stress symptoms (PTSS) are irritability, aggressive behavior, distressing memories and general impaired cognition and negative mood. Art therapy interventions, including mask-making, can potentially alleviate these symptoms. We tested the hypothesis that art conveys emotions and predicted that blinded viewers would be able to perceive changes in theoretically derived emotional profiles expressed in art made by military personnel with PTSS from the onset to the end of therapy. Five service members and veterans exhibiting PTSS were enrolled in an 8-session art therapy protocol, during which they artistically transformed papier-mâché masks at the beginning and end of the protocol. We found that blinded viewers without knowledge of the masks’ creation stage (onset or end of therapy) read initial masks as conveying more negative emotions (e.g., angry, upset, and challenged) and later masks as conveying more positive emotions (calm and pleasure). Based on the assessments from the blinded evaluators, we infer the emotional transition experienced by the participants was expressed in the masks. In an exploratory arm of the study, we also found that viewers were better able to empathize with the negative emotions experienced by participants with PTSS when asked to explicitly take their perspective.
Social defeat stress induces liver injury by modulating endoplasmic reticulum stress in C57BL/6J mice
Authors: Gao XiaoLei , Zhao Tong , Hao Ran , Zhang ZhaoHui , Huang Guang-Biao
Published: March 2024

Social defeat stress is associated with endoplasmic reticulum (ER) stress, inflammation and apoptosis. ER stress is thought to contribute to many lifestyle diseases such as liver injury, cardiovascular dysfunction and depression. We investigated the expression of the ER stress markers RNA-dependent protein kinase-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α) and C/EBP homologous protein (CHOP), as well as inflammatory and apoptotic factors, to assess how social defeat stress induces liver injury. Furthermore, we evaluated the effects of the ER stress inhibitor phenylbutyric acid (PBA) and ER stress inducer thapsigargin (TG) on liver injury. Adult mice were divided into the control, social defeat, social defeat + PBA, TG, PBA and TG + PBA groups. The social defeat and social defeat + PBA groups were simultaneously exposed to social defeat stress for 10 days. The social defeat + PBA, TG, PBA and TG + PBA groups were treated with PBA or TG via intraperitoneal injections. PBA was injected 1 h before the TG injection into the TG + PBA group. Liver samples from six groups of mice were analyzed by histological analysis and western blotting. Social defeat stress promoted ER stress, increased the expression of inflammatory factors and induced apoptosis in the liver of socially defeated mice, which was reversed by PBA. Moreover, ER stress induces TG-induced liver injury by initiating ER stress. Social defeat stress initiates ER stress, promotes the expression of inflammatory and apoptotic factors, and induces liver injury. PBA suppresses liver injury caused by social defeat stress and TG treatment.
Stochastic and multi-objective design of photonic devices with machine learning
Authors: Manfredi Paolo , Waqas Abi , Melati Daniele
Published: March 2024

Compact and highly performing photonic devices are characterized by non-intuitive geometries, a large number of parameters, and multiple figures of merit. Optimization and machine learning techniques have been explored to handle these complex designs, but the existing approaches often overlook stochastic quantities. As an example, random fabrication uncertainties critically determines experimental device performance. Here, we present a novel approach for the stochastic multi-objective design of photonic devices combining unsupervised dimensionality reduction and Gaussian process regression. The proposed approach allows to efficiently identify promising alternative designs and model the statistic of their response. Incorporating both deterministic and stochastic quantities into the design process enables a comprehensive analysis of the device and of the possible trade-offs between different performance metrics. As a proof-of-concept, we investigate surface gratings for fiber coupling in a silicon-on-insulator platform, considering variability in structure sizes, silicon thickness, and multi-step etch alignment. We analyze 86 alternative designs presenting comparable performance when neglecting variability, discovering on the contrary marked differences in yield and worst-case figures for both fiber coupling efficiency and back-reflections. Pareto frontiers demonstrating optimized device robustness are identified as well, offering a powerful tool for the design and optimization of photonic devices with stochastic figures of merit.
Effects of exergames on student physical education learning in the context of the artificial intelligence era: a meta-analysis
Authors: Zhao Mengnan , Lu Xurui , Zhang Qi , Zhao Rutong , Wu Bohang , Huang Sheng , Li Sunnan
Published: March 2024

Whether the application of exergames in physical education (PE) courses can significantly improve student performance in PE learning is still controversial. This review explores the promoting effect of exergames on student PE learning and the conditions in which the effect of exergames can be maximized. Based on the PICOS method, two researchers independently searched the ProQuest database, EBSCO database, Web of Science (WoS) database, PubMed database, Chinese National Knowledge Infrastructure (CNKI) database, Wanfang database, and VIP database, evaluated the literature quality using the Cochrane system evaluation manual, and performed a meta-analysis of the included literature. A total of 16 randomized controlled trials involving 2962 subjects were included in this study. The meta-analysis showed that exergames effectively improved student performance in PE learning (SMD = 0.45, 95% CI: 0.27–0.63, P < 0.00001). Subgroup analysis indicated that better results could be achieved when exergames were introduced in small kindergarten classes and continued for 1–2 months.
Association between mammillary body atrophy and memory impairment in retired athletes with a history of repetitive mild traumatic brain injury
Authors: Miyata Mari , Takahata Keisuke , Sano Yasunori , Yamamoto Yasuharu , Kurose Shin , Kubota Manabu , Endo Hironobu , Matsuoka Kiwamu , Tagai Kenji , Oya Masaki , Hirata Kosei , Saito Fumie , Mimura Masaru , Kamagata Koji , Aoki Shigeki , Higuchi Makoto
Published: March 2024

Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV–adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK–SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann–Whitney U test, p < 0.05) underwent partial correlation analysis, adjusting for age and sex, to assess its connection with neuropsychological test results. Compared with the control group, the rmTBI group showed significantly lower the MBs volume/TBV ratio (0.13 ± 0.05 vs. 0.19 ± 0.03 × 10−3, p < 0.001). The MBs volume/TBV ratio correlated with visual memory, as assessed, respectively, by the Rey–Osterrieth Complex Figure test delayed recall (ρ = 0.62, p < 0.001). In conclusion, retired athletes with rmTBI have MB atrophy, potentially contributing to memory impairment linked to the Papez circuit disconnection.
Dynamic analysis of geomaterials using microwave sensing
Authors: Blanche Jamie , Mitchell Daniel , Shang Junlong , Flynn David , Pavuluri Sumanth , Desmulliez Marc
Published: March 2024

Precise characterization of geomaterials improves subsurface energy extraction and storage. Understanding geomaterial property, and the complexities between petrophysics and geomechanics, plays a key role in maintaining energy security and the transition to a net zero global carbon economy. Multiple sectors demand accurate and rapid characterization of geomaterial conditions, requiring the extraction of core plugs in the field for full-field characterization and analysis in the laboratory. We present a novel technique for the non-invasive characterization of geomaterials by using Frequency Modulated Continuous Wave (FMCW) radar in the K-band, representing a new application of microwave radar. We collect data through the delivery of FMCW wave interactions with geomaterials under static and dynamic conditions and show that FMCW can detect fluid presence, differentiate fluid type, indicate the presence of metallic inclusions and detect imminent failure in loaded sandstones by up to 15 s, allowing for greater control in loading up to a failure event. Such precursors have the potential to significantly enhance our understanding of, and ability to model, geomaterial dynamics. This low-cost sensing method is easily deployable, provides quicker and more accessible data than many state-of-the-art systems, and new insights into geomaterial behavior under dynamic conditions.
Exploring the potential of Ziziphus nummularia and luteolin-7-O-glucoside as tubulin inhibitors in cancer therapy and survival
Authors: Alghamdi Sahar Saleh , Alghashem Sara Abdulaziz , Ali Rizwan , Alsubait Arwa , Suliman Rasha Saad , Mohammed Afrah E. , Alehaideb Zeyad , Alshafi Raghad Abdullah , Alturki Allulu Yousef , Rahman Ishrat
Published: March 2024

Cancer is responsible for approximately 10 million deaths worldwide, with 70% of the deaths occurring in low- and middle-income countries; as such safer and more effective anti-cancer drugs are required. Therefore, the potential benefits of Ziziphus nummularia and Ziziphus spina-christi as sources of anti-cancer agents were investigated. Z. nummularia and Z. spina-christi extracts were prepared using chloroform, ethanol, ethyl acetate, and water. The extracts’ anti-cancer properties were determined using the MTT Cell Viability Assay in four cancer cell lines: breast (KAIMRC2 and MDA-MB-231), colorectal (HCT8), and liver (HepG2). The ApoTox-Glo Triplex Assay and high-content imaging (HCI)-Apoptosis Assay were used to assess KAIMRC2 and HCT8 cells further. In addition, KAIMRC2 cells were tested for microtubule staining, and AKT/mTOR protein expression was determined by western blot analysis. Liquid chromatography-mass spectrometry (LC–MS) was performed to identify the secondary metabolites in the ethanol and ethyl acetate extracts, followed by in silico techniques to predict molecular targets and interactions, safety, and pharmacokinetic profile for identified metabolites. Out of the eight extracts, the ethanolic extract of Z. nummularia, exhibited the most potent activity against KAIMRC2 cells with an IC50 value of 29.2 μg/ml. Cancer cell treatment with the ethanolic extract of Z. nummularia resulted in a dose-dependent decrease in cell viability with increased apoptosis and cytotoxic effects. Microtubule staining showed a disrupted microtubular network. The ethanolic extract treatment of KAIMRC2 cells led to upregulated expression of pAKT and pmTOR. In silico studies predicted luteolin-7-O-glucoside to be a ligand for tubulin with the highest docking score (− 7.686) and similar binding interactions relative to the native ligand. Further computational analysis of the metabolites showed acceptable pharmacokinetic and safety profiles, although ethanolic extract metabolites were predicted to have cardiotoxic effects. Ethanolic extraction is optimal for solubilizing active anticancer metabolites from Z. nummularia, which may act by causing M-phase arrest via inhibition of tubulin polymerization. Luteolin-7-O-glucoside is the lead candidate for further research and development as an anti-cancer agent. In addition, this study suggests that herbal treatment could switch on mechanisms of adaptation and survival in cancer cells.
Nilotinib-induced alterations in endothelial cell function recapitulate clinical vascular phenotypes independent of ABL1
Authors: Pinheiro Emily A. , DeKeyser Jean-Marc , Lenny Brian , Sapkota Yadav , Burridge Paul W.
Published: March 2024

Nilotinib is a highly effective treatment for chronic myeloid leukemia but has been consistently associated with the development of nilotinib-induced arterial disease (NAD) in a subset of patients. To date, which cell types mediate this effect and whether NAD results from on-target mechanisms is unknown. We utilized human induced pluripotent stem cells (hiPSCs) to generate endothelial cells and vascular smooth muscle cells for in vitro study of NAD. We found that nilotinib adversely affects endothelial proliferation and migration, in addition to increasing intracellular nitric oxide. Nilotinib did not alter endothelial barrier function or lipid uptake. No effect of nilotinib was observed in vascular smooth muscle cells, suggesting that NAD is primarily mediated through endothelial cells. To evaluate whether NAD results from enhanced inhibition of ABL1, we generated multiple ABL1 knockout lines. The effects of nilotinib remained unchanged in the absence of ABL1, suggesting that NAD results from off- rather than on-target signaling. The model established in the present study can be applied to future mechanistic and patient-specific pharmacogenomic studies.