bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell biological network inference using a heterogeneous graph transformer
Authors: Ma Anjun , Wang Xiaoying , Li Jingxian , Wang Cankun , Xiao Tong , Liu Yuntao , Cheng Hao , Wang Juexin , Li Yang , Chang Yuzhou , Li Jinpu , Wang Duolin , Jiang Yuexu , Su Li , Xin Gang , Gu Shaopeng , Li Zihai , Liu Bingqiang , Xu Dong , Ma Qin
Published: February 2023

Single-cell multi-omics (scMulti-omics) allows the quantification of multiple modalities simultaneously to capture the intricacy of complex molecular mechanisms and cellular heterogeneity. Existing tools cannot effectively infer the active biological networks in diverse cell types and the response of these networks to external stimuli. Here we present DeepMAPS for biological network inference from scMulti-omics. It models scMulti-omics in a heterogeneous graph and learns relations among cells and genes within both local and global contexts in a robust manner using a multi-head graph transformer. Benchmarking results indicate DeepMAPS performs better than existing tools in cell clustering and biological network construction. It also showcases competitive capability in deriving cell-type-specific biological networks in lung tumor leukocyte CITE-seq data and matched diffuse small lymphocytic lymphoma scRNA-seq and scATAC-seq data. In addition, we deploy a DeepMAPS webserver equipped with multiple functionalities and visualizations to improve the usability and reproducibility of scMulti-omics data analysis.
Batch alignment of single-cell transcriptomics data using deep metric learning
Authors: Yu Xiaokang , Xu Xinyi , Zhang Jingxiao , Li Xiangjie
Published: February 2023

scRNA-seq has uncovered previously unappreciated levels of heterogeneity. With the increasing scale of scRNA-seq studies, the major challenge is correcting batch effect and accurately detecting the number of cell types, which is inevitable in human studies. The majority of scRNA-seq algorithms have been specifically designed to remove batch effect firstly and then conduct clustering, which may miss some rare cell types. Here we develop scDML, a deep metric learning model to remove batch effect in scRNA-seq data, guided by the initial clusters and the nearest neighbor information intra and inter batches. Comprehensive evaluations spanning different species and tissues demonstrated that scDML can remove batch effect, improve clustering performance, accurately recover true cell types and consistently outperform popular methods such as Seurat 3, scVI, Scanorama, BBKNN, Harmony et al. Most importantly, scDML preserves subtle cell types in raw data and enables discovery of new cell subtypes that are hard to extract by analyzing each batch individually. We also show that scDML is scalable to large datasets with lower peak memory usage, and we believe that scDML offers a valuable tool to study complex cellular heterogeneity.
Recent decrease of the impact of tropical temperature on the carbon cycle linked to increased precipitation
Authors: Zhang Wenmin , Schurgers Guy , Peñuelas Josep , Fensholt Rasmus , Yang Hui , Tang Jing , Tong Xiaowei , Ciais Philippe , Brandt Martin
Published: February 2023

The atmospheric CO2 growth rate (CGR) variability is largely controlled by tropical temperature fluctuations. The sensitivity of CGR to tropical temperature $$\left({{{{\rm{\gamma }}}}}_{{{{\rm{CGR}}}}}^{{{{\rm{T}}}}}\right)$$

γ

CGR

T

has strongly increased since 1960, but here we show that this trend has ceased. Here, we use the long-term CO2 records from Mauna Loa and the South Pole to compute CGR, and show that $${{{{\rm{\gamma }}}}}_{{{{\rm{CGR}}}}}^{{{{\rm{T}}}}}$$

γ

CGR

T

increased by 200% from 1960–1979 to 1979–2000 but then decreased by 117% from 1980–2001 to 2001–2020, almost returning back to the level of the 1960s. Variations in $${{{{\rm{\gamma }}}}}_{{{{\rm{CGR}}}}}^{{{{\rm{T}}}}}$$

γ

CGR

T

are significantly correlated with changes in precipitation at a bi-decadal scale. These findings are further corroborated by results from a dynamic vegetation model, collectively suggesting that increases in precipitation control the decreased $${{{{\rm{\gamma }}}}}_{{{{\rm{CGR}}}}}^{{{{\rm{T}}}}}$$

γ

CGR

T

during recent decades. Our results indicate that wetter conditions have led to a decoupling of the impact of the tropical temperature variation on the carbon cycle.
Effect of microgravity on mechanical loadings in lumbar spine at various postures: a numerical study
Authors: Wu Biao , Gao Xin , Qin Bing , Baldoni Michele , Zhou Lu , Qian Zhiyu , Zhu Qiaoqiao
Published: February 2023

The aim of this study was to quantitatively analyze the mechanical change of spinal segments (disc, muscle, and ligament) at various postures under microgravity using a full-body musculoskeletal modeling approach. Specifically, in the lumbar spine, the vertebra were modeled as rigid bodies, the intervertebral discs were modeled as 6-degree-of-freedom joints with linear force-deformation relationships, the disc swelling pressure was deformation dependent, the ligaments were modeled as piecewise linear elastic materials, the muscle strength was dependent on its functional cross-sectional area. The neutral posture and the “fetal tuck” posture in microgravity (short as “Neutral 0G” and “Fetal Tuck 0G”, in our simulation, the G constant was set to 0 for simulating microgravity), and for comparison, the relaxed standing posture in 1G and 0G gravity (short as “Neutral 1G” and “Standing 0G”) were simulated. Compared to values at Neutral 1G, the mechanical response in the lower spine changed significantly at Neutral 0G. For example, the compressive forces on lumbar discs decreased 62–70%, the muscle forces decreased 55.7–92.9%, while disc water content increased 7.0–10.2%, disc height increased 2.1–3.0%, disc volume increased 6.4–9.3%, and ligament forces increased 59.5–271.3% at Neutral 0G. The fetal tuck 0G reversed these changes at Neutral 0G back toward values at Neutral 1G, with magnitudes much larger than those at Neutral 1G. Our results suggest that microgravity has significant influences on spinal biomechanics, alteration of which may increase the risks of disc herniation and degeneration, muscle atrophy, and/or ligament failure.
Immunization with matrix-, nucleoprotein and neuraminidase protects against H3N2 influenza challenge in pH1N1 pre-exposed pigs
Authors: Vatzia Eleni , Feest Katherine , McNee Adam , Manjegowda Tanuja , Carr B. Veronica , Paudyal Basudev , Chrun Tiphany , Maze Emmanuel A. , Mccarron Amy , Morris Susan , Everett Helen E. , MacLoughlin Ronan , Salguero Francisco J. , Lambe Teresa , Gilbert Sarah C. , Tchilian Elma
Published: February 2023

There is an urgent need for influenza vaccines providing broader protection that may decrease the need for annual immunization of the human population. We investigated the efficacy of heterologous prime boost immunization with chimpanzee adenovirus (ChAdOx2) and modified vaccinia Ankara (MVA) vectored vaccines, expressing conserved influenza virus nucleoprotein (NP), matrix protein 1 (M1) and neuraminidase (NA) in H1N1pdm09 pre-exposed pigs. We compared the efficacy of intra-nasal, aerosol and intra-muscular vaccine delivery against H3N2 influenza challenge. Aerosol prime boost immunization induced strong local lung T cell and antibody responses and abrogated viral shedding and lung pathology following H3N2 challenge. In contrast, intramuscular immunization induced powerful systemic responses and weak local lung responses but also abolished lung pathology and reduced viral shedding. These results provide valuable insights into the development of a broadly protective influenza vaccine in a highly relevant large animal model and will inform future vaccine and clinical trial design.
City-scale synthetic individual-level vehicle trip data
Authors: Li Guilong , Chen Yixian , Wang Yimin , Nie Peilin , Yu Zhi , He Zhaocheng
Published: February 2023

Trip data that records each vehicle’s trip activity on the road network describes the operation of urban traffic from the individual perspective, and it is extremely valuable for transportation research. However, restricted by data privacy, the trip data of individual-level cannot be opened for all researchers, while the need for it is very urgent. In this paper, we produce a city-scale synthetic individual-level vehicle trip dataset by generating for each individual based on the historical trip data, where the availability and trip data privacy protection are balanced. Privacy protection inevitably affects the availability of data. Therefore, we have conducted numerous experiments to demonstrate the performance and reliability of the synthetic data in different dimensions and at different granularities to help users properly judge the tasks it can perform. The result shows that the synthetic data is consistent with the real data (i.e., historical data) on the aggregated level and reasonable from the individual perspective.
Analysis of economic forecasting in the post-epidemic era: evidence from China
Authors: Li Xin
Published: February 2023

This paper presents a predictive analysis of the Chinese economy in the post-epidemic era. Five major public health emergencies historically similar to the COVID-19 epidemic are used as the control group, and a fuzzy mathematical model is applied to forecast and analyze China’s economy after the COVID-19 epidemic. The forecast results show that China’s overall economy will have recovered to the pre-epidemic level in about 1 year, with the fastest recovery in individual economic indicators, followed by government final consumption and imports, then CPI, fiscal revenue, exports and money supply, and the slowest recovery in employment. Finally, a combination of all the parties makes policies and recommendations for China’s economic and social development in the post-epidemic era.
Four-year follow-up on fatigue and sleep quality of a three-armed partly randomized controlled study in breast cancer survivors with cancer-related fatigue
Authors: Kröz M. , Quittel F. , Reif M. , Zerm R. , Pranga D. , Bartsch C. , Brinkhaus B. , Büssing A. , Gutenbrunner C. ,   the CRF study group, Brink Fadime ten , Berger Bettina , Weninger Annette , Girke Matthias , Müller-Glinz Augustina , Heckmann Christian
Published: February 2023

Cancer-related fatigue (CRF) is a frequent long-term symptom in non-metastasized breast cancer patients (BC). This 4-year follow-up intended to compare the long-term effects of a 10-week multimodal therapy (MT: sleep education, psychoeducation, eurythmy- and painting therapy) and combination therapy [CT: MT plus aerobic training (AT)] to AT-control. BC-patients were randomized or allocated by preference to three arms in a comprehensive cohort study. Primary outcome was a composite score including Pittsburgh Sleep Quality Index (PSQI) and Cancer Fatigue Scale (CFS-D), captured at baseline, after 10 weeks of intervention (T1), 6 months later (T2), and after 4 years (T3). We exploratively tested for superiority of MT and CT versus AT after 4 years (T3) based on the statistical model of the main analysis. Of 126 (65 randomized) BC-patients included, 105 started treatments and 79 were re-assessed for long-term effects (T3). MT and CT were superior over AT after 4 years regarding PSQI/CFS-D and PSQI sum-score, respectively (all p < 0.05), but not for CFS-D. The multimodal and combination treatment for breast cancer patients with CRF indicates sustainable long-term superiority over aerobic training for the outcomes sleep quality and combined sleep quality/fatigue. A confirmative randomized controlled trial is warranted.
Effect of fissure angle on energy evolution and failure characteristics of fractured rock under uniaxial cyclic loading
Authors: Zhao Yongqiang , Li Quanshen , Zhang Kai , Yang Yingming , Gu Xuebin
Published: February 2023

To study the influence of fissure angle on the rock damage process and energy evolution characteristics, uniaxial cyclic loading and unloading tests were conducted on fractured rock specimens with different prefabricated fissure angles. The stress–strain curves, mechanical properties, and failure characteristics were analyzed. Subsequently, the energy evolution characteristics and failure mechanisms were investigated. The results showed that the stress–strain curves of fractured specimens fluctuated in the pre-peak phase and rapidly declined in post-peak phase. The peak stresses and strains of fractured specimens initially decreased and then increased with an increase in the fissure angle, whereas the elastic modulus first increased and then decreased. With an increase in the fissure angle, specimen failure changed from shear damage to tensile damage. The input, elastic, and dissipation energies of fractured specimens non-linearly increased with an increase in cyclic loading and unloading. As the number of cycles increased, the energy density decreased in segments with an increase in the fissure angle, and there was a rapid increase in the dissipation energy density before failure occurred. The results can provide a reference for the study of fractured rock failures and their prevention and control design in the field.
Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn's disease based on three machine learning methods
Authors: Chen Zi-An , Ma Hui-hui , Wang Yan , Tian Hui , Mi Jian-wei , Yao Dong-Mei , Yang Chuan-Jie
Published: February 2023

Crohn's disease (CD) is a complex autoimmune disorder presumed to be driven by complex interactions of genetic, immune, microbial and even environmental factors. Intrinsic molecular mechanisms in CD, however, remain poorly understood. The identification of novel biomarkers in CD cases based on larger samples through machine learning approaches may inform the diagnosis and treatment of diseases. A comprehensive analysis was conducted on all CD datasets of Gene Expression Omnibus (GEO); our team then used the robust rank aggregation (RRA) method to identify differentially expressed genes (DEGs) between controls and CD patients. PPI (protein‒protein interaction) network and functional enrichment analyses were performed to investigate the potential functions of the DEGs, with molecular complex detection (MCODE) identifying some important functional modules from the PPI network. Three machine learning algorithms, support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and least absolute shrinkage and selection operator (LASSO), were applied to determine characteristic genes, which were verified by ROC curve analysis and immunohistochemistry (IHC) using clinical samples. Univariable and multivariable logistic regression were used to establish a machine learning score for diagnosis. Single-sample GSEA (ssGSEA) was performed to examine the correlation between immune infiltration and biomarkers. In total, 5 datasets met the inclusion criteria: GSE75214, GSE95095, GSE126124, GSE179285, and GSE186582. Based on RRA integrated analysis, 203 significant DEGs were identified (120 upregulated genes and 83 downregulated genes), and MCODE revealed some important functional modules in the PPI network. Machine learning identified LCN2, REG1A, AQP9, CCL2, GIP, PROK2, DEFA5, CXCL9, and NAMPT; AQP9, PROK2, LCN2, and NAMPT were further verified by ROC curves and IHC in the external cohort. The final machine learning score was defined as [Expression level of AQP9 × (2.644)] + [Expression level of LCN2 × (0.958)] + [Expression level of NAMPT × (1.115)]. ssGSEA showed markedly elevated levels of dendritic cells and innate immune cells, such as macrophages and NK cells, in CD, consistent with the gene enrichment results that the DEGs are mainly involved in the IL-17 signaling pathway and humoral immune response. The selected biomarkers analyzed by the RRA method and machine learning are highly reliable. These findings improve our understanding of the molecular mechanisms of CD pathogenesis.
Rescue and in vitro characterization of a divergent TBEV-Eu strain from the Netherlands
Authors: Hoornweg Tabitha E. , Godeke Gert-Jan , Hoogerwerf Marieke N. , van Kasteren Puck B. , de Vries Ankje , Sprong Hein , Verjans Georges M. G. M. , van Riel Debby , Reimerink Johan H. J. , Rockx Barry , Reusken Chantal B. E. M.
Published: February 2023

Tick-borne encephalitis virus (TBEV) may cause tick-borne encephalitis (TBE), a potential life-threatening infection of the central nervous system in humans. Phylogenetically, TBEVs can be subdivided into three main subtypes, which differ in endemic region and pathogenic potential. In 2016, TBEV was first detected in the Netherlands. One of two detected strains, referred to as Salland, belonged to the TBEV-Eu subtype, yet diverged ≥ 2% on amino acid level from other members of this subtype. Here, we report the successful rescue of this strain using infectious subgenomic amplicons and its subsequent in vitro characterization by comparison to two well-characterized TBEV-Eu strains; Neudoerfl and Hypr. In the human alveolar epithelial cell line A549, growth kinetics of Salland were comparable to the high pathogenicity TBEV-Eu strain Hypr, and both strains grew considerably faster than the mildly pathogenic strain Neudoerfl. In the human neuroblastoma cell line SK-N-SH, Salland replicated faster and to higher infectious titers than both reference strains. All three TBEV strains infected primary human monocyte-derived dendritic cells to a similar extent and interacted with the type I interferon system in a similar manner. The current study serves as the first in vitro characterization of the novel, divergent TBEV-Eu strain Salland.
Predictors of shoulder dystocia at the time of operative vaginal delivery: a prospective cohort study
Authors: Bouchghoul Hanane , Hamel Jean-François , Mattuizzi Aurélien , Ducarme Guillaume , Froeliger Alizée , Madar Hugo , Sentilhes Loïc
Published: February 2023

Our aim was to identify factors associated with shoulder dystocia following an attempted operative vaginal delivery (aOVD) in a prospective cohort study and to evaluate whether these factors can be used to accurately predict shoulder dystocia by building a score of shoulder dystocia risk. This was a planned secondary analysis of a prospective cohort study of deliveries with aOVD at term from 2008–2013. Cases were defined as women with shoulder dystocia following an aOVD defined as a delivery that requires additional obstetric maneuvers following failure of gentle downward traction on the fetal head to effect delivery of the shoulders. Multivariate logistic regression analyses were performed to determine risk factors for shoulder dystocia. Shoulder dystocia occurred in 57 (2.7%) of the 2118 women included. In the whole cohort, women with shoulder dystocia more often had a history of shoulder dystocia (3.5% vs. 0.2%, p = 0.01), and there was a significant interaction between aOVD and gestational age and the duration of the second stage of labor: women with shoulder dystocia more often had a gestational age > 40 weeks and a second stage of labor longer than 3 h specifically for midpelvic aOVD. In multivariable analysis, a history of shoulder dystocia was the only factor independently associated with shoulder dystocia following aOVD (aOR 27.00, 95% CI 4.10–178.00). The AUC for the receiver operating characteristic curve generated using a multivariate model with term interaction with head station was 0.70 (95% CI 0.62–0.77). The model failed to accurately predict shoulder dystocia.
Mutant structure of metabolic switch protein in complex with monomeric c-di-GMP reveals a potential mechanism of protein-mediated ligand dimerization
Authors: Dubey Badri Nath , Shyp Viktoriya , Fucile Geoffrey , Sondermann Holger , Jenal Urs , Schirmer Tilman
Published: February 2023

Bacterial second messengers c-di-GMP and (p)ppGpp have broad functional repertoires ranging from growth and cell cycle control to the regulation of biofilm formation and virulence. The recent identification of SmbA, an effector protein from Caulobacter crescentus that is jointly targeted by both signaling molecules, has opened up studies on how these global bacterial networks interact. C-di-GMP and (p)ppGpp compete for the same SmbA binding site, with a dimer of c-di-GMP inducing a conformational change that involves loop 7 of the protein that leads to downstream signaling. Here, we report a crystal structure of a partial loop 7 deletion mutant, SmbA∆loop in complex with c-di-GMP determined at 1.4 Å resolution. SmbA∆loop binds monomeric c-di-GMP indicating that loop 7 is required for c-di-GMP dimerization. Thus the complex probably represents the first step of consecutive c-di-GMP binding to form an intercalated dimer as has been observed in wild-type SmbA. Considering the prevalence of intercalated c-di-GMP molecules observed bound to proteins, the proposed mechanism may be generally applicable to protein-mediated c-di-GMP dimerization. Notably, in the crystal, SmbA∆loop forms a 2-fold symmetric dimer via isologous interactions with the two symmetric halves of c-di-GMP. Structural comparisons of SmbA∆loop with wild-type SmbA in complex with dimeric c-di-GMP or ppGpp support the idea that loop 7 is critical for SmbA function by interacting with downstream partners. Our results also underscore the flexibility of c-di-GMP, to allow binding to the symmetric SmbA∆loop dimer interface. It is envisaged that such isologous interactions of c-di-GMP could be observed in hitherto unrecognized targets.
Developmental programming: adverse sexually dimorphic transcriptional programming of gestational testosterone excess in cardiac left ventricle of fetal sheep
Authors: Ramamoorthi Elangovan Venkateswaran , Saadat Nadia , Ghnenis Adel , Padmanabhan Vasantha , Vyas Arpita K.
Published: February 2023

Adverse in-utero insults during fetal life alters offspring’s developmental trajectory, including that of the cardiovascular system. Gestational hyperandrogenism is once such adverse in-utero insult. Gestational testosterone (T)-treatment, an environment of gestational hyperandrogenism, manifests as hypertension and pathological left ventricular (LV) remodeling in adult ovine offspring. Furthermore, sexual dimorphism is noted in cardiomyocyte number and morphology in fetal life and at birth. This study investigated transcriptional changes and potential biomarkers of prenatal T excess-induced adverse cardiac programming. Genome-wide coding and non-coding (nc) RNA expression were compared between prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30 to 90 of gestation; Term: 147 days) and control ovine LV at day 90 fetus in both sexes. Prenatal T induced differential expression of mRNAs in the LV of female (2 down, 5 up) and male (3 down, 1 up) (FDR < 0.05, absolute log2 fold change > 0.5); pathways analysis demonstrated 205 pathways unique to the female, 382 unique to the male and 23 common pathways. In the male, analysis of ncRNA showed differential regulation of 15 lncRNAs (14 down, 1 up) and 27 snoRNAs (26 down and 1 up). These findings suggest sexual dimorphic modulation of cardiac coding and ncRNA with gestational T excess.
NMR-based metabolomics of plasma from dairy calves infected with two primary causal agents of bovine respiratory disease (BRD)
Authors: Santos-Rivera Mariana , Fitzkee Nicholas C. , Hill Rebecca A. , Baird Richard E. , Blair Ellianna , Thoresen Merrilee , Woolums Amelia R. , Meyer Florencia , Vance Carrie K.
Published: February 2023

Each year, bovine respiratory disease (BRD) results in significant economic loss in the cattle sector, and novel metabolic profiling for early diagnosis represents a promising tool for developing effective measures for disease management. Here, 1H-nuclear magnetic resonance (1H-NMR) spectra were used to characterize metabolites from blood plasma collected from male dairy calves (n = 10) intentionally infected with two of the main BRD causal agents, bovine respiratory syncytial virus (BRSV) and Mannheimia haemolytica (MH), to generate a well-defined metabolomic profile under controlled conditions. In response to infection, 46 metabolites (BRSV = 32, MH = 33) changed in concentration compared to the uninfected state. Fuel substrates and products exhibited a particularly strong effect, reflecting imbalances that occur during the immune response. Furthermore, 1H-NMR spectra from samples from the uninfected and infected stages were discriminated with an accuracy, sensitivity, and specificity ≥ 95% using chemometrics to model the changes associated with disease, suggesting that metabolic profiles can be used for further development, understanding, and validation of novel diagnostic tools.
Bayesian estimation reveals that reproducible models in Systems Biology get more citations
Authors: Höpfl Sebastian , Pleiss Jürgen , Radde Nicole E.
Published: February 2023

The Systems Biology community has taken numerous actions to develop data and modeling standards towards FAIR data and model handling. Nevertheless, the debate about incentives and rewards for individual researchers to make their results reproducible is ongoing. Here, we pose the specific question of whether reproducible models have a higher impact in terms of citations. Therefore, we statistically analyze 328 published models recently classified by Tiwari et al. based on their reproducibility. For hypothesis testing, we use a flexible Bayesian approach that provides complete distributional information for all quantities of interest and can handle outliers. The results show that in the period from 2013, i.e., 10 years after the introduction of SBML, to 2020, the group of reproducible models is significantly more cited than the non-reproducible group. We show that differences in journal impact factors do not explain this effect and that this effect increases with additional standardization of data and error model integration via PEtab. Overall, our statistical analysis demonstrates the long-term merits of reproducible modeling for the individual researcher in terms of citations. Moreover, it provides evidence for the increased use of reproducible models in the scientific community.
Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing
Authors: Reuter Peggy , Walter Magdalena , Kohl Susanne , Weisschuh Nicole
Published: February 2023

Achromatopsia is an autosomal recessive cone photoreceptor disease that is frequently caused by pathogenic variants in the CNGA3 gene. Here, we present a systematic functional analysis of 20 CNGA3 splice site variants detected in our large cohort of achromatopsia patients and/or listed in common variant databases. All variants were analyzed by functional splice assays based on the pSPL3 exon trapping vector. We demonstrated that ten variants, both at canonical and non-canonical splice sites, induced aberrant splicing, including intronic nucleotide retention, exonic nucleotide deletion and exon skipping, resulting in 21 different aberrant transcripts. Of these, eleven were predicted to introduce a premature termination codon. The pathogenicity of all variants was assessed based on established guidelines for variant classification. Incorporation of the results of our functional analyses enabled re-classification of 75% of variants previously classified as variants of uncertain significance into either likely benign or likely pathogenic. Our study is the first in which a systematic characterization of putative CNGA3 splice variants has been performed. We demonstrated the utility of pSPL3 based minigene assays in the effective assessment of putative splice variants. Our findings improve the diagnosis of achromatopsia patients, who may thus benefit from future gene-based therapeutic strategies.
MosChito rafts as effective and eco-friendly tool for the delivery of a Bacillus thuringiensis-based insecticide to Aedes albopictus larvae
Authors: Pitton Simone , Negri Agata , Pezzali Giulia , Piazzoni Marco , Locarno Silvia , Gabrieli Paolo , Quadri Roberto , Mastrantonio Valentina , Urbanelli Sandra , Porretta Daniele , Bandi Claudio , Epis Sara , Caccia Silvia
Published: February 2023

Adult mosquito females, through their bites, are responsible for the transmission of different zoonotic pathogens. Although adult control represents a pillar for the prevention of disease spread, larval control is also crucial. Herein we characterized the effectiveness of a suitable tool, named “MosChito raft”, for the aquatic delivery of a Bacillus thuringiensis var. israelensis (Bti) formulate, a bioinsecticide active by ingestion against mosquito larvae. MosChito raft is a floating tool composed by chitosan cross-linked with genipin in which a Bti-based formulate and an attractant have been included. MosChito rafts (i) resulted attractive for the larvae of the Asian tiger mosquito Aedes albopictus, (ii) induced larval mortality within a few hours of exposure and, more importantly, (iii) protected the Bti-based formulate, whose insecticidal activity was maintained for more than one month in comparison to the few days residual activity of the commercial product. The delivery method was effective in both laboratory and semi-field conditions, demonstrating that MosChito rafts may represent an original, eco-based and user-friendly solution for larval control in domestic and peri-domestic aquatic habitats such as saucers and artificial containers in residential or urban environments.
Effect of bulky anions on the liquid-liquid phase transition in phosphonium ionic liquids: Ambient and high-pressure dielectric studies
Authors: Yao B. , Paluch M. , Wojnarowska Z.
Published: February 2023

Although the first-order liquid–liquid phase transition (LLT) has been reported to exist in various systems (i.e., phosphorus, silicon, water, triphenyl phosphite, etc.), it is still one of the most challenging problems in the field of physical science. Recently, we found that this phenomenon occurs in the family of trihexyl(tetradecyl)phosphonium [P666,14]+ based ionic liquids (ILs) with different anions (Wojnarowska et al in Nat Commun 13:1342, 2022). To understand the molecular structure–property relationships governing LLT, herein, we examine ion dynamics of two other quaternary phosphonium ILs containing long alkyl chains in cation and anion. We found that IL with the anion containing branched –O–(CH2)5–CH3 side chains does not reveal any signs of LLT, while IL with shorter alkyl chains in the anion brings a hidden LLT, i.e., it overlaps with the liquid-glass transition. Ambient pressure dielectric and viscosity measurements revealed a peculiar behavior of ion dynamics near Tg for IL with hidden LLT. Moreover, high-pressure studies have shown that IL with hidden LLT has relatively strong pressure sensitivity compared to the one without first-order phase transition. At the same time, the former exposes the inflection point indicating the concave-convex character of logτσ(P) dependences.
circRNA-ZCCHC14 affects the chondrogenic differentiation ability of peripheral blood-derived mesenchymal stem cells by regulating GREM1 through miR-181a
Authors: Zhao Daohong , Chen Hong , Zhong Jia , Zhou Xizong , Zhang Jun , Zhang Yuhao
Published: February 2023

circRNAs play an important role in the progression of osteoarthritis (OA). Therefore, we aimed to reveal the mechanism of action of circRNA-ZCCHC14 in OA. OA animal and cell models were constructed, and clinical samples were collected. The expression of circRNA-ZCCHC14 and miR-181a was detected by RT‒qPCR. The chondrogenic differentiation ability of peripheral blood-derived mesenchymal stem cells (PBMSCs) was detected by Alcian blue staining. The expression of chondrogenic differentiation-related proteins was detected by Western blotting. Double fluorescein experiments verified the targeting relationship of miR-181a with circRNA-ZCCHC14 and GREM1. Upregulation of circRNA-ZCCHC14 was observed in blood, in BMP-2- and TGF-β3-treated PBMSCs from OA patients and in animal models. Knockdown of circRNA-ZCCHC14 promoted the chondrogenic differentiation ability of PBMSCs. circRNA-ZCCHC14 was found to bind to miR-181a and negatively regulate miR-181a expression. Inhibition of miR-181a reversed the promoting effect of circRNA-ZCCHC14 knockdown on the chondrogenic differentiation ability of PBMSCs. GREM1 was identified as a target of miR-181a. Overexpression and knockdown of GREM1 regulated the expression of BMP2, which in turn affected the chondrogenic differentiation ability of PBMSCs, indicating that GREM1 and BMP2 have antagonistic effects and that they jointly regulate the chondrogenic differentiation of PBMSCs. circRNA-ZCCHC14 may promote the chondrogenic differentiation ability of PBMSCs by regulating miR-181a and inhibiting the expression of GREM1.
Cytotoxic and chemomodulatory effects of Phyllanthus niruri in MCF-7 and MCF-7ADR breast cancer cells
Authors: Abdel-Sattar Ola E. , Allam Rasha Mosa , Al-Abd Ahmed M. , Avula Bharathi , Katragunta Kumar , Khan Ikhlas A. , El-Desoky Ahmed M. , Mohamed Shanaz O. , El-Halawany Ali , Abdel-Sattar Essam , Meselhy Meselhy R.
Published: February 2023

The members of the genus Phyllanthus have long been used in the treatment of a broad spectrum of diseases. They exhibited antiproliferative activity against various human cancer cell lines. Breast cancer is the most diagnosed cancer and a leading cause of cancer death among women. Doxorubicin (DOX) is an anticancer agent used to treat breast cancer despite its significant cardiotoxicity along with resistance development. Therefore, this study was designed to assess the potential cytotoxicity of P. niruri extracts (and fractions) alone and in combination with DOX against naïve (MCF-7) and doxorubicin-resistant breast cancer cell lines (MCF-7ADR). The methylene chloride fraction (CH2Cl2) showed the most cytotoxic activity among all tested fractions. Interestingly, the CH2Cl2-fraction was more cytotoxic against MCF-7ADR than MCF-7 at 100 µg/mL. At sub-cytotoxic concentrations, this fraction enhanced the cytotoxic effect of DOX against the both cell lines under investigation (IC50 values of 0.054 µg/mL and 0.14 µg/mL vs. 0.2 µg/mL for DOX alone against MCF-7) and (1.2 µg/mL and 0.23 µg/mL vs. 9.9 µg/mL for DOX alone against MCF-7ADR), respectively. Further, TLC fractionation showed that B2 subfraction in equitoxic combination with DOX exerted a powerful synergism (IC50 values of 0.03 µg/mL vs. 9.9 µg/mL for DOX alone) within MCF-7ADR. Untargeted metabolite profiling of the crude methanolic extract (MeOH) and CH2Cl2 fraction exhibiting potential cytotoxicity was conducted using liquid chromatography diode array detector-quadrupole time-of-flight mass spectrometry (LC-DAD-QTOF). Further studies are needed to separate the active compounds from the CH2Cl2 fraction and elucidate their mechanism(s) of action.
DeepAction: a MATLAB toolbox for automated classification of animal behavior in video
Authors: Harris Carl , Finn Kelly R. , Kieseler Marie-Luise , Maechler Marvin R. , Tse Peter U.
Published: February 2023

The identification of animal behavior in video is a critical but time-consuming task in many areas of research. Here, we introduce DeepAction, a deep learning-based toolbox for automatically annotating animal behavior in video. Our approach uses features extracted from raw video frames by a pretrained convolutional neural network to train a recurrent neural network classifier. We evaluate the classifier on two benchmark rodent datasets and one octopus dataset. We show that it achieves high accuracy, requires little training data, and surpasses both human agreement and most comparable existing methods. We also create a confidence score for classifier output, and show that our method provides an accurate estimate of classifier performance and reduces the time required by human annotators to review and correct automatically-produced annotations. We release our system and accompanying annotation interface as an open-source MATLAB toolbox.
Large network community detection by fast label propagation
Authors: Traag Vincent A. , Šubelj Lovro
Published: February 2023

Many networks exhibit some community structure. There exists a wide variety of approaches to detect communities in networks, each offering different interpretations and associated algorithms. For large networks, there is the additional requirement of speed. In this context, the so-called label propagation algorithm (LPA) was proposed, which runs in near-linear time. In partitions uncovered by LPA, each node is ensured to have most links to its assigned community. We here propose a fast variant of LPA (FLPA) that is based on processing a queue of nodes whose neighbourhood recently changed. We test FLPA exhaustively on benchmark networks and empirical networks, finding that it can run up to 700 times faster than LPA. In partitions found by FLPA, we prove that each node is again guaranteed to have most links to its assigned community. Our results show that FLPA is generally preferable to LPA.
Association of glaucoma and lifestyle with incident cardiovascular disease: a longitudinal prospective study from UK Biobank
Authors: Choi Jin A , Lee Su-Nam , Jung Sang-Hyuk , Won Hong-Hee , Yun Jae-Seung
Published: February 2023

The shared pathophysiological features of the cerebrovascular disease (CVD) and glaucoma suggest an association between the two diseases. Using the prospective UK Biobank cohort, we examined the associations between glaucoma and incident CVD and assessed the extent to which a healthy lifestyle reduced the CVD risk in subjects with glaucoma, using a scoring system consisting of four factors: current smoking, obesity, regular physical activity, and a healthy diet. During a mean follow-up time of 8.9 years, 22,649 (4.9%) incident CVD cases were documented. Multivariable Cox regression analyses revealed that subjects with glaucoma were significantly more likely to exhibit incident CVD (hazard ratio [HR]:1.19, 95% confidence interval [CI] 1.03–1.37; p = 0.016) than controls. In the further subgroup analyses, glaucoma increased incident CVD risk both in the young (40–55 years) and the old (56–70 years) and in both sexes, with higher risk in the young (HR: 1.33, CI 1.02–1.74) and female subjects (HR: 1.32, CI 1.14–1.52). When we analyze the associations between glaucoma and incident CVD by lifestyle factors, the highest absolute risks were observed in individuals with both glaucoma and an unhealthy lifestyle (HR: 2.66, CI 2.22–3.19). In conclusion, glaucoma was an independent risk factor for incident CVD. A healthy lifestyle was associated with a substantially lower risk for CVD incidence among adults with glaucoma.
A hyperaldosteronism subtypes predictive model using ensemble learning
Authors: Karashima Shigehiro , Kawakami Masaki , Nambo Hidetaka , Kometani Mitsuhiro , Kurihara Isao , Ichijo Takamasa , Katabami Takuyuki , Tsuiki Mika , Wada Norio , Oki Kenji , Ogawa Yoshihiro , Okamoto Ryuji , Tamura Kouichi , Inagaki Nobuya , Yoshimoto Takanobu , Kobayashi Hiroki , Kakutani Miki , Fujita Megumi , Izawa Shoichiro , Suwa Tetsuya , Kamemura Kohei , Yamada Masanobu , Tanabe Akiyo , Naruse Mitsuhide , Yoneda Takashi ,   JPAS/JRAS Study Group, Karashima Shigehiro , Kometani Mitsuhiro , Kurihara Isao , Ichijo Takamasa , Katabami Takuyuki , Tsuiki Mika , Wada Norio , Oki Kenji , Ogawa Yoshihiro , Okamoto Ryuji , Tamura Kouichi , Inagaki Nobuya , Yoshimoto Takanobu , Kobayashi Hiroki , Kakutani Miki , Fujita Megumi , Izawa Shoichiro , Suwa Tetsuya , Kamemura Kohei , Yamada Masanobu , Tanabe Akiyo , Naruse Mitsuhide , Yoneda Takashi , Ito Hiroshi , Takeda Yoshiyu , Rakugi Hiromi , Yamamoto Koichi , Soma Masayoshi , Yanase Toshihiko , Fukuda Hisashi , Hashimoto Shigeatsu , Ohno Yuichi , Takahashi Katsutoshi , Shibata Hirotaka , Fujii Yuichi , Suzuki Tomoko , Ogo Atsushi , Sakamoto Ryuichi , Kai Tatsuya , Fukuoka Tomikazu , Miyauchi Shozo
Published: February 2023

This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.
Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
Authors: Mayer Brian P. , Kennedy Daniel J. , Lau Edmond Y. , Valdez Carlos A.
Published: February 2023

Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (Ka ~ 100–200 M-1) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of Ka = 66,500 M−1, the largest value reported for such an inclusion complex to date. One dimensional 1H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.
Nasopharyngeal SARS-CoV-2 may not be dispersed by a high-flow nasal cannula
Authors: Suzuki Tetsuya , Morioka Shinichiro , Yamamoto Kei , Saito Sho , Iida Shun , Teruya Katsuji , Takasaki Jin , Hojo Masayuki , Hayakawa Kayoko , Kutsuna Satoshi , Miyamoto Sho , Ozono Seiya , Suzuki Tadaki , Kodama Eiichi N. , Ohmagari Norio
Published: February 2023

A high-flow nasal cannula (HFNC) therapy plays a significant role in providing respiratory support to critically ill patients with coronavirus disease 2019 (COVID-19); however, the dispersion of the virus owing to aerosol generation is a matter of concern. This study aimed to evaluate if HFNC disperses the virus into the air. Among patients with COVID-19 admitted to private rooms with controlled negative pressure, we enrolled those admitted within 10 days of onset and requiring oxygenation through a conventional nasal cannula or HFNC therapy. Of the 17 patients enrolled, we obtained 22 samples (11 in the conventional nasal cannula group and 11 in the HFNC group). Viral RNA was detected in 20 nasopharyngeal swabs, and viable viruses were isolated from three nasopharyngeal swabs. Neither viral RNA nor viable virus was detected in the air sample at 0.5 m regardless of the oxygen-supplementation device. We detected viral RNA in two samples in the conventional nasal cannula group but not in the HFNC therapy group in gelatin filters located 3 m from the patient and the surface of the ventilation. This study directly demonstrated that despite viral RNA detection in the nasopharynx, viruses may not be dispersed by HFNC therapy. This warrants further research to determine if similar results can be obtained under different conditions.
The importance of temporal-fine structure to perceive time-compressed speech with and without the restoration of the syllabic rhythm
Authors: Gransier Robin , Peeters Sara , Wouters Jan
Published: February 2023

Intelligibility of time-compressed (TC) speech decreases with increasing speech rate. However, intelligibility can be restored by ‘repackaging’ the TC speech by inserting silences between the syllables so that the original ‘rhythm’ is restored. Although restoration of the speech rhythm affects solely the temporal envelope, it is unclear to which extent repackaging also affects the perception of the temporal-fine structure (TFS). Here we investigate to which extent TFS contributes to the perception of TC and repackaged TC speech in quiet. Intelligibility of TC sentences with a speech rate of 15.6 syllables per second (sps) and the repackaged sentences, by adding 100 ms of silence between the syllables of the TC speech (i.e., a speech rate of 6.1 sps), was assessed for three TFS conditions: the original TFS and the TFS conveyed by an 8- and 16-channel noise vocoder. An overall positive effect on intelligibility of both the repackaging process and of the amount of TFS available to the listener was observed. Furthermore, the benefit associated with the repackaging TC speech depended on the amount of TFS available. The results show TFS contributes significantly to the perception of fast speech even when the overall rhythm/envelope of TC speech is restored.
Investigation of SAMD1 ablation in mice
Authors: Campbell Bruce , Weber Lisa M. , Engle Sandra J. , Ozolinš Terence R. S. , Bourassa Patricia , Aiello Robert , Liefke Robert
Published: February 2023

SAM domain-containing protein 1 (SAMD1) has been implicated in atherosclerosis, as well as in chromatin and transcriptional regulation, suggesting a versatile and complex biological function. However, its role at an organismal level is currently unknown. Here, we generated SAMD1−/− and SAMD1+/− mice to explore the role of SAMD1 during mouse embryogenesis. Homozygous loss of SAMD1 was embryonic lethal, with no living animals seen after embryonic day 18.5. At embryonic day 14.5, organs were degrading and/or incompletely developed, and no functional blood vessels were observed, suggesting failed blood vessel maturation. Sparse red blood cells were scattered and pooled, primarily near the embryo surface. Some embryos had malformed heads and brains at embryonic day 15.5. In vitro, SAMD1 absence impaired neuronal differentiation processes. Heterozygous SAMD1 knockout mice underwent normal embryogenesis and were born alive. Postnatal genotyping showed a reduced ability of these mice to thrive, possibly due to altered steroidogenesis. In summary, the characterization of SAMD1 knockout mice suggests a critical role of SAMD1 during developmental processes in multiple organs and tissues.