Dictys: dynamic gene regulatory network dissects developmental continuum with single-cell multiomics.

Gene regulatory networks (GRNs) are key determinants of cell function and identity and are dynamically rewired during development and disease. Despite decades of advancement, challenges remain in GRN inference, including dynamic rewiring, causal inference, feedback loop modeling and context specificity. To address these challenges, we develop Dictys, a dynamic GRN inference and analysis method that leverages multiomic single-cell assays of chromatin accessibility and gene expression, context-specific transcription factor footprinting, stochastic process network and efficient probabilistic modeling of single-cell RNA-sequencing read counts. Dictys improves GRN reconstruction accuracy and reproducibility and enables the inference and comparative analysis of context-specific and dynamic GRNs across developmental contexts. Dictys' network analyses recover unique insights in human blood and mouse skin development with cell-type-specific and dynamic GRNs. Its dynamic network visualizations enable time-resolved discovery and investigation of developmental driver transcription factors and their regulated targets. Dictys is available as a free, open-source and user-friendly Python package.

Hundred-Fold Enhancement in the Anomalous Hall Effect Induced by Hydrogenation.

The anomalous Hall effect (AHE) is one of the most fascinating transport properties in condensed matter physics. However, the AHE magnitude, which mainly depends on net spin polarization and band topology, is generally small in oxides and thus limits potential applications. Here, we demonstrate a giant enhancement of AHE in a LaCoO3-induced 5d itinerant ferromagnet SrIrO3 by hydrogenation. The anomalous Hall resistivity and anomalous Hall angle, which are two of the most critical parameters in AHE-based devices, are found to increase to 62.2 µΩ·cm and 3%, respectively, showing an unprecedentedly large enhancement ratio of ∼10000%. Theoretical analysis suggests the key roles of Berry curvature in enhancing AHE. Furthermore, the hydrogenation concomitantly induces the significant elevation of Curie temperature from 75 to 160 K and 40-fold reinforcement of coercivity. Such giant regulation and very large AHE magnitude observed in SrIrO3 could pave the path for 5d oxide devices.

Integrative bioinformatics analysis to identify ferroptosis-related genes in non-obstructive azoospermia.

PURPOSE: The objective of this study was to discern ferroptosis-related genes (FRGs) linked to non-obstructive azoospermia and investigate the associated molecular mechanisms. METHOD: A dataset related to azoospermia was retrieved from the Gene Expression Omnibus database, and FRGs were sourced from GeneCards. Ferroptosis-related differentially expressed genes (FRDEGs) were discerned. Subsequently, these genes underwent analyses encompassing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, as well as protein-protein interaction (PPI) networks and assessments of functional similarity. Following the identification of hub genes, an exploration of immune infiltration, single-cell expression, diagnostic utility, and interactions involving hub genes, RNA-binding proteins (RBPs), transcription factors (TFs), microRNAs (miRNAs), and drugs was conducted. RESULTS: A total of 35 differentially expressed FRGs were discerned. These genes demonstrated enrichment in functions and pathways associated with ferroptosis. From the PPI network, eight hub genes were selected. Functional similarity analysis highlighted the potential pivotal roles of HMOX1 and GPX4 in azoospermia. Analysis of immune cell infiltration indicated a significant decrease in activated dendritic cells in the azoospermia group, with notable correlations between hub genes, particularly SAT1 and HMGCR, and immune cell infiltration. Unique expression patterns of hub genes across various cell types in the human testis were observed, with GPX4 prominently enriched in spermatid/sperm. Eight hub genes exhibited robust diagnostic value (AUC > 0.75). Lastly, a comprehensive hub gene-miRNA-TF-RBP-drug network was constructed. CONCLUSION: In summary, our investigation unveiled eight FRDEGs associated with azoospermia, which hold potential as biomarkers for the diagnosis and treatment of azoospermia.

The coevolution of bullying and friendship networks.

The coevolution of bullying and friendship networks and the moderating effects of classroom bullying popularity norms were examined in a sample of 965 students (52.1% boys) in 22 fourth- and fifth-grade classes. Longitudinal social network analysis showed that children were more likely to bully their friends' victims (bully influence effect) and to be bullied by their friends' bullies (victim influence effect); two children bullying the same child were likely to be friends (bully selection effect), and two victims bullied by the same child were likely to be friends (victim selection effect). Bullying popularity norms served as moderators, and the bully selection effect was significant weaker in the context of low bullying popularity norms. This study adds understanding of bullying as a group process and provides implications for preventing school bullying.

Graded nutritional interventions in patients with dysphagia after stroke: an assessment of the effectiveness of therapeutic strategies for different swallowing functions.

OBJECTIVE: To evaluate the efficacy of graded nutrition intervention strategy in improving patients with different degrees of impaired swallowing function after stroke. METHODS: According to the way of nursing, the patients were divided into two group. The main outcome measure was Kota swallowing index (WSI) score, and the secondary outcome was complications during the intervention. SF-36 scale was used to evaluate the improvement of quality of life before and intervention. RESULTS: The WSI score in the control group was 62.34 ± 10.23 at 1 week after treatment, 70.52 ± 13.45 at 6 weeks after treatment, and 80.48 ± 9.87 at 12 weeks after treatment, while that in the intervention group was 71.45 ± 9.68 at 1 week after treatment, 75.81 ± 11.78 at 6 weeks after treatment, and 84.12 ± 14.32 at 12 weeks after treatment. The WSI scores of the intervention group were significantly higher than those of the control group (t = 5.634, p < 0.001), suggesting better swallowing function of the patients The incidence of pulmonary infection, malnutrition and gastroesophageal reflux in the intervention group was significantly lower than that in the control group (p < 0.05). There was no significant difference in throat inflammation and dehydration between the two groups (p > 0.05). In addition, graded nutrition interventions significantly improved patients' quality of life, including dimensions of physical functioning, role physics, physical pain, and social functioning. CONCLUSION: Compared with conventional treatment, personalized graded nutrition intervention can significantly improve the swallowing function and reduce the pulmonary infection rate in patients with swallowing disorders after stroke.

Nodeless Superconductivity in Kagome Metal CsV3Sb5 with and without Time Reversal Symmetry Breaking.

The kagome metal CsV3Sb5 features an unusual competition between the charge-density-wave (CDW) order and superconductivity. Evidence for time reversal symmetry breaking (TRSB) inside the CDW phase has been accumulating. Hence, the superconductivity in CsV3Sb5 emerges from a TRSB normal state, potentially resulting in an exotic superconducting state. To reveal the pairing symmetry, we first investigate the effect of nonmagnetic impurity. Our results show that the superconducting critical temperature is insensitive to disorder, pointing to conventional s-wave superconductivity. Moreover, our measurements of the self-field critical current (Ic,sf), which is related to the London penetration depth, also confirm conventional s-wave superconductivity with strong coupling. Finally, we measure Ic,sf where the CDW order is removed by pressure and superconductivity emerges from the pristine normal state. Our results show that s-wave gap symmetry is retained, providing strong evidence for the presence of conventional s-wave superconductivity in CsV3Sb5 irrespective of the presence of the TRSB.

Scoliosis due to scar contracture caused by infection after cyst-peritoneal shunt: a case report and literature review.

BACKGROUND: Cyst-peritoneal (CP) shunt is one of the most common methods for the treatment of intracranial arachnoid cysts (ACs). Infection is a common postoperative complication. We report a patient with scoliosis due to scar contracture caused by infection after CP shunt. CASE DESCRIPTION: A 12-year-old boy underwent CP shunt surgery for the left frontoparietotemporal AC when he was 2 years old. At the age of 7 years, he underwent a shunt catheter removal procedure because of the infection caused by the fistula leading from the subcutaneous tunnel to the body surface. However, contracture of the subcutaneous scar from fistula infection caused scoliosis and limited range of motion of the right arm. At the age of 12, the patient received scar lysis and his symptoms improved. CONCLUSION: We presented the first case of scoliosis due to scar contracture caused by infection after CP shunt. In this case, timely release of scar tissue can effectively correct scoliosis and limb movement limitation.

Uniaxial Strain and Hydrostatic Pressure Engineering of the Hidden Magnetism in La1-xCaxMnO3 (0 ≤ x ≤ 1/2) Thin Films.

Here, using various substrates, we demonstrate that the in-plane uniaxial strain engineering can enhance the Jahn-Teller distortions and promote selective orbital occupancy to induce an emergent antiferromagnetic insulating (AFI) phase at x = 1/3 of La1-xCaxMnO3. Such an AFI phase depends not only on the magnitude of epitaxial strain but also on the symmetry of the substrates. Using the large uniaxial strain imparted by DyScO3(001) substrate, the AFI ground state is achieved in a wide range of doping levels (0 ≤ x ≤ 1/2), leaving an extended AFI phase diagram. Moreover, it is found that hydrostatic pressure can tune the AFI phase back to a hidden ferromagnetic metallic phase, accompanied by the formation of accommodation strain. The coaction of the accommodation strain, uniaxial strain, and hydrostatic pressure produces complex phase competition and evolution, and the result may shed light on phase space control of other functional perovskites with the competing magnetic interactions.

Up-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells.

Neoadjuvant chemoradiation (nCRT) followed by radical surgery is the preferred option for locally advanced colorectal cancer (CRC) treatment. However, chemo/radio-resistance remains a main obstacle in CRC therapy. In the study, we analyzed the mRNA expression profiling of CRC patients and revealed that the aberrant expression of fibronectin type III domain containing 1 (FNDC1) was associated with disease progression and poor prognosis in CRC. FNDC1 expression was consistently increased in multiple independent cohorts of CRC. Upregulated FNDC1 in pretreated primary tumor tissues predicted a poor response to nCRT, recurrence, and poor disease-free survival in nCRT-treated CRC patients. FNDC1 overexpression accelerated CRC cell survival on 5-FU or radiation treatment both in vitro and in vivo, whereas FNDC1 inhibition sensitized CRC cells to chemoradiation. In addition, FNDC1 accelerated stem cell-like properties of CRC cells. Furthermore, tumor tissues from non-responders exhibited higher activation of PI3K/Akt signaling than those from responders. FNDC1 depletion repressed 5-FU or irradiation-induced activation of PI3K/AKT in CRC cells. More importantly, pharmacological inhibition of PI3K/Akt signaling effectively decreased the effect of FNDC1 on chemoradiation resistance. Taken together, our study reveals the potential function of FNDC1 as a biomarker to predict nCRT sensitivity in CRC and a therapeutic target in CRC treatment.

Superconducting Sr2RuO4 Thin Films without Out-of-Phase Boundaries by Higher-Order Ruddlesden-Popper Intergrowth.

Ruddlesden-Popper (RP) phases (An+1BnO3n+1, n = 1, 2,···) have attracted intensive research with diverse functionalities for device applications. However, the realization of a high-quality RP-phase film is hindered by the formation of out-of-phase boundaries (OPBs) that occur at terrace edges, originating from lattice mismatch in the c-axis direction with the A'B'O3 (n = ∞) substrate. Here, using strontium ruthenate RP-phase Sr2RuO4 (n = 1) as a model system, an experimental approach for suppressing OPBs was developed. By tuning the growth parameters, the Sr3Ru2O7 (n = 2) phase was formed in a controlled manner near the film-substrate interface. This higher-order RP-phase then blocked the subsequent formation of OPBs, resulting in nearly defect-free Sr2RuO4 layer at the upper region of the film. Consequently, the Sr2RuO4 thin films exhibited superconductivity up to 1.15 K, which is the highest among Sr2RuO4 films grown by pulsed laser deposition. This work paves the way for synthesizing pristine RP-phase heterostructures and exploring their unique physical properties.

The Construction of Civil Scientific Literacy in China from the Perspective of Science Education.

On 25 June 2021, the State Council issued the new Outline of the National Action Scheme for Scientific Literacy for All Chinese Citizens (2020-2035) (Outline of Scientific Literacy). In order to provide reference for its implementation, this study analyzes the achievements and obstacles in the implementation of the old Outline of Scientific Literacy (2006-2010-2020) based on the results of all previous surveys on civic scientific literacy (CSL) in China and from the perspective of science education. The results showed a continued steady growth in CSL, from 1.6 in 2005 to 10.56% in 2020. Specifically, male, urban, and younger adults were more likely to qualify as possessing CSL. Moreover, education level was found to be positively related to CSL. The study also found that in China, the effectiveness of formal science education has been hampered by the long-term division of the arts and sciences, examination-oriented education, the urban-rural gap, and the aging population. In terms of informal education, 37.2% of Chinese citizens visited science museums in 2020, and the Internet plays an increasing important role. Nowadays, Chinese science popularization lacks interaction, with limited opportunities for public engagement. There are deficiencies in both the country's formal and informal science education, meaning that there is still much room for improvement in the promotion of CSL in China.

Controllable Thickness Inhomogeneity and Berry Curvature Engineering of Anomalous Hall Effect in SrRuO3 Ultrathin Films.

In quantum matters hosting electron-electron correlation and spin-orbit coupling, spatial inhomogeneities, arising from competing ground states, can be essential for understanding exotic topological properties. A prominent example is Hall anomalies observed in SrRuO3 films, which were interpreted in terms of either magnetic skyrmion-induced topological Hall effect or inhomogeneous anomalous Hall effect (AHE). To clarify this ambiguity, we systematically investigated the evolution of AHE with controllable inhomogeneities in SrRuO3 film thickness (tSRO). By exploiting the step-flow growth of SrRuO3 films, we induced a microscopically ordered stripe pattern with one-unit-cell differences in tSRO. The associated spatial distribution of momentum-space Berry curvatures enables a two-channel AHE with hump-like Hall anomalies, which can be continuously engineered according to non-integer tSRO. We further microscopically characterized the stripe-like ferromagnetic domains and two-step magnetic switching behavior in the inhomogeneous SrRuO3 film. These unique features can be utilized to identify the two-channel AHE model and understand its microscopic origin.

An Arabidopsis Oxalyl-CoA Decarboxylase, AtOXC, Is Important for Oxalate Catabolism in Plants.

Considering the widespread occurrence of oxalate in nature and its broad impact on a host of organisms, it is surprising that so little is known about the turnover of this important acid. In plants, oxalate oxidase is the most well-studied enzyme capable of degrading oxalate, but not all plants possess this activity. Recently, acyl-activating enzyme 3 (AAE3), encoding an oxalyl-CoA synthetase, was identified in Arabidopsis. This enzyme has been proposed to catalyze the first step in an alternative pathway of oxalate degradation. Since this initial discovery, this enzyme and proposed pathway have been found to be important to other plants and yeast as well. In this study, we identify, in Arabidopsis, an oxalyl-CoA decarboxylase (AtOXC) that is capable of catalyzing the second step in this proposed pathway of oxalate catabolism. This enzyme breaks down oxalyl-CoA, the product of AtAAE3, into formyl-CoA and CO2. AtOXC:GFP localization suggested that this enzyme functions within the cytosol of the cell. An Atoxc knock-down mutant showed a reduction in the ability to degrade oxalate into CO2. This reduction in AtOXC activity resulted in an increase in the accumulation of oxalate and the enzyme substrate, oxalyl-CoA. Size exclusion studies suggest that the enzyme functions as a dimer. Computer modeling of the AtOXC enzyme structure identified amino acids of predicted importance in co-factor binding and catalysis. Overall, these results suggest that AtOXC catalyzes the second step in this alternative pathway of oxalate catabolism.

Ferroelectrically tunable magnetic skyrmions in ultrathin oxide heterostructures.

Magnetic skyrmions are topologically protected whirling spin texture. Their nanoscale dimensions, topologically protected stability and solitonic nature, together are promising for future spintronics applications. To translate these compelling features into practical spintronic devices, a key challenge lies in achieving effective control of skyrmion properties, such as size, density and thermodynamic stability. Here, we report the discovery of ferroelectrically tunable skyrmions in ultrathin BaTiO3/SrRuO3 bilayer heterostructures. The ferroelectric proximity effect at the BaTiO3/SrRuO3 heterointerface triggers a sizeable Dzyaloshinskii-Moriya interaction, thus stabilizing robust skyrmions with diameters less than a hundred nanometres. Moreover, by manipulating the ferroelectric polarization of the BaTiO3 layer, we achieve local, switchable and nonvolatile control of both skyrmion density and thermodynamic stability. This ferroelectrically tunable skyrmion system can simultaneously enhance the integratability and addressability of skyrmion-based functional devices.

Efficient and accurate causal inference with hidden confounders from genome-transcriptome variation data.

Mapping gene expression as a quantitative trait using whole genome-sequencing and transcriptome analysis allows to discover the functional consequences of genetic variation. We developed a novel method and ultra-fast software Findr for higly accurate causal inference between gene expression traits using cis-regulatory DNA variations as causal anchors, which improves current methods by taking into consideration hidden confounders and weak regulations. Findr outperformed existing methods on the DREAM5 Systems Genetics challenge and on the prediction of microRNA and transcription factor targets in human lymphoblastoid cells, while being nearly a million times faster. Findr is publicly available at https://github.com/lingfeiwang/findr.

Causal Transcription Regulatory Network Inference Using Enhancer Activity as a Causal Anchor.

Transcription control plays a crucial role in establishing a unique gene expression signature for each of the hundreds of mammalian cell types. Though gene expression data have been widely used to infer cellular regulatory networks, existing methods mainly infer correlations rather than causality. We developed statistical models and likelihood-ratio tests to infer causal gene regulatory networks using enhancer RNA (eRNA) expression information as a causal anchor and applied the framework to eRNA and transcript expression data from the FANTOM Consortium. Predicted causal targets of transcription factors (TFs) in mouse embryonic stem cells, macrophages and erythroblastic leukaemia overlapped significantly with experimentally-validated targets from ChIP-seq and perturbation data. We further improved the model by taking into account that some TFs might act in a quantitative, dosage-dependent manner, whereas others might act predominantly in a binary on/off fashion. We predicted TF targets from concerted variation of eRNA and TF and target promoter expression levels within a single cell type, as well as across multiple cell types. Importantly, TFs with high-confidence predictions were largely different between these two analyses, demonstrating that variability within a cell type is highly relevant for target prediction of cell type-specific factors. Finally, we generated a compendium of high-confidence TF targets across diverse human cell and tissue types.

Ferroelectric BiFeO3 as an Oxide Dye in Highly Tunable Mesoporous All-Oxide Photovoltaic Heterojunctions.

As potential photovoltaic materials, transition-metal oxides such as BiFeO3 (BFO) are capable of absorbing a substantial portion of solar light and incorporating ferroic orders into solar cells with enhanced performance. But the photovoltaic application of BFO has been hindered by low energy-conversion efficiency due to poor carrier transport and collection. In this work, a new approach of utilizing BFO as a light-absorbing sensitizer is developed to interface with charge-transporting TiO2 nanoparticles. This mesoporous all-oxide architecture, similar to that of dye-sensitized solar cells, can effectively facilitate the extraction of photocarriers. Under the standard AM1.5 (100 mW cm-2 ) irradiation, the optimized cell shows an open-circuit voltage of 0.67 V, which can be enhanced to 1.0 V by tailoring the bias history. A fill factor of 55% is achieved, which is much higher than those in previous reports on BFO-based photovoltaic devices. The results provide here a new viable approach toward developing highly tunable and stable photovoltaic devices based on ferroelectric transition-metal oxides.

Overcoming the Fundamental Barrier Thickness Limits of Ferroelectric Tunnel Junctions through BaTiO3/SrTiO3 Composite Barriers.

Ferroelectric tunnel junctions (FTJs) have attracted increasing research interest as a promising candidate for nonvolatile memories. Recently, significant enhancements of tunneling electroresistance (TER) have been realized through modifications of electrode materials. However, direct control of the FTJ performance through modifying the tunneling barrier has not been adequately explored. Here, adding a new direction to FTJ research, we fabricated FTJs with BaTiO3 single barriers (SB-FTJs) and BaTiO3/SrTiO3 composite barriers (CB-FTJs) and reported a systematic study of FTJ performances by varying the barrier thicknesses and compositions. For the SB-FTJs, the TER is limited by pronounced leakage current for ultrathin barriers and extremely small tunneling current for thick barriers. For the CB-FTJs, the extra SrTiO3 barrier provides an additional degree of freedom to modulate the barrier potential and tunneling behavior. The resultant high tunability can be utilized to overcome the barrier thickness limits and enhance the overall CB-FTJ performances beyond those of SB-FTJ. Our results reveal a new paradigm to manipulate the FTJs through designing multilayer tunneling barriers with hybrid functionalities.

A bispecific anti-ErbB2 antibody potently induces ErbB2 internalization and suppresses ErbB2-overexpressing tumor growth.

The anti-ErbB2 humanized antibody trastuzumab was approved for ErbB2-positive metastatic gastric and gastro-esophageal junction cancer in 2010. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2-targeting therapy. Down-regulation of surface receptors induced by monoclonal antibody (mAb) contributes to its antitumor efficacy. Previous studies have demonstrated that if two anti-ErbB2 mAbs did not compete with each other for binding to ErbB2, the combination of them can enhance ErbB2 internalization. In the present study, we investigated ErbB2 internalization-inducing ability of non-competitive anti-ErbB2 mAb combinations and surprisingly found that most of the mAb combinations tested did not down-regulate ErbB2. Only 4 of 18 non-competitive mAb pairs efficiently induced ErbB2 internalization. Interestingly, although the non-competitive anti-ErbB2 mAbs trastuzumab and pertuzumab, either alone or in combination, were ineffective at inducing ErbB2 internalization, TPL, a bispecific antibody engineered from trastuzumab and pertuzumab, potently down-regulated the ErbB2 molecule. Importantly, TPL exhibited a far greater antitumor effect on ErbB2-overexpressing gastric cancer cell line than trastuzumab plus pertuzumab, suggesting that it may be a promising agent for the treatment of gastric cancer.

Combined SRC inhibitor saracatinib and anti-ErbB2 antibody H2-18 produces a synergistic antitumor effect on trastuzumab-resistant breast cancer.

Despite of the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, trastuzumab resistance emerges as a major and common clinical problem. Thus, circumventing trastuzumab resistance has become an urgent need. Recently, Src inhibitor saracatinib has drawn great attention for its key role in trastuzumab response. As shown in our previous study, H2-18, an anti-ErbB2 antibody, could potently induce programmed cell death (PCD) in trastuzumab-resistant breast cancer cells. Here we combined H2-18 and a Src inhibitor, saracatinib, and studied the antitumor activity of this drug combination in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and saracatinib could synergistically inhibit cell proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cell lines in vitro. H2-18 plus saracatinib could also inhibit the HCC-1954 tumor growth more effectively in vivo than each drug alone. H2-18 plus saracatinib showed a significantly more potent PCD-inducing activity compared with either H2-18 or saracatinib alone. We conclude that enhanced PCD may contribute to the superior antitumor efficacy of this combination therapy. The combination of H2-18 and SRC inhibitor has the potential to be translated into clinic.