Historic dog furs unravel the origin and artificial selection of modern Nordic Lapphund and Elkhound dog breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100-200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

Cannabidiol mitigates radiation-induced intestine ferroptosis via facilitating the heterodimerization of RUNX3 with CBFß thereby promoting transactivation of GPX4.

Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor ß (CBFß) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.

Machine learning-based algorithm identifies key mitochondria-related genes in non-alcoholic steatohepatitis.

BACKGROUND: Evidence suggests that hepatocyte mitochondrial dysfunction leads to abnormal lipid metabolism, redox imbalance, and programmed cell death, driving the onset and progression of non-alcoholic steatohepatitis (NASH). Identifying hub mitochondrial genes linked to NASH may unveil potential therapeutic targets. METHODS: Mitochondrial hub genes implicated in NASH were identified via analysis using 134 algorithms. RESULTS: The Random Forest algorithm (RF), the most effective among the 134 algorithms, identified three genes: Aldo-keto reductase family 1 member B10 (AKR1B10), thymidylate synthase (TYMS), and triggering receptor expressed in myeloid cell 2 (TREM2). They were upregulated and positively associated with genes promoting inflammation, genes involved in lipid synthesis, fibrosis, and nonalcoholic steatohepatitis activity scores in patients with NASH. Moreover, using these three genes, patients with NASH were accurately categorized into cluster 1, exhibiting heightened disease severity, and cluster 2, distinguished by milder disease activity. CONCLUSION: These three genes are pivotal mitochondrial genes implicated in NASH progression.

Comparing the efficacy of 308-nm light-emitting diode and 308-nm excimer lamp for treating vitiligo: A randomized controlled trial.

BACKGROUND: In previous studies, the 308-nm light-emitting diode (LED) has been proven safe and effective for treating vitiligo. However, direct comparisons between the 308-nm LED and 308-nm excimer lamp (308-nm MEL) for the treatment of vitiligo are lacking. OBJECTIVE: To compare the efficacy of the 308-nm LED and 308-nm MEL for treating nonsegmental stable vitiligo. PATIENTS AND METHODS: This randomized controlled trial was conducted between January 2018 and August 2023. Enrolled patients were randomly assigned to either the 308-nm LED or the 308-nm MEL groups, both receiving 16 treatment sessions. Adverse events that occurred during the treatment were documented. RESULTS: In total, 269 stable vitiligo patches from 174 patients completed the study. A total of 131 lesions were included in the 308-nm LED group, and 138 lesions were included in the 308-nm MEL group. After 16 treatment sessions, 38.17% of the vitiligo patches in the 308-nm LED group achieved repigmentation of at least 50% versus 38.41% in the 308-nm MEL group. The two devices exhibited similar results in terms of efficacy for a repigmentation of at least 50% (p = .968). The incidence of adverse effects with the two phototherapy devices was comparable (p = .522). CONCLUSIONS: Treatment of vitiligo with the 308-nm LED had a similar efficacy rate to the 308-nm MEL, and the incidence of adverse effects was comparable between the two devices.

Microwave-assisted synthesis of highly sulfated mannuronate glycans as potential inhibitors against SARS-CoV-2.

Algae-based marine carbohydrate drugs are typically decorated with negative ion groups such as carboxylate and sulfate groups. However, the precise synthesis of highly sulfated alginates is challenging, thus impeding their structure-activity relationship studies. Herein we achieve a microwave-assisted synthesis of a range of highly sulfated mannuronate glycans with up to 17 sulfation sites by overcoming the incomplete sulfation due to the electrostatic repulsion of crowded polyanionic groups. Although the partially sulfated tetrasaccharide had the highest affinity for the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, the fully sulfated octasaccharide showed the most potent interference with the binding of the RBD to angiotensin-converting enzyme 2 (ACE2) and Vero E6 cells, indicating that the sulfated oligosaccharides might inhibit the RBD binding to ACE2 in a length-dependent manner.

Acid-Triggered Degradation of Three-In-One Ag2S Quantum Dots for In Situ Ratiometric NIR-II Fluorescence Imaging-Guided Ion/Gas Combination Therapy.

Smart theranostic nanoprobes with the integration of multiple therapeutic modalities are preferred for precise diagnosis and efficient therapy of tumors. However, it remains a big challenge to arrange the imaging and two or more kinds of therapeutic agents without weakening the intended performances. In addition, most existing fluorescence (FL) imaging agents suffer from low spatiotemporal resolution due to the short emission wavelength (<900 nm). Here, novel three-in-one Ag2S quantum dot (QD)-based smart theranostic nanoprobes were proposed for in situ ratiometric NIR-II FL imaging-guided ion/gas combination therapy of tumors. Under the acidic tumor microenvironment, three-in-one Ag2S QDs underwent destructive degradation, generating toxic Ag+ and H2S. Meanwhile, their FL emission at 1270 nm was weakened. Upon introduction of a downconversion nanoparticle (DCNP) as the delivery carrier and NIR-II FL reference signal unit, the formed Ag2S QD-based theranostic nanoprobes could achieve precise diagnosis of tumors through ratiometric NIR-II FL signals. Also, the generated Ag+ and H2S enabled specific ion/gas combination therapy toward tumors. By combining the imaging and therapeutic functions, three-in-one Ag2S QDs may open a simple yet reliable avenue to design theranostic nanoprobes.

Doping Engineering To Modulate Surface Plasmon Resonance and Enzyme-like Activities for Enhancing Photoacoustic Imaging-Guided Targeted Cancer Therapy in the Second Near-Infrared Window.

Biological imaging-guided targeted tumor therapy has been a soughtafter goal in the field of cancer diagnosis and treatment. To this end, we proposed a strategy to modulate surface plasmon resonance and endow WO3-x nanoparticles (NPs) with enzyme-like catalytic properties by doping Fe2+ in the structure of the NPs. Doping of the Fe2+ introduced oxygen vacancies into the structure of the NPs, inducing a red shift of the maximum absorption wavelength into the near-infrared II (NIR-II) region and enhancing the photoacoustic (PA) and photothermal properties of the NPs for more effective imaging-guided cancer therapy. Under NIR-II laser irradiation, the Fe-WO3-x NPs produced very strong NIR-II PA and photothermal effects, which significantly enhanced the PA imaging and photothermal treatment effects. On the other hand, Fe2+ in Fe-WO3-x could undergo Fenton reactions with H2O2 in the tumor tissue to generate ·OH for chemodynamic therapy. In addition, Fe-WO3-x can also catalyze the above reactions to produce more reactive oxygen species (ROS) and induce the oxidation of NADH to interfere with intracellular adenosine triphosphate (ATP) synthesis, thereby further improving the efficiency of cancer therapy. Specific imaging of tumor tissue and targeted synergistic therapy was achieved after ligation of a MUC1 aptamer to the surface of the Fe-WO3-x NPs by the complexing of -COOH in MUC1 with tungsten ions on the surface of the NPs. These results demonstrated that Fe-WO3-x NPs could be a promising diagnosis and therapeutic agent for cancer. Such a study opens up new avenues into the rational design of nanodiagnosis and treatment agents for NIR-II PA imaging and cancer therapy.

Resveratrol Inhibits Colorectal Cancer Cell Tumor Property by Activating the miR-769-5p/MSI1 Pathway.

Resveratrol exhibits inhibitory effects on the progression of various cancers including colorectal cancer (CRC), however, the underlying mechanism in regulating CRC development remains elusive. The present study aims to uncover the role and molecular mechanism of resveratrol in modulating CRC cell tumor properties. NCM460 cells, LoVo cells, SW480 cells, and BALB/c nude mice were utilized in this study. RNA levels of miR-769-5p and musashi RNA-binding protein 1 (MSI1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was assessed by western blotting or immunohistochemistry assay. Cell viability was analyzed by CCK-8 assay, while cell proliferation and apoptosis were evaluated by 5-Ethynyl-2'-deoxyuridine assay and flow cytometry analysis. Cell migration was investigated by transwell and wound-healing assays. The association between miR-769-5p and MSI1 was identified by a dual-luciferase reporter assay. Tumor formation was analyzed using a xenograft mouse model assay. Compared to control groups, miR-769-5p expression was downregulated, while MSI1 expression was upregulated in CRC tissues and cells. Resveratrol treatment led to increased miR-769-5p expression and decreased MSI1 expression in CRC cells. Resveratrol treatment or miR-769-5p upregulation inhibited CRC cell proliferation and migration, and induced apoptosis. These effects were enhanced after combined treatment with resveratrol and miR-769-5p mimics. MSI1 was identified as a target of miR-769-5p, and its overexpression attenuated the effects of miR-769-5p mimics on cell proliferation, migration, and apoptosis. Moreover, miR-769-5p overexpression enhanced the inhibitory effects of resveratrol on tumor growth in vivo. Resveratrol inhibited colorectal cancer cell tumor properties by activating the miR-769-5p/MSI1 pathway.

Spatial-temporal Bayesian accelerated failure time models for survival endpoints with applications to prostate cancer registry data.

Prostate cancer is the most common cancer after non-melanoma skin cancer and the second leading cause of cancer deaths in US men. Its incidence and mortality rates vary substantially across geographical regions and over time, with large disparities by race, geographic regions (i.e., Appalachia), among others. The widely used Cox proportional hazards model is usually not applicable in such scenarios owing to the violation of the proportional hazards assumption. In this paper, we fit Bayesian accelerated failure time models for the analysis of prostate cancer survival and take dependent spatial structures and temporal information into account by incorporating random effects with multivariate conditional autoregressive priors. In particular, we relax the proportional hazards assumption, consider flexible frailty structures in space and time, and also explore strategies for handling the temporal variable. The parameter estimation and inference are based on a Monte Carlo Markov chain technique under a Bayesian framework. The deviance information criterion is used to check goodness of fit and to select the best candidate model. Extensive simulations are performed to examine and compare the performances of models in different contexts. Finally, we illustrate our approach by using the 2004-2014 Pennsylvania Prostate Cancer Registry data to explore spatial-temporal heterogeneity in overall survival and identify significant risk factors.

A uniform step size, low-voltage piezoelectric motor with dual-channel force loop.

Recently, a variety of piezoelectric motors with remarkable performance have appeared. However, due to the hysteresis effect of piezoelectrics and stress return errors within the mechanical structures, the existing piezoelectric motors still face some challenges, such as inconsistent step size, high working voltage, and considerable speed variances during upward vs downward movements even under identical driving voltage signals. Here, we introduce a novel low-voltage piezoelectric motor with a dual-channel force loop based on piezoelectric stacks, in which each slider has two force loops connected with other sliders and the internal elastic preload element is installed, which can effectively address these issues. This new type of piezoelectric motor has low working voltage (starting voltage is only 0.8 V, significantly lower than that of conventional piezoelectric motors), large driving force, uniform step size, and excellent linearity.

Improving the sensing sensitivity of silver nanoparticle-based colorimetric biosensors from the point of salt.

The sensing sensitivity was improved for silver nanoparticles (AgNPs)-based colorimetric biosensors by using the most suitable salt to induce AgNPs aggregation. As for the salt composed of low-affinity anion and monovalent cation, the cation-dependent charge screening effect was the driving force for AgNPs aggregation. Apart from the charge screening effect, both the bridging of multivalent cation to the surface ligand of AgNP and the interaction between anion and Ag contributed to inducing AgNPs aggregation. Considering the higher aggregation efficiency of AgNPs resulted in a narrower sensing range, salt composed of low-affinity anion and monovalent cation was recommended for AgNPs-based colorimetric analysis, which was confirmed by fourfold higher sensitivity of DNA-21 detection using NaF than NaCl. This work inspires further thinking on improving the sensing performance of metal nanomaterials-based sensors from the point of colloidal surface science.

Polycomb protein binding and looping in the ON transcriptional state.

Polycomb group (PcG) proteins mediate epigenetic silencing of important developmental genes by modifying histones and compacting chromatin through two major protein complexes, PRC1 and PRC2. These complexes are recruited to DNA by CpG islands (CGIs) in mammals and Polycomb response elements (PREs) in Drosophila. When PcG target genes are turned OFF, PcG proteins bind to PREs or CGIs, and PREs serve as anchors that loop together and stabilize gene silencing. Here, we address which PcG proteins bind to PREs and whether PREs mediate looping when their targets are in the ON transcriptional state. While the binding of most PcG proteins decreases at PREs in the ON state, one PRC1 component, Ph, remains bound. Further, PREs can loop to each other and with presumptive enhancers in the ON state and, like CGIs, may act as tethering elements between promoters and enhancers. Overall, our data suggest that PREs are important looping elements for developmental loci in both the ON and OFF states.

Microstructure and Mechanical Properties of IN690 Ni-Based Alloy/316LN Stainless-Steel Dissimilar Ring Joint Welded by Inertia Friction Welding.

Inertia friction welding (IFW) was used to join large-diameter hollow bars made of Inconel 690 and 316LN successfully. The interfacial characteristics, microstructure, mechanical properties and fracture mechanism of welded joints under different process parameters were investigated. The results indicated that a joining mechanism with mechanical interlocking and metallurgical bonding was found in IFW joints. There was a significant mechanical mixing zone at the welding interface. The elemental diffusion layer was found in the "wrinkles" of the mechanical mixing zone. A tiny quantity of C elements accumulated on the friction and secondary friction surfaces. The tensile strength and impact toughness of the joints increased with the total welding energy input. Increasing the friction pressure could make the grain in all parts of the joint uniformly refined, thus enhancing the mechanical properties of welded joints. The maximum tensile strength and impact toughness of the welded joint were 639 MPa and 146 J/cm2, reaching 94% and 68% of that for Inconel 690, respectively, when the flywheel was initially set at 760 rpm, 200 MPa for friction pressure, and 388 kg/m2 for rotary inertia. Due to the Kirkendall effect in the welded joint, superior metallurgical bonding was at the welding interface close to the Inconel 690 side compared to the 316LN side.

Exploiting synthetic biology platforms for enhanced biosynthesis of natural products in Yarrowia lipolytica.

With the rapid development of synthetic biology, researchers can design, modify, or even synthesize microorganisms de novo, and microorganisms endowed with unnatural functions can be considered "artificial life" and facilitate the development of functional products. Based on this concept, researchers can solve critical problems related to the insufficient supply of natural products, such as low yields, long production cycles, and cumbersome procedures. Due to its superior performance and unique physiological and biochemical characteristics, Yarrowia lipolytica is a favorable chassis cell used for green biomanufacturing by numerous researchers. This paper mainly reviews the development of synthetic biology techniques for Y. lipolytica and summarizes the recent research progress on the synthesis of natural products in Y. lipolytica. This review will promote the continued innovative development of Y. lipolytica by providing theoretical guidance for research on the biosynthesis of natural products.

De Novo Design of Spiro-Type Hole-Transporting Material: Anisotropic Regulation Toward Efficient and Stable Perovskite Solar Cells.

2,2',7,7'-Tetrakis(N,N-di-p-methoxyphenyl)-amine-9,9'-spirobifluorene (Spiro-OMeTAD) represents the state-of-the-art hole-transporting material (HTM) in n-i-p perovskite solar cells (PSCs). However, its susceptibility to stability issues has been a long-standing concern. In this study, we embark on a comprehensive exploration of the untapped potential within the family of spiro-type HTMs using an innovative anisotropic regulation strategy. Diverging from conventional approaches that can only modify spirobifluorene with single functional group, this approach allows us to independently tailor the two orthogonal components of the spiro-skeleton at the molecular level. The newly designed HTM, SF-MPA-MCz, features enhanced thermal stability, precise energy level alignment, superior film morphology, and optimized interfacial properties when compared to Spiro-OMeTAD, which contribute to a remarkable power conversion efficiency (PCE) of 24.53% for PSCs employing SF-MPA-MCz with substantially improved thermal stability and operational stability. Note that the optimal concentration for SF-MPA-MCz solution is only 30 mg/ml, significantly lower than Spiro-OMeTAD (>70 mg/ml), which could remarkably reduce the cost especially for large-area processing in future commercialization. This work presents a promising avenue for the versatile design of multifunctional HTMs, offering a blueprint for achieving efficient and stable PSCs.

Multi-path Fusion in SFCF-Net for Enhanced Multi-frequency Electrical Impedance Tomography.

Multi-frequency electrical impedance tomography (mfEIT) offers a nondestructive imaging technology that reconstructs the distribution of electrical characteristics within a subject based on the impedance spectral differences among biological tissues. However, the technology faces challenges in imaging multi-class lesion targets when the conductivity of background tissues is frequency-dependent. To address these issues, we propose a spatial-frequency cross-fusion network (SFCF-Net) imaging algorithm, built on a multi-path fusion structure. This algorithm uses multi-path structures and hyper-dense connections to capture both spatial and frequency correlations between multi-frequency conductivity images, which achieves differential imaging for lesion targets of multiple categories through cross-fusion of information. According to both simulation and physical experiment results, the proposed SFCF-Net algorithm shows an excellent performance in terms of lesion imaging and category discrimination compared to the weighted frequency-difference, U-Net, and MMV-Net algorithms. The proposed algorithm enhances the ability of mfEIT to simultaneously obtain both structural and spectral information from the tissue being examined and improves the accuracy and reliability of mfEIT, opening new avenues for its application in clinical diagnostics and treatment monitoring.

Self-Feedback DNAzyme Motor for Cascade-Amplified Imaging of mRNA in Live Cells and In Vivo.

DNA motors have attracted extensive interest in biosensing and bioimaging. However, the amplification capacity of the existing DNA motor systems is limited since the products from the walking process are unable to feedback into the original DNA motor systems. As a result, the sensitivities of such systems are limited in the contexts of biosensing and bioimaging. In this study, we report a novel self-feedback DNAzyme motor for the sensitive imaging of tumor-related mRNA in live cells and in vivo with cascade signal amplification capacity. Gold nanoparticles (AuNPs) are modified with hairpin-locked DNAzyme walker and track strands formed by hybridizing Cy5-labeled DNA trigger-incorporated substrate strands with assistant strands. Hybridization of the target mRNA with the hairpin strands activates DNAzyme and promotes the autonomous walking of DNAzyme on AuNPs through DNAzyme-catalyzed substrate cleavage, resulting in the release of many Cy5-labeled substrate segments containing DNA triggers and the generation of an amplified fluorescence signal. Moreover, each released DNA trigger can also bind with the hairpin strand to activate and operate the original motor system, which induces further signal amplification via a feedback mechanism. This motor exhibits a 102-fold improvement in detection sensitivity over conventional DNAzyme motors and high selectivity for target mRNA. It has been successfully applied to distinguish cancer cells from normal cells and diagnose tumors in vivo based on mRNA imaging. The proposed DNAzyme motor provides a promising paradigm for the amplified detection and sensitive imaging of low-abundance biomolecules in vivo.

Bacteria Invade the Brain Following Sterile Intracortical Microelectrode Implantation.

Brain-machine interface performance is largely affected by the neuroinflammatory responses resulting in large part from blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings strongly suggest that certain gut bacterial constituents penetrate the BBB and are resident in various brain regions of rodents and humans, both in health and disease. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could amplify dysregulation of the microbiome-gut-brain axis. Here, we report that bacteria, including those commonly found in the gut, enter the brain following intracortical microelectrode implantation in mice implanted with single-shank silicon microelectrodes. Systemic antibiotic treatment of mice implanted with microelectrodes to suppress bacteria resulted in differential expression of bacteria in the brain tissue and a reduced acute inflammatory response compared to untreated controls, correlating with temporary improvements in microelectrode recording performance. Long-term antibiotic treatment resulted in worsening microelectrode recording performance and dysregulation of neurodegenerative pathways. Fecal microbiome composition was similar between implanted mice and an implanted human, suggesting translational findings. However, a significant portion of invading bacteria was not resident in the brain or gut. Together, the current study established a paradigm-shifting mechanism that may contribute to chronic intracortical microelectrode recording performance and affect overall brain health following intracortical microelectrode implantation.

A new method for vascular age estimation based on relative risk difference in vascular aging.

OBJECTIVE: The current models of estimating vascular age (VA) primarily rely on the regression label expressed with chronological age (CA), which does not account individual differences in vascular aging (IDVA) that are difficult to describe by CA. This may lead to inaccuracies in assessing the risk of cardiovascular disease based on VA. To address this limitation, this work aims to develop a new method for estimating VA by considering IDVA. This method will provide a more accurate assessment of cardiovascular disease risk. METHODS: Relative risk difference in vascular aging (RRDVA) is proposed to replace IDVA, which is represented as the numerical difference between individual predicted age (PA) and the corresponding mean PA of healthy population. RRDVA and CA are regard as the influence factors to acquire VA. In order to acquire PA of all samples, this work takes CA as the dependent variable, and mines the two most representative indicators from arteriosclerosis data as the independent variables, to establish a regression model for obtaining PA. RESULTS: The proposed VA based on RRDVA is significantly correlated with 27 indirect indicators for vascular aging evaluation. Moreover, VA is better than CA by comparing the correlation coefficients between VA, CA and 27 indirect indicators, and RRDVA greater than zero presents a higher risk of disease. CONCLUSION: The proposed VA overcomes the limitation of CA in characterizing IDVA, which may help young groups with high disease risk to promote healthy behaviors.

High-performance terahertz modulators induced by substrate field in Te-based all-2D heterojunctions.

High-performance active terahertz modulators as the indispensable core components are of great importance for the next generation communication technology. However, they currently suffer from the tradeoff between modulation depth and speed. Here, we introduce two-dimensional (2D) tellurium (Te) nanofilms with the unique structure as a new class of optically controlled terahertz modulators and demonstrate their integrated heterojunctions can successfully improve the device performances to the optimal and applicable levels among the existing all-2D broadband modulators. Further photoresponse measurements confirm the significant impact of the stacking order. We first clarify the direction of the substrate-induced electric field through first-principles calculations and uncover the unusual interaction mechanism in the photoexcited carrier dynamics associated with the charge transfer and interlayer exciton recombination. This advances the fundamental and applicative research of Te nanomaterials in high-performance terahertz optoelectronics.