Fusobacterium nucleatum infection modulates the transcriptome and epigenome of HCT116 colorectal cancer cells in an oxygen-dependent manner.

Fusobacterium nucleatum, a gram-negative oral bacterium, has been consistently validated as a strong contributor to the progression of several types of cancer, including colorectal (CRC) and pancreatic cancer. While previous in vitro studies have shown that intracellular F. nucleatum enhances malignant phenotypes such as cell migration, the dependence of this regulation on features of the tumor microenvironment (TME) such as oxygen levels are wholly uncharacterized. Here we examine the influence of hypoxia in facilitating F. nucleatum invasion and its effects on host responses focusing on changes in the global epigenome and transcriptome. Using a multiomic approach, we analyze epigenomic alterations of H3K27ac and global transcriptomic alterations sustained within a hypoxia and normoxia conditioned CRC cell line HCT116 at 24 h following initial infection with F. nucleatum. Our findings reveal that intracellular F. nucleatum activates signaling pathways and biological processes in host cells similar to those induced upon hypoxia conditioning in the absence of infection. Furthermore, we show that a hypoxic TME favors F. nucleatum invasion and persistence and therefore infection under hypoxia may amplify malignant transformation by exacerbating the effects induced by hypoxia alone. These results motivate future studies to investigate host-microbe interactions in tumor tissue relevant conditions that more accurately define parameters for targeted cancer therapies.

Determination of arbutin in vitro and in vivo by LC-MS/MS: Pre-clinical evaluation of natural product arbutin for its early medicinal properties.

ETHNOPHARMACOLOGICAL RELEVANCE: Arbutin is a naturally occurring glucoside extracted from plants, known for its antioxidant and tyrosinase inhibiting properties. It is widely used in cosmetic and pharmaceutical industries. With in-depth study of arbutin, its application in disease treatment is expanding, presenting promising development prospects. However, reports on the metabolic stability, plasma protein binding rate, and pharmacokinetic properties of arbutin are scarce. AIM OF THE STUDY: The aim of this study is to enrich the data of metabolic stability and pharmacokinetics of arbutin through the early pre-clinical evaluation, thereby providing some experimental basis for advancing arbutin into clinical research. MATERIALS AND METHODS: We developed an efficient and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determining arbutin in plasma. We investigated the metabolic and pharmacokinetic properties of arbutin through in vitro metabolism assay, cytochrome enzymes P450 (CYP450) inhibition studies, plasma protein binding rate analysis, Caco-2 cell permeability tests, and rat pharmacokinetics to understand its in vivo performance. RESULTS: In vitro studies show that arbutin is stable, albeit with some species differences. It exhibits low plasma protein binding (35.35 ± 11.03% âˆ¼ 40.25 ± 2.47%), low lipophilicity, low permeability, short half-life (0.42 ± 0.30 h) and high oral bioavailability (65 ± 11.6%). Arbutin is primarily found in the liver and kidneys and is eliminated in the urine. It does not significantly inhibit CYP450 up to 10 µM, suggesting a low potential for drug interactions. Futhermore, preliminary toxicological experiments indicate arbutin's safety, supporting its potential as a therapeutic agent. CONCLUSION: This study provides a comprehensive analysis the drug metabolism and pharmacokinetics (DMPK) of arbutin, enriching our understanding of its metabolism stability and pharmacokinetics properties, It establishes a foundation for further structural optimization, pharmacological studies, and the clinical development of arbutin.

Effect of Patellar Morphology on the Risk of Osteochondral Fracture after Patellar Dislocation: A Cross-sectional Study.

OBJECTIVE: The risk of osteochondral fracture (OCF) after patellar dislocation has been shown to be related to patellofemoral anatomy, but its relationship to patellar morphology remains unknown. The aim of this study was to investigate the associations between patellar morphology and the risk of OCF after patellar dislocation. METHODS: A total of 140 patients with patellar dislocation between January 2018 and June 2023 were enrolled in this study and divided into two groups. Sixty-five patellar dislocation patients with OCF were included in the OCF group, while 75 patellar dislocation patients without OCF were included in the non-OCF group. Computed tomography was used to compare measurements of patellar morphology including Wiberg classification, patellar width and thickness, Wiberg angle, Wiberg index, facet ratio, lateral patellar facet angle, and patellar tilt angle. A logistic regression model was performed to evaluate the correlations between patellar morphology and the risk of OCF after patellar dislocation. Receiver operating characteristic curves were used to calculate the area under the curve (AUC) and determine the diagnostic values of patellar morphology for OCF after patellar dislocation. Subgroup analyses for gender and age were conducted to compare the differences in patellar morphology of PD patients. RESULTS: Wiberg angle was significantly lower in the OCF group (p = 0.017), while Wiberg index (p = 0.002) and facet ratio (p = 0.023) were significantly higher in the OCF group. According to the results of logistic regression analysis, Wiberg angle (odds ratio [OR] = 0.96, p = 0.022) and Wiberg index (OR = 1.105, p = 0.032) were the final relevant factors for the occurrence of OCF after patellar dislocation. The AUC was 0.622 (95% confidence interval [CI]: 0.529-0.714) for Wiberg angle, 0.65 (95% CI: 0.558-0.742) for Wiberg index, and 0.702 (95% CI: 0.615-0.788) for the combination of Wiberg angle plus Wiberg index. CONCLUSION: Wiberg angle and Wiberg index were independent risk factors for the occurrence of osteochondral fracture after patellar dislocation. Moreover, Wiberg angle, Wiberg index, and the combination of Wiberg angle plus Wiberg index had good predictive diagnostic value for the occurrence of OCF after patellar dislocation.

Epigenomic tomography for probing spatially defined chromatin state in the brain.

Spatially resolved epigenomic profiling is critical for understanding biology in the mammalian brain. Single-cell spatial epigenomic assays were developed recently for this purpose, but they remain costly and labor intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here, we demonstrate an approach, epigenomic tomography, that maps spatial epigenomes of mouse brain at the scale of centimeters. We individually profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness. Tri-methylation of histone 3 at lysine 27 (H3K27me3) or acetylation of histone 3 at lysine 27 (H3K27ac) features across these slices were grouped into clusters based on their spatial variation patterns to form epigenomic brain maps. As a proof of principle, our approach reveals striking dynamics in the frontal cortex due to kainic-acid-induced seizure, linked with transmembrane ion transporters, exocytosis of synaptic vesicles, and secretion of neurotransmitters. Epigenomic tomography provides a powerful and cost-effective tool for characterizing brain disorders based on the spatial epigenome.

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.

Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it is best known for its role in store-operated Ca2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focused on a gain-of-function mutation that occurs in humans and mice (STIM1+/D84G mice), in which muscles exhibited constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca2+ transients, SR Ca2+ content, or excitation-contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope of STIM1+/D84G muscle disrupted nuclear-cytosolic coupling, causing severe derangement in nuclear architecture, DNA damage, and altered lamina A-associated gene expression. Functionally, we found that D84G STIM1 reduced the transfer of Ca2+ from the cytosol to the nucleus in myoblasts, resulting in a reduction of [Ca2+]N. Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca2+ signaling to nuclear stability in skeletal muscle.

Synthesis of Ternary and Quaternary Group III-Arsenide Colloidal Quantum Dots via High-Temperature Cation Exchange in Molten Salts: The Importance of Molten Salt Speciation.

Colloidal semiconductor nanocrystals are an important class of materials which have many desirable optoelectronic properties. In their bulk phases, gallium- and aluminum-containing III-V materials such as GaAs, GaP, and Al1-xGaxAs represent some of the most technologically important semiconductors. However, their colloidal synthesis by traditional methods is difficult due to the high temperatures needed to crystallize these highly covalent materials and the extreme reactivity of Ga- and Al- precursors toward organic solvents at such high temperatures. A recently developed paradigm shift in the synthesis of these materials is to use molten inorganic salts as solvents to prepare Ga- containing III-V colloidal nanocrystals by cation exchange of the corresponding indium pnictide (InPn) colloidal nanocrystals. There have been several successful applications of molten salt solvents to prepare III-phosphide colloidal nanocrystals. However, little is known about the nature of these reaction environments at the relevant reaction conditions and synthesis of III-arsenide colloidal nanocrystals remains challenging. Herein we report a detailed study on cation exchange of InPn nanocrystals using nominally Lewis basic molten salt solvents with added gallium halides. Surprisingly, these salt systems phase separate into two immiscible phases, and the nanocrystals preferentially segregate to one of the phases. Using a suite of in situ spectroscopy tools, we identify the phase the nanocrystals segregate to as Lewis neutral alkali tetrahalogallate molten salts. We apply in situ high-temperature Raman spectroscopy to identify the chemical species present in several molten salt compositions at experimentally relevant reaction conditions to elucidate a molecular basis for the reactivity observed. We then employ Lewis neutral KGaI4 molten salts to prepare high-quality In1-xGaxAs and In1-xGaxP nanocrystals and demonstrate that deviation from Lewis neutral conditions accelerate nanocrystal decomposition in the case of III-arsenide materials. Further, we expand to KAlI4-based molten salts to prepare In1-x-yGaxAlyAs nanocrystals which represent an example of solution-synthesized quaternary III-V nanocrystals. These insights provide a molecular basis for the rational development of molten salt solvents, thus allowing the preparation of a diverse array of multicomponent III-V colloidal nanocrystals.

A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression.

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms' tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.

The genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 days. We apply the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS offers a promising solution for single-cell methylomic studies requiring examination of a large cell population.

Hybrid organic-inorganic two-dimensional metal carbide MXenes with amido- and imido-terminated surfaces.

Two-dimensional (2D) transition-metal carbides and nitrides (MXenes) combine the electronic and mechanical properties of 2D inorganic crystals with chemically modifiable surfaces, which provides an ideal platform for both fundamental and applied studies of interfaces. Good progress has been achieved in the functionalization of MXenes with small inorganic ligands, but relatively little work has been reported on the covalent bonding of various organic groups to MXene surfaces. Here we synthesize a family of hybrid MXenes (h-MXenes) that incorporate amido- and imido-bonding between organic and inorganic parts by reacting halogen-terminated MXenes with deprotonated organic amines. The resulting hybrid structures unite tailorability of organic molecules with electronic connectivity and other properties of inorganic 2D materials. Describing the structure of h-MXene necessitates the integration of concepts from coordination chemistry, self-assembled monolayers and surface science. The optical properties of h-MXenes reveal coherent coupling between the organic and inorganic constituents. h-MXenes also exhibit superior stability against hydrolysis.

Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.

Genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are all based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 d. We applied the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS will pave the way for single-cell methylomic studies requiring examination of a large cell population.

Epigenetic regulation and therapeutic targets in the tumor microenvironment.

The tumor microenvironment (TME) is crucial to neoplastic processes, fostering proliferation, angiogenesis and metastasis. Epigenetic regulations, primarily including DNA and RNA methylation, histone modification and non-coding RNA, have been generally recognized as an essential feature of tumor malignancy, exceedingly contributing to the dysregulation of the core gene expression in neoplastic cells, bringing about the evasion of immunosurveillance by influencing the immune cells in TME. Recently, compelling evidence have highlighted that clinical therapeutic approaches based on epigenetic machinery modulate carcinogenesis through targeting TME components, including normalizing cells' phenotype, suppressing cells' neovascularization and repressing the immunosuppressive components in TME. Therefore, TME components have been nominated as a promising target for epigenetic drugs in clinical cancer management. This review focuses on the mechanisms of epigenetic modifications occurring to the pivotal TME components including the stroma, immune and myeloid cells in various tumors reported in the last five years, concludes the tight correlation between TME reprogramming and tumor progression and immunosuppression, summarizes the current advances in cancer clinical treatments and potential therapeutic targets with reference to epigenetic drugs. Finally, we summarize some of the restrictions in the field of cancer research at the moment, further discuss several interesting epigenetic gene targets with potential strategies to boost antitumor immunity.

Enhancing medical ethics education for medical students in clinical research: considerations and strategy analysis / Mejorando la educación ética médica para los estudiantes de medicina en la investigación clínica: consideraciones y análisis de estrategias / Melhorando a educação de ética médica para estudantes de medicina em pesquisa clínica: pensamentos e análise de estratégia

In recent years, the vigorous development of clinical researches carried out by medical schools is inseparable from the effective participation of medical students. However, as the number and categories of clinical research projects that medical students participate in increase, medical ethics related issues gradually occur. This article sorts out the ethical issues that arose in clinical researches, in which medical students participated, analyzes the underlying causes, and proposes solutions for the above-mentioned ethical issues, aiming to provide reference for medical ethics education and research project management for medical schools.

La participación efectiva de los estudiantes de medicina ha contribuido en gran medida al desarrollo exitoso de la investigación clínica en las escuelas de medicina de China en los últimos años. Sin embargo, con el creciente número y tipos de proyectos de investigación clínica en los que participan estudiantes de medicina, las cuestiones éticas se exponen gradualmente. Este trabajo enumera las cuestiones éticas que han surgido en la participación de los estudiantes de medicina en la investigación clínica en los últimos años, analiza las causas subyacentes y propone soluciones a las cuestiones éticas mencionadas anteriormente, con el objetivo de proporcionar referencia para la enseñanza de la ética médica y la gestión de proyectos de investigación para las escuelas de medicina.

A participação efetiva dos estudantes de medicina tem contribuído muito para o próspero desenvolvimento da pesquisa clínica nas escolas médicas da China nos últimos anos. No entanto, com o aumento do número e tipos de projetos de pesquisa clínica dos quais os estudantes de medicina participam, questões relacionadas à ética e à alfabetização são gradualmente expostas. Este artigo lista as questões éticas que surgiram na participação de estudantes de medicina em pesquisas clínicas nos últimos anos, analisa as causas subjacentes e propõe soluções para as questões éticas acima mencionadas, com o objetivo de fornecer referência para o ensino de ética médica e gestão de projetos de pesquisa para escolas médicas.

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.

Stromal interaction molecule 1 (STIM1) is a Ca 2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle where it is best known for its role in store operated Ca 2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focus on a gain of function mutation that occurs in humans and mice (STIM1 +/D84G mice) where muscles exhibit constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca 2+ transients, SR Ca 2+ content or excitation contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope of STIM1 +/D84G muscle disrupts nuclear-cytosolic coupling causing severe derangement in nuclear architecture, DNA damage, and altered lamina A associated gene expression. Functionally, we found D84G STIM1 reduced the transfer of Ca 2+ from the cytosol to the nucleus in myoblasts resulting in a reduction of [Ca 2+ ] N . Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca 2+ signaling to nuclear stability in skeletal muscle.

JMJD8 regulates neuropathic pain by affecting spinal cord astrocyte differentiation.

The demethylase JmjC structural domain-containing protein 8 (JMJD8) has been demonstrated to be involved in cellular inflammatory responses. Neuropathic pain (NP) is a chronic pain, and it is unclear whether JMJD8 is involved in the regulation of NP. Using a chronic constriction injury (CCI) mouse model of NP, we investigated the expression levels of JMJD8 during NP and the influences of JMJD8 on regulating pain sensitivity. We found that JMJD8 expression in the spinal dorsal horn was reduced after CCI. Immunohistochemistry showed that JMJD8 was colabeled with GFAP in naïve mice. Knockdown of JMJD8 in the spinal dorsal horn astrocytes induced pain behavior. Further study showed that overexpression of JMJD8 in the spinal dorsal horn astrocytes not only reversed pain behavior but also activated the spinal dorsal horn A1 astrocytes. These results suggest that JMJD8 may modulate pain sensitivity by affecting activated the spinal dorsal horn A1 astrocytes and may be a potential therapeutic target for NP.

Transcriptome Analysis of the Mouse Medial Prefrontal Cortex in a Chronic Constriction Injury Model.

The medial prefrontal cortex (mPFC) is critical for both the sensory and emotional/cognitive components of pain. However, the underlying mechanism remains largely unknown. Here, we examined changes in the transcriptomic profiles in the mPFC of mice with chronic pain using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery. RNA-seq was conducted 4 weeks after CCI surgery. Compared with contral group, RNA-seq identified a total 309 and 222 differentially expressed genes (DEGs) in the ipsilateral and contralateral mPFC of CCI model mice, respectively. GO analysis indicated that the functions of these genes were mainly enriched in immune- and inflammation-related processes such as interferon-gamma production and cytokine secretion. KEGG analysis further showed the enrichment of genes involved in the neuroactive ligand-receptor interaction signaling pathway and Parkinson disease pathway that have been reported to be importantly involved in chronic neuralgia and cognitive dysfunction. Our study may provide insights into the possible mechanisms underlying neuropathic pain and pain-related comorbidities.

Synthesis of Colloidal GaN and AlN Nanocrystals in Biphasic Molten Salt/Organic Solvent Mixtures under High-Pressure Ammonia.

Group III nitrides are of great technological importance for electronic devices. These materials have been widely manufactured via high-temperature methods such as physical vapor transport (PVT), chemical vapor deposition (CVD), and hydride vapor phase epitaxy (HVPE). The preparation of group III nitrides by colloidal synthesis methods would provide significant advantages in the form of optical tunability via size and shape control and enable cost reductions through scalable solution-based device integration. Solution syntheses of III-nitride nanocrystals, however, have been scarce, and the quality of the synthesized products has been unsatisfactory for practical use. Here, we report that incorporating a molten salt phase in solution synthesis can provide a viable option for producing crystalline III-nitride nanomaterials. Crystalline GaN and AlN nanomaterials can be grown in a biphasic molten-salt/organic-solvent mixture under an ammonia atmosphere at moderate temperatures (less than 300 °C) and stabilized under ambient conditions by postsynthetic treatment with organic surface ligands. We suggest that microscopic reversibility of monomer attachment, which is essential for crystalline growth, can be achieved in molten salt during the nucleation and the growth of the III-nitride nanocrystals. We also show that increased ammonia pressure increases the size of the GaN nanocrystals produced. This work demonstrates that use of molten salt and high-pressure reactants significantly expands the chemical scope of solution synthesis of inorganic nanomaterials.

Comparative Clinical Evaluation of Trapezoidal, Envelope, and Tunnel Type Coronally Advanced Flap in the Treatment of Gingival Recession: A Network Meta-Analysis of Randomized Clinical Trials.

This study evaluated the efficacy of trapezoidal coronally advanced flap (tCAF), envelope coronally advanced flap (eCAF), and coronally advanced tunnel flap (TUN) in treating gingival recession (GR) through a network meta-analysis. Eligible articles from the PubMed, Embase, and Cochrane Library databases published up to September 2020 were selected to identify randomized controlled trials (RCTs) on tCAF, eCAF, and TUN treatments. Sample size, treatment time, and outcome measures including complete root coverage (CRC), root coverage esthetic score (RES), and other data were extracted from the article, and integrated analysis was conducted. In total, 10 RCTs met the inclusion criteria, involving 310 patients. Direct meta-analysis showed no significant differences in CRC among the three surgical methods; A significant difference was seen for RES, with TUN worse than tCAF (weighted mean difference: -0.73; 95% CI: -1.44, -0.02; P = .045). The network meta-analysis showed no statistical significance in the cross-comparison of tCAF, eCAF, and TUN. However, eCAF had the most significant effect on improving CRC (SUCRA = 69.2) and RES (SUCRA = 85.0). eCAF has the best prognosis in the treatment of GR, followed by tCAF and TUN. This may influence the surgeon's treatment choice, as eCAF may be more effective in root coverage procedures.

Pollution characteristics and source identification of farmland soils in Pb-Zn mining areas through an integrated approach.

Long-term mining activities have caused serious heavy metals contamination of farmland soils. In this study, we investigated the concentrations, distributions, accumulations, potential ecological risk, and sources of eight heavy metals in farmland soils of Pb-Zn mining areas. According to the soil standard GB15618-2018, Cd was the most contaminated, followed by Pb and Zn. The geo-accumulation index showed that Pb, Zn, Cd, and Hg accumulated seriously. The potential risk index indicated that Cd, Hg, and Pb were the main environmental risk elements. An integrated approach combining multivariate statistical analysis, PMF, and GIS mapping was used to analyze the sources of heavy metals. Four main sources were identified and quantified: (1) mining activities source, the main source of Cd (71.09%) and Zn (61.88%); (2) agricultural activities source, dominated by Hg (73.01%); (3) atmospheric deposition sources, with Pb (85.11%) as the main contributor; (4) natural source, characterized by Cr (72.96%), Ni (66.04%), As (55.98%) and Cu (37.70%). This study would help us understand the pollution characteristics and sources of farmland soils in mining areas and provide basic information for the next step of pollution control and remediation.

Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus.

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light-mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino-ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)-positive neurons in the vLGN (vLGNPenk). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGNPenk neurons. In addition, activation of the projections from vLGNPenk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGNPenk-DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.

Single-cell analysis reveals that cancer-associated fibroblasts stimulate oral squamous cell carcinoma invasion via the TGF-ß/Smad pathway.

Although substantial progress has been made in cancer biology and treatment, the prognosis of oral squamous cell carcinoma (OSCC) is still not satisfactory because of local tumor invasion and frequent lymph node metastasis. The tumor microenvironment (TME) is a potential target in which cancer-associated fibroblasts (CAFs) are of great significance due to their interactions with cancer cells. However, the exact mechanism is still unclear. Therefore, we focus on the crosstalk between cancer cells and CAFs and discover that CAFs are the main source of TGF-ß1. Transwell assays and western blot analysis further prove that CAFs activate the TGF-ß1/Smad pathway to promote OSCC invasion. Through survival analysis, we confirm that CAF overexpression is correlated with poor overall survival in OSCC. To further elucidate the origin and role of CAFs in OSCC, we analyze single-cell RNA sequencing (scRNA-seq) data from 14 OSCC tumor samples and identify four distinct cell types, including CAFs, in the TME, indicating high intratumoral heterogeneity. Then, two subtypes of CAFs, namely, myofibroblasts (mCAFs) and inflammatory CAFs (iCAFs), are further distinguished. Based on the differentially upregulated genes of mCAFs and iCAFs, GO enrichment analysis reveals their different roles in OSCC progression. Furthermore, the gene expression pattern is dynamically altered across pseudotime, potentially taking part in the transformation from epithelial to mCAFs or iCAFs through the epithelial to mesenchymal transition.