CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis.

Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease, and so far, there is no specific targeted therapy. Here, we report that CXCL16 is upregulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis and, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (HGF) in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE and suggest that CXCL16 signaling could be a potential therapeutic target for RE. © 2022 The Pathological Society of Great Britain and Ireland.

The dynamic cellular and molecular features during the development of radiation proctitis revealed by transcriptomic profiling in mice.

BACKGROUND: Radiation proctitis (RP) is the most common complication of radiotherapy for pelvic tumor. Currently there is a lack of effective clinical treatment and its underlying mechanism is poorly understood. In this study, we aimed to dynamically reveal the mechanism of RP progression from the perspective of RNomics using a mouse model, so as to help develop reasonable therapeutic strategies for RP. RESULTS: Mice were delivered a single dose of 25 Gy rectal irradiation, and the rectal tissues were removed at 4 h, 1 day, 3 days, 2 weeks and 8 weeks post-irradiation (PI) for both histopathological assessment and RNA-seq analysis. According to the histopathological characteristics, we divided the development process of our RP animal model into three stages: acute (4 h, 1 day and 3 days PI), subacute (2 weeks PI) and chronic (8 weeks PI), which could recapitulate the features of different stages of human RP. Bioinformatics analysis of the RNA-seq data showed that in the acute injury period after radiation, the altered genes were mainly enriched in DNA damage response, p53 signaling pathway and metabolic changes; while in the subacute and chronic stages of tissue reconstruction, genes involved in the biological processes of vessel development, extracellular matrix organization, inflammatory and immune responses were dysregulated. We further identified the hub genes in the most significant biological process at each time point using protein-protein interaction analysis and verified the differential expression of these genes by quantitative real-time-PCR analysis. CONCLUSIONS: Our study reveals the molecular events sequentially occurred during the course of RP development and might provide molecular basis for designing drugs targeting different stages of RP development.

Denoising Diffusion MRI via Graph Total Variance in Spatioangular Domain.

Diffusion MRI (DMRI) plays an essential role in diagnosing brain disorders related to white matter abnormalities. However, it suffers from heavy noise, which restricts its quantitative analysis. The total variance (TV) regularization is an effective noise reduction technique that penalizes noise-induced variances. However, existing TV-based denoising methods only focus on the spatial domain, overlooking that DMRI data lives in a combined spatioangular domain. It eventually results in an unsatisfactory noise reduction effect. To resolve this issue, we propose to remove the noise in DMRI using graph total variance (GTV) in the spatioangular domain. Expressly, we first represent the DMRI data using a graph, which encodes the geometric information of sampling points in the spatioangular domain. We then perform effective noise reduction using the powerful GTV regularization, which penalizes the noise-induced variances on the graph. GTV effectively resolves the limitation in existing methods, which only rely on spatial information for removing the noise. Extensive experiments on synthetic and real DMRI data demonstrate that GTV can remove the noise effectively and outperforms state-of-the-art methods.

Inter-transformation between silver nanoparticles and Ag+ induced by humic acid under light or dark conditions.

The fate and toxicity of silver nanoparticles (AgNPs) and ions in water bodies is largely determined by the natural organic matter (NOM)-mediated redox cycling. However, the process of NOM-mediated redox cycling in the day/night cycles remains elusive. In this study, the inter-transformation between AgNPs and Ag+ ion caused by humic acid (HA) was investigated under controlled light and dark conditions. It was shown that HA induced the reduction of Ag+ into AgNPs in simulated sunlight, and also oxidize AgNPs to release Ag+ in darkness. Kinetics data demonstrated that the rates of AgNPs formation and dissolution increased along with the increment of HA concentrations. Along with the pH increase, the reduction of Ag+ accelerated, but the oxidative dissolution of AgNPs was inhibited. In day-night cycles, the AgNPs and Ag+ concentrations exhibited similar wave-shaped change curves. The peaks of AgNPs and Ag+ ion appeared at 7 p.m. and 7 a.m., respectively. The toxicity of AgNPs/Ag+ to Escherichia coli was determined primarily by the concentration of dissolved Ag+, but also affected by the particle-specific toxicity. The dual role of HA implied that previous reports about the photo-reduction of Ag+ to AgNPs by NOM should be reconsidered, and the oxidizability of HA in darkness strongly affect the transformation and toxicity of AgNPs in water.

Cysteine-enhanced reductive degradation of nitrobenzene using nano-sized zero-valent iron by accelerated electron transfer.

As an aliphatic amino acid, cysteine (CYS) is diffuse in the living cells of plants and animals. However, little is known of its role in the reactivity of nano-sized zero-valent iron (NZVI) in the degradation of pollutants. This study shows that the introduction of CYS to the NZVI system can help improve the efficiency of reduction, with 30% more efficient degradation and a reaction rate constant nine times higher when nitrobenzene (NB) is used as probe compound. The rates of degradation of NB were positively correlated with the range of concentrations of CYS from 0 to 10 mmol/L. The introduction of CYS increased the maximum concentration of Fe(III) by 12 times and that of Fe(II) by four times in this system. A comparison of systems featuring only CYS or Fe(II) showed that the direct reduction of NB was not the main factor influencing its CYS-stimulated removal. The reduction in the concentration of CYS was accompanied by the generation of cystine (CY, the oxidized form of cysteine), and both eventually became stable. The introduction of CY also enhanced NB degradation due to NZVI, accompanied by the regeneration of CYS. This supports the claim that CYS can accelerate electron transfer from NZVI to NB, thus enhancing the efficiency of degradation of NB.

Effects of zero-valent iron nanoparticles and quinclorac coexposure on the growth and antioxidant system of rice (Oryza sativa L.).

Quinclorac (3,7-dichloroquinoline-8-carboxylic acid, QNC) is a highly selective auxin herbicide that is typically applied to paddy rice fields. Its residue is a serious problem in crop rotations. In this study, Oryza sativa L. seedlings was used as a model plant to explore its biochemical response to abiotic stress caused by QNC and nZVI coexposure, as well as the interactions between QNC and nZVI treatments. Exposure to 5 and 10 mg/L QNC reduced the fresh biomass by 26.6% and 33.9%, respectively, compared to the control. The presence of 50 and 250 mg/L nZVI alleviated the QNC toxicity, but the nZVI toxicity was aggravated by the coexist of QNC. Root length was enhanced upon exposure to low or medium doses of both QNC and nZVI, whereas root length was inhibited under high-dose coexposure. Both nZVI and QNC, either alone or in combination, significantly inhibited the biosynthesis of chlorophyll, and the inhibition rate increased with elevated nZVI and QNC concentration. It was indicated that nZVI or QNC can affect the plant photosynthesis, and there was a significant interaction between the two treatments. Effects of QNC on the antioxidant response of Oryza sativa L. differed in the shoots and roots; generally, the introduction of 50 and 250 mg/L nZVI alleviated the oxidative stress (POD in shoots, SOD and MDA in roots) induced by QNC. However, 750 mg/kg nZVI seriously damaged Oryza sativa L. seedlings, which likely resulted from active iron deficiency. QNC could be removed from the culture solution by nZVI; as a result, nZVI suppressed QNC uptake by 20%-30%.

Probing Tissue Microarchitecture of the Baby Brain via Spherical Mean Spectrum Imaging.

During the first years of life, the human brain undergoes dynamic spatially-heterogeneous changes, invo- lving differentiation of neuronal types, dendritic arbori- zation, axonal ingrowth, outgrowth and retraction, synaptogenesis, and myelination. To better quantify these changes, this article presents a method for probing tissue microarchitecture by characterizing water diffusion in a spectrum of length scales, factoring out the effects of intra-voxel orientation heterogeneity. Our method is based on the spherical means of the diffusion signal, computed over gradient directions for a set of diffusion weightings (i.e., b -values). We decompose the spherical mean profile at each voxel into a spherical mean spectrum (SMS), which essentially encodes the fractions of spin packets undergoing fine- to coarse-scale diffusion proce- sses, characterizing restricted and hindered diffusion stemming respectively from intra- and extra-cellular water compartments. From the SMS, multiple orientation distribution invariant indices can be computed, allowing for example the quantification of neurite density, microscopic fractional anisotropy ( µ FA), per-axon axial/radial diffusivity, and free/restricted isotropic diffusivity. We show that these indices can be computed for the developing brain for greater sensitivity and specificity to development related changes in tissue microstructure. Also, we demonstrate that our method, called spherical mean spectrum imaging (SMSI), is fast, accurate, and can overcome the biases associated with other state-of-the-art microstructure models.

Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation.

Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and a critical regulator of a variety of cellular processes as well as tumor progression. Therefore, more substrates must be identified in the physiology or disease context. Here, we found that TRIM65 is upregulated and associated with poor survival in colorectal cancer (CRC). More specifically, high expression of TRIM65 is associated with CRC metastasis and recurrence. Ectopic overexpression of TRIM65 in CRC cell lines enhanced proliferation, invasion, and migration, while knockdown of TRIM65 expression had the opposite effects. Furthermore, we identified a new substrate of TRIM65, namely ARHGAP35, a Rho GTPase-activating protein (GAP) that is involved in polarized cell migration. Phenotypically, forced expression of TRIM65 induces increased production of migration-related structures, focal adhesions, and/or filopodia and enhances CRC metastasis to the liver or the lung in a mouse model. Mechanistic studies revealed that TRIM65 mediates ubiquitination of ARHGAP35, whose degradation leads to elevated Rho GTPase activity. In addition, we identified several phosphorylation sites on TRIM65. In sum, we reveal a novel TRIM65-GAP-Rho regulatory axis that modulates the actin cytoskeleton and the migration behavior of CRC cells, and the TRIM65-ARHGAP35 interaction might be a valuable therapeutic target in CRC.

Probing Brain Micro-architecture by Orientation Distribution Invariant Identification of Diffusion Compartments.

Precise quantification of brain tissue micro-architecture using diffusion MRI is hampered by the conflation of diffusion-attenuated signals from micro-environments that can be orientationally heterogeneous due to complex fiber configurations, such as crossing, fanning, and bending, and compartmentally heterogeneous due to variability in tissue organization. In this paper, we introduce a method, called Spherical Mean Spectrum Imaging (SMSI), for quantification of tissue microstructure. SMSI does not assume a fixed number of compartments, but characterizes the signal as a spectrum of fine- to coarse-scale diffusion processes. Using SMSI, multiple orientation distribution invariant indices can be computed, allowing for example the quantification of neurite density, microscopic fractional anisotropy (µFA), per-axon axial/radial diffusivity, and free/restricted isotropic diffusivity. We show that SMSI is fast, accurate, and can overcome biases in state-of-the-art microstructure models. We demonstrate its application in probing microstructural changes in the baby brain during the first two years of life.

Downregulation of TRIM58 expression is associated with a poor patient outcome and enhances colorectal cancer cell invasion.

TRIM58 is a member of the tripartite motif protein (TRIM) family of E3 ubiquitin ligases. Aberrant gene methylation of TRIM58 has been reported in liver and lung cancer and indicates a poor patient prognosis. However, the expression level and functional role of TRIM58 in colorectal cancer (CRC) have yet to be elucidated. In the present study, we found that TRIM58 expression was significantly suppressed in human CRC and was inversely correlated with CRC progression. Additionally, overall survival was significantly reduced in patients with low TRIM58 expression in CRC tumors. In vitro studies demonstrated that ectopic TRIM58 overexpression strongly inhibited CRC cell invasion but had minimal effects on cell proliferation, colonization and migration. Furthermore, TRIM58 suppression enhanced the expression of epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) genes. Thus, our findings suggest that TRIM58 is a potential prognostic marker of CRC and functions as a tumor-suppressor gene via inhibition of cancer cell invasion through EMT and MMP activation.

Role of Angiogenesis in Chronic Radiation Proctitis: New Evidence Favoring Inhibition of Angiogenesis Ex Vivo.

BACKGROUND: Chronic radiation proctitis (CRP), a common complication after radiotherapy for pelvic malignancies, compromises patient quality of life. Vascular damage and aberrant angiogenesis in the mucosal layer are essential histological features, but changes to the submucosal layer are unclear. Thus, we evaluated the histological characteristics and distribution changes of key angiogenic factors in full-layered human CRP samples. METHODS: Thirty paraffin-embedded CRP and twenty-nine non-CRP tissues were used to evaluate histopathological changes. Immunohistochemistry with anti-CD34 antibody was performed to calculate microvascular density (MVD). Frozen tissues from eight CRP patients and five non-CRP controls were collected and analyzed by antibody array, which contained sixty human angiogenesis-related factors. Quality controls with positive and negative controls were performed during antibody array analysis. Two differentially expressed factors were confirmed by ELISA. RESULTS: CRP lesions showed vasculopathy, fibrosis, mucosal ulceration, edema, and inflammatory cell infiltration. Human angiogenesis antibody array and ELISA confirmed the increased angiostatin in CRP lesions. Immunohistochemical staining showed dispersed distribution of angiostatin throughout the mucosal and submucosal layers in CRP lesions, while angiostatin accumulated within the vessel lumens in non-CRP tissues. MVD significantly decreased in the submucosal layer of CRP, suggesting a potential association with increased angiostatin. CONCLUSIONS: Angiostatin increased and had a distinct distribution in CRP lesions. Compensatory telangiectasia in the mucosa, vessel stenosis, and reduced MVD might attenuate blood flow in the submucosa and contribute to CRP progression. Restoration of vascular functionality by promoting angiogenesis in the submucosal layer may help alleviate CRP in clinical practice.

Embarrassingly Parallel Acceleration of Global Tractography via Dynamic Domain Partitioning.

Global tractography estimates brain connectivity by organizing signal-generating fiber segments in an optimal configuration that best describes the measured diffusion-weighted data, promising better stability than local greedy methods with respect to imaging noise. However, global tractography is computationally very demanding and requires computation times that are often prohibitive for clinical applications. We present here a reformulation of the global tractography algorithm for fast parallel implementation amendable to acceleration using multi-core CPUs and general-purpose GPUs. Our method is motivated by the key observation that each fiber segment is affected by a limited spatial neighborhood. In other words, a fiber segment is influenced only by the fiber segments that are (or can potentially be) connected to its two ends and also by the diffusion-weighted signal in its proximity. This observation makes it possible to parallelize the Markov chain Monte Carlo (MCMC) algorithm used in the global tractography algorithm so that concurrent updating of independent fiber segments can be carried out. Experiments show that the proposed algorithm can significantly speed up global tractography, while at the same time maintain or even improve tractography performance.

Accelerating Global Tractography Using Parallel Markov Chain Monte Carlo.

Global tractography estimates brain connectivity by determining the optimal configuration of signal-generating fiber segments that best describes the measured diffusion-weighted data, promising better stability than local greedy methods with respect to imaging noise. However, global tractography is computationally very demanding and requires computation times that are often prohibitive for clinical applications. We present here a reformulation of the global tractography algorithm for fast parallel implementation amendable to acceleration using multi-core CPUs and general-purpose GPUs. Our method is motivated by the key observation that each fiber segment is affected by a limited spatial neighborhood. That is, a fiber segment is influenced only by the fiber segments that are (or can potentially be) connected to its both ends and also by the diffusion-weighted signal in its proximity. This observation makes it possible to parallelize the Markov chain Monte Carlo (MCMC) algorithm used in the global tractography algorithm so that updating of independent fiber segments can be done concurrently. The experiments show that the proposed algorithm can significantly speed up global tractography, while at the same time maintain or improve tractography performance.

[Spatial heterogeneity of soil organic matter and its response to disturbance in karst peak cluster depressions].

By using geostatistic methods, this paper studied the spatial variation and distribution of soil organic matter as well as its ecological processes and related mechanisms in four typical disturbed areas (cropland, man-made forest, secondary forest, and primary forest) of karst peak cluster depressions in northwest Guangxi of China. Eighty soil samples (0-20 cm) were collected from an aligned grid of 10 m x 10 m for the analysis of soil organic matter. The soil organic matter content increased significantly (P < 0.05) with the decrease of disturbance and the vegetation succession from crop to man-made forest to secondary forest to primary forest. Soil organic matter content had good spatial autocorrelation in all of the four typical disturbed areas, but its spatial heterogeneity differed. Gaussian model fitted best to the semivariance functions of soil organic matter content in the study areas except secondary forest area where exponential model fitted well. In cropland area, the spatial autocorrelation of soil organic matter was at medium level, with the C0/(C0 + C) being 26.5%; while in the other three areas, the spatial autocorrelation was at high level, with the C0/(C0 + C) being 9.0%-22.6%. The range and scale of the spatial autocorrelation of soil organic matter in cropland and man-made forest areas were larger than those in the other two areas, possibly due to the strong human disturbance and the homogeneity of low energy. The range of the spatial autocorrelation of soil organic matter in primary forest area was large due to the high vegetation coverage, while that in secondary forest area was the lowest due to the diverse vegetation communities and their uneven distribution. The low fractal value (D) of semivariance functions of soil organic matter in man-made forest and primary forest areas suggested that a strong spatial dependence existed, while the high D in cropland and secondary forest areas suggested a great random variance of spatial distribution of soil organic matter occurred. The spatial pattern of soil organic matter presented a unimodal distribution in cropland and man-made forest areas, a concave distribution in secondary forest area, and a gibbous distribution in primary forest area. To reduce human disturbance would be helpful to the soil quality improvement, rapid vegetation restoration, and ecological reconstruction of karst degenerative ecosystems.

[A spatial heterogeneity of surface soil moisture content in dry season in Mulun National Natural Reserve in Karst area].

By the methods of classical statistics and geostatistics, the spatial heterogeneity of surface soil (0-5 cm and 5-10 cm layers) moisture content in dry season in the typical sloping fields and depressions in Mulun National Natural Reserve in Karst area were studied. The results indicated that in study area, the surface soil moisture content in dry season was still higher, and showed a fine semivariogram structure as a whole. The spatial distribution of moisture content in 0-5 cm and 5-10 cm soil layers, both for sloping fields and for depressions, fitted exponential model well. Under the same stand conditions, the moisture content in the two soil layers had the similar spatial structure and distribution pattern; while under different stand conditions, there existed obvious difference in the same soil layer. The spatial pattern of surface soil moisture content in sloping fields was characterized by medium spatial autocorrelation, clear patches with well continuum, relatively slow variation of Moran's I index, while that in depressions was characterized by strong spatial autocorrelation, larger variation of Moran' s I index, and more fragmented patches. Therefore, topography, micro-physiognomy, precipitation, human disturbance, and especially vegetation were the most important factors affecting the spatial pattern of soil moisture content in the Mulun National Natural Reserve, and to preserve primary forest should have favorable effect on the regulation of the spatial heterogeneity of soil moisture content in the Reserve.