Accurate and consistent segmentation of infant brain MR images plays an important role in quantifying patterns of early brain development, especially in longitudinal studies. However, due to rapid maturation and myelination of brain tissues in the first year of life, the intensity contrast of gray and white matter undergoes dramatic changes. In fact, the contrast inverse around 6-8 months of age, when the white and gray matter tissues are isointense and hence exhibit the lowest contrast, posing significant challenges for segmentation algorithms. In this paper, we propose a longitudinally guided level set method to segment serial infant brain MR images acquired from 2 weeks up to 1.5 years of age, including the isointense images. At each single-time-point, the proposed method makes optimal use of T1, T2 and the diffusion-weighted images for complimentary tissue distribution information to address the difficulty caused by the low contrast. Moreover, longitudinally consistent term, which constrains the distance across the serial images within a biologically reasonable range, is employed to obtain temporally consistent segmentation results. Application of our method on 28 longitudinal infant subjects, each with 5 longitudinal scans, shows that the automated segmentations from the proposed method match the manual ground-truth with much higher Dice Ratios than other single-modality, single-time-point based methods and the longitudinal but voxel-wise based methods. The software of the proposed method is publicly available in NITRC (http://www.nitrc.org/projects/ibeat).

This study was designed to characterize the location, morphology and ultrastructure of telocytes (TCs) in human scalp tissue. After obtaining approval for this study and informed consent from the patient, a scalp specimen was obtained. The distribution and morphology of TCs in human scalp tissue was assessed by immunohistochemical staining of CD34 and CD117/c-KIT, and the ultrastructure of TCs was investigated using transmission electron microscopy (TEM). Immunohistochemical staining of CD34 revealed that TCs were located in the connective tissue of human scalp, and were concentrated around hair follicles (HFs), blood vessels, sweat glands, sebaceous glands and adipose lobules. Immunohistochemical staining of CD117 revealed that TCs were mainly located in the dermis of human scalp, surrounding the HFs and sweat glands. Under TEM, TCs were seen and confirmed by their special morphological features. These cells were spindle-shaped, had small cell bodies and long thin processes, and surrounded stem cell clusters in the bulge region of HFs. These results demonstrate that TCs in human scalp were positive for CD34 and CD117, and their strategic positioning surrounding stem cells suggests their possible involvement in local regeneration, remodeling and homeostasis of the skin.

Quantification of brain development as well as disease-induced pathologies in neonates often requires precise delineation of white matter, grey matter and cerebrospinal fluid. Unlike adults, tissue segmentation in neonates is significantly more challenging due to the inherently lower tissue contrast. Most existing methods take a voxel-based approach and are limited to working with images from a single time-point, even though longitudinal scans are available. We take a different approach by taking advantage of the fact that the pattern of the major sulci and gyri are already present in the neonates and generally preserved but fine-tuned during brain development. That is, the segmentation of late-time-point image can be used to guide the segmentation of neonatal image. Accordingly, we propose a novel longitudinally guided level-sets method for consistent neonatal image segmentation by combining local intensity information, atlas spatial prior, cortical thickness constraint, and longitudinal information into a variational framework. The minimization of the proposed energy functional is strictly derived from a variational principle. Validation performed on both simulated and in vivo neonatal brain images shows promising results.

In order to find a convenient and stable way to trace human skin fibroblasts (HSFs) in three-dimensional tissue engineering scaffolds for a long time, in this experiment, Graphene Oxide Quantum Dots (GOQDs), Amino Graphene Quantum Dots (AGQDs) and Carboxyl Graphene Quantum Dots (CGQDs) were used as the material source for labeling HSFs. Exploring the possibility of using it as a long-term tracer of HSFs in three-dimensional tissue engineering scaffolds, the contents of the experiment are as follows: the HSFs were cultured in a cell-culture medium composed of three kinds of Graphene Quantum Dots for 24 h, respectively; (1) using Cell Counting Kit 8 (CCK8), Transwell migration chamber and Phalloidin-iFlior 488 to detect the effect of Graphene Quantum Dots on the biocompatibility of HSFs; (2) using a living cell workstation to detect the fluorescence labeling results of three kinds of Graphene Quantum Dots on HSFs, and testing the fluorescence attenuation of HSFs for 7 days; (3) the HSFs labeled with Graphene Quantum Dots were inoculated on the three-dimensional chitosan demethylcellulose sodium scaffold, and the living cell workstation was used to detect the spatial distribution of the HSFs on the three-dimensional scaffold through the fluorescence properties of the HSFs.. Experimental results: (1) the results of CCK8, Transwell migration, and FITC-Phalloidin cytoskeleton test showed that the three kinds of Graphene Quantum Dots had no effect on the biological properties of HSFs (p < 0.05); (2) the results of the fluorescence labeling experiment showed that only AGQDs could make HSFs fluorescent, and cells showed orange−red fluorescence; (3) the results of long-range tracing of HSFs which were labeled by with AGQDs showed that the fluorescence life of the HSFs were as long as 7 days; (4) The spatial distribution of HSFs can be detected on the three-dimensional scaffold based on their fluorescence properties, and the detection time can be up to 7 days.

Adipose tissue has a primary role in lipid and glucose metabolism as a storage site for fatty acids, and also functions as an endocrine organ, producing large numbers of hormones and cytokines. Adipose dysfunction triggers a number of obesity‑associated health problems. The aim of the present study was, therefore, to investigate the molecular mechanisms of white adipose tissue (WAT). The GSE9954 microarray data were downloaded from the Gene Expression Omnibus. Adipose‑specific genes were identified through limma package analysis, based on samples of WAT and 17 other types of non‑adipose tissue obtained from mice. Process and pathway enrichment analyses were performed for these genes. Finally, protein‑protein interaction (PPI) and co‑expression networks were constructed and analyzed. In total, 202 adipose‑specific genes were identified, which were involved in key biological processes (including fat cell differentiation and lipid metabolic process) and one key pathway [namely, the adenine monophosphate‑activated protein kinase (AMPK) signaling pathway]. Construction of the PPI network and further molecular complex detection revealed the presence of 17 key genes, including acetyl‑CoA carboxylase α, peroxisome proliferator‑activated receptor (PPAR) γ and leptin, that were involved in the AMPK, PPAR and insulin signaling pathways. In addition, amine oxidase copper containing 3 and adrenoceptor beta 3 were communication hubs in the co‑expression network of adipose‑specific genes. In conclusion, the present study promotes our understanding of the underlying molecular mechanisms of WAT, and may offer an insight into the prevention and treatment of obesity‑associated diseases caused by adipose dysfunction.

The selective induction of tumor vascular thrombosis using truncated tissue factor (tTF) delivered via a target ligand is a promising novel antitumor strategy. In the present study, an anti‑neuropilin‑1 (NRP‑1) monoclonal antibody (mAb)‑streptavidin (SA):tTF‑biotin (B) composite system was established. In this system, anti‑NRP‑1‑mAb located tTF to the tumor vascular endothelial cell surface and induced vascular embolization. Due to their high binding affinity, SA and B were used to enhance thrombogenic activity. mAb was conjugated with SA using a coupling method with water‑soluble 1‑ethyl‑3‑(3‑dimethylaminopropyl) carbodiimide and N‑hydroxysulfosuccinimide. Biotinylated tTF (tTF‑B) was prepared using a B‑labeling kit subsequent to the generation and purification of fusion protein tTF. Confocal microscopy and flow cytometry indicated that the anti‑NRP‑1‑mAb‑SA conjugate retained mAb targeting activity. The preservation of B‑conjugate binding capacity was confirmed using a competitive ELISA, and factor X‑activation analysis revealed that tTF‑B retained the procoagulant activity exhibited by tTF. Live imaging was performed to assess mAb‑SA distribution and tumor‑targeting capability, and this yielded promising results. The results of in vivo studies in mice with subcutaneous xenografts demonstrated that this composite system significantly induced tumor vascular thrombosis and inhibited tumor growth, whereas these histological changes were not observed in normal organs.

Bile acid (BA) metabolism is tightly controlled by nuclear receptor signaling to coordinate regulation of BA synthetic enzymes and transporters. Here we reveal a molecular cascade consisting of the antiapoptotic protein BCL2, nuclear receptor Shp, and long non-coding RNA (lncRNA) H19 to maintain BA homeostasis. Bcl2 was overexpressed in liver of C57BL/6J mice using adenovirus mediated gene delivery for two weeks. Hepatic overexpression of Bcl2 caused drastic accumulation of serum BA and bilirubin levels and dysregulated BA synthetic enzymes and transporters. Bcl2 reactivation triggered severe liver injury, fibrosis and inflammation, which were accompanied by a significant induction of H19. Bcl2 induced rapid SHP protein degradation via the activation of caspase-8 pathway. The induction of H19 in Bcl2 overexpressed mice was contributed by a direct loss of Shp transcriptional repression. H19 knockdown or Shp re-expression largely rescued Bcl2-induced liver injury. Strikingly different than Shp, the expression of Bcl2 and H19 was hardly detectable in adult liver but was markedly increased in fibrotic/cirrhotic human and mouse liver. We demonstrated for the first time a detrimental effect of Bcl2 and H19 associated with cholestatic liver fibrosis and an indispensable role of Shp to maintain normal liver function.

Adult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis.

Accurately analyzing the rapid structural evolution of human brain in the first year of life is a key step in early brain development studies, which requires accurate deformable image registration. However, due to (a) dynamic appearance and (b) large anatomical changes, very few methods in the literature can work well for the registration of two infant brain MR images acquired at two arbitrary development phases, such as birth and one-year-old.

The first year of life is the most critical time period for structural and functional development of the human brain. Combining longitudinal MR imaging and finite strain theory, this study aimed to provide new insights into normal brain development through a biomechanical framework. Thirty-three normal infants were longitudinally imaged using MRI from 2 weeks to 1 year of age. Voxel-wise Jacobian determinant was estimated to elucidate volumetric changes while Lagrange strains (both normal and shear strains) were measured to reveal directional growth information every 3 months during the first year of life. Directional normal strain maps revealed that, during the first 6 months, the growth pattern of gray matter is anisotropic and spatially inhomogeneous with higher left-right stretch around the temporal lobe and interhemispheric fissure, anterior-posterior stretch in the frontal and occipital lobes, and superior-inferior stretch in right inferior occipital and right inferior temporal gyri. In contrast, anterior lateral ventricles and insula showed an isotropic stretch pattern. Volumetric and directional growth rates were linearly decreased with age for most of the cortical regions. Our results revealed anisotropic and inhomogeneous brain growth patterns of the human brain during the first year of life using longitudinal MRI and a biomechanical framework.

Prenatal opioid exposure has been linked to altered neurodevelopment and visual problems such as strabismus and nystagmus. The neural substrate underlying these alterations is unclear. Resting-state functional connectivity MRI (rsfMRI) is an advanced and well-established technique to evaluate brain networks. Few studies have examined the effects of prenatal opioid exposure on resting-state network connectivity in infancy. In this pilot study, we characterized network connectivity in opioid-exposed infants (n = 19) and controls (n = 20) between 4-8 weeks of age using both a whole-brain connectomic approach and a seed-based approach. Prenatal opioid exposure was associated with differences in distribution of betweenness centrality and connection length, with positive connections unique to each group significantly longer than common connections. The unique connections in the opioid-exposed group were more often inter-network connections while unique connections in controls and connections common to both groups were more often intra-network. The opioid-exposed group had smaller network volumes particularly in the primary visual network, but similar network strength as controls. Network topologies as determined by dice similarity index were different between groups, particularly in visual and executive control networks. These results may provide insight into the neural basis for the developmental and visual problems associated with prenatal opioid exposure.

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play critical roles in both innate and adaptive immunity. However, little information about HSPs from marbled eel Anguilla marmorata is known. In this study, the full-length Amhsp90 (2527 bp), Amhsp70 (2443 bp) and Amhsc70 (2247 bp) were first cloned from A. marmorata, using rapid amplification of cDNA ends, containing open reading frames of 2181, 1932 and 1950 bp in length, and encoding proteins with 726, 643 and 649 amino acids, respectively. The deduced amino acid sequences of three Amhsps shared a high homology similarity with other migratory fish. Real-time fluorescent quantitative polymerase chain reaction was used to evaluate tissue-specific distribution and mRNA expression levels of three Amhsps subjected to infection with Aeromonas hydrophila. The mRNA expression of three Amhsps in eight tested tissues, namely liver, heart, muscle, gill, spleen, kidney, brain and intestine, of juvenile A. marmorata was evaluated to reveal the major expression distribution in liver, intestine, muscle and heart. After pathogen challenge treatments, mRNA transcriptions of three Amhsps revealed a significant regulation at various time points in the same tissue. All these findings suggest that Amhsps may be involved in the immune response in A. marmorata.

Longitudinal brain image analysis is critical for revealing subtle but complex structural and functional changes of brain during aging or in neurodevelopmental disease. However, even with the rapid increase of clinical research and trials, a software toolbox dedicated for longitudinal image analysis is still lacking publicly. To cater for this increasing need, we have developed a dedicated 4D Adult Brain Extraction and Analysis Toolbox (aBEAT) to provide robust and accurate analysis of the longitudinal adult brain MR images. Specially, a group of image processing tools were integrated into aBEAT, including 4D brain extraction, 4D tissue segmentation, and 4D brain labeling. First, a 4D deformable-surface-based brain extraction algorithm, which can deform serial brain surfaces simultaneously under temporal smoothness constraint, was developed for consistent brain extraction. Second, a level-sets-based 4D tissue segmentation algorithm that incorporates local intensity distribution, spatial cortical-thickness constraint, and temporal cortical-thickness consistency was also included in aBEAT for consistent brain tissue segmentation. Third, a longitudinal groupwise image registration framework was further integrated into aBEAT for consistent ROI labeling by simultaneously warping a pre-labeled brain atlas to the longitudinal brain images. The performance of aBEAT has been extensively evaluated on a large number of longitudinal MR T1 images which include normal and dementia subjects, achieving very promising results. A Linux-based standalone package of aBEAT is now freely available at http://www.nitrc.org/projects/abeat.

Areas and spatial distribution information of paddy rice are important for managing food security, water use, and climate change. However, there are many difficulties in mapping paddy rice, especially mapping multi-season paddy rice in rainy regions, including differences in phenology, the influence of weather, and farmland fragmentation. To resolve these problems, a novel multi-season paddy rice mapping approach based on Sentinel-1A and Landsat-8 data is proposed. First, Sentinel-1A data were enhanced based on the fact that the backscattering coefficient of paddy rice varies according to its growth stage. Second, cropland information was enhanced based on the fact that the NDVI of cropland in winter is lower than that in the growing season. Then, paddy rice and cropland areas were extracted using a K-Means unsupervised classifier with enhanced images. Third, to further improve the paddy rice classification accuracy, cropland information was utilized to optimize distribution of paddy rice by the fact that paddy rice must be planted in cropland. Classification accuracy was validated based on ground-data from 25 field survey quadrats measuring 600 m × 600 m. The results show that: multi-season paddy rice planting areas effectively was extracted by the method and adjusted early rice area of 1630.84 km², adjusted middle rice area of 556.21 km², and adjusted late rice area of 3138.37 km². The overall accuracy was 98.10%, with a kappa coefficient of 0.94.

Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7-63 fold) in mouse serum on day 1 after 0.5-10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice's serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5-25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

Purpose: Radiotherapy is a promising treatment option for lung cancer, but patients' responses vary. The purpose of the study was to investigate the potential of radiomics and clinical signature for predicting the radiotherapy sensitivity and overall survival of inoperable stage III and IV non-small-cell lung cancer (NSCLC) patients. Materials: This retrospective study collected 104 inoperable stage III and IV NSCLC patients at the Yunnan Cancer Hospital from October 2016 to September 2020. They were divided into radiation-sensitive and non-sensitive groups. We used analysis of variance (ANOVA) to select features and support vector machine (SVM) to build the radiomic model. Furthermore, the logistic regression method was used to screen out clinically relevant predictive factors and construct the combined model of radiomics-clinical features. Finally, survival was estimated using the Kaplan-Meier method. Results: There were 40 patients in the radiation-sensitive group and 64 in the non-sensitive group. These patients were divided into training set (73 cases) and testing set (31 cases) according to the ratio of 7:3. Nine radiomics features and one clinical feature were significantly associated with radiotherapy sensitivity. Both the radiomics model and combined model have good predictive performance (the areas under the curve (AUC) values of the testing set were 0.864 (95% confidence interval [CI]: 0.683-0.996) and 0.868 (95% CI: 0.689-1.000), respectively). Only platelet level status was associated with overall survival. Conclusion: The combined model constructed based on radiomics and clinical features can effectively identify the radiation-sensitive population and provide valuable clinical information. Patients with higher platelet levels may have a poor prognosis.

The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network-International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-β signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase >3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.

Tong-Xie-Yao-Fang (TXYF) has been widely used for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in traditional Chinese medicine. However, its mechanism of action in the treatment of IBS-D remains to be fully understood. Recent reports have shown that Clostridium species in the gut can induce 5-HT production in the colon, which then contributes to IBS-D. Due to the wide use of TXYF in the clinical treatment of IBS-D and the close relationship between gut microbiota and IBS-D, we hypothesize that TXYF treats IBS-D by modulating gut microbiota and regulating colonic 5-HT levels. In this study, variation analysis of 16S rRNA was conducted to evaluate changes in the distribution of gut microbiota in IBS-D model rats after TXYF treatment. Moreover, we investigated whether TXYF could affect colonic 5-HT levels in IBS-D model rats. We then performed fecal transplantation experiments to confirm the effects of TXYF on gut microbiota and 5-HT levels. We found that TXYF treatment can ameliorate IBS-D and regulate 5-HT levels in colon tissue homogenates. TXYF treatment also affected the diversity of gut microbiota and altered the relative abundance of Akkermansia and Clostridium sensu stricto 1 in gut flora populations. Finally, we showed that fecal transplantation from TXYF-treated rats could relieve IBS-D and regulate 5-HT levels in colon tissue homogenates. In conclusion, the present study demonstrates that TXYF treatment diminishes colonic 5-HT levels and alleviates the symptoms of IBS-D by favorably affecting microbiota levels in gut flora communities.

The discovery of microRNAs (miRNAs) is a remarkable breakthrough in the field of life science, and they are important actors which regulate gene expression in diverse cellular processes. Recently, several reports indicated that miRNAs can also target viruses and regulate virus replication. Here we discovered 36 pig-encoded miRNAs and 22 human-encoded miRNAs which have putative targets in swine influenza virus (SIV) and Swine-Origin 2009 A/H1N1 influenza virus (S-OIV) genes respectively. Interestingly, the putative interactions of ssc-miR-124a, ssc-miR-136 and ssc-miR-145 with their SIV target genes had been found to be maintained almost throughout all of the virus evolution. Enrichment analysis of previously reported miRNA gene expression profiles revealed that three miRNAs are expressed at higher levels in human lung or trachea tissue. The hsa-miR-145 and hsa-miR-92a putatively target the HA gene and hsa-miR-150 putatively targets the PB2 gene. Analysis results based on the location distribution from which virus was isolated and sequence conservation imply that some putative miRNA-mediated host-virus interactions may characterize the location-specificity.

Alterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed.