Design of a novel gamma camera with large field of view for 16N diagnosis in the primary loop of nuclear reactor.

The assessment of the concentration and distribution of l6N, derived from 16O in the cooling water exposed to neutron irradiation, is essential for ensuring radiation safety during nuclear reactor operation. The imaging method allows for the visualization of the intensity distribution of these l6N by capturing gamma-rays emitted during their decay process. However, the existing gamma camera is exclusively compatible with gamma-rays below 2 MeV. In this paper, a novel gamma camera featuring a thick double-conical penumbra aperture, a pixelated Lu1.8Y0.2SiO5:Ce scintillator array, and a position-sensitive photomultiplier tube is proposed to address this limitation. This innovative design offers a large field of view (FOV) and is suitable for high energy extended gamma source imaging. The optimization of key parameters of the camera was conducted, and a FOV of 60° and an angular resolution of up to 4.57° were achieved. Imaging simulations, including a simplified model of the primary loop of the pressurized-water reactor by GEANT4 code and image reconstruction using the expectation maximum algorithm, demonstrated that the proposed gamma camera could obtain a satisfactory spatial resolution for diagnosing the distribution of 16N in the primary loop of a nuclear reactor.

SPARC stabilizes ApoE to induce cholesterol-dependent invasion and sorafenib resistance in hepatocellular carcinoma.

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastasis. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC.

Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

Genetic screen identified PRMT5 as a neuroprotection target against cerebral ischemia.

Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remain largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. PRMT5 was identified as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. PRMT5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that PRMT5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, mice were treated with middle cerebral artery occlusion with the PRMT5 inhibitor EPZ015666 and found that PRMT5 inhibition sustains protection against neuronal death in vivo. Together, these findings revealed a novel epigenetic mechanism of PRMT5 in cerebral ischemia and uncovered a potential target for neuroprotection.

miR-107-5p ameliorates neurological damage, oxidative stress, and immune responses in mice with Alzheimer's disease by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor-kappaB(NF-κB) pathway.

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR-107-5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR-107-5p (to overexpress miR-107-5p) or BAY11-7082 (an NF-κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin-eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid-Aß (Aß1-40/42) contents, and inflammatory factors (TNF-α, IL-6, IL-1ß) in hippocampal tissues were measured using ROS kits and enzyme-linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR-107-5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual-luciferase assay. miR-107-5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF-κB p65 protein expression in the nucleus and cytoplasm were assessed via RT-qPCR and Western blot. Overexpression of miR-107-5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aß1-40 and Aß1-42 levels, diminished neuronal injuries, decreased ROS and TNF-α, IL-6, and IL-1ß levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR-107-5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF-κB p65 in the NF-κB pathway. Inhibition of the NF-κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR-107-5p exerts its beneficial effects by suppressing the TLR4/NF-κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.

Projected impacts of climate change on the habitat of Xerophyta species in Africa.

Climate change poses a serious long-term threat to biodiversity. To effectively reduce biodiversity loss, conservationists need to have a thorough understanding of the preferred habitats of species and the variables that affect their distribution. Therefore, predicting the impact of climate change on species-appropriate habitats may help mitigate the potential threats to biodiversity distribution. Xerophyta, a monocotyledonous genus of the family Velloziaceae is native to mainland Africa, Madagascar, and the Arabian Peninsula. The key drivers of Xerophyta habitat distribution and preference are unknown. Using 308 species occurrence data and eight environmental variables, the MaxEnt model was used to determine the potential distribution of six Xerophyta species in Africa under past, current and future climate change scenarios. The results showed that the models had a good predictive ability (Area Under the Curve and True Skill Statistics values for all SDMs were more than 0.902), indicating high accuracy in forecasting the potential geographic distribution of Xerophyta species. The main bioclimatic variables that impacted potential distributions of most Xerophyta species were mean temperature of the driest quarter (Bio9) and precipitation of the warmest quarter (Bio18). According to our models, tropical Africa has zones of moderate and high suitability for Xerophyta taxa, which is consistent with the majority of documented species localities. The habitat suitability of the existing range of the Xerophyta species varied based on the climate scenario, with most species experiencing a range loss greater than the range gain regardless of the climate scenario. The projected spatiotemporal patterns of Xerophyta species help guide recommendations for conservation efforts.

Ethnobotanical study of traditional medicinal plants used by the local Gamo people in Boreda Abaya District, Gamo Zone, southern Ethiopia.

BACKGROUND: Medicinal plants have been used for centuries and are still relied upon by over 80% of the Ethiopian population. The people of Gamo, southern Ethiopia, have a rich cultural and traditional lifestyle with a long history of using plant resources for various uses including traditional herbal medicine. However, their traditional knowledge of traditional medicinal plants in Boreda Abaya District has not been explored Ethnobotanically yet, despite preserving diverse indigenous traditional medicinal plants. Hence, the study aimed to document and analyze traditional medicinal plants and associated traditional knowledge and practices used by local people. MATERIALS AND METHODS: Quantitative ethnobotanical data were collected via semi-structured interviews, face-to-face conversations, group discussions, and guided field trips between September 2022 and February 2023. In total, 92 informants participated, of which 25 were key informants. Quantitative data indices (informant consensus factor-ICF-and use report-Ur) were computed by MS Excel spreadsheet software. Scientific names of medicinal plants were checked via World Flora Online. RESULTS: In the present study, we recorded 188 traditional medicinal plant species belonging to 163 genera and 73 plant families. Lamiaceae (16 species), Asteraceae (16 species), Fabaceae (11 species), and Euphorbiaceae (8 species) contributed highest number of species and were found to be predominant family in the area. Leaves and seeds were most frequently used plant parts, and pounding (46%) was the main method to prepare remedies. The sudden sickness disease category scored the highest consensus (ICF: 0.35), followed by blood and circulatory-related disease categories (ICF: 0.33). The highest number of plant taxa (61 species) used to treat dermal disease has a 71-use report score, while fewer plant taxa (21 species) were utilized to treat genitourinary system-related disease category, having 25 use reports. Ocimum lamiifolium (Ur:56) and Moringa stenopetala (Ur:51) are widely used species and received highest use report value. CONCLUSION: Gamo people possess extensive traditional knowledge of ethnomedicine. The region's vegetation hosts diverse medicinal species, but deforestation, agriculture, and droughts threaten them. Local conservation practices require scientific support, prioritizing species having higher use reports (Ur), and in-depth investigations of promising species for drug development are essential.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Brain connectomics improve prediction of 1-year decreased quality of life in breast cancer: A multi-voxel pattern analysis.

PURPOSE: Whether brain connectomics can predict 1-year decreased Quality of Life (QoL) in patients with breast cancer are unclear. A longitudinal study was utilized to explore their prediction abilities with a multi-center sample. METHODS: 232 breast cancer patients were consecutively enrolled and 214 completed the 1-year QoL assessment (92.2%). Resting state functional magnetic resonance imaging was collected before the treatment and a multivoxel pattern analysis (MVPA) was performed to differentiate whole-brain resting-state connectivity patterns. Net Reclassification Improvement (NRI) as well as Integrated Discrimination Improvement (IDI) were calculated to estimate the incremental value of brain connectomics over conventional risk factors. RESULTS: Paracingulate Gyrus, Superior Frontal Gyrus and Frontal Pole were three significant brain areas. Brain connectomics yielded 7.8-17.2% of AUC improvement in predicting 1-year decreased QoL. The NRI and IDI ranged from 20.27 to 54.05%, 13.21-33.34% respectively. CONCLUSION: Brain connectomics contribute to a more accurate prediction of 1-year decreased QoL in breast cancer. Significant brain areas in the prefrontal lobe could be used as potential intervention targets (i.e., Cognitive Behavioral Group Therapy) to improve long-term QoL outcomes in breast cancer.

Profiling targets and potential target pairs of CAR-T cell therapy in clinical trials.

Since the approval of the first chimeric antigen receptor (CAR)-T product in 2017, the number of new CAR-T clinical trials worldwide exceeds 100 per year. 1649 clinical studies have been conducted to explore possible future clinical applications of targets or target pairs through different biotechnologies. In this study, we aim to take a data-driven analytical approach to explore potential dual-target pairs based on clinical trial information. We screened 1283 non-withdrawal interventional CAR-T clinical trials spanning 96 different targets and 74 target pairs from clinicaltrials.gov. Through the Circos plot and temporal network plots, the information between targets and indications was visualized. Based on the assumption that two targets of a target pair must target the same indication, five new target pairs were inferred, including CD19/CD7, CD19/CD5, CD19/CD37, and CD19/BAFFR and validated by expression pattern, literature and patent information. This study provides novel support for target profiling of CAR-T from the perspective of clinical trials and also provides a reference for researchers and developers to select new targets or target pairs of CAR-T cell therapy.

The horizontal gene transfer of perchlorate reduction genomic island in three bacteria from an ecological niche.

Three new strains of dissimilatory perchlorate-reducing bacteria (DPRB), QD19-16, QD1-5, and P3-1, were isolated from an active sludge. Phylogenetic trees based on 16S rRNA genes indicated that QD19-16, QD1-5, and P3-1 belonged to Brucella, Acidovorax, and Citrobacter, respectively, expanding the distribution of DPRB in the Proteobacteria. The three strains were gram-negative and facultative anaerobes with rod-shaped cells without flagella, which were 1.0-1.6 µm long and 0.5-0.6 µm wide. The three DPRB strains utilized similar broad spectrum of electron donors and acceptors and demonstrated a similar capability to reduce perchlorate within 6 days. The enzyme activity of perchlorate reductase in QD19-16 toward chlorate was higher than that toward perchlorate. The high sequence similarity of the perchlorate reductase operon and chlorite dismutase genes in the perchlorate reduction genomic islands (PRI) of the three strains implied that they were monophyletic origin from a common ancestral PRI. Two transposase genes (tnp1 and tnp2) were found in the PRIs of strain QD19-16 and QD1-5, but were absent in the strain P3-1 PRI. The presence of fragments of IR sequences in the P3-1 PRI suggested that P3-1 PRI had previously contained these two tnp genes. Therefore, it is plausible to suggest that a common ancestral PRI transferred across the strains Brucella sp. QD19-16, Acidovorax sp. QD1-5, and Citrobacter sp. P3-1 through horizontal gene transfer, facilitated by transposases. These results provided a direct evidence of horizontal gene transfer of PRI that could jump across phylogenetically unrelated bacteria through transposase. KEY POINTS: • Three new DPRB strains can effectively remove high concentration of perchlorate. • The PRIs of three DPRB strains are acquired from a single ancestral PRI. • PRIs are incorporated into different bacteria genome through HGT by transposase.

The genus Balanophora J. R. Forst. & G. Forst. - Its use in traditional medicine, phytochemistry, and pharmacology: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Natural products, particularly medicinal plants, have been utilized in traditional medicine for millennia to treat various diseases. The genus Balanophora (Balanophoraceae) consists of 23 accepted species. These species are the most controversial flowering plants, with highly reduced morphologies and are found parasitizing on the roots of their host. They have been used in traditional medicine as a remedy for stomach pain, detumescence, uterine prolapse, wounds, syphilis, gonorrhea, treating injuries from falls, and other conditions. However, there is no review of this genus on its traditional uses, phytochemistry, and pharmacology. AIM: The present narrative review discusses the scientific data supporting the traditional uses of Balanophora species. The available information on its botanical properties, traditional uses, chemical contents, pharmacological activities, and toxicity was summarized to help comprehend current research and offer a foundation for future research. MATERIALS AND METHODS: The materials used in combining data on the genus Balanophora comprises online sources such as Web of Science, Google Scholar, Science Direct, and Chinese National Knowledge Infrastructure (CNKI) for Chinese-related materials. World Flora online was used in validating the scientific names of this genus while ChemBio Draw Ultra Version 22.2 software was employed in drawing the phytochemical compounds. RESULTS: Nine Balanophora species including B. harlandii, B. japonica, B. polyandra, B. fungosa, B. fungosa subsp. indica, B. laxiflora, B. abbreviata, B. tobiracola, and B. involucrata have been documented as vital sources of traditional medicines in different parts of Asia. A total of 159 secondary metabolites have been isolated and identified from the ten species of this genus comprising tannins, flavonoids, sterols, lignans, chalcones, terpenes, and phenylpropanoids. Among these compounds, tannins, lignans, terpenoids, chalcones and phenolic acids contribute to the pharmacological activities of the species in this genus with several biological activities both in vitro and in vivo such as anti-inflammatory, anti-oxidant, hypoglycemic activity, cytotoxicity, anti-microbial, melanin synthesis etc. CONCLUSION: This review summarizes the available literature on the traditional uses, pharmacological properties, and phytoconstituents of Balanophora species indicating that they contain fascinating chemical compounds with diverse biological activities. The traditional uses of the species in this genus have been confirmed by scientific data such as antimicrobial, hemostatic effect, gastroprotective activity and others. However, many species in this genus are yet unknown in terms of their botanical uses, chemical composition and biological activities. Thus, more research into the scientific connections between traditional medicinal uses and pharmacological activities, mode of action of the isolated bioactive constituents, and toxicity of other Balanophora species is needed to determine their efficacy and therapeutic potential for safe clinical application.

Digital holographic interferometry for diagnosing the density profile of laser-produced collisionless shock.

A digital holographic interferometry based on Fresnel biprism has been developed to measure the electron density profile of laser-produced collisionless shocks in laboratory, which used the Fourier transform method to solve the wrapped phase. The discontinuous surfaces of shocks will produce the break and split of the interference fringes, which cannot be processed by the conventional path-following phase unwrapping algorithm when reconstructing the real phase of the plasma. Therefore, we used a least-squares method to extract the real phase, which is proportional to the line-integrated electron density. We obtained fine density profiles of collisionless shocks in the line-integrated density region around 1018 cm-2 with a density resolution of 3.38 × 1016 cm-2. The shock structure is in well agreement with that measured by the dark-field schlieren methods and that predicted by shock jump condition. Synthetic holograms are used to confirm the effectiveness of our algorithm, and it is shown that correct results can still be obtained even if part of the diagnostic light is refracted out of the optical system by the shock.

Case report: Differential diagnosis of highly amplified anti-CD5 CAR T cells and relapsed lymphoma cells in a patient with refractory ALK positive anaplastic large cell lymphoma.

Background: Anaplastic Large Cell Lymphoma (ALCL) is one of the most common subtypes of T-cell lymphoma. Among these, refractory and relapsed (r/r) ALK positive ALCL lacks effective therapies. The chimeric antigen receptor-modified T (CAR-T) cell therapy holds great promise as a therapeutic strategy for this disease. However, it is not known yet whether anti-CD5 CAR-T cells are sufficient for the definitive treatment of relapsed ALK+ ALCL, nor the role of accurate laboratory-based diagnoses during CAR-T treatment. Case presentation: The adolescent patient received autologous T cells containing sequences encoding VH domains specific to CD5. Following the infusion, there was an increase in both the copy number and proportion of CAR-T cells in peripheral blood. IL-6 and ferritin levels in the patient exhibited significant fluctuations, with increases of 13 and 70 folds respectively, compared to baseline after the treatment. Additionally, adverse effects were observed, including grade 4 rash, grade 1 headache, nausea, and neck-pain. Surprisingly, a relapsed disease phenotype was identified based on the results of PET/CT and histopathological analysis of the inguinal lymph node biopsy. After conducting a thorough diagnostic assessment, which included flow cytometry, next-generation sequencing (NGS), examination of immune-related gene rearrangements, and analysis of the immune repertoire of T-cell receptors (TCR), we conclusively determined that the hyperplastic T cells identified in the lymph node were the result of an expansion of CAR-T cells. Ultimately, the patient has attained complete remission (CR) and has sustained a disease-free survival state for 815 days as of the cutoff date on August 30, 2023. Conclusion: Taken together, the results demonstrate that anti-CD5 CAR-T cells can induce a clinical response in r/r ALK+ ALCL patient. Furthermore, this case underscores the importance of utilizing advanced technologies with high sensitivity and accuracy for biological detection in clinical laboratory diagnosis and prognosis in CAR-T cell treatment. Trial registration number: NCT04767308.

GAABind: a geometry-aware attention-based network for accurate protein-ligand binding pose and binding affinity prediction.

Protein-ligand interactions are increasingly profiled at high-throughput, playing a vital role in lead compound discovery and drug optimization. Accurate prediction of binding pose and binding affinity constitutes a pivotal challenge in advancing our computational understanding of protein-ligand interactions. However, inherent limitations still exist, including high computational cost for conformational search sampling in traditional molecular docking tools, and the unsatisfactory molecular representation learning and intermolecular interaction modeling in deep learning-based methods. Here we propose a geometry-aware attention-based deep learning model, GAABind, which effectively predicts the pocket-ligand binding pose and binding affinity within a multi-task learning framework. Specifically, GAABind comprehensively captures the geometric and topological properties of both binding pockets and ligands, and employs expressive molecular representation learning to model intramolecular interactions. Moreover, GAABind proficiently learns the intermolecular many-body interactions and simulates the dynamic conformational adaptations of the ligand during its interaction with the protein through meticulously designed networks. We trained GAABind on the PDBbindv2020 and evaluated it on the CASF2016 dataset; the results indicate that GAABind achieves state-of-the-art performance in binding pose prediction and shows comparable binding affinity prediction performance. Notably, GAABind achieves a success rate of 82.8% in binding pose prediction, and the Pearson correlation between predicted and experimental binding affinities reaches up to 0.803. Additionally, we assessed GAABind's performance on the severe acute respiratory syndrome coronavirus 2 main protease cross-docking dataset. In this evaluation, GAABind demonstrates a notable success rate of 76.5% in binding pose prediction and achieves the highest Pearson correlation coefficient in binding affinity prediction compared with all baseline methods.

Differential expression of circular RNAs in interleukin 6-promoted osteogenic differentiation of human stem cells from apical papilla.

INTRODUCTION: Studies have shown that interleukin 6 (IL-6) can regulate stem cell osteogenic differentiation; however, the exact mechanism is not clear. Circular RNAs (circRNAs) are closed circular non-coding RNAs that are involved in the process of stem cell osteogenic differentiation. Therefore, the purpose of this present study was to investigate the effect of IL-6 treatment on osteogenic differentiation of human apical tooth papillae stem cells (hSCAPs), and to detect the difference in circRNA expression using gene microarray technology. METHODS: After extraction and identification of hSCAPs, alkaline phosphatase (ALP) activity, alizarin red staining, and calcium ion quantitative assay were used to determine the changes of ALP enzyme, mineralized nodules, and matrix calcium levels before and after IL-6 treatment of hSCAPs gene microarray technology was used to analyze the changes in circRNA expression levels before and after IL-6 induction of mineralization. The four selected circRNAs were validated by qRT-PCR. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the potential functions and biological signaling pathways of circRNAs. Finally, these data are integrated and analyzed to construct circRNA-microRNA-mRNA networks. RESULTS: Alp and Alizarin red staining confirmed that IL-6 promoted the osteogenic differentiation of hSCAPs. The gene microarray results identified 132 differentially expressed circRNAs, of which 117 were upregulated and 15 were downregulated. Bioinformatic analysis predicted that the circRNA-406620/miR-103a-3p/FAT atypical cadherin 4 (FAT4) pathway might be involved in regulating IL-6 to promote osteogenic differentiation of hSCAPs. CONCLUSION: Differentially expressed circRNAs might be closely involved in regulating IL-6 to promote osteogenic differentiation of hSCAPs.

A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma.

BACKGROUND: Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report. METHODS: Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines. RESULTS: After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro. CONCLUSIONS: The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

Comparative study on main compounds and hypoglycemic effects of dispensing granules of Coptidis Rhizoma and Scutellaria-Coptis herb couple with traditional decoction.

BACKGROUND: The clinical applications of dispensing granules (DG) have increased dramatically. However, it is controversial whether the DG has the same quality and efficacy compared with traditional decoction (TD). In this study, the contents of main compounds, hypoglycemic effects, and potential mechanism of Coptidis Rhizoma (CR) and Scutellaria-coptis (SC), constituted of a 1:1 mixture of CR and Scutellariae Radix (SR), in the forms of TD and DG were compared. METHODS: The quantitative analysis was performed on an UPLC-PDA method. The 6-weeks-old male db/db mice were used as Type 2 Diabetes Mellitus (T2DM) mouse modle to investigate the antidiabetic effects of CR and SC in TD form (CR TD and SC TD), as well as CR and SC in DG form (CR DG and SC DG). RESULTS: The total content of five alkaloids in CR TD ranged from 71.00 to 78.62 mg, whereas in CR DG it ranged from 38.77 to 53.68 mg in CR DG per 1 g of decoction pieces. Compared to CR TD, CR DG exhibited a 36% reduction on average. For SC samples, the precipitation occurred in the processing of TD but not in the DG, and the relative ratio of alkaloids to flavonoids was determined to be 1:1 in TD and 1:2 in DG. Furthermore, the animal experiments showed that the CR DG (equivalent to 3 g decoction pieces/kg) had almost the same hypoglycemic effect as CR TD when they were administered for 6 weeks. Compared with SC DG (equivalent to 6 g decoction pieces/kg), SC TD showed a better trend in ameliorating T2DM via ameliorating pancreatic structure and function, and activating Akt/AMPK/GLUT4 signaling pathways. CONCLUSION: This study indicated that the contents of main compounds were generally higher in CR TD than CR DG originated from the same raw materials. Additionally, changes in the contents of the primary components validated that the compound interactions are exclusive to SC TD during co-decoction, rather than SC DG. The disparate prossing of SC DG and SC TD caused differences both in chemical composition and hypoglycemic effect, suggesting that the substitutability of DG and TD requires further research.

Research on the 3D Reverse Time Migration Technique for Internal Defects Imaging and Sensor Settings of Pressure Pipelines.

Although pressure pipelines serve as a secure and energy-efficient means of transporting oil, gas, and chemicals, they are susceptible to fatigue cracks over extended periods of cyclic loading due to the challenging operational conditions. Their quality and efficiency directly affect the safe operation of the project. Therefore, a thorough and precise characterization approach towards pressure pipelines can proactively mitigate safety risks and yield substantial economic and societal benefits. At present, the current mainstream 2D ultrasound imaging technology faces challenges in fully visualizing the internal defects and topography of pressure pipelines. Reverse time migration (RTM), widely employed in geophysical exploration, has the capability to visualize intricate geological structures. In this paper, we introduced the RTM into the realm of ultrasonic non-destructive testing, and proposed a 3D ultrasonic RTM imaging method for internal defects and sensor settings of pressure pipelines. To accurately simulate the extrapolation of wave field in 3D pressure pipelines, we set the absorbing boundary and double free boundary in cylindrical coordinates. Subsequently, using the 3D ultrasonic RTM approach, we attained higher-precision 3D imaging of internal defects in the pressure pipelines through suppressing imaging artifacts. By comparing and analyzing the imaging results of different sensor settings, the design of the observation system is optimized to provide a basis for the imaging and interpretation of actual data. Both simulations and actual field data demonstrate that our approach delivers top-notch 3D imaging of pipeline defects (with an imaging range accuracy up to 97.85%). This method takes into consideration the complexities of multiple scattering and mode conversions occurring at the base of the defects as well as the optimal sensor settings.

Molecular Mechanism Analysis of Protopine Against Triple Negative Breast Cancer.

In this study, we utilized a pharmacological network and bioinformatics approach to investigate the molecular mechanism underlying the resistance of Protopine (PRO) against Triple Negative Breast Cancer (TNBC). To uncover the underlying mechanism of PRO, we employed network pharmacology analysis. We collected and enriched targets using various databases such as TCMSP, SwissTargetPrediction, PubChem, Genecards, and DAVID. Furthermore, we constructed Potential targets network and components-disease-core targets network by STRING 11.5 and Cytoscape 3.7.1 to investigate the association of targets of PRO with disease targets of TNBC. The results of the network pharmacology approach indicated that PRO may play a key role in protein phosphorylation, protein autophosphorylation, Progesterone-mediated oocyte maturation signaling pathway, PI3K-Akt signaling pathway, and acting as targets such as PRKACA, JAK2, CDK2, LRRK2, CCNE1, KDR, JAK1. Our findings suggest that PRO exerts its effects against TNBC through multi-channel and multi-target mechanisms. Therefore, this study provides a basis for further research on the mechanism of action of PRO.