A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer.

Angiogenesis is an essential factor affecting the occurrence and development of solid tumors. SET And MYND Domain Containing 2 (SMYD2) serves as an oncogene in various cancers. However, whether SMYD2 is involved in tumor angiogenesis remains unclear. Here, we report that SMYD2 expression is associated with microvessel density in colorectal cancer (CRC) tissues. SMYD2 promotes CRC angiogenesis in vitro and in vivo. Mechanistically, SMYD2 physically interacts with HNRNPK and mediates lysine monomethylation at K422 of HNRNPK, which substantially increases RNA binding activity. HNRNPK acts by binding and stabilizing EGFL7 mRNA. As an angiogenic stimulant, EGFL7 enhances CRC angiogenesis. H3K4me3 maintained by PHF8 mediates the abnormal overexpression of SMYD2 in CRC. Moreover, targeting SMYD2 blocks CRC angiogenesis in tumor xenografts. Treatment with BAY-598, a functional inhibitor of SMYD2, can also synergize with apatinib in patient-derived xenografts. Overall, our findings reveal a new regulatory axis of CRC angiogenesis and provide a potential strategy for antiangiogenic therapy.

Progressive trajectories of schizophrenia across symptoms, genes, and the brain.

BACKGROUND: Schizophrenia is characterized by complex psychiatric symptoms and unclear pathological mechanisms. Most previous studies have focused on the morphological changes that occur over the development of the disease; however, the corresponding functional trajectories remain unclear. In the present study, we aimed to explore the progressive trajectories of patterns of dysfunction after diagnosis. METHODS: Eighty-six patients with schizophrenia and 120 healthy controls were recruited as the discovery dataset. Based on multiple functional indicators of resting-state brain functional magnetic resonance imaging, we conducted a duration-sliding dynamic analysis framework to investigate trajectories in association with disease progression. Neuroimaging findings were associated with clinical symptoms and gene expression data from the Allen Human Brain Atlas database. A replication cohort of patients with schizophrenia from the University of California, Los Angeles, was used as the replication dataset for the validation analysis. RESULTS: Five stage-specific phenotypes were identified. A symptom trajectory was characterized by positive-dominated, negative ascendant, negative-dominated, positive ascendant, and negative surpassed stages. Dysfunctional trajectories from primary and subcortical regions to higher-order cortices were recognized; these are associated with abnormal external sensory gating and a disrupted internal excitation-inhibition equilibrium. From stage 1 to stage 5, the importance of neuroimaging features associated with behaviors gradually shifted from primary to higher-order cortices and subcortical regions. Genetic enrichment analysis identified that neurodevelopmental and neurodegenerative factors may be relevant as schizophrenia progresses and highlighted multiple synaptic systems. CONCLUSIONS: Our convergent results indicate that progressive symptoms and functional neuroimaging phenotypes are associated with genetic factors in schizophrenia. Furthermore, the identification of functional trajectories complements previous findings of structural abnormalities and provides potential targets for drug and non-drug interventions in different stages of schizophrenia.

High-accuracy calibration method for an underwater one-mirror galvanometric laser scanner.

Three-dimensional (3D) perception of deep-sea targets is the key to autonomous operation of underwater equipment (e.g., underwater robots). Underwater one-mirror galvanometric line-laser scanner has advantages for short-range measurement, but it is difficult to achieve high calibration accuracy due to installation errors and refraction effects. For this reason, in this paper, a high-accuracy refraction-considered and installation-error-independent calibration method is proposed for the vision system. Firstly, to address the difficulty of aligning the incident light plane with the galvanometer shaft, a high-accuracy land-based installation-error-independent model is proposed, which avoids the influence of the installation errors and allows the real shaft axis and the light-plane cluster poses to be calculated using only three light planes. Subsequently, considering the underwater refraction, a 3D model is established for simulating refractive behaviors of the light-plane cluster, and then a partition-based method is proposed for calibrating the underwater light-plane cluster, which further improves the calibration accuracy of the scanner in underwater measurement scenarios. Finally, a one-mirror galvanometric laser scanner is developed in the laboratory to verify the calibration accuracy and to perform the 3D measurement experiments of underwater targets. The results show that the calibration accuracy of the proposed land-based installation-error-independent model is improved 2 times more compared with the traditional installation-error-dependent model. Additionally, the measurement accuracy of the scanner for the standard sphere is 11.98 µm and 12.75 µm in the air and underwater measurement scenarios, and the two measurements are in good agreement. The above results comprehensively verify the high accuracy of the calibration method proposed in this paper.

SMC1A facilitates gastric cancer cell proliferation, migration, and invasion via promoting SNAIL activated EMT.

BACKGROUND: Structural maintenance of chromosomes protein 1 A (SMC1A) is a crucial subunit of the cohesion protein complex and plays a vital role in cell cycle regulation, genomic stability maintenance, chromosome dynamics. Recent studies demonstrated that SMC1A participates in tumorigenesis. This reseach aims to explore the role and the underlying mechanisms of SMC1A in gastric cancer (GC). MATERIALS AND METHODS: RT-qPCR and western blot were used to examine the expression levels of SMC1A in GC tissues and cell lines. The role of SMC1A on GC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed. Furthermore,the mechanism of SMC1A action was investigated. RESULTS: SMC1A was highly expressed in GC tissues and cell lines. The high expression of SMC1A indicated the poor overall survival of GC patients from Kaplan-Meier Plotter. Enhancing the expression of SMC1A in AGS cells remarkably promoted cell proliferation in vitro and in vivo, migration and invasion, Conversely, knockdown of SMC1A in HGC27 cells inhibited cell proliferation, migration and invasion. Moreover, it's observed that SMC1A promoted EMT and malignant cell behaviors via regulating SNAIL. CONCLUSION: Our study revealed that SMC1A promotes EMT process by upregulating SNAIL, which contributes to gastric cancer cell proliferation, migration and invasion. Therefore, targeting SMC1A may be a potential strategy to improve GC therapy.

Hsa_circ_0007460 affects the survival of intracellular Mycobacterium tuberculosis by regulating autophagy and apoptosis of macrophages.

Circular RNA (circRNA) is a category of non-coding RNAs characterized by the absence of a 5'-cap and 3'-poly(A) tail, and participates in the physiological processes of various human diseases. Nonetheless, the diagnostic and functional significance of circRNAs in active pulmonary tuberculosis (ATB) remains uncertain. Consequently, the purpose of this study is to investigate whether hsa_circ_0007460 can be employed as a potential diagnostic biomarker in ATB patients and explore its function. The result of real-time quantitative fluorescent PCR (RT-qPCR) validated a notable increase in the expression of hsa_circ_0007460 in the peripheral blood of 32 ATB patients, as well as in THP-1 human macrophages infected with Bacillus Calmette Guerin (BCG) which is an attenuated strain of Mycobacterium bovis. Additionally, the receiver operating curve (ROC) illustrated that the area under the ROC curve (AUC), sensitivity and specificity were 0.7474, 76.67%, and 78.13% respectively. RNase R, Actinomycin D and other experiments confirmed that hsa_circ_0007460 was stabler than its linear mRNA, indicating that hsa_circ_0007460 has potential as a diagnostic biomarker of ATB. Furthermore, Western blot (WB), Cell Counting Kit-8 (CCK-8), plate counting, and immunofluorescence experiments revealed that hsa_circ_0007460 could regulate apoptosis and autophagy of macrophages. The downstream miRNAs and mRNAs were subsequently predicted using bioinformatics, and the hsa circ 0007460/hsa-miR-3127-5p/PATZ1 axis was built. These above results suggest that hsa_circ_0007460 is substantially up-regulated in the peripheral blood of patients with ATB and can be utilized as a potential diagnostic biomarker. In addition, hsa_circ_0007460 can promote apoptosis of macrophages and inhibit autophagy of macrophages, thereby promoting the survival of BCG.

Single-lens multi-mirror laser stereo vision-based system for measuring internal thread geometrical parameters.

Oilfield pipes with out-of-tolerance internal thread can lead to failures, so the internal thread geometric parameters need to be measured. To tackle the problem of the low efficiency, poor accuracy, easy wear, and poor accessibility of existing methods, a single-lens multi-mirror laser stereo vision-based system for measuring geometric parameters of the internal thread is proposed, which allows the measurement of three parameters in one setup by completely reproducing the three-dimensional (3D) tooth profiles of the internal thread. In the system design, to overcome the incomplete representation of imaging parameters caused by insufficient consideration of dimensions and structural parameters of the existing models, an explicit 3D optical path model without a reflecting prism is first proposed. Then, considering the intervention of the reflecting prism, a calculation model for the suitable prism size and the final imaging parameters of the vision system is proposed, which ensures the measurement accessibility and accuracy by solving the problem that the existing system design only depends on experience without theoretical basis. Finally, based on the American Petroleum Institute standard, internal thread geometric parameters are obtained from the vision-reconstructed 3D tooth profiles. According to the optimized structural parameters, a vision system is built for measuring the internal thread geometric parameters of two types of oilfield pipes. Accuracy verification and typical internal thread measurement results show that the average measurement errors of the vision system proposed for the pitch, taper, and tooth height are 0.0051 mm, 0.6055 mm/m, and 0.0071 mm, respectively. Combined with the vision measurement time of 0.5 s for the three parameters, the above results comprehensively verify the high accuracy and high efficiency of the vision-based system.

Vision measurement system for geometric parameters of tubing internal thread based on double-mirrored structured light.

Geometric parameter measurement of tubing internal thread is critical for oil pipeline safety. In response to the shortcomings of existing methods for measuring internal thread geometric parameters, such as low efficiency, poor accuracy, and poor accessibility, this paper proposes a vision system for measuring internal thread geometric parameters based on double-mirrored structured light. Compared to previous methods, our system can completely reproduce the internal thread tooth profiles and allows multi-parameter measurement in one setup. To establish the correlation between the structural and imaging parameters of the vision system, three-dimensional (3D) optical path models (OPMs) for the vision system considering the mirror effect of the prism is proposed, which extends the scope of the optical path analysis and provides a theoretical foundation for designing the structural parameters of the vision system. Moreover, modeling and three-step calibration methods for the vision system are proposed to realize high-accuracy restoration from the two-dimensional (2D) virtual image to the actual 3D tooth profiles. Finally, a vision measurement system is developed, and experiments are carried out to verify the accuracy and measure the three geometric parameters (i.e., taper, pitch, and tooth height) of typical internal threads. Based on the validation results using the reference system, the vision measurement accuracy and efficiency are 6.7 and 120 times that of the traditional system, which verifies the measurement effectiveness and accuracy of the vision system proposed in this paper.

Characteristics of disrupted topological organization in white matter functional connectome in schizophrenia.

BACKGROUND: Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function. METHODS: Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (ß) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks. RESULTS: At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and ß only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions. CONCLUSIONS: These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.

Characterization of multiple soluble immune checkpoints in individuals with different Mycobacterium tuberculosis infection status and dynamic changes during anti-tuberculosis treatment.

BACKGROUND: Immune checkpoints are crucial for the maintenance of subtle balance between self-tolerance and effector immune responses, but the role of soluble immune checkpoints (sICs) in Mycobacterium tuberculosis (M. tb) infection remains unknown. We assessed the levels of multiple sICs in individuals with distinct M. tb infection status, and their dynamic changes during anti-tuberculosis treatment. METHODS: We enrolled 24 patients with pulmonary tuberculosis, among which 10 patients were diagnosed with tuberculous pleurisy (TBP), 10 individuals with latent tuberculosis infection (LTBI), and 10 healthy volunteers from Wuxi Fifth People's Hospital and Huashan Hospital between February 2019 and May 2021. Plasma concentrations of thirteen sICs were measured at enrollment and during anti-tuberculosis treatment using luminex-based multiplex assay. sICs levels in tuberculous pleural effusion (TPE) and their relations to laboratory test markers of TPE were also assessed in TBP patients. RESULTS: The circulating levels of sPD-1, sPD-L1, sCTLA-4, sBTLA, sGITR, sIDO, sCD28, sCD27 and s4-1BB were upregulated in tuberculosis patients than in healthy controls. A lower sPD-L1 level was found in LTBI individuals than in tuberculosis patients. In TBP patients, the levels of sPD-1, sPD-L2, sCD28, sCD80, sCD27, sTIM-3, sLAG-3, sBTLA, s4-1BB and sIDO increased significantly in TPE than in plasma. In TPE, sBTLA and sLAG-3 correlated positively with the adenosine deaminase level. sIDO and sCD80 correlated positively with the lactate dehydrogenase level and the percentage of lymphocytes in TPE, respectively. Meanwhile, sCD27 correlated negatively with the specific gravity and protein level in TPE. In tuberculosis patients, the circulating levels of sBTLA and sPD-L1 gradually declined during anti-tuberculosis treatment. CONCLUSIONS: We characterized the changing balance of sICs in M. tb infection. And our results revealed the relations of sICs to laboratory test markers and treatment responses in tuberculosis patients, indicating that certain sICs may serve as potential biomarkers for disease surveillance and prognosis of tuberculosis.

A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains.

BACKGROUND: Antibiotic-resistant Gram-negative bacteria are becoming a major public health threat such as the important opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study investigated enhancement of the linezolid spectrum, which is normally used to treat Gram-positive bacteria, at inhibiting P. aeruginosa growth. METHODS: The checkerboard test or time-kill assay were carried out to determine the antibacterial effects of linezolid in cooperation with polymyxin B octapeptide PBOP (LP) against P. aeruginosa based on in vitro model. The protective effect of LP against P. aeruginosa infection was assessed based on a Caenorhabditis elegans (C. elegans) model. RESULTS: The synergistic activity and antibacterial effects were significantly increased against P. aeruginosa by LP treatment, while linezolid and PBOP as monotherapies exhibited no remarkably bactericidal activity against the clinical strains. Additionally, LP treatment modified biofilm production, morphology, swimming motility of P. aeruginosa, and protected C. elegans from P. aeruginosa infection. CONCLUSIONS: This research demonstrates that LP combination has significant synergistic activity against P. aeruginosa, and PBOP is potential to be an activity enhancer. Notably, this strategy improved the antibacterial activity spectrum of linezolid and other anti-Gram-positive agents and represents an effective choice to surmount the antibiotic resistance of bacteria in the long term.

Gracillin inhibits apoptosis and inflammation induced by lipopolysaccharide (LPS) to alleviate cardiac injury in mice via improving miR-29a.

Sepsis induces critical myocardial dysfunction, resulting in an increased mortality. Gracillin (GRA) is a natural steroidal saponin, showing strong capacities of anti-inflammation, but its pharmacological effects on lipopolysaccharide (LPS)-induced acute cardiac injury still remain unclear. In this study, we attempted to explore if GRA was effective to attenuate cardiac injury in LPS-challenged mice and the underlying mechanisms. First, we found that GRA treatments markedly up-regulated the expression of miR-29a in cardiomyocytes. LPS-induced cytotoxicity in cardiomyocytes was significantly alleviated by GRA treatment, as evidenced by the improved cell viability and reduced lactate dehydrogenase (LDH) release. In addition, LPS-triggered apoptotic cell death was clearly ameliorated in cardiomyocytes co-treated with GRA. Notably, LPS-exposed cells showed significantly reduced expression of miR-29a, while being rescued by GRA treatment. In vivo, LPS apparently impaired cardiac function in mice, which was, however, alleviated by GRA administration. In addition, GRA markedly attenuated apoptosis in hearts of LPS-challenged mice by decreasing the expression of cleaved Caspase-3. LPS-triggered inflammatory response in cardiac tissues was also suppressed by GRA through blocking nuclear factor κB (NF-κB) signaling pathway. We also found that miR-29a expression was highly reduced in hearts of LPS-treated mice but was rescued by GRA pretreatment. Besides, miR-29a mimic alleviated LPS-induced apoptosis and inflammation in cardiomyocytes; however, LPS-caused effects were further accelerated by miR-29a. Of note, the protective effects of GRA on LPS-injured cardiac tissues were significantly abrogated by miR-29a suppression. In conclusion, our findings demonstrated that GRA exerted an effective role against LPS-induced acute cardiac injury through impeding apoptosis and inflammation regulated by miR-29a.

A CRISPR-Cas9 system for multiple genome editing and pathway assembly in Candida tropicalis.

Genetic manipulation is among the most important tools for synthetic biology; however, modifying multiple genes is extremely time-consuming and can sometimes be impossible when dealing with gene families. Here, we present a clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein 9 (Cas9) system for use in the diploid yeast Candida tropicalis that is vastly superior to traditional techniques. This system enables the rapid and reliable introduction of multiple genetic deletions or mutations, as well as a stable expression using an integrated CRISPR-Cas9 cassette or a transient CRISPR-Cas9 cassette, together with a short donor DNA. We further show that the system can be used to promote the in vivo assembly of multiple DNA fragments and their stable integration into a target locus (or loci) in C. tropicalis. Based on this system, we present a platform for the biosynthesis of ß-carotene and its derivatives. These results enable the practical application of C. tropicalis and the application of the system to other organisms.

Development and evaluation of a rapid detection assay for severe fever with thrombocytopenia syndrome virus based on reverse-transcription recombinase polymerase amplification.

Rapid detection of severe fever with thrombocytopenia syndrome virus (SFTSV) is crucial for its control and surveillance. In this study, a rapid isothermal real-time reverse-transcription recombinase polymerase amplification (RT-RPA) assay was developed for the detection of SFTSV. The detection limit at 95% probability was 241 copies per reaction. A test of 120 serum samples of suspected severe fever with thrombocytopenia syndrome (SFTS) patients revealed that the sensitivity and specificity of the RT-RPA assay was approximately 96.00% (95%CI: 80.46%-99.79%) and 98.95% (95% CI: 94.28%-99.95%), respectively; the kappa value was 0.9495 (P＜0.001). The Bland-Altman analysis showed that 87.50% of the different data points were located within the 95% limits of agreement, indicating a good correlation between the results from RT-RPA assays and those of RT-qPCR assays. In conclusion, the rapid and efficient RT-RPA assay can be a promising candidate for point-of-care detection method of SFTSV.

MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40.

An increasing body of evidence indicates that inflammation and apoptosis are involved in the development of acute myocardial infarction (AMI). In this study, we sought to investigate the specific role and the underlying regulatory mechanism of miR-145-5p in myocardial ischemic injury. H9c2 cardiac cells were exposed to hypoxia to establish a model of myocardial hypoxic/ischemic injury. We found that miR-145-5p was notably down-regulated, while CD40 expression was highly elevated in H9c2 cells following exposure to acute hypoxia. Additionally, hypoxia markedly enhanced the inflammatory response, as reflected by an increase in the secretion of the cytokines IL-1ß, TNF-α, and IL-6, whereas the introduction of miR-145-5p effectively suppressed inflammatory factor production triggered by hypoxia. Furthermore, we observed hypoxia stimulation significantly augmented apoptosis accompanied by a decrease in the expression of Bcl-2 and an increase in the expression of Bax, Caspase-3, and Caspase-9. However, augmentation of miR-145-5p led to a dramatic prevention of hypoxia-induced apoptosis. Importantly, we identified CD40 as a direct target of miR-145-5p. Interestingly, the depletion of CD40 with small interfering RNAs (siRNAs) apparently repressed the production of inflammatory cytokines and apoptosis in the setting of acute hypoxic treated. Taken together, these data demonstrated that miR-145-5p may function as a cardiac-protective molecule in myocardial ischemic injury by ameliorating inflammation and apoptosis via negative regulation of CD40. The study gives evidence that miR-145-5p provides an interesting strategy for protecting cardiomyocytes from hypoxia-induced inflammatory response and apoptosis.

A novel prediction method about single components of analog circuits based on complex field modeling.

Few researches pay attention to prediction about analog circuits. The few methods lack the correlation with circuit analysis during extracting and calculating features so that FI (fault indicator) calculation often lack rationality, thus affecting prognostic performance. To solve the above problem, this paper proposes a novel prediction method about single components of analog circuits based on complex field modeling. Aiming at the feature that faults of single components hold the largest number in analog circuits, the method starts with circuit structure, analyzes transfer function of circuits, and implements complex field modeling. Then, by an established parameter scanning model related to complex field, it analyzes the relationship between parameter variation and degeneration of single components in the model in order to obtain a more reasonable FI feature set via calculation. According to the obtained FI feature set, it establishes a novel model about degeneration trend of analog circuits' single components. At last, it uses particle filter (PF) to update parameters for the model and predicts remaining useful performance (RUP) of analog circuits' single components. Since calculation about the FI feature set is more reasonable, accuracy of prediction is improved to some extent. Finally, the foregoing conclusions are verified by experiments.

Finite element study on three osteotomy methods for treating thoracolumbar osteoporotic fracture vertebral collapse complicated with neurological dysfunction.

BACKGROUND: Surgical methods for patients with osteoporotic fracture vertebral collapse complicated with neurological dysfunction are still a topic of debate. We designed an improved osteotomy for the treatment of osteoporotic compression fracture patients with neurological dysfunction. Compared with traditional osteotomy methods such as pedicle subtraction osteotomy (PSO) and bone-disc-bone osteotomy (BDBO), the osteotomy range is reduced. Therefore, we use a finite element method to analyze the biomechanical conditions of these three osteotomy methods and provide a mechanical theoretical basis for the surgical treatment of these three osteotomy methods. METHODS: Based on the CT scan of a patient with L1 osteoporotic fracture vertebral collapse and neurological dysfunction, the finite element model was constructed by importing Mimics software, and three different osteotomy models were established. The forces and displacements of internal fixation device, T1-L5 whole segment, T10 vertebral body, and T10/11 intervertebral disc were recorded under different working conditions. RESULTS: The displacement levels of internal fixation device, T1-L5 spine, T10 vertebral body, and T10/11 intervertebral disc in the modified osteotomy group were between BDBO group and PSO group. The stress in BDBO group was concentrated in titanium mesh and its maximum stress was much higher than that in PSO group and modified osteotomy group. The mechanical distribution of T10/11 intervertebral disc showed that the maximum stress distribution of the three osteotomy methods was similar. CONCLUSION: The relatively simple modified osteotomy has certain advantages in stress and displacement. In contrast, the stability of BDBO group was poor, especially in the lumbar intervertebral disc and lumbar body. For this type of osteotomy patients, it is recommended to avoid postoperative flexion so as not to increase the load.

Fully automated assessment of the future liver remnant in a blood-free setting via CT before major hepatectomy via deep learning.

OBJECTIVES: To develop and validate a deep learning (DL) model for automated segmentation of hepatic and portal veins, and apply the model in blood-free future liver remnant (FLR) assessments via CT before major hepatectomy. METHODS: 3-dimensional 3D U-Net models were developed for the automatic segmentation of hepatic veins and portal veins on contrast-enhanced CT images. A total of 170 patients treated from January 2018 to March 2019 were included. 3D U-Net models were trained and tested under various liver conditions. The Dice similarity coefficient (DSC) and volumetric similarity (VS) were used to evaluate the segmentation accuracy. The use of quantitative volumetry for evaluating resection was compared between blood-filled and blood-free settings and between manual and automated segmentation. RESULTS: The DSC values in the test dataset for hepatic veins and portal veins were 0.66 ± 0.08 (95% CI: (0.65, 0.68)) and 0.67 ± 0.07 (95% CI: (0.66, 0.69)), the VS values were 0.80 ± 0.10 (95% CI: (0.79, 0.84)) and 0.74 ± 0.08 (95% CI: (0.73, 0.76)), respectively No significant differences in FLR, FLR% assessments, or the percentage of major hepatectomy patients were noted between the blood-filled and blood-free settings (p = 0.67, 0.59 and 0.99 for manual methods, p = 0.66, 0.99 and 0.99 for automated methods, respectively) according to the use of manual and automated segmentation methods. CONCLUSION: Fully automated segmentation of hepatic veins and portal veins and FLR assessment via blood-free CT before major hepatectomy are accurate and applicable in clinical cases involving the use of DL. CRITICAL RELEVANCE STATEMENT: Our fully automatic models could segment hepatic veins, portal veins, and future liver remnant in blood-free setting on CT images before major hepatectomy with reliable outcomes. KEY POINTS: Fully automatic segmentation of hepatic veins and portal veins was feasible in clinical practice. Fully automatic volumetry of future liver remnant (FLR)% in a blood-free setting was robust. No significant differences in FLR% assessments were noted between the blood-filled and blood-free settings.

Activating CD8+ T Cells by Pt(IV) Prodrug-Based Nanomedicine and aPD-L1 Antibody for Enhanced Cancer Immunotherapy.

Recent years have witnessed substantial progress in cancer immunotherapy, specifically T cell-based therapies. However, the application of T cell therapies has been primarily limited to hematologic malignancies, with limited success in the treatment of solid tumors. The main challenge in treating solid tumor is immune escape, which is characterized by reduced antigenicity, diminished immunogenicity, and the development of suppressive tumor immune microenvironments. To address these obstacles and restore T cell-mediated anti-tumor responses, a novel nanoparticle formulation known as PRA@Oxa-c16 is developed. This innovative approach combines retinoic acid and Pt(IV) to specifically target and overcome immune escape. Notably, the therapeutic efficacy of PRA@Oxa-c16 primarily relies on its ability to induce anti-tumor T cell responses, in contrast to the cytotoxicity associated with conventional chemotherapeutic agents. When combined with an immune checkpoint blockade, anti-programmed death-ligand 1 antibody, PRA@Oxa-c16 effectively eliminates solid tumors and induces immune memory responses, which prevent tumor metastasis and recurrence. This promising approach holds great potential for enhancing the treatment of solid tumors with T cell-based immunotherapy.

The hsa_circ_0002371/hsa-miR-502-5p/ATG16L1 axis modulates the survival of intracellular Mycobacterium tuberculosis and autophagy in macrophages.

Circular RNAs (circRNAs) play a critical role in pathological mechanisms of Mycobacterium tuberculosis (Mtb) and can be used as a new biomarker for active tuberculosis (ATB) diagnosis. Therefore, we identified significantly dysregulated circRNAs in ATB patients and healthy controls (HC) and explored their molecular mechanism. We found that hsa_circ_0002371 was significantly up-regulated in PBMCs of ATB patients and Mycobacterium tuberculosis H37Rv- or Mycobacterium bovis bacillus Calmette Guerin (BCG)-infected THP-1 cells. Functional experiments demonstrated that hsa_circ_0002371 inhibited autophagy in BCG-infected THP-1 cells and promoted intracellular BCG survival rate. In terms of mechanism, hsa_circ_0002371 facilitated the expression of hsa-miR-502-5p, as shown by bioinformatics and dual-luciferase reporter gene analysis, respectively. Notably, hsa-miR-502-5p inhibited autophagy via suppressing autophagy related 16 like 1 (ATG16L1) in BCG-infected macrophages and thus promoting intracellular BCG growth. In summation, hsa_circ_0002371 increased the suppression of hsa-miR-502-5p on ATG16L1 and inhibited autophagy to promote Mtb growth in macrophages. In Conclusion, our data suggested that hsa_circ_0002371 was significantly up-regulated in the PBMCs of ATB patients compared with HC. The hsa_circ_0002371/hsa-miR-502-5p/ATG16L1 axis promoted the survival of intracellular Mtb and inhibited autophagy in macrophages. Our findings suggested hsa_circ_0002371 could act as a potential diagnostic biomarker and therapeutic target.