Assessment of central nervous system vasculitis in children based on high-resolution vascular wall imaging.

Objectives: Central nervous system vasculitis (CNSV) is a rare disease. High-resolution vessel wall imaging (HR-VWI) enables the identification of inflammatory changes within the vessel wall. Few studies have applied HR-VWI to assess CNSV in children. This study delves into the utility of HR-VWI for diagnosing and treating CNSV in children, with the aim of enhancing clinical diagnosis and efficacy evaluation. Methods: Imaging data were acquired from children who underwent HR-VWI examinations. The study meticulously analysed clinical data and laboratory tests to discern the characteristics and distribution patterns of diverse vasculitis forms. Results: In children, CNSV mainly involves medium vessels with grade 1 and 2 stenosis (grade 4 stenosis is rare), and the imaging features generally show centripetal and moderate enhancement, suggesting that this feature is specific for the diagnosis of CNSV. High-grade stenosis, concentric enhancement and strong enhancement of the vasculature indicate more severe disease activity. Remarkably, HR-VWI proved to be significantly more sensitive than magnetic resonance angiography in detecting CNSV. Among the 13 cases subjected to imaging review, 8 demonstrated a reduction or resolution of vessel wall inflammation. In contrast, five patients exhibited worsening inflammation in the vessel wall. HR-VWI demonstrated that changes in vessel wall inflammation were closely correlated with changes in brain parenchymal lesions and symptoms. Conclusion: This study underscores the diagnostic value of HR-VWI in CNSV assessment and treatment monitoring, offering a quantitative evaluation of CNSV in children.

Excavation method optimization and mechanical responses investigating of a shallow buried super large section tunnels: a case study in Zhejiang.

The construction of super large section (SLS) shallow buried tunnels involves challenges related to their large span, high flat rate, and complex construction process. Selecting an appropriate excavation method is crucial for ensuring stability, controlling costs, and managing the construction timeline. This study focuses on the selection of excavation methods and the mechanical responses of SLS tunnels in different types of surrounding rock. The research is based on the Yangjiashan tunnel project in Zhejiang Province, China, which is a four-line highway tunnel with a span of 21.3 m. Three sequential excavation methods were proposed and simulated using the three-dimensional finite difference method: the "upper first and lower later" side drift (SD) method, the central diaphragm method, and the top heading and bench (HB) method. The mechanical response characteristics of tunnel construction under these methods were investigated, including rock deformation, rock pressure, and the internal forces acting on the primary support. By comparing the performance of the three construction methods in rock masses of Grades III to V, the study aimed to determine the optimal construction method for SLS tunnels considering factors such as safety, cost, and schedule. Field tests were conducted to evaluate the effectiveness of the optimized construction scheme. The results of the field monitoring indicated that the "upper first and lower later" SD method in Grade V rock mass and the HB method in Grade III to IV rock mass are feasible and cost-effective under certain conditions. The research findings provide valuable insights for the design and construction of SLS tunnels in complex conditions, serving as a reference for engineers and project managers.

Mechanosensitive channel MscL gating transitions coupling with constriction point shift.

The mechanosensitive channel of large conductance (MscL) acts as an "emergency release valve" that protects bacterial cells from acute hypoosmotic stress, and it serves as a paradigm for studying the mechanism underlying the transduction of mechanical forces. MscL gating is proposed to initiate with an expansion without opening, followed by subsequent pore opening via a number of intermediate substates, and ends in a full opening. However, the details of gating process are still largely unknown. Using in vivo viability assay, single channel patch clamp recording, cysteine cross-linking, and tryptophan fluorescence quenching approach, we identified and characterized MscL mutants with different occupancies of constriction region in the pore domain. The results demonstrated the shifts of constriction point along the gating pathway towards cytoplasic side from residue G26, though G22, to L19 upon gating, indicating the closed-expanded transitions coupling of the expansion of tightly packed hydrophobic constriction region to conduct the initial ion permeation in response to the membrane tension. Furthermore, these transitions were regulated by the hydrophobic and lipidic interaction with the constricting "hot spots". Our data reveal a new resolution of the transitions from the closed to the opening substate of MscL, providing insights into the gating mechanisms of MscL.

Development and validation of a major adverse limb events prediction model for peripheral arterial disease with frailty.

OBJECTIVE: To investigate the risk factors for major limb adverse events (MALE) in peripheral arterial disease (PAD) combined with frailty and to develop and validate a risk prediction model of MALE. METHODS: This prospective study was performed in the vascular surgery department of patients in six hospitals in southwest China. Prospective collection of patients with PAD combined with frailty from February 1 to December 20, 2021, with MALE as the primary outcome, and followed for 1 year. The cohort was divided into a development cohort and a validation cohort. In the development cohort, a multivariate risk prediction model was developed to predict MALE using random forests for variable selection and multivariable Cox regression analysis. The model is represented by a visualized nomogram and a web-based calculator. The model performance was tested with the validation cohort and assessed using the C-statistic and calibration plots. RESULTS: A total of 1179 patients were prospectively enrolled from February 1 to December 20, 2021. Among 816 patients with PAD who were included in the analysis, the median follow-up period for this study was 9 ± 4.07 months, the mean age was 74.64 ± 9.43 years, and 249 (30.5%) were women. Within 1 year, 222 patients (27.2%) developed MALE. Target lesion revascularizations were performed in 99 patients (12.1%), and amputations were performed in 131 patients (16.1%). The mortality rate within the whole cohort was 108 patients (13.2%). After controlling for competing risk events (death), the cumulative risk of developing MALE was not statistically different. Prealbumin (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.41-0.89; P = .010), percutaneous coronary intervention (HR, 2.31; 95% CI, 1.26-4.21; P = .006), Rutherford classification (HR, 1.77; 95% CI, 1.36-2.31; P < .001), white blood cell (HR, 1.85; 95% CI, 1.20-2.87; P = .005), high altitude area (HR, 3.1; 95% CI, 1.43-6.75; P = .004), endovascular treatment (HR, 10.2; 95% CI, 1.44-72.50; P = .020), and length of stay (HR, 1.01; 95% CI, 1.00-1.03; P = .012) were risk factors for MALE. The MALE prediction model had a C-statistic of 0.76 (95% CI, 0.70-0.79). The C-statistic was 0.68 for internal validation and 0.66 for external validation for the MALE prediction model. The MALE prediction model for PAD presented an interactive nomogram and a web-based network calculator. CONCLUSIONS: In this study, the MALE prediction model has a discriminative ability to predict MALE among patients with PAD in frailty. The MALE model can optimize clinical decision-making for patients with PAD in frailty.

OsJAZ4 Fine-Tunes Rice Blast Resistance and Yield Traits.

JAZ proteins function as transcriptional regulators that form a jasmonic acid-isoleucine (JA-Ile) receptor complex with coronatine insensitive 1 (COI1) and regulate plant growth and development. These proteins also act as key mediators in signal transduction pathways that activate the defense-related genes. Herein, the role of OsJAZ4 in rice blast resistance, a severe disease, was examined. The mutation of OsJAZ4 revealed its significance in Magnaporthe oryzae (M. oryzae) resistance and the seed setting rate in rice. In addition, weaker M. oryzae-induced ROS production and expression of the defense genes OsO4g10010, OsWRKY45, OsNAC4, and OsPR3 was observed in osjaz4 compared to Nipponbare (NPB); also, the jasmonic acid (JA) and gibberellin4 (GA4) content was significantly lower in osjaz4 than in NPB. Moreover, osjaz4 exhibited a phenotype featuring a reduced seed setting rate. These observations highlight the involvement of OsJAZ4 in the regulation of JA and GA4 content, playing a positive role in regulating the rice blast resistance and seed setting rate.

Pharmacological profiling of a berbamine derivative for lymphoma treatment.

ABSTRACT: Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared with BBM, PA4 showed improved potency and specificity and was more cytotoxic against lymphoma and leukemia than against other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased reactive oxygen species production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model. Pharmacokinetics studies demonstrated quick absorption into plasma after oral administration, with a maximum concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hours. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma.

A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity.

Mechanosensitive (MS) ion channels are a ubiquitous type of molecular force sensor sensing forces from the surrounding bilayer. The profound structural diversity in these channels suggests that the molecular mechanisms of force sensing follow unique structural blueprints. Here we determine the structures of plant and mammalian OSCA/TMEM63 proteins, allowing us to identify essential elements for mechanotransduction and propose roles for putative bound lipids in OSCA/TMEM63 mechanosensation. Briefly, the central cavity created by the dimer interface couples each subunit and modulates dimeric OSCA/TMEM63 channel mechanosensitivity through the modulating lipids while the cytosolic side of the pore is gated by a plug lipid that prevents the ion permeation. Our results suggest that the gating mechanism of OSCA/TMEM63 channels may combine structural aspects of the 'lipid-gated' mechanism of MscS and TRAAK channels and the calcium-induced gating mechanism of the TMEM16 family, which may provide insights into the structural rearrangements of TMEM16/TMC superfamilies.

Facile Synthesis of ZrO2-SiO2 Antireflective Films with Good Mechanical Performances for Perovskite Solar Cells.

Antireflective (AR) films are widely applied in solar cells to reduce the reflectivity toward sunlight, thus improving the photoelectric conversion efficiency (PCE) of solar cells. However, AR films are still suffering from poor mechanical properties and low transmittance in photovoltaic applications. Herein, a ZrO2-SiO2 composite film with enhanced mechanical properties was successfully synthesized by a facile sol-gel method, whose pencil hardness increased from less than 6B to B compared with the pure SiO2 film synthesized with the same alkali-catalyzed method. Moreover, the ZrO2-SiO2 film with a Zr/Si mole ratio (nZr/Si) of 0.06 exhibited a high transmittance gain (ΔT) of 3.0%, and an obvious increase (1.32%) in PCE was observed in a perovskite solar cell compared with the cell covered by a bare glass. Additionally, both the short-circuit current density (JSC) and PCE of perovskite solar cells have a non-linear increasing relationship with the average transmittance (Tavg) of the ZrO2-SiO2 composite film. In this sense, this work can provide a facile way to prepare AR films effectively improving performances of solar cells.

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel.

The transmembrane voltage gradient is a general physico-chemical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of the selectivity filter and ion permeation pathway with delayed rectifier properties and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464 and Q472 from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional potassium ion occupied at positions S6 confers the delayed rectifier property and Cole-Moore effects. These results provide insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.

Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells.

Reduced responsiveness of precursor B-acute lymphoblastic leukemia (BCP-ALL) to chemotherapy can be inferred when leukemia cells persist after 28 days of initial treatment. Survival of these long-term persister (LTP) / minimal residual disease (MRD) cells is partly due to bone marrow stromal cells that protect them under conditions of chemotherapy stress. We used RNA-seq to analyse BCP-ALL cells that survived a long-term, 30-day vincristine chemotherapy treatment while in co-culture with bone marrow stromal cells. RNAs of as many as 10% of the protein-encoding genes were differentially expressed. There was substantial overlap with genes associated with MRD cell persistence reported in other studies. The top pathway regulated in the LTP cells was that involving p53, a master regulator of a spectrum of responses relevant to drug resistance and cytotoxic drug exposure including control of autophagy. We tested a select number of genes for contribution to BCP-ALL cell survival using Cas9/CRISPR in a 2-step selection, initially for overall effect on cell fitness, followed by 21 days of exposure to vincristine. Many genes involved in autophagy and lysosomal function were found to contribute to survival both at steady-state and during drug treatment. We also identified MYH9, NCSTN and KIAA2013 as specific genes contributing to fitness of BCP-ALL cells. CD44 was not essential for growth under steady state conditions but was needed for survival of vincristine treatment. Finally, although the drug transporter ABCC1/MRP1 is not overexpressed in BCP-ALL, a functional gene was needed for DTP cells to survive treatment with vincristine. This suggests that addition of possible ABCC1 inhibitors during induction therapy could provide benefit in eradication of minimal residual disease in patients treated with a chemotherapy regimen that includes vincristine.

Improving the Quality of Maternity Care: Learning From Malpractice.

OBJECTIVE: This study aimed to depict the characteristics, injury outcomes, and payment of obstetric malpractice lawsuits to better understand the medicolegal burden in obstetrics and categorize the causes of obstetric malpractice lawsuits using The National Health Service Litigation Authority coding taxonomy for further quality improvement in maternity care. METHODS: We reviewed and retrieved key information on court records of legal trials from China Judgment Online between 2013 and 2021. RESULTS: A total of 3441 obstetric malpractice lawsuits successfully claimed were reviewed in this study, with a total indemnity payment of $139,875,375. After peaking in 2017, the number of obstetric malpractice claims begins to decline. Of the 2424 hospitals that were sued, 8.3% (201/2424) were referred to as "repeat defendant" because they were involved in multiple lawsuits. Death and injury were the outcomes in 53.4% and 46.6% of the cases, respectively. The most common outcome type was neonatal death, which made up 29.8% of all cases. The median indemnity payment for death was higher compared with injury ( P < 0.05). In terms of detailed injury outcomes, the major neonatal injury had higher median indemnity payments than neonatal death and fetal death ( P < 0.05). The median indemnity payment of the major maternal injury was higher than that of maternal death ( P < 0.05). The leading causes of obstetric malpractice were the management of birth complications and adverse events (23.3%), management of labor (14.4%), career decision making (13.7%), fetal surveillance (11.0%), and cesarean section management (9.5%). The cause for 8.7% of cases was high payment (≥$100, 000). As indicated by the results of the multivariate analysis, the hospitals in the midland of China (odds ratio [OR], 0.476; 95% confidence interval [CI], 0.348-0.651), the hospitals in the west of China (OR, 0.523; 95% CI, 0.357-0.767), and the secondary hospitals (OR, 0.587; 95% CI, 0.356-0.967) had lower risks of high payment. Hospitals with ultimate liability (OR, 9.695; 95% CI, 4.072-23.803), full liability (OR, 16.442; 95% CI, 6.231-43.391), major neonatal injury (OR, 12.326; 95% CI, 5.836-26.033), major maternal injury (OR, 20.885; 95% CI, 7.929-55.011), maternal death (OR, 18.783; 95% CI, 8.887-39.697), maternal death with child injury (OR, 54.682; 95% CI, 10.900-274.319), maternal injury with child death (OR, 6.935; 95% CI, 2.773-17.344), and deaths of both mother and child (OR, 12.770; 95% CI, 5.136-31.754) had higher risks of high payment. In the causative domain, only anesthetics had a higher risk of high payment (OR, 5.605; 95% CI, 1.347-23.320), but anesthetic-related lawsuits made up just 1.4% of all cases. CONCLUSIONS: The healthcare systems had to pay a significant amount as a result of obstetric malpractice lawsuits. Greater efforts are required to minimize serious injury outcomes and improve obstetric quality in the risky domains.

RLSegNet: An Medical Image Segmentation Network Based on Reinforcement Learning.

In the area of medical image segmentation, the spatial information can be further used to enhance the image segmentation performance. And the 3D convolution is mainly used to better utilize the spatial information. However, how to better utilize the spatial information in the 2D convolution is still a challenging task. In this paper, we propose an image segmentation network based on reinforcement learning (RLSegNet), which can translate the image segmentation process into a serial of decision-making problem. The proposed RLSegNet is a U-shaped network, which is composed of three components: the feature extraction network, the Mask Prediction Network (MPNet), and the up-sampling network with the cascade attention module. The deep semantic feature in the image is first extracted by adopting the feature extraction network. Then, the Mask Prediction Network (MPNet) is proposed to generate the prediction mask for the current frame based on the prior knowledge (segmentation result). And the proposed cascade attention module is mainly used to generate the weighted feature mask so that the up-sampling network pays more attention to the interesting region. Specifically, the state, action and reward used in the reinforcement learning are redesigned in the proposed RLSegNet to translate the segmentation process as the decision-making process, which performs as the reinforcement learning to realize the brain tumor segmentation. Extensive experiments are conducted on the BRATS 2015 dataset to evaluate the proposed RLSegNet. The experimental results demonstrate that the proposed method can achieve a better segmentation performance, in comparison with other state-of-the-art methods.

SINR- and MI-Based Double-Robust Waveform Design.

Owing to cognitive radar breaking the open-loop receiving-transmitting mode of traditional radar, adaptive waveform design for cognitive radar has become a central issue in radar system research. In this paper, the method of radar transmitted waveform design in the presence of clutter is studied. Since exact characterizations of the target and clutter spectra are uncommon in practice, a single-robust transmitted waveform design method is introduced to solve the problem of the imprecise target spectrum or the imprecise clutter spectrum. Furthermore, considering that radar cannot simultaneously obtain precise target and clutter spectra, a novel double-robust transmitted waveform design method is proposed. In this method, the signal-to-interference-plus-noise ratio and mutual information are used as the objective functions, and the optimization models for the double-robust waveform are established under the transmitted energy constraint. The Lagrange multiplier method was used to solve the optimal double-robust transmitted waveform. The simulation results show that the double-robust transmitted waveform can maximize SINR and MI in the worst case; the performance of SINR and MI will degrade if other transmitted waveforms are employed in the radar system.

Galectin-1 and Galectin-3 in B-Cell Precursor Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP-ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 are lectins with overlapping specificity for binding polyLacNAc glycans. Both are expressed by bone marrow stromal cells and by hematopoietic cells but show different patterns of expression, with Galectin-3 dynamically regulated by extrinsic factors such as chemotherapy. In a comparison of Galectin-1 x Galectin-3 double null mutant to wild-type murine BCP-ALL cells, we found reduced migration, inhibition of proliferation, and increased sensitivity to drug treatment in the double knockout cells. Plant-derived carbohydrates GM-CT-01 and GR-MD-02 were used to inhibit extracellular Galectin-1/-3 binding to BCP-ALL cells in co-culture with stromal cells. Treatment with these compounds attenuated migration of the BCP-ALL cells to stromal cells and sensitized human BCP-ALL cells to vincristine and the targeted tyrosine kinase inhibitor nilotinib. Because N-glycan sialylation catalyzed by the enzyme ST6Gal1 can regulate Galectin cell-surface binding, we also compared the ability of BCP-ALL wild-type and ST6Gal1 knockdown cells to resist vincristine treatment when they were co-cultured with Galectin-1 or Galectin-3 knockout stromal cells. Consistent with previous results, stromal Galectin-3 was important for maintaining BCP-ALL fitness during chemotherapy exposure. In contrast, stromal Galectin-1 did not significantly contribute to drug resistance, and there was no clear effect of ST6Gal1-catalysed N-glycan sialylation. Taken together, our results indicate a complicated joint contribution of Galectin-1 and Galectin-3 to BCP-ALL survival, with different roles for endogenous and stromal produced Galectins. These data indicate it will be important to efficiently block both extracellular and intracellular Galectin-1 and Galectin-3 with the goal of reducing BCP-ALL persistence in the protective bone marrow niche during chemotherapy.

Targeting disordered-structured domain interactions in Galectin-3 based on NMR and enhanced MD.

Intrinsically disordered regions (IDRs) are common and important functional domains in many proteins. However, IDRs are difficult to target for drug development due to the lack of defined structures that would facilitate the identification of possible drug-binding pockets. Galectin-3 is a carbohydrate-binding protein of which overexpression has been implicated in a wide variety of disorders, including cancer and inflammation. Apart from its carbohydrate-recognition/binding domain (CRD), Galectin-3 also contains a functionally important disordered N-terminal domain (NTD) that contacts the C-terminal domain (CTD) and could be a target for drug development. To overcome challenges involved in inhibitor design due to lack of structure and the highly dynamic nature of the NTD, we used a protocol combining nuclear magnetic resonance data from recombinant Galectin-3 with accelerated molecular dynamics (MD) simulations. This approach identified a pocket in the CTD with which the NTD makes frequent contact. In accordance with this model, mutation of residues L131 and L203 in this pocket caused loss of Galectin-3 agglutination ability, signifying the functional relevance of the cavity. In silico screening was used to design candidate inhibitory peptides targeting the newly discovered cavity, and experimental testing of only three of these yielded one peptide that inhibits the agglutination promoted by wild-type Galectin-3. NMR experiments further confirmed that this peptide indeed binds to a cavity in the CTD, not within the actual CRD. Our results show that it is possible to apply a combination of MD simulations and NMR experiments to precisely predict the binding interface of a disordered domain with a structured domain, and furthermore use this predicted interface for designing inhibitors. This procedure can potentially be extended to many other targets in which similar IDR interactions play a vital functional role.

Embigin facilitates monocarboxylate transporter 1 localization to the plasma membrane and transition to a decoupling state.

Cell-surface ancillary glycoproteins basigin or embigin form heterodimeric complexes with proton-coupled monocarboxylate transporters (MCTs), facilitating the membrane trafficking of MCTs and regulating their transport activities. Here, we determine the cryoelectron microscopy (cryo-EM) structure of the human MCT1-embigin complex and observe that embigin forms extensive interactions with MCT1 to facilitate its localization to the plasma membrane. In addition, the formation of the heterodimer effectively blocks MCT1 from forming a homodimer through a steric hindrance effect, releasing the coupling between two signature motifs and driving a significant conformation change in transmembrane helix 5 (TM5) of MCTs. Consequently, the substrate-binding pocket alternates between states of homodimeric coupling and heterodimeric decoupling states and exhibits differences in substrate-binding affinity, supporting the hypothesis that the substrate-induced motion originating in one subunit of the MCT dimer could be transmitted to the adjacent subunit to alter its substrate-binding affinity.

A miRNA-mediated attenuation of hepatocarcinogenesis in both hepatocytes and Kupffer cells.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate a variety of physiological and pathological functions. miR-26a is one of the many miRNAs that have been identified as regulators of cancer development and as potential anticancer drug targets. However, the specific cellular and molecular mechanisms by which miR-26a attenuates hepatocarcinogenesis are still elusive. Here, we interrogated mouse models with miR-26a cell-specific overexpression in either hepatocytes or myeloid cells to show that miR-26a strongly attenuated the chemical-induced hepatocellular carcinoma (HCC). miR-26a overexpression broadly inhibited the inflammatory response in both hepatocytes and macrophages by decreasing several key oncogenic signaling pathways in HCC promotion. These findings thus reveal new insights into a concerted role of miR-26a in both hepatocytes and Kupffer cells to suppress hepatocarcinogenesis, thereby highlighting the potential use of miR-26a mimetics as potential approaches for the prevention and treatment of HCC.

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia.

Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of ST6GAL1 at diagnosis, with high ST6Gal1 in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates.

Enhanced Performance of Carbon-Selenide Composite with La0.9Ce0.1NiO3 Perovskite Oxide for Outstanding Counter Electrodes in Platinum-Free Dye-Sensitized Solar Cells.

For large-scale applications, dye-sensitized solar cells (DSSCs) require the replacement of the scarce platinum (Pt)-based counter electrode (CE) with efficient and cheap alternatives. In this respect, low-cost perovskite oxides (ABO3) have been introduced as promising additives to composite-based CEs in Pt-free DSSCs. Herein, we synthesized composites from La0.9Ce0.1NiO3 (L) perovskite oxide and functionalized-multiwall-carbon-nanotubes wrapped in selenides derived from metal-organic-frameworks (f-MWCNT-ZnSe-CoSe2, "F"). L and F were then mixed with carbon black (CB) in different mass ratios to prepare L@CB, F@CB, and L@F@CB composites. The electrochemical analysis revealed that the L@F@CB composite with a mass ratio of 1.5:3:1.5 exhibits better electrocatalytic activity than Pt. In addition, the related DSSC reached a better PCE of 7.49% compared to its Pt-based counterpart (7.09%). This improved performance is the result of the increase in the oxygen vacancy by L due to the replacement of La with Ce in its structure, leading to more active sites in the L@F@CB composites. Moreover, the F@CB composite favors the contribution to the high electrical conductivity of the hybrid carbon nanotube-carbon black, which also offers good stability to the L@F@CB CE by not showing any obvious change in morphology and peak-to-peak separation even after 100 cyclic voltammetry cycles. Consequently, the corresponding L@F@CB-based device achieved enhanced stability. Our work demonstrates that L@F@CB composites with a low cost are excellent alternatives to Pt CE in DSSCs.

Apparent Diffusion Coefficient as a Noninvasive Biomarker for the Early Response in Hepatocellular Carcinoma After Transcatheter Arterial Chemoembolization Using Drug-eluting Beads.

BACKGROUND: Prognostic evaluation for Hepatocellular Carcinoma (HCC) after Transcatheter Arterial Chemoembolization (TACE) using Drug-Eluting Beads (DEBs) is essential for guiding the personalized treatment and follow-up strategy. Apparent Diffusion Coefficient (ADC) has been reported as a biomarker in conventional TACE. OBJECTIVE: This study aimed to evaluate the diagnostic value of ADCbaseline, ADC change, and ADCratio in predicting the early objective response for HCC after DEB-TACE. METHODS: This prospective single-center study included 32 consecutive patients undergoing dynamic contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging before and 1 month after DEB-TACE. After DEB-TACE, patients were grouped based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria into responders (complete response [CR], partial response [PR]) and nonresponders (stable disease [SD], progressive disease [PD]). The Mann- Whitney U test and receiver operating characteristic (ROC) curves were performed to assess the statistical differences in ADCbaseline, ADC change, and ADCratio between responders and nonresponders. RESULTS: At post-DEB-TACE follow-up MRI, 62.5% (n = 20, 11 CRs, and 9 PRs) of patients showed objective response, and 37.5% (n = 12, 7 SDs, and 5 PDs) did not respond to chemoembolization. Nonresponders had a significantly higher ADCbaseline value than responders (p < 0.001). The ROC for identifying the response to chemoembolization demonstrated that the threshold ADCbaseline value of 0.920 × 10-3 mm2/s had 100% sensitivity and 70% specificity. The ADC change and ADCratio of responders were higher than that of nonresponders (p < 0.001). CONCLUSION: ADCbaseline, ADC change, and ADCratio may be utilized as a noninvasive biomarker for predicting the early response of HCC to DEB-TACE.