Search Results (19)

Background: Macrophage-mediated cancer cell phagocytosis has demonstrated considerable therapeutic potential. While the initiation of phagocytosis, facilitated by interactions between cancer cell surface signals and macrophage receptors, has been characterized, the mechanisms underlying its sustentation and attenuation post-initiation remain poorly understood. Methods: Through comprehensive phosphoproteomic profiling, we interrogated the temporal evolution of the phosphorylation profiles within macrophages during cancer cell phagocytosis. Results: Our findings reveal that activation of the mTOR pathway occurs following the initiation of phagocytosis and is crucial in sustaining phagocytosis of cancer cells. mTOR inhibition impaired the phagocytic capacity, but not affinity, of the macrophages toward the cancer cells by delaying phagosome maturation and impeding the transition between non-phagocytic and phagocytic states of macrophages. Conclusions: Our findings delineate the intricate landscape of macrophage phagocytosis and highlight the pivotal role of the mTOR pathway in mediating this process, offering valuable mechanistic insights for therapeutic interventions. Full article

The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the β-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1—a key insulin signaling gene—significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit. Full article

Flexible multielectrode arrays with glassy carbon (GC) electrodes and metal interconnection (hybrid MEAs) have shown promising performance in multi-channel neurochemical sensing. A primary challenge faced by hybrid MEAs fabrication is the adhesion of the metal traces with the GC electrodes, as prolonged electrical and mechanical stimulation can lead to adhesion failure. Previous devices with GC electrodes and interconnects made of a homogeneous material (all GC) demonstrated exceptional electrochemical stability but required miniaturization for enhanced tissue integration and chronic electrochemical sensing. In this study, we used two different methods for the fabrication of all GC-MEAs on thin flexible substrates with miniaturized features. The first method, like that previously reported, involves a double pattern-transfer photolithographic process, including transfer-bonding on temporary polymeric support. The second method requires a double-etching process, which uses a 2 µm-thick low stress silicon nitride coating of the Si wafer as the bottom insulator layer for the MEAs, bypassing the pattern-transfer and demonstrating a novel technique with potential advantages. We confirmed the feasibility of the two fabrication processes by verifying the practical conductivity of 3 µm-wide 2 µm-thick GC traces, the GC microelectrode functionality, and their sensing capability for the detection of serotonin using fast scan cyclic voltammetry. Through the exchange and discussion of insights regarding the strengths and limitations of these microfabrication methods, our goal is to propel the advancement of GC-based MEAs for the next generation of neural interface devices. Full article

Technological advances in MRI-guided radiation therapy (MRIgRT) have improved real-time visualization of the prostate and its surrounding structures over CT-guided radiation therapy. Seminal studies have demonstrated safe dose escalation achieved through ultrahypofractionation with MRIgRT due to planning target volume (PTV) margin reduction and treatment gating. On-table adaptation with MRI-based technologies can also incorporate real-time changes in target shape and volume and can reduce high doses of radiation to sensitive surrounding structures that may move into the treatment field. Ongoing clinical trials seek to refine ultrahypofractionated radiotherapy treatments for prostate cancer using MRIgRT. Though these studies have the potential to demonstrate improved biochemical control and reduced side effects, limitations concerning patient treatment times and operational workflows may preclude wide adoption of this technology outside of centers of excellence. In this review, we discuss the advantages and limitations of MRIgRT for prostate cancer, as well as clinical trials testing the efficacy and toxicity of ultrafractionation in patients with localized or post-prostatectomy recurrent prostate cancer. Full article

Deflectometry is a non-destructive, full-field phase measuring method, which is usually used for inspecting optical specimens with special characteristics, such as highly reflective or specular surfaces, as well as free-form surfaces. One of the important steps in the Deflectometry method is to retrieve the surface from slope data of points on the sample map or surface reconstruction. This paper proposes a modal reconstruction method using an adjustable number of Zernike polynomials. In addition, the proposed method enables the analyses on practical surfaces that require an infinite number of Zernike terms to be represented. Experiments on simulated surfaces indicated that the algorithm is able to reveal the number of major-contributing Zernike terms, as well as reconstruct the surface with a micrometer-scale from slope data with a signal-to-noise ratio of 10. Full article

With the huge demands of an aging society, it is urgent to develop a new generation of non-toxic titanium alloy to match the modulus of human bone. Here, we prepared bulk Ti2448 alloys by powder metallurgy technology, and focused on the influence of the sintering process on the porosity, phase composition, and mechanical properties of the initial sintered samples. Furthermore, we performed solution treatment on the samples under different sintering parameters to further adjust the microstructure and phase composition, so as to achieve strength enhancement and reduction of Young’s modulus. Solution treatment can effectively inhibit the continuous α phase precipitated along the grain boundaries of the β matrix, which is beneficial to the fracture resistance. Therefore, the water-quenched sample exhibits good mechanical properties due to the absence of acicular α-phase. Samples sintered at 1400 °C and subsequently water quenched have excellent comprehensive mechanical properties, which benefit from high porosity and the smaller feature size of microstructure. To be specific, the compressive yield stress is 1100 MPa, the strain at fracture is 17.5%, and the Young’s modulus is 44 GPa, which are more applicable to orthopedic implants. Finally, the relatively mature sintering and solution treatment process parameters were screened out for reference in actual production. Full article

The effect of graphene (GN) on the transport of CIP and NOR in porous media is investigated by a combination of batch experiments, column experiments and mathematical models. The results obtained by batch experiments show that GN has great adsorption capacity to two antibiotic contaminants, and the maximum adsorption amounts based on the Langmuir model calculation are 270.67 mg/g and 178.36 mg/g, respectively. The column experiments suggest the mobility of CIP and NOR decreases with the mass fraction of GN packed in porous media, and the mass recovery rates of CIP and NOR increase with flow velocity. As the concentration of Na⁺ increases, the mobility of CIP and NOR is enhanced. However, Ca²⁺ has a significant enhancement effect on the mobility of CIP and NOR. Moreover, the transport processes of CIP and NOR in the column are predicted by a BDST mathematical model, and the calculated results are in good agreement with the experimental results. The relationships between kinetic parameters related to QNs’ mobility and GN content, flow velocity and ionic strength are obtained by a regression analysis, which can be used to predict the mobility of CIP and NOR in porous media. Full article

Approximately 50–80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1^+/−) reduced the Bmal1 protein levels by ~50–75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1^+/− mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD. Full article

The evolution of nature created delicate structures and organisms. With the advancement of technology, especially the rise of additive manufacturing, bionics has gradually become a popular research field. Recently, researchers have concentrated on soft robotics, which can mimic the complex movements of animals by allowing continuous and often responsive local deformations. These properties give soft robots advantages in terms of integration and control with human tissue. The rise of additive manufacturing technologies and soft matters makes the fabrication of soft robots with complex functions such as bending, twisting, intricate 3D motion, grasping, and stretching possible. In this paper, the advantages and disadvantages of the additive manufacturing process, including fused deposition modeling, direct ink writing, inkjet printing, stereolithography, and selective laser sintering, are discussed. The applications of 3D printed soft matter in bionics, soft robotics, flexible electronics, and biomedical engineering are reviewed. Full article

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment. Full article

Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8⁺ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy. Full article

Neurogenic lower urinary tract (NLUT) dysfunction in paediatric patients can arise after congenital or acquired conditions that affect bladder innervation. With some patients, urinary tract dysfunction remains and is more difficult to treat without understanding the pathophysiology. We measured in vitro detrusor smooth muscle function of samples from such bladders and any association with altered Wnt-signalling pathways that contribute to both foetal development and connective tissue deposition. A comparator group was tissue from children with normally functioning bladders. Nerve-mediated and agonist-induced contractile responses and passive stiffness were measured. Histology measured smooth muscle and connective tissue proportions, and multiplex immunohistochemistry recorded expression of protein targets associated with Wnt-signalling pathways. Detrusor from the NLUT group had reduced contractility and greater stiffness, associated with increased connective tissue content. Immunohistochemistry showed no major changes to Wnt-signalling components except down-regulation of c-Myc, a multifunctional regulator of gene transcription. NLUT is a diverse term for several diagnoses that disrupt bladder innervation. While we cannot speculate about the reasons for these pathophysiological changes, their recognition should guide research to understand their ultimate causes and develop strategies to attenuate and even reverse them. The role of changes to the Wnt-signalling pathways was minor. Full article

Through the establishment of a comprehensive evaluation index system, this paper analyzes the allocation of science and technology resources in the Yangtze River Delta urban agglomeration from 2014 to 2020, evaluates the allocation efficiency of science and technology resources from the perspective of multi input and output, and understands the advantages and disadvantages of regional resource allocation. The research results show that: (1) under the guidance of the national strategic policy of actively promoting the development of world-class urban agglomerations, the allocation efficiency of science and technology resources in various provinces and cities of the Yangtze River Delta continues to optimize, and the allocation level of some regions shows a rapid development trend; (2) R&D personnel and R&D funds are the core factors that affect the efficiency of science and technology resource allocation; (3) the marketization of resource allocation is helpful to improve its allocation efficiency; and (4) improving the transformation rate of scientific and technological achievements, opening up the channel for innovative products, technologies, and services to enter the market, and enabling innovative enterprises to make profits can provide strong and lasting incentives for the improvement of scientific and technological resource allocation efficiency. Based on the research conclusions, this paper puts forward countermeasures and suggestions to improve the allocation efficiency of scientific and technological resources in the Yangtze River Delta urban agglomeration from the aspects of human resources and material resources, and provides a theoretical reference for the coordinated and sustainable development of the Yangtze River Delta City Group under the background of the implementation of the urban agglomeration strategy and the construction of a scientific and technological infrastructure platform. Full article

This paper considers a non-orthogonal multiple access (NOMA) downlink network, where a hybrid of NOMA and beamforming designs is developed to enhance the channel capacity. We aim to improve the system performance in terms of rate fairness and power consumption. Hence, a multi-objective problem with a joint optimization of user equipment pairing, power control, and quality-of-service requirements is addressed. To efficiently solve the problem, we propose two low-complexity algorithms based on the inner-approximation method, with the first algorithm using the relaxation method and the second one using graph theory. Numerical results are provided to demonstrate the effectiveness of the two proposed algorithms in comparison with the exhaustive search and existing methods. Full article

Background: The steady decline in breast cancer (bca) mortality has come at the cost of increasingly toxic and expensive adjuvant therapies. Trials evaluating the addition of 2 or 3 years of cyclin-dependent kinase 4/6 (cdk4/6) inhibitors to adjuvant endocrine therapy (et) are ongoing, but the willingness of patients to take such additional therapy is unknown. Methods: We surveyed 100 consecutive postmenopausal women with nonmetastatic estrogen receptor–positive bca who had initiated adjuvant et within the preceding 2 years. Participants were asked about perceived recurrence risk, bca worry, and overall health. They were then asked about their willingness to accept 2 years of treatment with an additional oral drug that would reduce recurrence by 40% for a range of baseline recurrence risks in 2 hypothetical scenarios. Results: Mean age of the 99 evaluable participants was 61.7 years. In the scenario with no drug toxicity, 85% of respondents were likely to accept the new drug for a reduction in recurrence to 30% from 50%, but only 49% would take the drug if risk was reduced to 3% from 5%. In a scenario with drug-induced fatigue, the corresponding drug acceptance rates were 55% and 39% respectively. For the second scenario, bca worry was correlated with increased willingness to take the drug, even for only a 2% absolute reduction in recurrence risk. Conclusions: The willingness of patients with estrogen receptor–positive bca to take an adjuvant cdk4/6 inhibitor will greatly depend on the expected benefit and toxicities described to them as well as on worry about bca recurrence. Full article