The range of potential applications of compact laser-plasma ion sources motivates the development of new acceleration schemes to increase achievable ion energies and conversion efficiencies. Whilst ...the evolving nature of laser-plasma interactions can limit the effectiveness of individual acceleration mechanisms, it can also enable the development of hybrid schemes, allowing additional degrees of control on the properties of the resulting ion beam. Here we report on an experimental demonstration of efficient proton acceleration to energies exceeding 94 MeV via a hybrid scheme of radiation pressure-sheath acceleration in an ultrathin foil irradiated by a linearly polarised laser pulse. This occurs via a double-peaked electrostatic field structure, which, at an optimum foil thickness, is significantly enhanced by relativistic transparency and an associated jet of super-thermal electrons. The range of parameters over which this hybrid scenario occurs is discussed and implications for ion acceleration driven by next-generation, multi-petawatt laser facilities are explored.
Since its inception, significant progress has been made in understanding additive manufacturing (AM) processes and the structure and properties of the fabricated metallic components. Because the ...field is rapidly evolving, a periodic critical assessment of our understanding is useful and this paper seeks to address this need. It covers the emerging research on AM of metallic materials and provides a comprehensive overview of the physical processes and the underlying science of metallurgical structure and properties of the deposited parts. The uniqueness of this review includes substantive discussions on refractory alloys, precious metals and compositionally graded alloys, a succinct comparison of AM with welding and a critical examination of the printability of various engineering alloys based on experiments and theory. An assessment of the status of the field, the gaps in the scientific understanding and the research needs for the expansion of AM of metallic components are provided.
To evaluate the performance of the Prostate Health Index (PHI) in magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion prostate biopsy for the detection of clinically significant ...prostate cancer (csPCa). We prospectively enrolled 164 patients with at least one Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) ≥ 3 lesions who underwent MRI-TRUS fusion prostate biopsy. Of the PSA-derived biomarkers, the PHI had the best performance in predicting csPCa (AUC 0.792, CI 0.707-0.877) in patients with PI-RADS 4/5 lesions. Furthermore, the predictive power of PHI was even higher in the patients with PI-RADS 3 lesions (AUC 0.884, CI 0.792-0.976). To minimize missing csPCa, we used a PHI cutoff of 27 and 7.4% of patients with PI-RADS 4/5 lesions could have avoided a biopsy. At this level, 2.0% of cases with csPCa would have been missed, with sensitivity and NPV rates of 98.0% and 87.5%, respectively. However, the subgroup of PI-RADS 3 was too small to define the optimal PHI cutoff. PHI was the best PSA-derived biomarker to predict csPCa in MRI-TRUS fusion prostate biopsies in men with PI-RADS ≥ 3 lesions, especially for the patients with PI-RADS 3 lesions who gained the most value.
Additive manufacturing (AM), also known as 3D printing, is gaining wide acceptance in diverse industries for the manufacturing of metallic components. The microstructure and properties of the ...components vary widely depending on printing process and process parameters, and prediction of causative variables that affect structure, properties and defects is helpful for their control. Since models are most useful when they can correctly predict experimental observations, we focus on the available mechanistic models of AM that have been adequately validated. Specifically, the applications of transport phenomena models in the studies of solidification, residual stresses, distortion, formation of defects and the evolution of microstructure and properties are critically reviewed. The functionality of AM models in understanding of the printability of commonly used AM alloys and the fabrication of functionally graded alloys are also assessed. Opportunities for future research are identified considering the gaps in knowledge in modeling. The uniqueness of this review includes substantive discussions of the rapid certification of the AM components aided by scale models, bidirectional models, cloud based big data, machine learning and digital twins of AM hardware.
Loss of 1p36 heterozygosity commonly occurs with MYCN amplification in neuroblastoma tumors, and both are associated with an aggressive phenotype. Database searches identified five microRNAs that map ...to the commonly deleted region of 1p36 and we hypothesized that the loss of one or more of these microRNAs contributes to the malignant phenotype of MYCN-amplified tumors. By bioinformatic analysis, we identified that three out of the five microRNAs target MYCN and of these miR-34a caused the most significant suppression of cell growth through increased apoptosis and decreased DNA synthesis in neuroblastoma cell lines with MYCN amplification. Quantitative RT-PCR showed that neuroblastoma tumors with 1p36 loss expressed lower level of miR-34a than those with normal copies of 1p36. Furthermore, we demonstrated that MYCN is a direct target of miR-34a. Finally, using a series of mRNA expression profiling experiments, we identified other potential direct targets of miR-34a, and pathway analysis demonstrated that miR-34a suppresses cell-cycle genes and induces several neural-related genes. This study demonstrates one important regulatory role of miR-34a in cell growth and MYCN suppression in neuroblastoma.
In this paper, we propose a new design of flow channel and stack arrangement based on the numerical study considering the effect of the flow channel design on the stack performance and analyze the ...thermal stress of a planar anode-supported solid oxide fuel cell stack. We also attempt to simplify the cell stack design without affecting its performance and propose an easier sealing method of cell stacks through the study of the thermal stress distribution. The results indicate that the new design, created by changing the cathode flow channel to a porous current collector, with a 6.3% increase in power density, an 8.6% increase in electrical efficiency. Both more uniform flow and current density distribution can be obtained as compared with a conventional counter-flow design. In addition, we propose a new design direction of cell stack, which could be simpler and easier to fabricate, in which material can easily undertake the resulting stress based on the thermal stress analysis.
•Propose an optimized design of current collector in a planar anode-support SOFC.•Propose a very simple stack design that can produce very uniform flow distribution.•Propose a new stack design with lower stress distribution with cheaper material.
Boson sampling is a problem strongly believed to be intractable for classical computers, but can be naturally solved on a specialized photonic quantum simulator. Here, we implement the first ...time-bin-encoded boson sampling using a highly indistinguishable (∼94%) single-photon source based on a single quantum-dot-micropillar device. The protocol requires only one single-photon source, two detectors, and a loop-based interferometer for an arbitrary number of photons. The single-photon pulse train is time-bin encoded and deterministically injected into an electrically programmable multimode network. The observed three- and four-photon boson sampling rates are 18.8 and 0.2 Hz, respectively, which are more than 100 times faster than previous experiments based on parametric down-conversion.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (
) ...is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2
), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (
)-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and ...emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2
) glutamatergic neurons. Viral expression of p11 in D2
PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2
neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2
PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.
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