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This work details a novel approach to access the [7,6]-spirocyclic fragment of 13-desmethyl spirolide C. A more efficient synthesis of the key lactam dienophile is reported, and a comprehensive investigation of the Diels-Alder reaction is included.

Objectives To explore the molecular mechanisms underlying aggressive progression of papillary thyroid microcarcinoma and identify potential biomarkers. Methods Samples were collected and sequenced using tandem mass tag-labeled liquid chromatography–tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified and further analyzed using Mfuzz and protein–protein interaction analysis (PPI). Parallel reaction monitoring (PRM) and immunohistochemistry (IHC) were performed to validate the DEPs. Results Five thousand, two hundred and three DEPs were identified and quantified from the tumor/normal comparison group or the N1/N0 comparison group. Mfuzz analysis showed that clusters of DEPs were enriched according to progressive status, followed by normal tissue, tumors without lymphatic metastases, and tumors with lymphatic metastases. Analysis of PPI revealed that DEPs interacted with and were enriched in the following metabolic pathways: apoptosis, tricarboxylic acid cycle, PI3K-Akt pathway, cholesterol metabolism, pyruvate metabolism, and thyroid hormone synthesis. In addition, 18 of the 20 target proteins were successfully validated with PRM and IHC in another 20 paired validation samples. Based on machine learning, the five proteins that showed the best performance in discriminating between tumor and normal nodules were PDLIM4, ANXA1, PKM, NPC2, and LMNA. FN1 performed well in discriminating between patients with lymph node metastases (N1) and N0 with an AUC of 0.690. Finally, five validated DEPs showed a potential prognostic role after examining The Cancer Genome Atlas database: FN1, IDH2, VDAC1, FABP4, and TG. Accordingly, a nomogram was constructed whose concordance index was 0.685 (confidence interval: 0.645–0.726). Conclusions PDLIM4, ANXA1, PKM, NPC2, LMNA, and FN1 are potential diagnostic biomarkers. The five-protein nomogram could be a prognostic biomarker.

The cubic illumination metre has been taken as the most thorough and practical tool for the field measurement of vector illuminance so far. However, uncertainty in the measurement of scalar illuminance has influenced its reliability. This study determined how the errors of the existing approaches were generated using illustrations and simulations based on the illuminance solid concept. Following the error analysis of the existing approaches, potential alternative solutions for improving its accuracy were proposed. This study can help pave the way for developing more accurate vector illuminance-based metrics in natural lighting environments using a cubic metre.

Changes to the community of symbiotic bacteria and fungi in the brown planthopper, Nilaparvata lugens Stål, were measured at different times after exposure to conidial suspensions of Metarhizium flavoviride Gams and Roszypal. Over all concentrations tested, bacterial species associated with N. lugens comprised 8 phyla, 17 classes, 22 orders, 26 families, and 31 genera of which the relative proportions of Arsenophonus, Burkholderia, Enterobacter, Pseudomonas, Stenotrophomonas, and Bacteroides were highest. The relative abundance and diversity of bacteria were highest in the carrier control (0.05% Tween-80 only). Fungi comprised 1 phyla, 5 classes, 10 orders, 13 families, and 18 genera, with Metarhizium being the dominant taxon in specimens from all treatment groups. Metarhizium spp. was greatest in the concentrations of 107 and 108 conidia/ml at 72 hours after exposure, reaching 94.82% and 93.74% of taxonomic units, respectively. We deduced that M. flavoviride competes for nutrition with midgut microorganisms; therefore, exposure to a pathogenic fungus will change the abundance and diversity of bacterial and fungal microorganisms in the midguts of hosts, and pathogens will impact the structure of bacterial communities in the host midgut with an alteration in the bacterial species composition. We observed that following the exposure of N. lugens to M. flavoviride, Metarhizium spp. dominated in the midgut of the host, the abundance and diversity of midgut fungal microorganisms decreased, and the dominant bacterial species in the midgut shifted.

Human linguistic units are hierarchical, and our brain responds differently when processing linguistic units during sentence comprehension, especially when the modality of the received signal is different (auditory, visual, or audio-visual). However, it is unclear how the brain processes and integrates language information at different linguistic units (words, phrases, and sentences) provided simultaneously in audio and visual modalities. To address the issue, we presented participants with sequences of short Chinese sentences through auditory or visual or combined audio- visual modalities, while electroencephalographic responses were recorded. With a frequency tagging approach, we analyzed the neural representations of basic linguistic units (i.e., characters/monosyllabic words) and higher-level linguistic structures (i.e., phrases and sentences) across the three modalities separately. We found that audio-visual integration occurs at all linguistic units, and the brain areas involved in the integration varied across different linguistic levels. In particular, the integration of sentences activated the local left prefrontal area. Therefore, we used continuous theta-burst stimulation (cTBS) to verify that the left prefrontal cortex plays a vital role in the audio-visual integration of sentence information. Our findings suggest the advantage of bimodal language comprehension at hierarchical stages in language-related information processing and provide evidence for the causal role of the left prefrontal regions in processing information of audio-visual sentences.

Deoxynivalenol (DON) is widely present in grain-based feeds and food. It has attracted great attention due to its high contamination rate and strong toxicity. The objective of this study was to analyse the toxic effects of DON on the liver and kidneys of weaned rabbits. 45 weaned male rabbits were allocated into control, low DON dose (0.5 mg/kg body weight), and high DON dose (1.5 mg/kg body weight) groups. Saline or DON was administrated intragastrically in the empty stomach of rabbits every morning. After 24 days of treatment, liver and kidney samples were collected for histological, reverse transcription-quantitative polymerase chain reaction (qRT-PCR), and immunohistochemistry analyses. Haematoxylin eosin staining showed that 0.5 mg/kg BW DON caused mild damage to the liver and kidney morphology, while 1.5 mg/kg body weight DON resulted in hepatic vacuolation and necrosis, as well as tubular stenosis and lesions. Data from qRT-PCR, Western blot, and immunohistochemistry revealed that the mRNA and protein expression and the distribution range of extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase were increased in the liver and kidneys. In conclusion, DON at the tested concentrations damaged the liver and kidneys of rabbits by affecting the expression of key proteins from the mitogen-activated protein kinase signalling pathway. The damage extent was proportional to the amount of DON ingested.

PURPOSE Metastatic breast cancer (mBrCa) is most often an incurable disease with only modest responses to available immunotherapies. This study investigates the immunogenicity of somatic mutations in breast cancer and explores the therapeutic efficacy in a pilot trial of mutation-reactive tumor-infiltrating lymphocytes (TILs) in patients with metastatic disease. PATIENTS AND METHODS Forty-two patients with mBrCa refractory to previous lines of treatment underwent surgical resection of a metastatic lesion(s), isolation of TIL cultures, identification of exomic nonsynonymous tumor mutations, and immunologic screening for neoantigen reactivity. Clinically eligible patients with appropriate reactivity were enrolled into one cohort of an ongoing phase II pilot trial of adoptive cell transfer of selected neoantigen-reactive TIL, with a short course of pembrolizumab (ClinicalTrials.gov identifier: NCT01174121 ). RESULTS TILs were isolated and grown in culture from the resected lesions of all 42 patients with mBrCa, and a median number of 112 (range: 6-563) nonsynonymous mutations per patient were identified. Twenty-eight of 42 (67%) patients contained TIL that recognized at least one immunogenic somatic mutation (median: 3 neoantigens per patient, range: 1-11), and 13 patients demonstrated robust reactivity appropriate for adoptive transfer. Eight patients remained clinically eligible for treatment, and six patients were enrolled on a protocol of adoptive cell transfer of enriched neoantigen-specific TIL, in combination with pembrolizumab (≤ 4 doses). Objective tumor regression was noted in three patients, including one complete response (now ongoing over 5.5 years) and two partial responses (6 and 10 months). CONCLUSION Most patients with breast cancer generated a natural immune response targeting the expressed products of their cancer mutations. Adoptive transfer of TIL is a highly personalized experimental option for patients with mBrCa shown to be capable of mediating objective responses in this pilot trial and deserves further study.

X-ray bursts are among the brightest stellar objects frequently observed in the sky by space-based telescopes. A type-I X-ray burst is understood as a violent thermonuclear explosion on the surface of a neutron star, accreting matter from a companion star in a binary system. The bursts are powered by a nuclear reaction sequence known as the rapid proton capture process (rp process), which involves hundreds of exotic neutron-deficient nuclides. At so-called waiting-point nuclides, the process stalls until a slower β+ decay enables a bypass. One of the handful of rp process waiting-point nuclides is 64Ge, which plays a decisive role in matter flow and therefore the produced X-ray flux. Here we report precision measurements of the masses of 63Ge, 64,65As and 66,67Se—the relevant nuclear masses around the waiting-point 64Ge—and use them as inputs for X-ray burst model calculations. We obtain the X-ray burst light curve to constrain the neutron-star compactness, and suggest that the distance to the X-ray burster GS 1826–24 needs to be increased by about 6.5% to match astronomical observations. The nucleosynthesis results affect the thermal structure of accreting neutron stars, which will subsequently modify the calculations of associated observables.

Plasma-based acceleration has emerged as a promising candidate as an accelerator technology for a future linear collider or a next-generation light source. We consider the plasma wakefield accelerator (PWFA) concept where a plasma wave wake is excited by a particle beam and a trailing beam surfs on the wake. For a linear collider, the energy transfer efficiency from the drive beam to the wake and from the wake to the trailing beam must be large, while the emittance and energy spread of the trailing bunch must be preserved. One way to simultaneously achieve this when accelerating electrons is to use longitudinally shaped bunches and nonlinear wakes. In the linear regime, there is an analytical formalism to obtain the optimal shapes. In the nonlinear regime, however, the optimal shape of the driver to maximize the energy transfer efficiency cannot be precisely obtained because currently no theory describes the wake structure and excitation process for all degrees of nonlinearity. In addition, the ion channel radius is not well defined at the front of the wake where the plasma electrons are not fully blown out by the drive beam. We present results using a novel optimization method to effectively determine a current profile for the drive and trailing beam in PWFA that provides low energy spread, low emittance, and high acceleration efficiency. We parameterize the longitudinal beam current profile as a piecewise-linear function and define optimization objectives. For the trailing beam, the algorithm converges quickly to a nearly inverse trapezoidal trailing beam current profile similar to that predicted by the ultrarelativistic limit of the nonlinear wakefield theory. For the drive beam, the beam profile found by the optimization in the nonlinear regime that maximizes the transformer ratio also resembles that predicted by linear theory. The current profiles found from the optimization method provide higher transformer ratios compared with the linear ramp predicted by the relativistic limit of the nonlinear theory.

This paper presents a numerical investigation of the interaction of back-to-back mechanically stabilized earth (MSE) walls under static loading. The numerical model was validated using measurements from instrumented field back-to-back MSE walls. A parametric study was then conducted to investigate the effects of horizontal distance between the MSE walls, soil friction angle, and wall height on the interaction of back-to-back MSE walls. Maximum facing displacement, lateral soil thrust behind reinforced soil zone, and required reinforcement tensile force generally increase nonlinearly with increasing horizontal distance up to a certain critical value, and the effects of interaction between back-to-back MSE walls are stronger for lower friction angle and higher wall. The critical horizontal distances for different soil friction angles and wall heights are generally close to the theoretical Federal Highway Administration (FHWA) values for the full active failure wedge to be developed and could be approximated as 0.5. The FHWA method significantly underestimates the lateral soil thrusts for the range of horizontal distances involving interaction between back-to-back MSE walls but significantly overestimates the required reinforcement tensile strengths. Design recommendations on lateral soil thrust and required reinforcement tensile strength calculations that account for the interaction between back-to-back MSE walls are provided.

Adoptive cellular therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from patient-specific mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. We performed whole-exome sequencing on 163 patients with metastatic solid cancers, identified 78 who had TP53 missense mutations, and through immunologic screening, identified 21 unique T-cell reactivities. Here, we report a library of 39 T-cell receptors (TCR) targeting TP53 mutations shared among 7.3% of patients with solid tumors. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner in vitro and in vivo. Twelve patients with chemorefractory epithelial cancers were treated with ex vivo–expanded autologous tumor-infiltrating lymphocytes (TIL) that were naturally reactive against TP53 mutations. However, limited clinical responses (2 partial responses among 12 patients) were seen. These infusions contained low frequencies of mutant p53–reactive TILs that had exhausted phenotypes and showed poor persistence. We also treated one patient who had chemorefractory breast cancer with ACT comprising autologous peripheral blood lymphocytes transduced with an allogeneic HLA-A*02–restricted TCR specific for p53R175H. The infused cells exhibited an improved immunophenotype and prolonged persistence compared with TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these proof-of-concept data suggest that the library of TCRs targeting shared p53 neoantigens should be further evaluated for the treatment of patients with advanced human cancers. See related Spotlight by Klebanoff, p. 919

To evaluate the longitudinal association of eggs consumption with cognitive function in Chinese elderly.Prospective cohort study.9028 participants aged ≥60 years from Zhejiang Ageing and Health Cohort Study without cognitive impairment at baseline survey.Cognitive function was assessed through the Mini-Mental State Examination (MMSE) at baseline and three waves of follow-up (2015, 2016, and 2019-2020). Data on eggs consumption was collected in the diet habits section within the questionnaire at baseline. Log-binomial regression models with the Generalized Estimating Equations, controlled for an extensive range of potential confounders, were used to evaluate the association and estimate relative risks (RRs).After 6 years of follow-up, 3266 (36.18%) participants were indicated as cognitive impairment by MMSE at least once. Compared with non-consumers or less-than-weekly consumers, participants consuming 0.1-2.9 eggs/week and 3.0-5.9 eggs/week had 18% (RR=0.82, 95%CI 0.76-0.89) and 9% (RR=0.91, 95%CI 0.84-0.99) lower risks of cognitive impairment respectively, whereas no association was found in those consuming ≥6.0 eggs/week (P=0.32). Moreover, infrequent lower-quantity consumption (1-2 days/week and 0.1-1.9 eggs/day), infrequent higher-quantity consumption (1-2 days/week and ≥2.0 eggs/day), and frequent lower-quantity consumption (≥3 days/week and 0.1-1.9 eggs/day) were associated with better cognitive performance, whereas null association was found among frequent higher-quantity consumers (≥3 days/week and ≥2.0 eggs/day). The sensitivity analyses yielded consistent results to the main analysis.Limited eggs consumption is prospectively related to a lower risk of cognitive impairment in Chinese elderly.

No information is available regarding the utilization of iron (Fe) from different Fe sources at a target tissue level. To detect differences in Fe metabolic utilization among Fe sources, the effect of intravenously injected Fe on growth performance, hematological indices, tissue Fe concentrations and Fe-containing enzyme activities and gene expressions of Fe-containing enzymes or protein in broilers was investigated. On d 22 post-hatching, a total of 432 male chickens were randomly allotted to 1 of 9 treatments in a completely randomized design. Chickens were injected with either a 0.9% (wt/vol) NaCl solution (control) or a 0.9% NaCl solution supplemented with Fe sulphate or 1 of 3 organic Fe sources. The 3 organic Fe sources were Fe chelates with weak (Fe-MetW), moderate (Fe-ProM) or extremely strong (Fe-ProES) chelation strengths. The 2 Fe dosages were calculated according to the Fe absorbabilities of 10% and 20% every 2 d for a duration of 20 d. Iron injection did not affect (P > 0.05) ADFI, ADG or FCR during either 1 to 10 d or 11 to 20 d after injections. Hematocrit and Fe concentrations in the liver and kidney on d 10 after Fe injections, and Fe concentrations in the liver or pancreas and ferritin heavy-chain (FTH1) protein expression level in the liver or spleen on d 20 after Fe injections increased (P ≤ 0.05) as injected Fe dosages increased. When the injected Fe level was high at 20% Fe absorbability, the chickens injected with Fe-ProtES had lower (P

Flutter suppression is an important measure to improve fatigue life and enhance the performance of aircraft in modern aircraft design. In order to design more effective controllers for flutter suppression with high efficiency, an efficient reduced-order framework for active/passive hybrid flutter suppression is proposed. The traditional CFD-based ROMs have been successfully applied to active flutter suppression with high accuracy and efficiency. But, when a structure modification is made such as in aeroelastic tailoring and aeroelastic structural optimisation, the structural model should be updated, and the expensive, time-consuming CFD-based ROMs have to be reconstructed; such a process is impractical for passive flutter suppression. To overcome the realistic challenge, an efficient reduced-order framework for active/passive hybrid flutter suppression is proposed by extending an efficient aeroelastic CFD-based POD/ROM which we have developed. The proposed framework is demonstrated and evaluated using an improved AGARD 445.6 wing model. The results show that the proposed framework can accurately predict the aeroelastic response for active/passive hybrid flutter suppression with high efficiency. It provides a powerful tool for active/passive hybrid flutter suppression, and therefore, is ideally suited to design more effective controllers, and may have the potential to reduce the overall cost of aircraft design.

To assess value of placental vascularization indices (PVIs) for predicting preeclampsia (PE) and fetal growth restriction (FGR) in different stages of pregnancy in high-risk women.PVIs derived from 3-dimensional power doppler(3DPD) imaging were measured at seven stages of pregnancy: 11-13Adverse outcomes occurred in 10.9% of pregnancies. Statistical differences appeared in 32-36VI and VFI were valuable for predicting PE and FGR at the 32-36

Supplementary Figure from Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor–Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors

Adoptive cellular therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from patient-specific mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. We performed whole-exome sequencing on 163 patients with metastatic solid cancers, identified 78 who had TP53 missense mutations, and through immunologic screening, identified 21 unique T-cell reactivities. Here, we report a library of 39 T-cell receptors (TCR) targeting TP53 mutations shared among 7.3% of patients with solid tumors. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner in vitro and in vivo. Twelve patients with chemorefractory epithelial cancers were treated with ex vivo–expanded autologous tumor-infiltrating lymphocytes (TIL) that were naturally reactive against TP53 mutations. However, limited clinical responses (2 partial responses among 12 patients) were seen. These infusions contained low frequencies of mutant p53–reactive TILs that had exhausted phenotypes and showed poor persistence. We also treated one patient who had chemorefractory breast cancer with ACT comprising autologous peripheral blood lymphocytes transduced with an allogeneic HLA-A*02–restricted TCR specific for p53R175H. The infused cells exhibited an improved immunophenotype and prolonged persistence compared with TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these proof-of-concept data suggest that the library of TCRs targeting shared p53 neoantigens should be further evaluated for the treatment of patients with advanced human cancers.See related Spotlight by Klebanoff, p. 919

Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers.Significance:TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.This article is highlighted in the In This Issue feature, p. 983

The potential phosphorylation motifs of human SIRT3 were predicted by searching the data base using the combination of software Netphos2.0 server and Automotif server

Supplementary Figures 1-9

A list of genes that were found to be somatically mutated in pt3713 and all of the major information needed for our genomic study

Local mice xenograft tumor radiation settings showing the images of xenograft tumors derived from HCT116 cells harboring Thr150/Ser159 mutant or wild type SIRT3

Supplementary Materials and Methods