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Background: Neoadjuvant radiotherapy and chemotherapy, followed by surgical resection, are standard treatments for locally advanced rectal cancer (LARC). Emerging evidence has shown the efficacy of anti-programmed cell death protein 1 (anti-PD-1) therapy for patients with mismatch repair-deficient (dMMR) colorectal cancer, particularly in managing metastatic disease. Several ongoing clinical trials evaluating the efficacy of anti-PD-1 therapy in patients with dMMR LARC have reported outstanding responses. Patients and methods: Here, we present the VOLTAGE-2 study (EPOC 2201), a non-randomized, single-arm, phase II trial that aims to investigate the efficacy and safety of nivolumab monotherapy for 1 year in patients with dMMR-resectable LARC. Patients with clinical complete response (cCR) or near-complete response (nCR) will be observed with non-operative management (NOM) using the Memorial Sloan Kettering Regression Schema.The primary endpoint will be investigator-determined 2-year cCR rate for nivolumab monotherapy. We will investigate the surrogacy of circulating tumor DNA assay as a cCR using whole-genome sequencing (WGS)-based molecular residual disease (MRD) assay and will evaluate the biomarkers of the response to anti-PD-1 antibody using whole-exome sequencing (WES) plus whole-transcriptome sequencing (WTS)-based tumor genomics and immune microenvironment evaluations. We plan to carry out spatiotemporal trans-omics analyses using artificial intelligence and deep learning-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic imaging, quality of life, and clinical features.

Abstract We present Magnetospheric Multiscale observations of an electron‐scale reconnecting current sheet in the mixing region along the trailing edge of a Kelvin‐Helmholtz vortex during southward interplanetary magnetic field conditions. Within this region, we observe intense electrostatic wave activity, consistent with lower‐hybrid waves. These waves lead to the transport of high‐density magnetosheath plasma across the boundary layer into the magnetosphere and generate a mixing region with highly compressed magnetic field lines, leading to the formation of a thin current sheet associated with electron‐scale reconnection signatures. Consistencies between these reconnection signatures and a realistic, local, fully‐kinetic simulation modeling this current sheet indicate a temporal evolution of the observed electron‐scale reconnection current sheet. The multi‐scale and inter‐process character of this event can help us understand plasma mixing connected to the Kelvin‐Helmholtz instability and the temporal evolution of electron‐scale reconnection.

As a result of the large difference in heat capacity between land and ocean, global climate and atmospheric circulation patterns over the supercontinent of Pangaea were significantly different from those of today. Modelling experiments indicate a seasonal alternation in cross-equatorial flow induced by the seasonal reversal in the direction of the monsoonal circulation; however, there are large discrepancies between model-generated surface wind patterns and the reported palaeowind directions from aeolian dune records. Here, we present the spatial distribution of dune slip-face azimuths recorded in the Lower Jurassic aeolian sandstones over a wide area of the western United States (palaeolatitude: ∼19–27∘ N). The azimuth data for dune slip faces reveal a bidirectional and oblique angular pattern that resembles the internal structures of modern longitudinal dunes. Based on the spatial pattern of slip-face directions and outcrop evidence, we suggest that most Lower Jurassic aeolian sandstones were NNE–SSW- to NNW–SSE-oriented longitudinal dunes, which likely formed as the result of a combination of westerly, northwesterly, and northeasterly palaeowinds. The reconstructed palaeowind pattern at ∼19–27∘ N appears to be consistent with the model-generated surface wind pattern and its seasonal alternation. The reconstructed palaeowind patterns also suggest an influence of orbitally induced changes in atmospheric pressure patterns over Pangaea.

Resuspension of 137Cs from the contaminated ground surface to the atmosphere is essential for understanding the environmental behaviors of 137Cs and estimating external and inhalation exposure of residents. Kajino et al. (2016) assessed the 137Cs resuspension flux from bare soil and forest ecosystems in eastern Japan in 2013 using a numerical simulation constrained by surface air concentration measurements. However, the simulation was found to underestimate the observed deposition amounts by 2 orders of magnitude. The reason for this underestimation is that the simulation assumed that resuspended 137Cs is carried by submicron aerosols, which have low deposition rates. Based on the observational indications that soil dust and bioaerosols are the major carriers of resuspended 137Cs, a new simulation is performed with higher deposition rates constrained by both surface concentrations and deposition amounts. In the new estimation, the total areal annual resuspension of 137Cs in 2013 is 25.7 TBq, which is equivalent to 0.96 % of the initial deposition (2.68 PBq). Due to the rapid deposition rates, the annual redeposition amount is also large at 10.6 TBq, approximately 40 % of the resuspended 137Cs. The resuspension rate through the atmosphere (0.96 % yr−1) seems slow, but it (2.6 × 10−5 d−1) may not be negligibly small compared to the actual decreasing trend of the ambient gamma dose rate obtained in Fukushima Prefecture after the radioactive decay of 137Cs plus 134Cs in 2013 is subtracted (1.0–7.9 × 10−4 d−1): resuspension can account for 1 %–10 % of the decreasing rate due to decontamination and natural decay through land surface processes. The current simulation underestimated the 137Cs deposition in Fukushima city in winter by more than an order of magnitude, indicating the presence of additional resuspension sources. The site of Fukushima city is surrounded by major roads. Heavy traffic on wet and muddy roads after snow removal operations could generate superlarge (approximately 100 µm in diameter) road dust or road salt particles, which are not included in the model but might contribute to the observed 137Cs at the site.

Background Although R0 surgery is recommended for stage IV colorectal cancer, the degree of required lymphadenectomy has not been established. The aim of this study was to investigate the prognostic impact of high ligation (HL) of the feeding artery and the number of retrieved lymph nodes after R0 surgery for colorectal cancer and synchronous colorectal cancer liver metastasis (CRLM). Methods This was a multi‐institutional retrospective analysis of patients with colorectal cancer and synchronous CRLM who had R0 surgery between January 1997 and December 2007. Clinical and pathological features were compared in patients who underwent HL and those who had a low ligation (LL). Kaplan–Meier analysis was performed to estimate the effect of HL on overall survival (OS). The impact of several risk factors on survival was analysed using the Cox proportional hazards model. Results Of 549 patients, 409 (74·5 per cent) had HL. Median follow‐up was 51·4 months. HL significantly improved the 5‐year OS rate (58·2 per cent versus 49·3 per cent for LL; P = 0·017). Multivariable analysis revealed HL to be a significant prognostic factor compared with LL (5‐year mortality: hazard ratio (HR) 0·68, 95 per cent c.i. 0·51 to 0·90; P = 0·007). In subgroup analysis, the positive effect of HL on OS was greatest in patients with lymph node metastasis. Conclusion HL of the feeding artery was associated with improved OS in patients with colorectal cancer and synchronous CRLM after R0 surgery.

Zebrafish are a powerful animal model for small molecule screening. Small molecule treatments of zebrafish embryos usually require that the chorion, an acellular envelope enclosing the embryo, is removed in order for chemical compounds to access the embryo from the bath medium. For large-scale studies requiring hundreds of embryos, manual dechorionation, using forceps, can be a time-consuming and limiting process. Pronase is a non-specific protease that is widely used as an enzymatic alternative for dechorionating zebrafish embryos. However, whether pronase treatments alter the effects of subsequent small molecule treatments has not been addressed. Here, we provide a detailed protocol for large-scale pronase dechorionation of zebrafish embryos. We tested whether pronase treatment can influence the efficacy of drug treatments in zebrafish embryos. We used a zebrafish model for Duchenne muscular dystrophy (DMD) to investigate whether the efficacies of trichostatin-A (TSA) or salermide + oxamflatin, small molecule inhibitors known to ameliorate the zebrafish dmd muscle degeneration phenotype, are significantly altered when embryos are treated with pronase versus manual dechorionation. We also tested the effects of pronase on the ability of the anthracycline cancer drug doxorubicin to induce cardiotoxicity in zebrafish embryos. When comparing pronase- versus forceps-dechorionated embryos used in these small molecule treatments, we found no appreciable effects of pronase on animal survival or on the effects of the small molecules. The significant difference that was detected was a small improvement in the ability of salermide + oxamflatin to ameliorate the dmd phenotype in pronase-treated embryos when compared with manual dechorionation. Our study supports the use of pronase treatment as a dechorionation method for zebrafish drug screening experiments.

This research numerically studies the formation of a detached plasma and the energy loss processes during hydrogen (H) gas puffing by using the 1D-3 V Particle-In-Cell (PIC) code. In this study, the 1D-3 V PIC with Monte Carlo Collision (MCC) and cumulative scattering angle Coulomb collision has been developed for investigating the kinetic behavior of the detached plasma. The plasma density increases near the target plate with increasing neutral pressure. The flow velocity, the ion temperature, and the electron temperature are reduced toward the target plate when gas puffing is performed by enhancing the charge-exchange (CX), the ionization, and the excitation loss. For the 15 mTorr neutral pressure case, all of the Te||, Te⊥, Ti||, and Ti⊥ reduce to less than 1 eV. The heat flux on the target plate reduces with the increment of neutral pressure. The heat flux is remarkably suppressed for the 15 mTorr neutral pressure. The sheath and the presheath potential drop on the target are affected with changing neutral pressure. The power loss terms are enhanced according to the increase of H neutral pressure. For all cases, the CX loss is shown to be higher than 70%. The excitation loss and ionization loss are shown to be nearly 15% and 6%, respectively. The recombination loss is found to be small, but it increases with increasing neutral pressure.

The westerly wind travelling at high altitudes over eastern Asia transports aerosols from the Asian deserts and urban areas to downwind areas such as Japan. These long-range-transported aerosols include not only mineral particles but also microbial particles (bioaerosols), that impact the ice-cloud formation processes as ice nuclei. However, the detailed relations of airborne bacterial dynamics to ice nucleation in high-elevation aerosols have not been investigated. Here, we used the aerosol particles captured in the snow cover at altitudes of 2450 m on Mt Tateyama to investigate sequential changes in the ice-nucleation activities and bacterial communities in aerosols and elucidate the relationships between the two processes. After stratification of the snow layers formed on the walls of a snow pit on Mt Tateyama, snow samples, including aerosol particles, were collected from 70 layers at the lower (winter accumulation) and upper (spring accumulation) parts of the snow wall. The aerosols recorded in the lower parts mainly came from Siberia (Russia), northern Asia and the Sea of Japan, whereas those in the upper parts showed an increase in Asian dust particles originating from the desert regions and industrial coasts of Asia. The snow samples exhibited high levels of ice nucleation corresponding to the increase in Asian dust particles. Amplicon sequencing analysis using 16S rRNA genes revealed that the bacterial communities in the snow samples predominately included plant associated and marine bacteria (phyla Proteobacteria) during winter, whereas during spring, when dust events arrived frequently, the majority were terrestrial bacteria of phyla Actinobacteria and Firmicutes. The relative abundances of Firmicutes (Bacilli) showed a significant positive relationship with the ice nucleation in snow samples. Presumably, Asian dust events change the airborne bacterial communities over Mt Tateyama and carry terrestrial bacterial populations, which possibly induce ice-nucleation activities, thereby indirectly impacting climate change.

Vortex-induced reconnection originates from non-linear vortex flows due to Kelvin-Helmholtz instability in the Earth’s magnetosphere. Here, the authors perform a large-scale kinetic simulation to unveil dynamics of the vortex-induced reconnection and resulting turbulent mixing process.

Aerosol particles, including airborne microorganisms, are transported through the free troposphere from the Asian continental area to the downwind area in East Asia and can influence climate changes, ecosystem dynamics, and human health. However, the variations present in airborne bacterial communities in the free troposphere over downwind areas are poorly understood, and there are few studies that provide an in-depth examination of the effects of long-range transport of aerosols (natural and anthropogenic particles) on bacterial variations. In this study, the vertical distributions of airborne bacterial communities at high altitudes were investigated and the bacterial variations were compared between dust events and non-dust events.Aerosols were collected at three altitudes from ground level to the free troposphere (upper level: 3000 or 2500 m; middle level: 1200 or 500 m; and low level: 10 m) during Asian dust events and non-dust events over the Noto Peninsula, Japan, where westerly winds carry aerosols from the Asian continental areas. During Asian dust events, air masses at high altitudes were transported from the Asian continental area by westerly winds, and laser imaging detection and ranging (lidar) data indicated high concentrations of non-spherical particles, suggesting that dust-sand particles were transported from the central desert regions of Asia. The air samples collected during the dust events contained 10–100 times higher concentrations of microscopic fluorescent particles and optical particle counter (OPC) measured particles than in non-dust events. The air masses of non-dust events contained lower amounts of dust-sand particles. Additionally, some air samples showed relatively high levels of black carbon, which were likely transported from the Asian continental coasts. Moreover, during the dust events, microbial particles at altitudes of > 1200 m increased to the concentrations ranging from 1. 2 × 106 to 6. 6 × 106 particles m−3. In contrast, when dust events disappeared, the microbial particles at > 1200 m decreased slightly to microbial-particle concentrations ranging from 6. 4 × 104 to 8. 9 × 105 particles m−3.High-throughput sequencing technology targeting 16S rRNA genes (16S rDNA) revealed that the bacterial communities collected at high altitudes (from 500 to 3000 m) during dust events exhibited higher diversities and were predominantly composed of natural-sand/terrestrial bacteria, such as Bacillus members. During non-dust periods, airborne bacteria at high altitudes were mainly composed of anthropogenic/terrestrial bacteria (Actinobacteria), marine bacteria (Cyanobacteria and Alphaproteobacteria), and plant-associated bacteria (Gammaproteobacteria), which shifted in composition in correspondence with the origins of the air masses and the meteorological conditions. The airborne bacterial structures at high altitudes suggested remarkable changes in response to air mass sources, which contributed to the increases in community richness and to the domination of a few bacterial taxa.

We present the first results of a data analysis method, developed by Sonnerup and Hasegawa (2011), for reconstructing three-dimensional (3-D), magnetohydrostatic structures from data taken as two closely spaced satellites traverse the structures. The method is applied to a magnetic flux transfer event (FTE), which was encountered on 27 June 2007 by at least three (TH-C, TH-D, and TH-E) of the five THEMIS probes near the subsolar magnetopause. The FTE was sandwiched between two oppositely directed reconnection jets under a southward interplanetary magnetic field condition, consistent with its generation by multiple X-line reconnection. The recovered 3-D field indicates that a magnetic flux rope with a diameter of ~ 3000 km was embedded in the magnetopause. The FTE flux rope had a significant 3-D structure, because the 3-D field reconstructed from the data from TH-C and TH-D (separated by ~ 390 km) better predicts magnetic field variations actually measured along the TH-E path than does the 2-D Grad–Shafranov reconstruction using the data from TH-C (which was closer to TH-E than TH-D and was at ~ 1250 km from TH-E). Such a 3-D nature suggests that the field lines reconnected at the two X-lines on both sides of the flux rope are entangled in a complicated way through their interaction with each other. The generation process of the observed 3-D flux rope is discussed on the basis of the reconstruction results and the pitch-angle distribution of electrons observed in and around the FTE.