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After successfully inhibiting the first wave of COVID-19 transmission through a city lockdown, Wuhan implemented a series of policies to gradually lift restrictions and restore daily activities. Existing studies mainly focus on the intercity recovery under a macroscopic view. How does the intracity mobility return to normal? Is the recovery process consistent among different subareas, and what factor affects the post-pandemic recovery? To answer these questions, we sorted out policies adopted during the Wuhan resumption, and collected the long-time mobility big data in 1105 traffic analysis zones (TAZs) to construct an observation matrix (

Purpose To compare the merits and demerits of percutaneous robot-assisted screw fixation for nondisplaced pelvic fractures with other treatments via long-term follow-up. Methods This was a retrospective analysis of nondisplaced pelvic fractures treated between January 2015 and December 2021. The number of fluoroscopy exposures, operative duration, intraoperative blood loss, surgical complications, screw placement accuracy and Majeed score were compared among the nonoperative group (24 cases), open reduction and internal fixation (ORIF) group (45 cases), free-hand empirical screw fixation (FH) group (10 cases) and robot-assisted screw fixation (RA) group (40 cases). Results There was less intraoperative blood loss in the RA and FH groups than in the ORIF group. The number of fluoroscopy exposures in the RA group was lower than that in the FH group but much higher than that in the ORIF group. There were five cases of wound infection in the ORIF group and no surgical complications in the FH or RA group. The medical expenses were higher in the RA group than in the FH group, with no significant difference from the ORIF group. The Majeed score was lowest in the nonoperative group three months after injury (64.5±12.0) but lowest in the ORIF group one year after injury (88.6±4.1). Conclusion Percutaneous RA for nondisplaced pelvic fractures is effective and minimally invasive and does not increase medical expenses compared with ORIF. Therefore, it is the best choice for patients with nondisplaced pelvic fractures.

Intestinal mucosa barrier injury and immunity imbalance contribute to chronic kidney disease (CKD) progression. Type 3 innate lymphoid cells (ILC3s) are essential for normal intestinal homeostasis. Nevertheless, the relationship between ILC3s and CKD remains largely unknown. The aim of this study was to investigate the relationship linking ILC3s to clinical indicators among patients with renal dysfunction. The levels of circulating ILC3s and dendritic cells, as well as their subsets, in patients with renal dysfunction and healthy controls were determined through flow cytometry. The levels of human plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using enzyme-linked immunosorbent assay. Renal function was evaluated by measuring the estimated glomerular filtration rate (eGFR), as well as the levels of serum creatinine, blood urea nitrogen (BUN), and uric acid. The results revealed that the proportion of peripheral ILC3s was significantly decreased in patients with renal dysfunction. This reduction was positively associated with the levels of eGFR, and inversely associated with the levels of BUN and uric acid. Similarly, the percentage of circulating C-C motif chemokine receptor 6-positive (CCR6 +) ILC3s was also obviously reduced, and demonstrated positive and negative associations with the levels of eGFR and BUN, respectively. Furthermore, the levels of CCR6 + ILC3s correlated positively with those of GM-CSF, as well as type 1 conventional dendritic cells (cDC1s), which also decreased in parallel with kidney function. Thus, the reduction of ILC3s, particularly CCR6 + ILC3s, was related to worsening kidney function in patients with renal dysfunction. This effect may delay renal function impairment by regulating cDC1s via the secretion of GM-CSF, indicating that CCR6 + ILC3s may serve as efficient biomarkers for evaluating kidney function.

Blood pressure variability (BPV) has been shown to correlate with poor outcomes in patients with intracerebral hemorrhage (ICH) and traumatic brain injury. However, this association has not been elucidated in patients with traumatic cervical spinal cord injury (cSCI). We hypothesized that 24-hour BPV from time of admission is associated with worse outcomes in patients with cSCI.We performed a retrospective chart review analysis of adult patients at Huashan Hospital Fudan University between January 2006 and September 2022. We included isolated patients with traumatic cSCI within 6 hours of injury. Outcomes of patients with cSCI were assessed using 6-month American Spinal Injury Association (ASIA) impairment scale grade, and were dichotomized into poor (ASIA grade A-C, or decreasing ASIA grade compared with baseline) and good (ASIA grade D and E, or increasing ASIA grade compared with baseline) outcome groups. Blood pressures (BPs) were recorded during the first 24 hours of hospital course. BP was analyzed in the hyperacute period, from 0 to 4-5 hours; and in the acute period, from 4-5 to 24-25 hours after admission. BPV was analyzed by standard deviation (SD), coefficient of variation (CV), and successive variation (SV) of systolic BP (SBP).We analyzed 105 patients' charts. The first BP assessment, on emergency department arrival, at median 267 minutes (interquartile range, 152-312 minutes) after onset of injury was mean 152.2 mm Hg (SD, 51.8 mm Hg). The second BP assessment, on neurosurgical intensive care unit arrival, was mean 148.1 mm Hg (53.2 mm Hg). Poor outcomes occurred in 63 patients (60%). In univariate analysis, univariate quintile analysis or multivariate analysis, SBPBPV during the first 24 hours after injury in patients with traumatic cSCI was independently associated with poor functional outcome at 3 months. Stabilization of BPV during the hyperacute and acute period may be a therapeutic target to improve functional outcomes of these patients.

Recently, radioresistant cancer cells surviving radiotherapy have been suggested to show more aggressive phenotypes than parental cells, and the underlying mechanisms may be associated with cancer stem cells. This study provided novel mechanistic insights for E3 ubiquitin ligase CHIP in stem cell properties and radioresistance of non-small cell lung cancer (NSCLC). After bioinformatic prediction for key genes involved, NSCLC tissues and cells were collected to measure the expression of CHIP and PBK. E3 ubiquitin ligase CHIP was poorly expressed, while PBK was highly expressed in NSCLC tissues and cells. CHIP reduced the protein stability of PBK through the ubiquitin-protease pathway to repress the activation of ERK pathway. Based on the gain- or loss-of-function experiments, it was noted that restoration of CHIP curtailed stem cell properties and radioresistance in NSCLC, as manifested by inhibited sphere formation and cell proliferation, decreased number of CD133

Gut microbiota are significantly associated with the occurrence and development of inflammatory bowel disease (IBD). Panax notoginseng saponins (PNS) could be used for colitis and to modulate gut microbiota. However, the mechanism behind the effects of PNS on anti-colitis that are pertinent to gut microbiota is largely unknown. This study aimed to evaluate the anti-colitis effects of PNS and explore the involved mechanism as it is related to gut microbiota. Results showed that PNS significantly alleviated dextran sulfate sodium (DSS)-induced colitis. Meanwhile, after PNS treatment, the tight junction proteins were enhanced and proinflammatory cytokines, such as TNF-[Formula: see text], IL-6, IL-1[Formula: see text], and IL-17, were decreased. Furthermore, Bacteroides spp. were significantly increased after modeling, while PNS reduced their abundance and significantly increased the amount of Akkermansia spp. in vivo. Importantly, Akkermansia spp. and Bacteroides spp. were correlated with the IBD disease indicators. Moreover, fecal microbiota transplantation (FMT) experiments confirmed that PNS-reshaped gut microbiota significantly alleviated DSS-induced colitis, while A. muciniphila significantly reduced the levels of the LPS-induced cellular inflammatory factors IL-1[Formula: see text] and TNF-[Formula: see text]. In conclusion, PNS alleviated colitis pertinent to the upregulation of Akkermania spp. and downregulation of Bacteroides spp. in the gut.

The proliferation and steroid hormone synthesis of granulosa cells (GCs) are essential for ovarian follicle growth and ovulation, which are necessary to support the normal function of the follicle. Numerous studies suggest that miRNAs play key roles in this process. In this study, we report a novel role for miR-10a-5p that inhibits ovarian GCs proliferation and progesterone (P4) synthesis in chicken. Specifically, we found that miR-10a-5p significantly decreased the P4 secretion by quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. Moreover, we observed that miR-10a-5p can inhibit the proliferation of chicken GCs through the investigation of cell proliferation gene expression, cell counting kit 8 (CCK-8), cell cycle progression, and 5-ethynyl-2'-deoxyuridine (EdU) assay. Then we screened a target gene MAPRE1 of miR-10a-5p, which can promote P4 synthesis and proliferation of GCs. To explore how miR-10a-5p affects cell cycle by MAPRE1, we investigated the interaction between MAPRE1 and cyclin-dependent kinase 2 (CDK2) by Co-Immunoprecipitation (Co-IP), and then we found that MAPRE1 can form a complex with CDK2. In addition, miR-10a-5p was found to inhibit CDK2 expression by repressing the expression of MAPRE1. Overall, our results indicate that miR-10a-5p regulates the proliferation and P4 synthesis of chicken GCs by targeting MAPRE1 to suppress CDK2.

The radiation resistance of cancer stem cells poses a critical obstacle for management of non-small-cell lung cancer (NSCLC). It is interesting to note that E3 ubiquitin ligase CHIP is involved in radiation resistance and stemness phenotypes in NSCLC, while the downstream mechanisms remain elusive. Therefore, this study is aimed at exploring the possible molecular mechanism of E3 ubiquitin ligase CHIP in radiation resistance of NSCLC stem cells. Cancer and adjacent normal tissues of NSCLC patients were collected to determine expression of CHIP, Hsp90β, and MAST1. CD133+ cells were isolated from the NSCLC tissues and the lung cancer cell line A549 by flow cytometric sorting. Accordingly, downregulated CHIP and upregulated Hsp90β and MAST1 were observed in cancer tissues from NSCLC patients and in NSCLC stem cells. Sphere formation assay, colony formation assay, and flow cytometry were performed to examine self-renewal ability, survival, and apoptosis of NSCLC stem cells. An animal model of tumor xenograft was developed in nude mice to observe the tumorigenic ability and radiation resistance of NSCLC stem cells. CHIP overexpression was demonstrated to inhibit the NSCLC stem cell properties and radiation resistance in vitro and in vivo. Mechanistically, CHIP promoted MAST1 ubiquitination by blocking Hsp90β interaction with MAST1, thus inhibiting MAST1 protein stability. Furthermore, CHIP-mediated downregulation of MAST1 protein stability inhibited the NSCLC stem cell properties and radiation resistance. Collectively, CHIP promotes the ubiquitination of MAST1 by blocking the interaction of Hsp90β with MAST1, leading to decreased MAST1 protein stability, which suppressed NSCLC stem cell properties and radiation resistance.

Brain cancers, one of the most fatal malignancies, require accurate diagnosis for guided therapeutic intervention. However, conventional methods for brain cancer prognosis (imaging and tissue biopsy) face challenges due to the complex nature and inaccessible anatomy of the brain. Therefore, deep analysis of brain cancer is necessary to (i) detect the presence of a malignant tumor, (ii) identify primary or secondary origin, and (iii) find where the tumor is housed. In order to provide a diagnostic technique with such exhaustive information here, we attempted a liquid biopsy-based deep surveillance of brain cancer using a very minimal amount of blood serum (5 μL) in real time. We hypothesize that holistic analysis of serum can act as a reliable source for deep brain cancer surveillance. To identify minute amounts of tumor-derived material in circulation, we synthesized an ultrasensitive 3D nanosensor, adopted SERS as a diagnostic methodology, and undertook a DEEP neural network-based brain cancer surveillance. Detection of primary and secondary tumor achieved 100% accuracy. Prediction of intracranial tumor location achieved 96% accuracy. This modality of using patient sera for deep surveillance is a promising noninvasive liquid biopsy tool with the potential to complement current brain cancer diagnostic methodologies.

This study presents a simple technique for strengthening the adhesive-bond strength between aluminium (Al) substrate and carbon fibre reinforced polymer (CFRP) utilising resin pre-coating (RPC) with carbon nanotubes (CNTs). The CNT-containing RPC solution with 90 ​wt% acetone and 10 ​wt% resin (without hardener) was applied onto Al substrates, where micro-/nano-vertical channels had been created by chemical or mechanical surface treatments to accommodate CNTs. RPC was able to fill all micro-/nano-cavities over the Al substrate surface, then CNTs were pulled into those vertical micro-channels by the capillary action generated from acetone evaporation. Normal epoxy adhesive (resin ​+ ​hardener) was applied after the CNT-containing RPC treatment. CNTs bridging across the interface between the adhesive joint and Al substrate and sealing of micro-/nano-cavities by RPC effectively enhanced the interfacial shear bond strength between the Al substrate and CFRP by 30–100% depending on the Al substrate surface profiles. Al substrates with two different chemical treatments were compared in this study for the effectiveness of CNT interfacial reinforcement. Results from a steel substrate after sandblasting were also included for comparison.

Liquid biopsy for determining the presence of cancer and the underlying tissue of origin is crucial to overcome the limitations of existing tissue biopsy and imaging-based techniques by capturing critical information from the dynamic tumor heterogeneity. A newly emerging liquid biopsy with extracellular vesicles (EVs) is gaining momentum, but its clinical relevance is in question due to the biological and technical challenges posed by existing technologies. The biological barriers of existing technologies include the inability to generate fundamental details of molecular structure, chemical composition as well as functional variations in EVs by gathering simultaneous information on multiple intra-EV molecules, unavailability of holistic qualitative analysis, in addition to the inability to identify tissue of origin. Technological barriers include reliance on EV isolation with a few labeled biomarkers, resulting in the inability to generate comprehensive information on the disease. A more favorable approach would be to generate holistic information on the disease without the use of labels. Such a marker-free diagnosis is impossible with the existing liquid biopsy due to the unavailability clinically validated cancer stem cells (CSC)-specific markers and dependence of existing technologies on EV isolation, undermining the clinical relevance of EV-based liquid biopsy. Here, CSC EVs were employed as an independent liquid biopsy modality. We hypothesize that tracking the signals of CSCs in peripheral blood with CSC EVs will provide a reliable solution for accurate cancer diagnosis, as CSC are the originators of tumor contributing to tumor heterogeneity. We report nanoengineered 3D sensors of extremely small nano-scaled probes self-functionalized for SERS, enabling integrative molecular and functional profiling of otherwise undetectable CSC EVs. A substantially enhanced SERS and ultralow limit of detection (10 EVs per 10 μL) were achieved. This was attributed to the efficient probe-EV interaction due to the 3D networks of nanoprobes, ensuring simultaneous detection of multiple EV signals. We experimentally demonstrate the crucial role of CSC EVs in cancer diagnosis. We then completed a pilot validation of this modality for cancer detection as well as for identification of the tissue of origin. An artificial neural network distinguished cancer from noncancer with 100% sensitivity and 100% specificity for three hard to detect cancers (breast, lung, and colorectal cancer). Binary classification to distinguish one tissue of origin against all other achieved 100% accuracy, while simultaneous identification of all three tissues of origin with multiclass classification achieved up to 79% accuracy. This noninvasive tool may complement existing cancer diagnostics, treatment monitoring as well as longitudinal disease monitoring by validation with a large cohort of clinical samples.

Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. Methods Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. Results We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p Conclusion Taken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.

Atmospheric pressure fluctuation is one of the most important factors affecting the climate environment and gas emission in the fire area. In order to obtain the influence rule of the surface atmospheric pressure change on the gas sampling and abnormal emission in the mine closed goaf, the No. 1 coal mine in Dananhu, Xinjiang was taken as the research object. Using Fourier transform and Fisher harmonic analysis and other methods, the influence of the periodic variation of atmospheric pressure on the gas leakage and outflow in the closed goaf was studied. The results showed that there were three atmospheric pressure periods of 15.2d, 1d and 182.2d, and the probability was greater than 95%. The time period with the highest number of atmospheric pressure peaks was 7:00-8:00, which accounted for 20.2% of total occurrence number in a day. And the time periods with the highest number of atmospheric pressure trough were 2:00, 15:00 and 16:00, accounting for 27.4%. The peak-to-trough transition time was mainly concentrated around 6h, and the diurnal variation curve of atmospheric pressure was mainly bimodal. The atmospheric pressure change rate was mostly concentrated in 10~50 Pa/h. It was determined that the distance that the gas sampling pipe was pre-laid into the inner side of the closed wall should be greater than 44.4m, and the CO concentration and atmospheric pressure in the closed goaf were both periodic and negative with atmospheric pressure. The research results have important guiding significance for the disaster warning and environmental protection of the goaf.

Due to their low viscosity, high mobility, and high element contents, supercritical fluids are important agents in the cycling of elements. However, the chemical composition of supercritical fluids in natural rocks is poorly understood. Here, we investigate well-preserved primary multiphase fluid inclusions (MFIs) from an ultrahigh-pressure (UHP) metamorphic vein of the Bixiling eclogite in Dabieshan, China, thus providing direct evidence for the components of supercritical fluid occurring in a natural system. Via the 3D modeling of MFIs by Raman scanning, we quantitatively determined the major composition of the fluid trapped in the MFIs. Combined with the peak-metamorphic pressure–temperature conditions and the cooccurrence of coesite, rutile, and garnet, we suggest that the trapped fluids in the MFIs represent supercritical fluids in a deep subduction zone. The strong mobility of the supercritical fluids with respect to carbon and sulfur suggests that such fluids have profound effects on global carbon and sulfur cycling.

Carbonate and silicate metasomatism occurring in subduction zones is an important mechanism underlying mantle heterogeneity and compositional diversity of mantle-derived rocks. However, distinguishing between the two kinds of metasomatism is often difficult. Lithium (Li) and its isotopes have great potential in this regard because of the different Li isotopic compositions of recycled marine carbonate and silicate components. We report Li isotopic data from Cenozoic and Mesozoic alkali basalts of the West Qinling orogen in central China. Relative to those for normal basalts, very high δ7Li values (up to +11.2‰) were observed for the Cenozoic alkali basalts, but significantly and systematically lower values (as low as −3.3‰) were estimated for the Mesozoic alkali basalts. Their abnormal Li isotopic compositions, combined with major- and trace-element contents and Sr-Mg isotope ratios, indicate that the Cenozoic and Mesozoic alkali basalts originated from carbonated and silicated mantle sources, respectively, reflecting metasomatism of the mantle by slab-derived carbonate and silicate melts during Paleotethyan oceanic subduction. Interactions of such melts with the mantle peridotite in subduction channels can account for the elemental and isotopic differences of the studied alkali basalts. The present study demonstrates an effective way to distinguish between carbonate and silicate metasomatism in subduction zones by studying Li isotopic compositions of alkali basalts and highlights the prospect of Li isotopes in tracing the deep carbon cycle.

The concentrations of LSN3154567 in the dog plasma samples.

NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR.

Table S1: anti-proliferative activity of LSN3154567 against different cancer cell lines; Table S2: effects of NAM on the anti-proliferative activity of LSN3154567

Addition of NA rescued the inhibitory activity of LSN3154567.

Addition of NAM rescued the inhibitory activity of LSN3154567

Association of NAPRT1 expression level with sensitivity of cancer cells to NAMPT inhibition by LSN3154567 in the presence of NA

Supplementary Figure Legends & Tables

Figure S1. Efficacy of pemetrexed in Lewis Lung carcinoma model and metabolomic analysis of MC38 tumor bearing mice treated with 50 mg/kg of pemetrexed Figure S2. T cell inflamed phenotype induced by pemetrexed is modestly reduced in tumors upon combination with cisplatin Figure S3. Combination Effects of pemetrexed -/+ anti-PD-L1 in MC38, LLC and Colon26 tumor models Figure S4 (A) Mice bearing Colon26 tumors were treated starting 10 days after tumor implantation with pemetrexed (50 mg/kg, 5 days on, 2 days off, IP) and/or anti-PD-L1 (αPD-L1) (500 ug/mouse, weekly IP), and tumors were isolated after 14 days of treatment and single cell suspensions were subjected to flow cytometry analysis. FACS plots show representative data of intra-tumor CD45+ tumor-infiltrating lymphocyte (TIL) T cell (CD3+) and Myeloid cell (CD11b+) subsets frequencies; and percentage of Ki67+ CD4+ T effector cells based on the gating scheme indicated. (B) Spleens, TDLNs and tumors were isolated and antigen specific T cell responses were measured by IFNγ ELISpot, gp70 Tetramer staining (Tet) and Intracellular cytokine staining. (Left) CD8 T cells isolated from pooled spleens and TDLNs from individual mice were cultured alone (control) with irrelevant BALB/c tumor EMT6 or cognate Colon26 tumor cells overnight and number of IFNγ producing T cells was measured by ELISpot. (Middle) Freshly isolated CD8+ T cells from spleens and TDLNs were assessed for % of gp70 Tet+ cells. (Right) Freshly isolated tumors single cell suspensions were stimulated with PMA/ phorbol myristate acetate (PMA) and ionomycin with monensin for 4 hrs and the % of TNF-alpha positive and gp70 Tet+ CD8 T cells were measured from the Live CD45+, CD3+ T cells by FACS. Figure S5. Concordance between QuantiGene and nCounter gene expression data for in vitro activated T cells treated in the presence or absence of pemetrexed (related to Figure 6F). Supplementary Table 1. Ingenuity pathway analysis (IPA) of MC38 tumors treated with pemetrexed or paclitaxel with or without carboplatin Supplementary Table 2: IPA results for Colon26 experiment in Figure 4 sorted by functional class. Pemetrexed monotherapy in this experiment at this timepoint did not have enough differentially expressed genes to generate IPA results.

Purpose:Combination strategies leveraging chemotherapeutic agents and immunotherapy have held the promise as a method to improve benefit for patients with cancer. However, most chemotherapies have detrimental effects on immune homeostasis and differ in their ability to induce immunogenic cell death (ICD). The approval of pemetrexed and carboplatin with anti-PD-1 (pembrolizumab) for treatment of non–small cell lung cancer represents the first approved chemotherapy and immunotherapy combination. Although the clinical data suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy, the underlying mechanism remains unknown.Experimental Design:Mouse tumor models (MC38, Colon26) and high-content biomarker studies (flow cytometry, Quantigene Plex, and nCounter gene expression analysis) were deployed to obtain insights into the mechanistic rationale behind the efficacy observed with pemetrexed/anti-PD-L1 combination. ICD in tumor cell lines was assessed by calreticulin and HMGB-1 immunoassays, and metabolic function of primary T cells was evaluated by Seahorse analysis.Results:Pemetrexed treatment alone increased T-cell activation in mouse tumors in vivo, robustly induced ICD in mouse tumor cells and exerted T-cell–intrinsic effects exemplified by augmented mitochondrial function and enhanced T-cell activation in vitro. Increased antitumor efficacy and pronounced inflamed/immune activation were observed when pemetrexed was combined with anti-PD-L1.Conclusions:Pemetrexed augments systemic intratumor immune responses through tumor intrinsic mechanisms including immunogenic cell death, T-cell–intrinsic mechanisms enhancing mitochondrial biogenesis leading to increased T-cell infiltration/activation along with modulation of innate immune pathways, which are significantly enhanced in combination with PD-1 pathway blockade.See related commentary by Buque et al., p. 6890

Summary In deep well drilling, rock breaking has some problems, such as low rock breaking efficiency, serious thermal wear of cutters, short service life, and high cost. It is noticed that the application of CO2 drilling fluid in the oil and gas underbalanced drilling is an efficient approach to achieve the reduction of CO2 emissions. Thus, based on the rock-breaking advantages of CO2 jetting, a new rock-breaking method of combing high-pressure CO2 jet and polycrystalline diamond cutter (PDC) is proposed in our study. The cooling mechanism and influencing during rock breaking by using the high-pressure CO2 jet-PDC are conducted. With the test system during composite rock breaking of the high-pressure CO2 jet-PDC, the composite rock-breaking experiment of the high-pressure CO2 jet-PDC was carried out. In the experiment, the comparison of the CO2 jet, N2 jet, water jet, and without a jet was conducted and analyzed. And based on the numerical simulation analysis, the intense cooling mechanism was expounded. In the process during composite rock breaking of the high-pressure CO2 jet-PDC, the intense cooling mechanism was mainly attributed to three main reasons: the thermal effect of the jet flow, the expansion endothermic effect of the jetted flow, and the phase transformation cooling effect of the CO2 jet. The effects of rock samples, jet temperatures, jet flow pressures, and rock temperatures on the cutting temperature were experimentally explored, and finally, the intense cooling rules of composite rock breaking were obtained. The experimental results showed that the CO2 jet had a stronger cooling effect on granite than that of the sandstone. In a certain range, jet pressure was positively correlated with the cutting temperature, whereas jet temperature and heating time were negatively correlated with cutting temperature. The study provides the theoretical support for the CO2 application as a drilling medium in underbalanced drilling.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, are high likely co-administered in China. ZJP could significantly inhibit VEN pharmacokinetics in vitro and in rats through suppression of CYP2D6 activity. To date, however, no clinical study has demonstrated the clinical relevance. Here, the VEN pharmacokinetics at a single dose of VEN with or without co-administration of ZJP was compared. ZJP had a weak herb-drug interactions (HDI) on the pharmacokinetics of VEN. The geometric means of C

Human mesenchymal stem cells (hMSCs) were labeled with Dotarem or (Gd-DOTA)2- EM7 (EM7Gd2) via electroporation (EP). Cellular transmission electron microscopy (TEM) reveals free distribution of Gd agents and formation of EM7Gd2 clusters in the cytosol. Cellular magnetic resonance imaging (MRI) reveals that the free Gd agents induce MRI signal enhancement effect due to its fast exocytosis and subsequent interaction with intercellular water molecules. The EM7Gd2 clusters exhibits a longer intracellular retention time and induce a persistent MRI signal reduction effect. The cellular MRI results are interpreted by taking into account both T1 and T2 relaxation rates and their correlation with cellular binding structures of Dotarem and EM7Gd2.

Grounding electrode is an indispensable part in HVDC transmission projects. During its design and safety evaluation, step voltage is a crucial aspect. By reviewing and sorting out the present standards involving step voltage measurement and its safety limit, this paper illustrates the contradiction between the measurement methods and the safety evaluation. Reasons for the contradiction are explained by analyzing the principal of step voltage measurement and safety evaluation. The Open-circuit step voltage measurement method and the measurement method with a human body equivalent resistance paralleled are compared to find out their advantages and disadvantages. Suitable circumstances and corresponding safety criteria of these two methods are put forward. Method proposed in this paper can be applied to step voltage measurement and safety evaluation of HVDC grounding electrode, providing reference when revising the related standards.