Trogocytosis in CAR immune cell therapy: a key mechanism of tumor immune escape.

Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy.

The new N2, N4-diphenylpyridine-2,4-diamine deuterated derivatives as EGFR inhibitors to overcome C797S-mediated resistance.

A series of new deuterated and non-deuterated N2, N4-diphenylpyridine - 2,4-diamine derivatives were synthesized and evaluated as EGFR C797S-mediated resistance inhibitors. Most of these compounds exhibited potent antiproliferative activity against Baf3-EGFR L858R/T790M/C797S and Baf3-EGFR Del19/T790M/C797S cancel cell lines, with IC50 values in the nanomolar concentration range. Among them, compound 14l represented the most active compound with IC50 values of 8-11 nM. Interestingly, metabolic stability assay with rat liver microsomes indicated that the half-life of the deuterated derivative 14o was significantly increased compared to that of 14l. In xenograft mice models, 14o inhibited tumor growth with excellent inhibitory rate of 75.1 % at the dosage of 40 mg/kg, comparing 73.2 % of the TGI with its non-deuterated compound 14l, at a dosage of 80 mg/kg. Mechanism studies revealed that 14o was a potent EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S kinase inhibitor, which could downregulate the protein phosphorylation of EGFR and m-TOR signaling pathways, arrest cell cycle at G2/M phase by affecting the expression of CDC25C, and promote cell apoptosis by regulating the expression of cleaved caspase-3. In summary, 14o could serve as a promising deuterated compound for the development of highly efficient anticancer agents.

[Chemical analysis of classical prescription Qianghuo Shengshi Standard Decoction by UHPLC-Q Exactive Orbitrap MS].

A UHPLC-Q Exactive Orbitrap MS method was used to analyze the chemical constituents of the classical prescription Qianghuo Shengshi Standard Decoction(QHSS). UHPL conditions were as follows: Waters~(TM) UPLC~(TM) HSS T3 C_(18) column(2.1 mm×100 mm, 1.7 µm) and mobile phase of acetonitrile-0.1% formic acid aqueous solution. Mass spectrometry data of QHSS, each herb extract, and negative sample were collected in both positive and negative ion modes. The chemical constituents of QHSS were identified or tentatively identified based on the accurate molecular weight, retention time, MS fragmentation, comparison with reference substances, and literature reports. A total of 141 compounds were identified, including 18 amino acids, oligosaccharides, oligopeptides, and their derivatives, 19 phenolic acids, 44 coumarins, 18 flavonoids and chromones, 13 saponins, 17 phthalides, and 12 other components. This study comprehensively characterized the chemical constituents of QHSS, laying an experimental basis for the in-depth research on the material basis and quality control of QHSS.

Stable and Scalable Multistage Terahertz-Driven Particle Accelerator.

Particle accelerators that use electromagnetic fields to increase a charged particle's energy have greatly advanced the development of science and industry since invention. However, the enormous cost and size of conventional radio-frequency accelerators have limited their accessibility. Here, we demonstrate a miniaccelerator powered by terahertz pulses with wavelengths 100 times shorter than radio-frequency pulses. By injecting a short relativistic electron bunch to a 30-mm-long dielectric-lined waveguide and tuning the frequency of a 20-period terahertz pulse to the phase-velocity-matched value, precise and sustained acceleration for nearly 100% of the electrons is achieved with the beam energy spread essentially unchanged. Furthermore, by accurately controlling the phase of two terahertz pulses, the beam is stably accelerated successively in two dielectric waveguides with close to 100% charge coupling efficiency. Our results demonstrate stable and scalable beam acceleration in a multistage miniaccelerator and pave the way for functioning terahertz-driven high-energy accelerators.

TEMPO-Functionalized Nanoreactors from Bottlebrush Copolymers for the Selective Oxidation of Alcohols in Water.

Polymeric nanoreactors in water fabricated by the self-assembly of amphiphilic copolymers have attracted much attention due to their good catalytic performance without using organic solvents. However, the disassembly and instability of relevant nanostructures often compromise their potential applicability. Herein, the preparation of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-containing nanoreactors by the self-assembly of amphiphilic bottlebrush copolymers has been demonstrated. First, a macromonomer having a norbornenyl polymerizable group was prepared by RAFT polymerization of hydrophobic and hydrophilic monomers. The macromonomer was further subjected to ring-opening metathesis polymerization to produce an amphiphilic bottlebrush copolymer. Further, TEMPO, as a catalyst, was introduced into the hydrophobic block through the activated ester strategy. Finally, TEMPO-functionalized polymeric nanoreactors were successfully obtained by self-assembly in water. The nanoreactors exhibited excellent catalytic activities in selective oxidation of alcohols in water. More importantly, the reaction kinetics showed that the turnover frequency is greatly increased compared to that of the similar nanoreactor prepared from liner copolymers under the same conditions. The outstanding catalytic activities of the nanoreactors from bottlebrush copolymers could be attributed to the more stable micellar structure using the substrate concentration effect. This work presents a new strategy to fabricate stable nanoreactors, paving the way for highly efficient organic reactions in aqueous solutions.

HN1 promotes tumor associated lymphangiogenesis and lymph node metastasis via NF-κB signaling activation in cervical carcinoma.

Lymph node metastasis (LNM) is a critical cause for disease progression and treatment failure in cervical cancer. However, the mechanism underlying cervical cancer LNM remains unclear. In this study, HN1 was found to be dramatically upregulated in cervical cancer and patients with higher HN1 expression are more likely to exhibit a higher rate of LNM and lower survival rate. Univariate and multivariate Cox-regression analyses showed that HN1 is an independent prognostic factor in cervical cancer. Meanwhile, HN1 promotes lymphangiogenesis of cervical cancer in vitro. The in vivo experiment also indicates that HN1 enhances LNM in cervical cancer. Furthermore, we also found that HN1 activated the NF-κB signaling pathway to enhance the expression of downstream genes. Taken together, our study suggests that HN1 plays a crucial role in promoting LNM and acts as a prognostic biomarker in cervical cancer.

Femtosecond Relativistic Electron Beam with Reduced Timing Jitter from THz Driven Beam Compression.

We propose and demonstrate a method to reduce the pulse width and timing jitter of a relativistic electron beam through THz driven beam compression. In this method the longitudinal phase space of a relativistic electron beam is manipulated by a linearly polarized THz pulse copropagating in a dielectric tube such that the bunch tail has a higher velocity than the bunch head, which allows simultaneous reduction of both pulse width and timing jitter after passing through a drift. In this experiment, the beam is compressed by more than a factor of 4 from 130 fs to 28 fs with the arrival time jitter also reduced from 97 fs to 36 fs, opening up new opportunities in using pulsed electron beams for studies of ultrafast dynamics. This technique provides an effective way to manipulate beam longitudinal phase space with a THz pulse and may have a strong impact in accelerator and ultrafast science facilities that require femtosecond electron beams with tight synchronization to external lasers.

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway.

The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma-secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin-based chemotherapy may be a novel therapeutic approach for NR2F6-overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6-overexpressing EOC.

Terahertz Oscilloscope for Recording Time Information of Ultrashort Electron Beams.

We propose and demonstrate a terahertz (THz) oscilloscope for recording time information of an ultrashort electron beam. By injecting a laser-driven THz pulse with circular polarization into a dielectric tube, the electron beam is swept helically such that the time information is uniformly encoded into the angular distribution that allows one to characterize both the temporal profile and timing jitter of an electron beam. The dynamic range of the measurement in such a configuration is significantly increased compared to deflection with a linearly polarized THz pulse. With this THz oscilloscope, nearly 50-fold longitudinal compression of a relativistic electron beam to about 15 fs (rms) is directly visualized with its arrival time determined with 3 fs accuracy. This technique bridges the gap between streaking of photoelectrons with optical lasers and deflection of relativistic electron beams with radio-frequency deflectors, and should have wide applications in many ultrashort electron-beam-based facilities.

Observation of Field-Emission Dependence on Stored Energy.

Field emission from a solid metal surface has been continuously studied for a century over macroscopic to atomic scales. It is general knowledge that, other than the surface properties, the emitted current is governed solely by the applied electric field. A pin cathode has been used to study the dependence of field emission on stored energy in an L-band rf gun. The stored energy was changed by adjusting the axial position (distance between the cathode base and the gun back surface) of the cathode while the applied electric field on the cathode tip is kept constant. A very strong correlation of the field-emission current with the stored energy has been observed. While eliminating all possible interfering sources, an enhancement of the current by a factor of 5 was obtained as the stored energy was increased by a factor of 3. It implies that under certain circumstances a localized field emission may be significantly altered by the global parameters in a system.

Methionine Synthase 2 Represses Stem Cell Maintenance of Arabidopsis thaliana in Response to Salt Stress.

Salt stress represses the growth and development of plants that mainly depend on the continual propagation and differentiation of stem cells. WUSCHEL (WUS)/WUSCHEL-RELATED HOMEOBOX (WOX) family proteins determine stem cell fate in plants under ever-changing environments. It is not yet known how plant stem cell homeostasis is regulated under salt stress. Methionine synthase catalyzes the formation of methionine by methylating homocysteine in the one-carbon metabolism pathway. In this work, we investigated the role of Arabidopsis METHIONINE SYNTHASE 2 (AtMS2) in stem cell homeostasis under salt stress. The results showed that AtMS2 represses the stem cell maintenance of Arabidopsis in response to salt stress. Under normal growth conditions, AtMS2 is mainly localized in the cytoplasm. However, under salt stress, it exhibits significant accumulation in the nucleus. AtMS2 interacts with the WUS/WOX protein, and, together, they repress WUS/WOX expression by binding to its promoter. The mutation in AtMS2 resulted in enhanced salt tolerance. Therefore, AtMS2 might act as a key negative regulator to repress the stem cell maintenance and growth of Arabidopsis under salt stress.

Developing CAR-immune cell therapy against SARS-CoV-2: Current status, challenges and prospects.

Chimeric antigen receptor (CAR)-immune cell therapy has revolutionized the anti-tumor field, achieving efficient and precise tumor clearance by directly guiding immune cell activity to target tumors. In addition, the use of CAR-immune cells to influence the composition and function of the immune system and ultimately achieve virus clearance and immune system homeostasis has attracted the interest of researchers. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a global pandemic of coronavirus disease 2019 (COVID-19). To date, the rapidly mutating SARS-CoV-2 continues to challenge existing therapies and has raised public concerns regarding reinfection. In patients with COVID-19, the interaction of SARS-CoV-2 with the immune system influences the course of the disease, and the coexistence of over-activated immune system components, such as macrophages, and severely compromised immune system components, such as natural killer cells, reveals a dysregulated immune system. Dysregulated immune-induced inflammation may impair viral clearance and T-cell responses, causing cytokine storms and ultimately leading to patient death. Here, we summarize the research progress on the use of CAR-immune cells against SARS-CoV-2 infection. Furthermore, we discuss the feasibility, challenges and prospect of CAR-immune cells as a new immune candidate therapy against SARS-CoV-2.

Preparation of Polysaccharide-Protein Hydrogels with an Ultrafast Self-Healing Property as a Superior Oral Delivery System of Probiotics.

Oral administration of probiotic supplements can effectively regulate intestinal disorders. However, harsh gastrointestinal conditions greatly limit the bioavailability of probiotics. In this work, biomass-derived polysaccharide-protein hydrogels (Dex-sBSA hydrogels) were constructed as an oral probiotic delivery system. The hydrogel encapsulation significantly promoted the growth and proliferation of probiotics and protected them from gastric acid, bile salts, reactive oxygen species, and antibiotics. In vivo experiments demonstrated that the hydrogel encapsulation significantly enhanced the bioavailability of probiotics, of which the cell number in the intestine, colon, and cecum was 35 times, 8 times, and 203 times higher than the free one, respectively. Attributed to the superior ultrafast self-healing property, the Dex-sBSA hydrogel successfully prevented the probiotics from quick elimination and prolonged the retention time in the gut, providing great possibilities for colonization and proliferation. These results clearly indicate the great potential of the Dex-sBSA hydrogel as a superior oral delivery system for probiotics.

RNF219 Promotes Nasopharyngeal Carcinoma Progression by Activating the NF-κB Pathway.

In Southeast Asia, the prevalence of nasopharyngeal carcinoma (NPC) is high; however, the molecular mechanism governing the progression of NPC is unclear. The results of the present study revealed upregulation of ring finger protein 219 (RNF219) expression in NPC tissues and cells. Overexpression of RNF219 enhanced NPC cell invasion, migration, and proliferation; whereas knockdown of RNF219 had the opposite effects. Mechanistically, RNF219 activated the nuclear factor kappa B (NF-κB) pathway, mainly reflected by increased p65 nuclear translocation, and increased NF-κB pathway target gene expression. NF-κB pathway inhibition in cells overexpressing RNF219 resulted in reduced invasion, migration, and proliferation, confirming that progression of NPC was promoted by RNF219-mediated NF-κB pathway activation. In addition, the expression of RNF219 correlated positively with the activity of the NF-κB pathway, verifying that RNF219 regulates the activity of the NF-κB pathway in the clinical setting. Our results identified a novel therapeutic target that could promote the development of novel treatments for NPC.

Associations between Sleep and Mental Health in Adolescents: Results from the UK Millennium Cohort Study.

(1) Background: There is a growing interest in investigating the relationship between sleep and mental health development in adolescents. This study aims to further investigate this relationship by identifying the specific associations between several sleep problems in adolescents and several mental health areas, and the role of gender in these associations. (2) Methods: Data from the Millennium cohort survey containing 11,553 individuals at 13-14 years old was included. Nighttime sleep duration and bedtime during weekdays and weekends, night awakening frequency, and sleep onset latency were assessed using self-reported questionnaires. Affective symptom and emotional and behavioural problems were examined with self-reported questionnaires. (3) Results: Regression analyses and path analysis models suggested that frequent night awakening was associated with all the outcomes, and hyperactivity/inattention was the outcome that presented a higher number of significant associations with sleep patterns. Long sleep onset latency and late bedtime at school days were associated with higher risk of emotional and behavioural difficulties. Further, poor sleep seems to manifest more externally in males, while more internally in females. (4) Conclusions: Specific sleep problems should be considered when assessing mental health in adolescence, which would allow more targeted prevention and intervention strategies. Further, special attention should be given to gender differences when addressing sleep and mental health.

Iron status and mental disorders: A Mendelian randomization study.

Background: Mental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders. Methods: Genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses. Results: Genetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. Conclusion: Our findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.

Influential paths of ecosystem services on human well-being in the context of the sustainable development goals.

Ecosystem services (ESs) and their demands from people are closely related to human well-being (HWB). Understanding of the influential paths of ecosystem services on human well-being is significant to sustainable landscape management. This study explored the supply of ecosystem services and the ecosystem service supply-demand relationships (i.e. the ecological supply-demand ratio, ESDR) in the Central and Western Inner Mongolia, as well as HWB by combining the Millennium Ecosystem Assessment (MA) and the sustainable development goals of the United Nations (SDGs). A structural equation model (SEM) was built to quantify the influential paths of the ESs on the HWB. The results indicated that: (1) The HWB was improved during 2000-2018. (2) The supporting services promoted the provisioning services and the regulating services directly. (3) The provisioning services and the regulating services had positive direct influences on the HWB, and also affected the HWB through the ESDR indirectly. The combination of the supporting services and the ESDR presented a panorama of the influential paths of ecosystem services on the HWB and promoted the understanding of the driving mechanisms. Assessments on the ESs, the HWB in the context of SDGs, and their influential paths were instructive for decision-making towards sustainable landscape management.

The solvent effect modulates the formation of homogeneous polyphenol composite hydrogels with improved transparency and mechanical strength for antibacterial delayed sternal closure films.

The usage of delayed sternal closure films after thoracotomy surgery helps doctors deal with emergency conveniently. There is a growing demand to develop suturable, antibacterial and transparent films for delayed sternal closure. Although polyphenol incorporated hydrogels provide good suture ability, they lose transparency because of the heterogeneous distribution of polyphenols during the post-immersion process. Here, a solvent exchange method is proposed to fabricate homogeneous polyphenol composite hydrogels in a bottom-up manner, which utilizes the distinct solvent effect of DMSO and H2O to modulate the association and disassociation between polyphenols and the polymer backbones on demand. DMSO first provides a protective environment to turn off the intermolecular interactions and allows tannic acid (TA) to be dispersed into the polymer network PEG-lysozyme (PEG-LZM) homogeneously. The following water rehydration turns on the intermolecular interactions between titanic acid and PEG-lysozymes, and results in a homogeneous titanic acid toughened composite hydrogel (PEG-LZM-TA (DH)), which has an improved transparency and mechanical properties than those of the materials prepared by the post-immersion method. In addition, the TA integration provides antibacterial function to the hydrogels. We establish a rabbit delayed sternal closure model to demonstrate that PEG-LZM-TA (DH) films can be sutured to temporarily close the thoracic cavity of rabbits, provide a transparent window to inspect the wound at any time, and control the bacterial contamination efficiently. We further explore the solvent exchange method to other polyphenols and polymeric hydrogel composites. The results suggest that the solvent exchange method provides generic opportunities to fabricate homogeneous polyphenol strengthened hydrogel systems with high performance.

Phytochemical profile of Tibetan native fruit "Medog lemon" and its comparison with other cultivated species in China.

Tibet's native fruit resources have not been explored and remain underutilized due to geographical isolation. "Medog lemon" (ML), an ethno-species of wild citron, is an important functional food and dietary resource for the local people in southeastern Tibet. Herein comprehensive characterization of components of ML were firstly performed with an integrated strategy based on UHPLC-QE Orbitrap MS. A total of 196 components were characterized, among which 33 were detected from Citrus genus for the first time, and 55 were identified as potential new phytochemicals. The chemical comparison of ML with cultivated citron and fingered citron based on partial least squares-discriminant analysis model and univariate analysis revealed the distinct chemical composition of ML and in which more than 30 differentiated components were identified. The distinct morphological and chemical characters, as well as its good antioxidant properties, indicated ML as a potential new food resource that can be beneficial for human health.

Lipidomics Analysis Indicates Disturbed Hepatocellular Lipid Metabolism in Reynoutria multiflora-Induced Idiosyncratic Liver Injury.

The root of Reynoutria multiflora (Thunb.) Moldenke (syn.: Polygonum multiflorum Thunb., HSW) is a distinguished herb that has been popularly used in traditional Chinese medicine (TCM). Evidence of its potential side effect on liver injury has accumulated and received much attention. The objective of this study was to profile the metabolic characteristics of lipids in injured liver of rats induced by HSW and to find out potential lipid biomarkers of toxic consequence. A lipopolysaccharide (LPS)-induced rat model of idiosyncratic drug-induced liver injury (IDILI) was constructed and evident liver injury caused by HSW was confirmed based on the combination of biochemical, morphological, and functional tests. A lipidomics method was developed for the first time to investigate the alteration of lipid metabolism in HSW-induced IDILI rat liver by using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry coupled with multivariate analysis. A total of 202 characterized lipids, including phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), sphingomyelin (SM), phosphatidylinositol (PI), lysophosphatidylinositol (LPI), phosphatidylserine (PS), phosphoglycerols (PG), and ceramide (Cer), were compared among groups of LPS and LPS + HSW. A total of 14 out 26 LPC, 22 out of 47 PC, 19 out of 29 LPE, 16 out of 36 PE, and 10 out of 15 PI species were increased in HSW-treated rat liver, which indicated that HSW may cause liver damage via interfering the phospholipid metabolism. The present work may assist lipid biomarker development of HSW-induced DILI and it also provide new insights into the relationships between phospholipid perturbation and herbal-induced idiosyncratic DILI.