Repairing Host Damage Caused by Tobacco Mosaic Virus Stress: Design, Synthesis, and Mechanism Study of Novel Oxadiazole and Arylhydrazone Derivatives.

Tobacco mosaic virus (TMV), as one of the most traditional and extensive biological stresses, poses a serious threat to plant growth and development. In this work, a series of 1-phenyl/tertbutyl-5-amino-4-pyrazole oxadiazole and arylhydrazone derivatives was synthesized. Bioassay evaluation demonstrated that the title compounds (P1-P18) without a "thioether bond" lost their anti-TMV activity, while some of the ring-opening arylhydrazone compounds exhibited superior in vivo activity against TMV in tobacco. The EC50 value of title compound T8 for curative activity was 139 µg/mL, similar to that of ningnanmycin (NNM) (EC50 = 152 µg/mL). Safety analysis revealed that compound T8 had no adverse effects on plant growth or seed germination at a concentration of 250 µg/mL. Morphological observation revealed that compound T8 could restore the leaf tissue of a TMV-stressed host and the leaf stomatal aperture to normal. A mechanism study further revealed that compound T8 not only restored the photosynthetic and growth ability of the damaged host to normal levels but also enhanced catalase (CAT) activity and reduced the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in the damaged host, thereby reducing the oxidation damage to the host. TMV-green fluorescent protein (GFP) experiments further demonstrated that compound T8 not only slowed the transmission speed of TMV in the host but also inhibited its reproduction. All of the experimental results demonstrated that compound T8 could reduce the oxidative damage caused by TMV stress and regulate the photosynthetic ability of the host, achieving the ability to repair damage, to make the plant grow normally.

Leaf litter decomposition and its drivers differ between an invasive and a native plant: Management implications.

Litter decomposition is a key process of the carbon cycle in terrestrial and aquatic ecosystems. The dominant conceptual model of litter decomposition assumes that environmental conditions, litter traits, and decomposer composition control litter decomposition in a decreasing order, yet whether this hierarchical model applies to both invasive and native plant species is unknown. Here, by comparing a widespread invasive plant and its native counterpart in Chinese coastal saltmarshes, we aimed to examine whether the hierarchy of factors controlling litter decomposition varies with plant species in the face of plant invasions. Leaf litter of invasive Spartina alterniflora and native Phragmites australis was collected across an 18° latitudinal range to capture wide variation in litter traits. These leaf litter samples were transported to three saltmarsh sites of different latitudes and were incubated in litterbags varying in mesh size (0.1, 2, and 5 mm) to manipulate decomposer composition. After 90-day incubation, we found a parallel latitudinal pattern in leaf litter decomposition rate (k) between S. alterniflora and P. australis regardless of saltmarsh site and mesh size. Nonetheless, the k value of S. alterniflora was 2.2-fold higher than that of P. australis. Moreover, there was a shift in the hierarchy of factors controlling k values between S. alterniflora and P. australis: environmental conditions (climate and soil) dominated other factors in P. australis, whereas litter traits contributed more than environmental conditions in S. alterniflora. Overall, our findings show that leaf litter decomposition and its dominant controlling factors across broad geographical ranges can vary with plant invasions, having important implications for managing invasive plants in the context of conserving coastal blue carbon.

Sea Spray Aerosols Contain the Major Component of Human Lung Surfactant.

Marine phytoplankton influence the composition of sea spray aerosols (SSAs) by releasing various compounds. The biogenic surfactant dipalmitoylphosphatidylcholine (DPPC) is known to accumulate in the sea surface microlayer, but its aerosolization has never been confirmed. We conducted a 1 year SSA sampling campaign at the Belgian coast and analyzed the SSA composition. We quantified DPPC at a median and maximum air concentration of 7.1 and 33 pg m-3, respectively. This discovery may be of great importance for the field linking ocean processes to human health as DPPC is the major component of human lung surfactant and is used as excipient in medical aerosol therapy. The natural airborne exposure to DPPC seems too low to induce direct human health effects but may facilitate the effects of other marine bioactive compounds. By analyzing various environmental variables in relation to the DPPC air concentration, using a generalized linear model, we established that wave height is a key environmental predictor and that it has an inverse relationship. We also demonstrated that DPPC content in SSAs is positively correlated with enriched aerosolization of Mg2+ and Ca2+. In conclusion, our findings are not only important from a human health perspective but they also advance our understanding of the production and composition of SSAs.

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. METHODS: Here, we designed a dominant-negative form of PD-1, dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. RESULTS: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1+ tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. CONCLUSIONS: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

Association Between Body Composition and Frailty in Elder Inpatients.

PURPOSE: The study aimed to investigate the association between body composition and frailty in elder inpatients. PATIENTS AND METHODS: This is a cross-sectional study including 656 elder inpatients (275 females and 381 males) aged ≥65 years, from department of geriatrics of Zhejiang Hospital between January 2018 and March 2019. Sociodemographic, health-related data and anthropometric measurements were evaluated. Body composition was assessed by bioimpedance analysis (BIA), mainly including skeletal muscle mass, body fat mass, total body water, fat-free mass,percent body fat, basal metabolic rate. Frailty was assessed by Clinical Frailty Scale (CFS). Univariate logistic regression was used to analyze the association between body composition and frailty. RESULTS: Frailty was present in 43.9% of the participants. Frail inpatients showed higher waist circumference, body fat mass and percent body fat, non-frail inpatients showed greater upper arm circumference, calf circumference, skeletal muscle mass, total body water, fat-free mass and basal metabolic rate. Subjects with underweight (body mass index (BMI)<18.5 kg/m2; odds ratio (OR), 95% confidence interval (CI)=4.146 (1.286-13.368) P=0.017) and those with high waist circumference (OR 95% CI=1.428 (0.584-3.491) P<0.001), body fat mass (OR, 95% CI=1.143 (0.892-1.315) P<0.001) presented a higher risk of frailty compared to normal subjects. Skeletal muscle mass (OR; 95% CI=0.159 (0.064-0.396) P<0.001) was a protective factor for frailty. CONCLUSION: Frailty in elder Chinese inpatients was characterized by a body composition phenotype with underweight, high waist circumference, low skeletal muscle mass and high body fat mass. Underweight, abdominal obesity and sarcopenic obesity may, therefore, be targets for intervention of frailty.

Association between motoric cognitive risk syndrome and frailty among older Chinese adults.

BACKGROUND: Motoric cognitive risk syndrome (MCR) is a newly proposed predementia syndrome incorporating subjective cognitive complaints and slow gait. Previous studies have reported that subjective cognitive complaints and slow gait are associated with frailty in cognitively unimpaired older adults, but little is known about the link between MCR and frailty in older adults. Therefore, the aim of the study was to explore the associations of MCR and its components with frailty in older Chinese adults. METHODS: In an observational cross-sectional study, a total of 429 older adults aged 60 years and older were admitted to the geriatric department. According to MCR criteria, all participants were classified into 4 groups: 1) the MCR group; 2) the subjective cognitive complaints only group; 3) the slow gait only group; and 4) the healthy control group. Physical frailty was assessed by the Clinical Frailty Scale (CFS). Multivariate logistic regression analysis was used to examine the association between MCR and frailty in older adults. RESULTS: The prevalence rates of subjective cognitive complaints, slow gait and MCR were 15.9, 10.0 and 4.0%, respectively. After adjusting for confounding variables, the logistic regression analysis showed that slow gait (odds ratio [OR]: 3.40, 95% confidence interval [CI]: 1.40-8.23, P = 0.007) and MCR (OR: 5.53, 95% CI: 1.46-20.89, P = 0.012) were independently associated with frailty, but subjective cognitive complaints were not. CONCLUSIONS: MCR and slow gait were significantly associated with frailty in older Chinese adults. Further studies should prospectively determine the causal relationship between MCR and frailty.

Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer.

BACKGROUND: Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied. METHODS: We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity. RESULTS: M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model. CONCLUSION: These results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.

Identification, characterization, and expression analysis of auxin response factor (ARF) gene family in Brachypodium distachyon.

Auxin response factors (ARFs) are one type of essential family of transcription factors that bind with auxin response elements (AuxRE), and play vital roles in variety of plant development and physiological processes. Brachypodium distachyon, related to the major cereal grain species, were recently developed to be a good model organism for functional genomics research. So far, genome-wide overview of the ARF gene family in B. distachyon was not available. Here, a systemic analysis of ARF gene family members in B. distachyon was performed. A comprehensive overview of the characterization of the BdARFs was obtained by multiple bioinformatics analyses, including the gene and protein structure, chromosome locations, conserved motifs of proteins, phylogenetic analysis, and cis-elements in promoters of BdARF. Results showed that all BdARFs contained conserved DBD, MR, and CTD could be divided into four classes, Ia, IIa, IIb, and III. Expression profiles of BdARF genes indicated that they were expressed across various tissues and organs, which could be clustered into three main expression groups, and most of BdARF genes were involved in phytohormone signal transduction pathways and regulated physiological process in responding to multiple environmental stresses. And predicted regulatory network between B. distachyon ARFs and IAAs was also discussed. Our genomics analysis of BdARFs could yield new insights into the complexity of the control of BdARF genes and lead to potential applications in the investigation of the accurate regulatory mechanisms of ARFs in herbaceous plants.

Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments.

BACKGROUND: The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome-editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult. METHODS: In this study, we developed a tumor engraftment index (TEI) to quantify the immunodeficiency response to hematologic malignant cells and solid tumor cells of six immunodeficient mouse strains and C57BL/6 wild-type mouse (WT). RESULTS: Mice with a more severely impaired immune system attained a higher TEI score. We then validated that the NOD-scid-IL2Rg-/- (NSI) mice, which had the highest TEI score, were more suitable for xenograft and allograft experiments using multiple functional assays. CONCLUSIONS: The TEI score was effectively able to reflect the immunodeficiency of a mouse strain.

Loss of Angiopoietin-like 7 diminishes the regeneration capacity of hematopoietic stem and progenitor cells.

Successful expansion of hematopoietic stem cells (HSCs) would benefit the use of HSC transplants in the clinic. Angiopoietin-like 7 promotes the expansion of hematopoietic stem and progenitor cells (HSPC) in vitro and ex vivo. However, the impact of loss of Angptl7 on HSPCs in vivo has not been characterized. Here, we generated Angptl7-deficient mice by TALEN-mediated gene targeting and found that HSC compartments in Angptl7-null mice were compromised. In addition, wild type (WT) HSPCs failed to repopulate in the BM of Angptl7-null mice after serial transplantations while the engraftment of Angptl7-deficient HSPCs in WT mice was not impaired. These results suggest that Angptl7 is required for HSPCs repopulation in a non-cell autonomous manner.