Appropriate livestock grazing alleviates the loss of plant diversity and maintains community resistance in alpine meadows.

Alpine meadows constitute one of the major ecosystems on the Qinghai-Tibetan Plateau, with livestock grazing exerting a considerable impact on their biodiversity. However, the degree to which plant diversity influences community stability under different grazing intensities remains unclear in this region. This study conducted controlled grazing experiments across four levels of grazing intensity (no-, low-, medium-, and high-grazing) based on herbage utilization rate to assess the influence of grazing intensities on plant community structure and diversity-stability relationships. We discovered that high-grazing reduced plant diversity and attenuated the temporal stability and resistance of above-ground biomass. No- and low-grazing could alleviate plant biomass loss, with community resistance being optimal under low-grazing. The direct effects of livestock grazing on temporal stability were found to be negligible. Plant characteristics and diversity accounted for a substantial proportion of livestock grazing effects on community resistance (R2 = 0.46), as revealed by piecewise structural equation model analysis. The presence of plant diversity enhances the resistance of alpine meadows against disturbance and accelerates the recovery after grazing. Our results suggest that low-grazing intensity may represent a judicious option for preserving species diversity and community stability on the Qinghai-Tibetan Plateau.

Application of a Novel 68Ga-HER2 Affibody PET/CT Imaging in Breast Cancer Patients.

Background: Breast cancer is a heterogeneous disease, and the human epidermal growth factor receptor 2 (HER2) expression may vary considerably between primary and metastatic lesions, or even within a single lesion. Repeated biopsies cannot always be performed. In this feasibility trial, we assessed whether a novel 68Ga-NOTA-MAL-MZHER2 (68Ga-HER2) affibody PET/CT could determine the HER2 status of each lesion if there was a clinical need for it. Methods: 68Ga-HER2 affibody PET/CT was performed in breast cancer patients if HER2 status remained unclear after standard examinations (including bone scan, 18F-FDG PET/CT, CT, and feasible biopsy). All available images for each patient were evaluated through an independent review of two committee-certified radiologists with nuclear medicine expertise. In case of discrepancy, adjudication by a third radiologist was performed as needed. All radiologists were blinded to the clinical information. Results: Twenty-four patients were enrolled. 68Ga-HER2 affibody PET/CT was requested by physicians due to the following reasons: 6 with multiple primary cancers, 13 with metastases not amenable to biopsy or repeated biopsy, 6 with inconsistent HER2 status between primary and metastatic lesions, and 4 with different HER2 status within different metastases. The final PET report revealed that the 68Ga-HER2 affibody tumor uptake was considered positive in 16 patients, negative in 7 patients, and equivocal in one patient. The heterogeneity of 68Ga-HER2 affibody uptake was observed, with a maximal 8.5-fold difference within one patient and a maximal 11-fold difference between patients. 68Ga-HER2 affibody PET/CT demonstrated a high diagnostic accuracy in differentiating HER2-enriched breast cancer, with a sensitivity of 91.7% and a specificity of 84.6%, regardless of prior lines of anti-HER2 therapies. Conclusion: 68Ga-HER2 affibody PET/CT imaging could provide valuable information on HER2 expression of each tumor in the body of patients, which may help in personalized clinical decision-making. Its value is now under systemic assessment.

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Plant functional traits is connected with vegetation adaptability to the environment. The trade-off between plant functional traits reflects resource reintegration and acquisition under grazing pressures. We summarized the differences of plant functional traits under grazing disturbance, focused on the linkages between grazing disturbance and plant functional traits. We introduced that the variation of plant functional traits resulted from the coordination between plant genetic characteristics and environmental filtration, summarized the effects of grazing on nutritional and reproductive traits, and noted that plants could use survival and reproductive strategies to adapt to the grazing disturbance. We mainly focused on the effects of grazing on plant population, community and ecosystem. The expression of plant functional traits was different under grazing disturbance. Therefore, plant functional traits could be used as indicators to explain population growth and reproduction, community assembly, and ecosystem function. In order to better serve the ecological environment of grassland with plant functional traits, reasonable grazing resis-tant species could be screened according to plant functional traits. Based on life history characteristics of grassland plant population, the scientific grazing mechanism should be formulated, and the responses of plant functional traits and resource allocation to grazing disturbance should be conducted from the perspective of individual-based level in the future.

Phase II study of chidamide in combination with cisplatin in patients with metastatic triple-negative breast cancer.

BACKGROUND: Platinum-based regimens are the mainstay treatments for advanced triple-negative breast cancer (TNBC). Preclinical studies have shown that the histone deacetylase (HDAC) inhibitor chidamide induced antitumor effects in TNBC, and chidamide plus chemotherapy was shown to be tolerable in several malignancies. This study sought to investigate the efficacy and safety of a combination treatment of chidamide and cisplatin in metastatic TNBC patients. METHODS: In this phase II, single-arm study, women with metastatic TNBC were administered chidamide (20 mg twice weekly for 2 weeks on a 21-day cycle) and cisplatin (75 mg/m2 on a 21-day cycle). The primary endpoint was the objective response rate (ORR) by RECIST 1.1. The severity of adverse events was measured by the CTCAE 4.03. RESULTS: Sixteen patients were enrolled in this study. Of these, 15 were available for evaluation. In these 15 patients, confirmed objective responses were seen in 4 patients [26.67%, 95% confidence interval (CI): 10.9%, 51.95%]. The ORRs did not meet the predefined criteria (of a response by at least 5 of the 15 patients); thus, the study remained at stage I. The median progression-free survival (PFS) was 9.8 weeks; 4 patients had a PFS of >25 weeks. In relation to the treatment-related AEs ≥ grade 3, >2 patients had neutropenia (33%), thrombocytopenia (20%), leucopenia (20%), and vomiting (20%). CONCLUSIONS: The addition of chidamide did not improve the efficacy of cisplatin in the first-line treatment against advanced TNBC; thus, the phase II clinical trial did not progress any further. Our study appears to be the first to investigate the HDAC inhibitor in TNBC patients and showed disappointing results, which should inform future studies. Future research on cisplatin-based combination treatments for TNBC should consider selecting patients based on predictive biomarkers to increase the clinical benefits.

Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence.

The hexanucleotide repeat expansion, GGGGCC (G4C2), within the first intron of the C9orf72 gene is known to be the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 repeat expansions, either DNA or RNA, are able to form G-quadruplexes which induce toxicity leading to ALS/FTD. Herein, we report a novel crystal structure of d(G4C2)2 that self-associates to form an eight-layer parallel tetrameric G-quadruplex. Two d(G4C2)2 associate together as a parallel dimeric G-quadruplex which folds into a tetramer via 5'-to-5' arrangements. Each dimer consists of four G-tetrads connected by two CC propeller loops. Especially, the 3'-end cytosines protrude out and form C·C+•C·C+/ C·C•C·C+ quadruple base pair or C•C·C+ triple base pair stacking on the dimeric block. Our work sheds light on the G-quadruplexes adopted by d(G4C2) and yields the invaluable structural details for the development of small molecules to tackle neurodegenerative diseases, ALS and FTD.

Self-Assembly Cascade Reaction Platform for CD44 Positive Lung Cancer Therapy.

Lung cancer, as one of the most fatal cancers around the world, is responsible for the death of millions every year. Among various types of lung cancers, the ones overexpressing CD44 is usually associated higher cell proliferation with poorer prognosis. Therefore, finding a way to effectively treat CD44 positive lung cancer is urgently needed. Here in this study, negatively charged ultrasmall prussian blue nanoparticles (UPBNPs) was firstly synthesized and adsorbed to polyethyleneimine (PEI) together with glucose oxidase (Gox). Afterwards, the PEI was further complexed with hyaluronic acid (HA) to give a cascade reaction platform (HP/UPB-Gox) for CD44 positive lung cancer therapy. The HP/UPB-Gox with HA shell was able to positively target CD44 overexpressed A549 cells. Upon arriving at the tumor tissue, the Gox catalyzed the glucose of tumor to create H2O2, which further served as the substrate of UPBNPs, a peroxidase mimic, to finally give highly toxic hydroxyl radical (OH) for cancer therapy. Therefore, the cascade reaction formed between UPBNPs and Gox was expected to realize effective treatment on CD44 overexpressed lung cancer.

Structural basis of DNA replication origin recognition by human Orc6 protein binding with DNA.

The six-subunit origin recognition complex (ORC), a DNA replication initiator, defines the localization of the origins of replication in eukaryotes. The Orc6 subunit is the smallest and the least conserved among ORC subunits. It is required for DNA replication and essential for viability in all species. Orc6 in metazoans carries a structural homology with transcription factor TFIIB and can bind DNA on its own. Here, we report a solution structure of the full-length human Orc6 (HsOrc6) alone and in a complex with DNA. We further showed that human Orc6 is composed of three independent domains: N-terminal, middle and C-terminal (HsOrc6-N, HsOrc6-M and HsOrc6-C). We also identified a distinct DNA-binding domain of human Orc6, named as HsOrc6-DBD. The detailed analysis of the structure revealed novel amino acid clusters important for the interaction with DNA. Alterations of these amino acids abolish DNA-binding ability of Orc6 and result in reduced levels of DNA replication. We propose that Orc6 is a DNA-binding subunit of human/metazoan ORC and may play roles in targeting, positioning and assembling the functional ORC at the origins.

The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA.

Human telomeric guanine-rich DNA, which could adopt different G-quadruplex structures, plays important roles in protecting the cell from recombination and degradation. Although many of these structures were determined, the chair-type G-quadruplex structure remains elusive. Here, we present a crystal structure of the G-quadruplex composed of the human telomeric sequence d[GGGTTAGG8GTTAGGGTTAGG20G] with two dG to 8Br-dG substitutions at positions 8 and 20 with syn conformation in the K+ solution. It forms a novel three-layer chair-type G-quadruplex with two linking trinucleotide loops. Particularly, T5 and T17 are coplanar with two water molecules stacking on the G-tetrad layer in a sandwich-like mode through a coordinating K+ ion and an A6•A18 base pair. While a twisted Hoogsteen A12•T10 base pair caps on the top of G-tetrad core. The three linking TTA loops are edgewise and each DNA strand has two antiparallel adjacent strands. Our findings contribute to a deeper understanding and highlight the unique roles of loop and water molecule in the folding of the G-quadruplex.

Prognosis for residual islet ß-cell secretion function in young patients with newly diagnosed type 1 diabetes.

BACKGROUND: This study investigated possible predictors of residual islet ß-cell function (RBF) in young patients with newly diagnosed type 1 diabetes (T1D). METHODS: After analyzing RBF in 443 patients with T1D according to age at diagnosis and disease duration, 110 were followed-up over 18-60 months. A nomogram was developed by logistic regression to explore factors associated with long-term RBF. RESULTS: Of the 443 T1D patients (mean [±SD] age 20.28 ± 5.50 years; mean [±SD] diabetes duration 28.5 ± 14.6 months), RBF was preserved in 64.3%. Independent predictors for poor RBF outcome among the 110 patients in the follow-up cohort were age at onset (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.73-0.92; P < 0.001), high-risk human leukocyte antigen (HLA) status (OR 4.73; CI 1.28-17.52; P = 0.020), female sex (OR 3.39; CI 1.03-11.22; P = 0.045), and a history of diabetic ketoacidosis (DKA; OR 8.71; CI 2.31-32.83; P < 0.001). Baseline glutamic acid decarboxylase (GAD) antibody, family history of diabetes, body mass index, insulin dosage, and C-peptide and HbA1c levels were not associated with poor RBF outcome. Intensive glycemic control after T1D diagnosis may improve RBF within a mean (±SD) follow-up of 35.1 ± 13.8 months. The calibration plot for the probability of 2-, 3-, and 4-year RBF showed optimal agreement between nomogram-predicted and actual observed probabilities. CONCLUSIONS: Younger age of onset, female sex, higher HLA risk status, and a history of DKA were the main factors predicting long-term poor preserved ß-cell function. Glycemic control could improve RBF during the course of diabetes. The nomogram provides an individualized risk estimate of RBF in patients with newly diagnosed T1D within Chinese Han populations.

A chair-type G-quadruplex structure formed by a human telomeric variant DNA in K+ solution.

Guanine tracts of human telomeric DNA sequences are known to fold into eight different four-stranded structures that vary by the conformation of guanine nucleotides arranged in the stack of G-tetrads in their core and by different kinds and orders of connecting loops, called G-quadruplexes. Here, we present a novel G-quadruplex structure formed in K+ solution by a human telomeric variant d[(GGGTTA)2GGGTTTGGG], htel21T18. This variant DNA is located in the subtelomeric regions of human chromosomes 8, 11, 17, and 19 as well as in the DNase hypersensitive region and in the subcentromeric region of chromosome 5. Interestingly, single A18T substitution that makes htel21T18 different from the human telomeric sequence results in the formation of a three-layer chair-type G-quadruplex, a fold previously unknown among human telomeric repeats, with two loops interacting through the reverse Watson-Crick A6·T18 base pair. The loops are edgewise; glycosidic conformation of guanines is syn·anti·syn·anti around each tetrad, and each strand of the core has two antiparallel adjacent strands. Our results expand the repertoire of known G-quadruplex folding topologies and may provide a potential target for structure-based anticancer drug design.

Characterizations of distinct parallel and antiparallel G-quadruplexes formed by two-repeat ALS and FTD related GGGGCC sequence.

The large expansion of GGGGCC (G4C2) repeats of the C9orf72 gene have been found to lead to the pathogenesis of devastating neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The structural polymorphisms of C9orf72 HRE DNA and RNA may cause aberrant transcription and contribute to the development of ALS and FTD. Here we showed that the two-repeat G4C2 DNA, d(G4C2)2, simultaneously formed parallel and antiparallel G-quadruplex conformations in the potassium solution. We separated different folds of d(G4C2)2 by anion exchange chromatography, followed with characterizations by circular dichroism and nuclear magnetic resonance spectroscopy. The parallel d(G4C2)2 G-quadruplex folded as a symmetric tetramer, while the antiparallel d(G4C2)2 adopted the topology of an asymmetric dimer. These folds are distinct from the antiparallel chair-type conformation we previously identified for the d(G4C2)4 G-quadruplex. Our findings have demonstrated the conformational heterogeneity of the C9orf72 HRE DNA, and provided new insights into the d(G4C2)n folding. Meanwhile, the purified d(G4C2)2 G-quadruplex samples are suitable for further three-dimensional structure characterizations, which are required for the structure-based design of small molecules targeting ALS and FTD related C9orf72 HRE.

Highly dispersible PEGylated graphene/Au composites as gene delivery vector and potential cancer therapeutic agent.

Graphene/Au composites with a high positive charge, which is advantageous for the binding and condensation of negatively charged siRNA, are synthesized via an in situ reduction method, using PEI as a reductant and protective reagent. Owing to the sufficient amounts of amino groups, PEI-grafted graphene/Au composites can be further modified with methoxyl-PEG to acquire low cytotoxicity, novel blood compatibility, and optimal dispersibility in physiological environments. The obtained PEGylated PEI-grafted graphene/Au composites (PPGA) allow efficient loading of siRNA, forming PPGA/siRNA complexes to transport into HL-60 cells and downregulated anti-apoptosis Bcl-2 protein, indicating PPGA is a suitable platform for gene delivery. Moreover, PPGA display an enhanced photothermal response with respect to PPG under NIR laser irradiation, suggesting that PPGA can be used as an efficient photothermal agent.