Triple-network analysis of Alzheimer's disease based on the energy landscape.

Introduction: Research on the brain activity during resting state has found that brain activation is centered around three networks, including the default mode network (DMN), the salient network (SN), and the central executive network (CEN), and switches between multiple modes. As a common disease in the elderly, Alzheimer's disease (AD) affects the state transitions of functional networks in the resting state. Methods: Energy landscape, as a new method, can intuitively and quickly grasp the statistical distribution of system states and information related to state transition mechanisms. Therefore, this study mainly uses the energy landscape method to study the changes of the triple-network brain dynamics in AD patients in the resting state. Results: AD brain activity patterns are in an abnormal state, and the dynamics of patients with AD tend to be unstable, with an unusually high flexibility in switching between states. Also , the subjects' dynamic features are correlated with clinical index. Discussion: The atypical balance of large-scale brain systems in patients with AD is associated with abnormally active brain dynamics. Our study are helpful for further understanding the intrinsic dynamic characteristics and pathological mechanism of the resting-state brain in AD patients.

Frequency dependent whole-brain coactivation patterns analysis in Alzheimer's disease.

Background: The brain in resting state has complex dynamic properties and shows frequency dependent characteristics. The frequency-dependent whole-brain dynamic changes of resting state across the scans have been ignored in Alzheimer's disease (AD). Objective: Coactivation pattern (CAP) analysis can identify different brain states. This paper aimed to investigate the dynamic characteristics of frequency dependent whole-brain CAPs in AD. Methods: We utilized a multiband CAP approach to model the state space and study brain dynamics in both AD and NC. The correlation between the dynamic characteristics and the subjects' clinical index was further analyzed. Results: The results showed similar CAP patterns at different frequency bands, but the occurrence of patterns was different. In addition, CAPs associated with the default mode network (DMN) and the ventral/dorsal visual network (dorsal/ventral VN) were altered significantly between the AD and NC groups. This study also found the correlation between the altered dynamic characteristics of frequency dependent CAPs and the patients' clinical Mini-Mental State Examination assessment scale scores. Conclusion: This study revealed that while similar CAP spatial patterns appear in different frequency bands, their dynamic characteristics in subbands vary. In addition, delineating subbands was more helpful in distinguishing AD from NC in terms of CAP.

BJTJ-1837, a novel FXI activation-blocking antibody.

Background: Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. Objectives: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Methods: Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. Results: A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. Conclusion: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.

[Optimization of enzymolysis extraction of total anthraquinones from wild rhubarb (Rheum palmatum) via response surface methodology].

OBJECTIVE: To optimize the technology of enzymolysis extraction of total anthraquinones. METHODS: Used the total anthraquinone concentration extracted from rhubarb (Rheum palmatum, L) via enzymolysis as experimental assess index, effect of enzyme dose, enzyme solution temperature, enzyme solution time and pH on total anthraquinone extraction were investigated respectively based on single factor variance analysis. Furthermore, its extraction process was optimized based on response surface methodology. RESULTS: The yield of total anthraquinones demonstrated the top (3.1730 +/- 0.1023 mg/L) while the enzyme dose was up to 0.12 g, besides, for the enzyme solution time, the total anthraquinones yield exhibited a trend of increase with the increase of enzyme solution time and the top concentration of total anthraquinones was up to 2.1410 +/- 0.1252 mg/L while it was 48 h; Moreover, the top field of total anthraquinones were up to 2.2777 +/- 0.2133 mg/L and 4.1360 +/- 0.3877 mg/L while the pH and enzyme solution temperature were up to 4.8 and 50 degrees C in respectively. Finally, the most optimum enzymolysis extraction processing technology via response surface methodology was as follows: pH: 4.59, enzyme dose: 0.1 g as well as enzyme solution temperature: 45.86 degrees C. CONCLUSION: The condition of extraction processing technology is easily-controlled, simple and lower cost, and the final extraction concentration of total anthraquinone is up to 4.3231 mg/L under the processing technology above.

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma.

Necroptosis, which is recently recognized as a form of programmed cell death, plays a critical role in cancer biology, including tumorigenesis and cancer immunology. It was recognized not only to defend against tumor progression by suppressing adaptive immune responses but also to promote tumorigenesis and cancer metastasis after recruiting inflammatory responses. Thus the crucial role of necrosis in tumorigenesis has attracted increasing attention. Due to the heterogeneity of the tumor immune microenvironment (TIME) in lung adenocarcinoma (LUAD), the prognosis and the response to immunotherapy vary distinctly across patients, underscoring the need for a stratification algorithm for clinical practice. Although previous studies have formulated the crucial role of lncRNAs in tumorigenicity, the relationship between necroptosis-related lncRNAs, TIME, and the prognosis of patients with LUAD was still elusive. In the current study, a robust and novel prognostic stratification model based on Necroptosis-related LncRNA Risk Scoring (NecroLRS) and clinicopathological parameters was constructed and systemically validated in both internal and external validation cohorts. The expression profile of four key lncRNAs was further validated by qRT-PCR in 4 human LUAD cell lines. And a novel immune landscape alteration was observed between NecroLRS-High and -Low patients. To further elucidate the mechanism of necroptosis in the prognosis of LUAD from a single-cell perspective, a novel stratification algorithm based on K-means clustering was introduced to extract both malignant and NecroLRS-High subsets from epithelial cells. And the necroptosis-related immune infiltration landscape and developmental trajectory were investigated respectively. Critically, NecroLRS was found to be positively correlated with neutrophil enrichment, inflammatory immune response, and malignant phenotypes of LUAD. In addition, novel ligand-receptor pairs between NecroLRS-High cells and other immunocytes were investigated and optimal therapeutic compounds were screened to provide potential targets for future studies. Taken together, our findings reveal emerging mechanisms of necroptosis-induced immune microenvironment alteration on the deteriorative prognosis and may contribute to improved prognosis and individualized precision therapy for patients with LUAD.

The construction of a lymphoma cell-based, DC-targeted vaccine, and its application in lymphoma prevention and cure.

In recent years, Non-Hodgkin lymphoma (NHL) has been one of the most fast-growing malignant tumor diseases. NHL poses severe damages to physical health and a heavy burden to patients. Traditional therapies (chemotherapy or radiotherapy) bring some benefit to patients, but have severe adverse effects and do not prevent relapse. The relevance of emerging immunotherapy options (immune-checkpoint blockers or adoptive cellular methods) for NHL remains uncertain, and more intensive evaluations are needed. In this work, inspired by the idea of vaccination to promote an immune response to destroy tumors, we used a biomaterial-based strategy to improve a tumor cell-based vaccine and constructed a novel vaccine named Man-EG7/CH@CpG with antitumor properties. In this vaccine, natural tumor cells are used as a vector to load CpG-ODN, and following lethal irradiation, the formulations were decorated with mannose. The study of the characterization of the double-improved vaccine evidenced the enhanced ability of DCs targeting and improved immunocompetence, which displayed an antitumor function. In the lymphoma prevention model, the Man-EG7/CH@CpG vaccine restrained tumor formation with high efficiency. Furthermore, unlike the non-improved vaccine, the double-improved vaccine elicited an enhanced antitumor effect in the lymphoma treatment model. Next, to improve the moderate therapeutic effect of the mono-treatment method, we incorporated a chemotherapeutic drug (doxorubicin, DOX) into the process of vaccination and devised a combination regimen. Fortunately, a tumor inhibition rate of ~85% was achieved via the combination therapy, which could not be achieved by mono-chemotherapy or mono-immunotherapy. In summary, the strategy presented here may provide a novel direction in the establishment of a tumor vaccine and is the basis for a prioritization scheme of immuno-chemotherapy in enhancing the therapeutic effect on NHL.

Near-Infrared Responsive Doxorubicin Loaded Hollow Mesoporous Prussian Blue Nanoparticles Combined with Dissolvable Hyaluronic Acid Microneedle System for Human Oral Squamous Cell Carcinoma Therapy.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in developing countries particularly in those aged over 50. Traditional treatment is with surgery, radiotherapy, chemotherapy, or a combination of these which often results in considerable discomfort to the patient. Here we describe a potential alternative which employs a near-infrared (NIR) responsive dissolvable microneedle system (HMPBs&DOX@HA MNs) made of hyaluronic acid (HA) with hollow mesoporous Prussian blue nanoparticles (HMPBs) loaded with doxorubicin (DOX). HMPBs&DOX@HA MNs can easily penetrate the skin, and shows the ability to heat and maintain the internal temperature of tumor tissue at more than 60 C under the irradiation of an NIR laser. Besides, the DOX release behavior can also be regulated by the NIR laser. HMPBs&DOX@HA MNs reveals not only strong cell inhibition in vitro, but also prominent antitumor efficacy in vivo with all tumor-bearing mice cured in just one treatment and with no recurrence. This innovative transdermal drug delivery system minimizes the side effects while eliminating tumors. It has great potential to be an effective clinical treatment of OSCC.

Combined Behavioral and Mismatch Negativity Evidence for the Effects of Long-Lasting High-Definition tDCS in Disorders of Consciousness: A Pilot Study.

OBJECTIVE: To evaluate the effects of long-term High-definition transcranial direct current stimulation (HD-tDCS) over precuneus on the level of consciousness (LOC) and the relationship between Mismatch negativity (MMN) and the LOC over the therapy period in patients with Disorders of consciousness (DOCs). METHODS: We employed a with-in group repeated measures design with an anode HD-tDCS protocol (2 mA, 20 min, the precuneus) on 11 (2 vegetative state and nine minimally conscious state) patients with DOCs. MMN and Coma Recovery Scale-Revised (CRS-R) scores were measured at four time points: before the treatment of HD-tDCS (T0), after a single session of HD-tDCS (T1), after the treatment of 7 days (T2) and 14 days (T3). A frequency-deviant oddball paradigm with two deviation magnitudes (standard stimulus: 1000 Hz, small deviant stimuli: 1050 Hz, large deviant stimuli: 1200 Hz) was adopted to elicit MMN. RESULTS: Significant improvements of CRS-R score were found after 7-day (T2) and 14-day (T3) treatment compared with baseline (T0). Regarding the MMN, significant improvements of MMN amplitudes were observed after a single session of stimulation (T1), 7-day (T2) and 14-day treatment (T3) compared with baseline (T0). Additionally, there were significant negative correlations between CRS-R scores and MMN amplitudes elicited by both large and small deviant stimuli. CONCLUSION: Long-term HD-tDCS over precuneus might improve signs of consciousness in patients with DOCs as measured by CRS-R total scores, and MMN could be an assistant assessment in the course of tDCS treatment.

A biotherapy based on PSCs-in-3D spheroid-ameliorated biologics depletes in vivo cancer-sustaining stem cells.

CSCs are able to survive routine anticancer procedures and peripheral-immune attack. Here we develop and detail a framework of CSC elimination governed by 3D-biologics. Pluripotent cells-engineered 3D-biologics (PMSB) and control non-3D-biologics were prepared from placenta-based somatic stem cells (PSCs) and inoculated respectively into senile hosts bearing progressive mammary, lung, colon carcinomas and melanoma. We demonstrate that PMSB evokes in vivo central-immune microenvironment with subsequent re-expression of thymosin-α1 ~ ß4 in thymic cortex-medulla borderline for rapid MHC-unrestricted renewal of γδT-dominated immunocompetence. The post-renewal γδT-subsets could accurately bind and drive CSCs into apoptosis. Finally, with central/peripheral integral microenvironment renewal and TERT/Wnt/ß-catenin pathway blockade, the CSC-subsets are fully depleted, leading to substantial cure of diverse tumors by PMSB inoculation (P < 0.01), yet not by non-3D-biologics. Thus, our study may contribute to open up a new avenue for tumor remission via pluripotent cells-engineered 3D-biologics addressing quick renewal of central-thymus and peripheral immune-microenvironment.

Fluorescent and ultraviolet-visible spectroscopy studies on the antioxidation and DNA binding properties of binuclear Tb(III) complexes.

Tb(III) complexes were prepared from Tb(NO(3))(3)·6H(2)O and four Schiff-base ligands derived from 8-hydroxyquinoline-2-carboxaldehyde with aroylhydrazines. X-ray crystal and other structural analyses indicate that Tb(III) and every ligand can form a binuclear Tb(III) complex with 1:1 metal-to-ligand stoichiometry and nine-coordination at the Tb(III) center. Viscosity titration experiments and fluorescent and ultraviolet-visible (UV-Vis) spectroscopy results indicate that all the Tb(III) complexes can bind to Calf thymus DNA through intercalation with the binding constants at the order of magnitude of 10(6)-10(7) M(-1), and they may be used as potential anticancer drugs, but complexes containing active phenolic hydroxy groups may have stronger antitumor activities. Antioxidation results indicate that all the Tb(III) complexes have strong abilities of scavenging hydroxyl radicals and superoxide radicals, but complexes containing active phenolic hydroxy groups show stronger scavenging effects on hydroxyl radicals and complexes containing N-heteroaromatic substituent show stronger scavenging effects on superoxide radicals. However, Tb(III) emission with these systems is not observed, for these ligands rather are quenchers and unable to sensitize this metal ion.

[Gap features and renewal dynamics in secondary natural Pinus tabulaeformis forest in hilly loess region].

Taking the secondary natural Pinus tabulaeformis forest in hilly loess region as research object, the shape, size structure, distribution, gap-maker features, and renewal dynamics of gaps were investigated. The results showed that the areas of canopy gap (CG) and extended gap (EG) appeared to have a skewed and small gap- dominated distribution. The CGs had an average area of 31.15 m2, and those with an area of 20-40 m2 made up the highest proportions in number and area, accounting for 38.24% and 30.50%, respectively; while the EGs had an average area of 58.04 m2, and those with an area of 30-60 m2 made up the highest proportions in number and area, accounting for 36.77% and 27.79%, respectively. The average CG area accounted for 53.67% of the average EG area. The gaps were mainly elliptical, and their ages were mainly within 10-20 years, which occupied 33.82% of the total. The gaps were mainly with a height of 14-16 m, and those with a height of 18-22 m made up 36.8% of the total. The gaps were mainly formed by the trees being broken at their bases and the standing dead trees, which made up 47. 66% and 23.44% of all gap-makers, respectively, and thinning and unlawful felling were the major factors in gap formation. The tree deaths from lowered resistance due to tree- ageing, drought, and pest and diseases were one of the reasons for gap formation. The gap-makers per gap numbered 1.89 on average, and most of the gaps were formed by two gap-makers. The gap-makers were mainly Pinus tabulaeformis, followed by Populus davidiana, Betula platyphylla, and Quercus liaotungensis. The diameters of the gap-makers appeared to have a remarkably skewed normal distribution, and the diameters commonly ranged in 10-20 cm and 21-30 cm, taking up 25.0% and 45.31%, respectively. This skewed normal distribution agreed with the skewed area distribution of the gaps. In forest gap, trees had a better regeneration condition, and Chinese pine seedings had no age-discontinuity; while in the understory of Chinese pine, seedings had an obvious discontinuity in age-structure.

A comparative study of genetic diversity of peripheral and central populations of chukar partridge from Northwestern China.

Although it has long been presumed that peripheral populations tend to exhibit low genetic diversity because of isolation and genetic drift, results of empirical investigation remain ambiguous. Some chukar partridge (Alectoris chukar) populations have expanded their ranges, resulting in several peripheral populations, due to recent deforestation by human beings in the Longdong Loess Plateau of northwestern China. On the basis of mitochondrial DNA control-region data, we compare the genetic diversity of two peripheral populations, Honghui and Wangxia, and six central populations. The Wangxia population possessed high levels of genetic diversity. The Honghui population, however, exhibited low genetic variation. The degree of isolation was the primary factor affecting the genetic diversity of the two peripheral populations. A peripheral population that was not isolated exhibited higher genetic diversity than did an isolated peripheral population.