Assessment of lisdexamfetamine on executive function in rats: A translational cognitive research.

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.

Differential flatness-based adaptive robust tracking control for wheeled mobile robots with slippage disturbances.

Wheeled mobile robots (WMRs) have a wide range of applications in logistics transportation and industrial productions, among which the motion control has always been one of the hot spots in the current WMR researches. However, most of previous designed controllers assumed that the WMR motion had no slippage. Ignoring the slippage factors usually results in a decrease in control performance and even leads to unstable motion. To address such a challenge, a kinematic model with differential flatness is established through dynamic feedback-linearization, which comprehensively considers the multidirectional slippage of mobile robot, including longitudinal and steering slippage. Subsequently, benefited from the one-to-one mapping of states and inputs to flat outputs in differential flat system, an adaptive robust control (ARC) method is proposed to stabilize the system. Different from previous robust control studies, even if the knowledge of the upper bound of system uncertainties is unknown in advance, the proposed adaptive robust controller can still achieve satisfying performance by adaptive estimation of the upper bound of system uncertainties. The effectiveness and feasibility of the proposed method are confirmed by comparative experiments on WMR with slippage disturbance.

Multi-Responsive Afterglows from Aqueous Processable Amorphous Polysaccharide Films.

Polymer-based room-temperature phosphorescence (RTP) materials, especially polysaccharide-based RTP materials, earn sustained attention in the fields of anti-counterfeiting, data encryption, and optoelectronics owing to their green regeneration, flexibility, and transparency. However, those with both ultralong phosphorescence lifetime and excitation wavelength-dependent afterglow are rarely reported. Herein, a kind of amorphous RTP material with ultralong lifetime of up to 2.52 s is fabricated by covalently bonding sodium alginate (SA) with arylboronic acid in the aqueous phase. The resulting polymer film exhibits distinguished RTP performance with excitation-dependent emissions from cyan to green. Specifically, by co-doping with other fluorescent dyes, further regulation of the afterglow color from cyan to yellowish-green and near-white can be achieved through triplet-to-singlet Förster resonance energy transfer. In addition, the water-sensitive properties of hydrogen bonds endow the RTP property of SA-based materials with water/heat-responsive characteristics. On account of the color-tunable and stimuli-responsive afterglows, these smart materials are successfully applied in data encryption and anti-counterfeiting.

Legacy and alternative per-and polyfluoroalkyl substances (PFASs) in the Bohai Bay Rim: Occurrence, partitioning behavior, risk assessment, and emission scenario analysis.

The use of alternative per- and polyfluoroalkyl substances (PFASs) has been practiced because of the restrictions on legacy PFASs. However, knowledge gaps exist on the ecological risks of alternatives and relationships between restrictions and emissions. This study systematically analyzed the occurrence characteristics, water-sediment partitioning behaviors, ecological risks, and emissions of legacy and alternative PFASs in the Bohai Bay Rim (BBR). The mean concentration of total PFASs was 46.105 ng/L in surface water and 6.125 ng/g dry weight (dw) in sediments. As an alternative for perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (GenX) had a concentration second only to PFOA in surface water. In sediments, perfluorobutyric acid (PFBA) and GenX were the two predominant contaminants. In the water-sediment partitioning system, GenX, 9-chlorohexadecafluoro-3-oxanone-1-sulfonic acid (F-53B), and 11-chloroeicosafluoro-3-oxaundecane-1-sulfonic acid (8:2 Cl-PFESA) tended to be enriched towards sediments. The species sensitivity distribution (SSD) models revealed the low ecological risks of PFASs and their alternatives in the BBR. Moreover, predicted no-effected concentrations (PNECs) indicated that short-chain alternatives like PFBA and perfluorobutane sulfonate (PFBS) were safer for aquatic ecosystems, while caution should be exercised when using GenX and F-53B. Due to the incremental replacement of PFOA by GenX, cumulative emissions of 1317.96 kg PFOA and 667.22 kg GenX were estimated during 2004-2022, in which PFOA emissions were reduced by 59.2 % due to restrictions implemented since 2016. If more stringent restrictions are implemented from 2023 to 2030, PFOA emissions will further decrease by 85.0 %, but GenX emissions will increase by an additional 21.3 %. Simultaneously, GenX concentrations in surface water are forecasted to surge by 2.02 to 2.45 times in 2023. This study deepens the understanding of PFAS alternatives and assists authorities in developing policies to administer PFAS alternatives.

Domain definition and preliminary functional exploration of the endonuclease NOBP-1 in Strongyloides stercoralis.

BACKGROUND: Ribosome biogenesis is the process of assembling ribosome complexes that regulate cell proliferation and differentiation with potential regulatory effects on development. Many factors regulate ribosome biological processes. Nin one binding protein (Nob1) has received widespread attention as key genes regulating ribosome biogenesis-the 3' end of the 20S rRNA is cleaved by Nob1 at cleavage site D to form 18S rRNA, generating translationally capable 40S subunit. As a ribosome biogenesis factor, Nob1 may regulate the development of organisms, but almost nothing is known about the function of Nob1 for any parasitic nematode. We explored the functional role of NOBP-1 (the homologous gene of Nob1) encoding gene from a parasitic nematode-Strongyloides stercoralis. METHODS: The full-length cDNA, gDNA and promoter region of Ss-nobp-1 was identified using protein BLAST in WormBase ParaSite according to the Caenorhabditis elegans NOBP-1 sequence to analyze the gene structure. RNA sequencing (RNA-seq) data in wormbase were retrieved and analyzed to assess the transcript abundance of Ss-nobp-1 in seven developmental stages of S. stercoralis. The standard method for gonadal microinjection of constructs was carried out to determine the anatomic expression patterns of Ss-nobp-1. The interaction between Ss-NOBP-1 and partner of NOBP-1 (Ss-PNO-1) was assessed by yeast two-hybridization and bimolecular fluorescence complementarity (BiFC) experiments. RESULTS: The NOBP-1 encoding gene Ss-nopb-1 from the zoonotic parasite S. stercoralis has been isolated and characterized. The genomic DNA representing Ss-nobp-1 includes a 1599-bp coding region and encodes a protein comprising 403 amino acids (aa), which contains conserved PIN domain and zinc ribbon domain. RNA-seq analysis revealed that Ss-nobp-1 transcripts are present throughout the seven developmental stages in S. stercoralis and have higher transcription levels in iL3, L3 and P Female. Ss-nobp-1 is expressed mainly in the intestine of transgenic S. stercoralis larvae, and there is a direct interaction between Ss-NOBP-1 and Ss-PNO-1. CONCLUSIONS: Collectively, Ss-NOBP-1 has a potential role in embryo formation and the infective process, and findings from this study provide a sound foundation for investigating its function during the development of parasitic nematode.

Expression dosage effects of a small number of genes after the artificial doubling of weeping forsythia.

Whole genome doubling (WGD) plays a critical role in plant evolution, yet the mechanisms underlying the maintenance of overall equilibrium following an artificial doubling event, as well as its impact on phenotype and adaptability, remain unclear. By comparing the gene expression of naturally occurring weeping forsythia diploids and colchicine-induced autotetraploids under normal growth conditions and cold stress, we identified gene expression dosage responses resulting from ploidy change. Only a small proportion of effectively expressed genes showed dosage effect, and most genes did not exhibit significant expression differences. However, the genes that showed expression dosage effect were largely random. The autotetraploids had slower overall growth rates, possibly resulting from negative gene dosage effects on zeatin synthesis and multiple metabolic delays caused by other negative dosage genes. Our comparative analysis of cold response genes in diploids and autotetraploids revealed that genes related to "response to abscisic acid" and "cold acclimation" were key factors contributing to greater cold tolerance in the autotetraploids. In particular, gene expression related to "cold acclimation" might mitigate the effects of cold stress. Taken together, our findings suggested that overall gene expression equilibrium following WGD of weeping forsythia autotetraploids was achieved through the inactivation of the majority of duplicated genes. Our research provides new insights into the mechanisms regulating expression dosage balance following polyploidization events.

[Effects of pre-electroacupuncture on blood pressure and cardiac function in high-salt-induced hypertension rats].

OBJECTIVE: To observe the effects of pre-electroacupuncture at "Taichong"(LR3), "Neiguan"(PC6) and "Waiguan"(TE5) on blood pressure and cardiac function of high-salt-induced hypertension rats, so as to explore the possible mechanism of pre-electroacupuncture in improving hypertension. METHODS: Twenty-four SD rats were randomly divided into control group, high-salt group and pre-electroacupuncture group, with 8 rats in each group. The hypertension model was established by feeding high-salt diet for 7 weeks. In the pre-electroacupuncture group, rats received electroacupuncture intervention at bilate-ral LR3, PC6 and TE5 (2 Hz/15 Hz, 2 mA) for 30 min, once a day, from the first day of modeling, for a total of 7 weeks. The blood pressure of rats was monitored by caudal artery noninvasive blood pressure measurement technique before and at the 1st, 3rd, 5th and 7th week of modeling. At the 8th week of the experiment, left ventricular catheterization was performed and biological signal acquisition system was used to detect left ventricular hemodynamics indexes and analyze left ventricular function, the car-diac mass ratio was measured to evaluate the degree of myocardial hypertrophy. The mRNA expressions of atrial natriuretic peptide(ANP), myosin heavy chain 7(MYH7), α-smooth muscle actin(α-SMA), interleukin(IL)-1ß, and IL-6 of myocardial tissues were detected by quantitative real-time PCR. Sirius red staining was used to observe the degree of myocardial fibrosis. RESULTS: Compared with the control group, systolic blood pressure, diastolic blood pressure, mean arterial pressure, left ventricular end-diastolic pressure (LVEDP), cardiac mass ratio，and the mRNA expressions of ANP, MYH7, α-SMA, IL-1ß, and IL-6, and sirius red staining area of myocardium were all significantly increased(P<0.01,P<0.05)，maximal rate of rise and descent of left ventricular pressure(LVP±dP/dtmax) were decreased (P<0.05,P<0.01) in the high-salt group. Compared with the high-salt group, rats in the pre-electroacupuncture group had lower systolic blood pressure, diastolic blood pressure, mean arterial pressure, LVEDP，cardiac mass ratio，higher LVP±dP/dtmax,down-regulated mRNA expressions of ANP, MYH7, α-SMA, IL-1ß, IL-6, and smaller area of sirius red staining(P<0.05, P<0.01). CONCLUSION: Pre-electroacupuncture tends to lower blood pressure, improve cardiac function and reduce myocardial fibrosis in high-salt-induced hypertension rats, which may be associated with inhibiting inflammatory response.

Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.

The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising longevity which has both cell autonomous and cell non-autonomous contributions. CED-3 caspase cleavage limits phosphorylated PMK-1. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. PMK-1 works through a complex transcriptional program to regulate lysosome formation. During early aging, the absolute phospho-p38 amount is maintained but the reservoir of non-phospho-p38 diminishes to enhance signaling without hyperactivation. Our findings show that modulating the stoichiometry of non-phospho-p38 dynamically supports tissue-homeostasis during aging without hyper-activation of stress response.

Co-crystallization and Clustering Afforded Simultaneously Boosted Efficiency, Lifetime, and Color Tunability of Organic Afterglows.

Pure organic persistent room-temperature phosphorescence (p-RTP) is in urgent demand for advanced optoelectronic and bioelectronic applications. However, it remains an enormous challenge to modulate the emission colors while simultaneously boosting the phosphorescence lifetimes and efficiencies. Herein, we report the co-crystallization between melamine and cyclic imide-based non-conventional luminophores, which affords co-crystals owning multiple hydrogen bonds and effective clustering of electron-rich units, thus resulting in diverse emissive species with highly rigidified conformations and promoted spin-orbit coupling. Consequently, p-RTP co-crystals with simultaneously enhanced efficiencies and lifetimes of up to 12.0% and 898 ms, alongside remarkably improved color tunability, are obtained. These results may spur the future rational design of high-performance p-RTP materials and advance the mechanism of understanding of the origin of color-tunable phosphorescence.

Research progress on the prevention and treatment of hyperuricemia by medicinal and edible plants and its bioactive components.

Hyperuricemia is another common metabolic disease, which is considered to be closely related to the development of many chronic diseases, in addition to the "three highs." Currently, although drugs show positive therapeutic effects, they have been shown to produce side effects that can damage the body. There is growing evidence that medicinal and edible plants and their bioactive components have a significant effect on hyperuricemia. In this paper, we review common medicinal and edible plants with uric acid-lowering effects and summarize the uric acid-lowering mechanisms of different bioactive components. Specifically, the bioactive components are divided into five categories: flavonoids, phenolic acids, alkaloids, polysaccharides, and saponins. These active substances exhibit positive uric acid-lowering effects by inhibiting uric acid production, promoting uric acid excretion, and improving inflammation. Overall, this review examines the potential role of medicinal and edible plants and their bioactive components as a means of combating hyperuricemia, with the hope of providing some reference value for the treatment of hyperuricemia.

Comparative transcriptomics provides insights into the pathogenic immune response of brown leaf spots in weeping forsythia.

Weeping forsythia is an important ornamental, ecological and medicinal plant. Brown leaf spots limit the large-scale production of weeping forsythia as a medicinal crop. Alternaria alternata is a pathogen causing brown leaf spots in weeping forsythia; however, its pathogenesis and the immune response mechanisms of weeping forsythia remain unclear. In this study, we identified two mechanisms based on morphological anatomy, physiological indexes and gene expression analyses. Our results showed that A. alternata induced leaf stomata to open, invaded the mesophyll, dissolved the cell wall, destroyed the cell membrane and decreased the number of chloroplasts by up-regulating the expression of auxin-activated signaling pathway genes. Alternaria alternata also down-regulated iron-ion homeostasis and binding-related genes, which caused an increase in the levels of iron ions and reactive oxygen species in leaves. These processes eventually led to programmed cell death, destroying palisade and spongy tissues and causing the formation of iron rust spots. Alternaria alternata also caused defense and hypersensitive responses in weeping forsythia through signaling pathways mediated by flg22-like and elf18-like polypeptides, ethylene, H2O2 and bacterial secretion systems. Our study provides a theoretical basis for the control of brown leaf spots in weeping forsythia.

Tunable Luminescence of Nonaromatic Borate Esters.

While the majority of nonconventional luminophores consist of electron-rich heteroatoms, an emerging category with electron-deficient atoms (e. g. boron) have gained much attention. In this work, we focused on one of the most common boron-containing substances, namely bis(pinacolato)diboron (BE1) and its analogue bis(2,4-dimethylpentane-2,4-glycolato)diboron (BE2), whose empty p-orbitals of boron atoms and p-orbitals with lone pairs of oxygens form π frameworks. Both compounds are nonemissive in dilute solutions but depict remarkable photoluminescence (PL) at aggregate states, featuring aggregation-induced emission characteristics. Additionally, their PL can be easily tuned by various external factors, such as excitation wavelength, compression, and oxygen. These photophysical properties could well be explained by the clustering-triggered emission (CTE) mechanism.

A climate-water quality assessment framework for quantifying the contributions of climate change and human activities to water quality variations.

Water quality safety has attracted global attention and is closely related to the development of the social economy and human health. It is widely recognized that climate change and human activities significantly affect water quality changes. Therefore, quantifying the contributions of factors that drive long-term water quality changes is crucial for effective water quality management. Here, we built a climate-water quality assessment framework (CWQAF) based on climate-water quality response coefficients and trend analysis methods, to achieve this goal. Our results showed that the water quality improved significantly by 4.45%-20.54% from 2011 to 2020 in the Minjiang River basin (MRB). Human activities (including the construction of ecological projects, stricter discharge measures, etc.) were the main driving factors contributing 65%-77% of the improvement effect. Notably, there were differences in the contributions of human activities to water quality parameter changes, such as DO (increase (I): 0.12 mg/L, human contribution (HC): 66.8%), CODMn (decrease (D): 0.71 mg/L, HC: 67.2%), BOD5 (D: 1.10 mg/L, HC: 77.7%), CODCr (D: 4.20 mg/L, HC: 81.2%), TP (D: 0.13 mg/L,HC: 72.8%) and NH3-N (D: 0.40 mg/L, HC: 63.0%). Climate change explained 23%-35% of the variation in water quality. The water quality response to climate change was relatively significant with precipitation. For example, the downstream region was more susceptible to climate change than was the upstream region, as the downstream movement of precipitation centers strengthened the process of climatic factors affecting water quality changes in the MRB. Generally, although human activities were the main driving factor of water quality changes at the basin scale, the contribution of climate change could not be ignored. This study provided a manageable framework for the quantitative analysis of the influence of human activities and climate change on water quality to enable more precise and effective water quality management.

Comparative analysis of cold-responsive genes under short-term cold stimulation and cold-adaptive genes under long-term heterogeneous environments reveals a cold adaptation mechanism in weeping forsythia.

Identifying cold-related genes can provide insights into the cold adaptation mechanism of weeping forsythia. In this study, we compared the changes in gene expressions and physiological and biochemical indices under short-term cold stimulation with the changes in gene sequences under a long-term heterogeneous environment to investigate the cold adaptation mechanism in weeping forsythia. The data of adaptive gene sequence changes, e.g., single nucleotide polymorphisms, were obtained from previous landscape genomics studies. The physiological and biochemical indicators and transcriptome results showed that weeping forsythia initiated a series of programs, including increasing cell osmotic pressures, scavenging ROS, activating the defense mechanism that crosses with pathogen infection, and upregulating CBF/DREB1 transcription factor 1, to cope with short-term cold stress. A reanalysis of landscape genomic data suggested that weeping forsythia responded to long-term heterogeneous cold stress by the differentiation of genes related to synthesis of aromatic substances and adenosine triphosphate. Our results supported the hypothesis that the adaptation mechanisms of species to short-term environmental stimulation and long-term stress in heterogeneous environments are different. The differences in cold tolerance among populations are not necessarily obtained by changing cold-responsive gene sequences. This study provides new insights into the cold adaptation mechanisms of plants.

A processable, scalable, and stable full-color ultralong afterglow system based on heteroatom-free hydrocarbon doped polymers.

Although room-temperature phosphorescence (RTP) organic materials are a widely-studied topic especially popular in recent decades, long-lived RTP able to fulfil broad time-resolved application requirements reliably, are still rare. Polymeric materials doped with phosphorescent chromophores generally feature high productivity and diverse applications, compared with their crystalline counterparts. This study proves that pure polycyclic aromatic hydrocarbons (PAHs) may even outperform chromophores containing hetero- or heavy-atoms. Full-color (blue, green, orange and red) polymer-PAHs with lifetimes >5000 ms under ambient conditions are constructed, which provide impressive values compared to the widely reported polymer-based RTP materials in the respective color regions. The polymer-PAHs could be fabricated on a large-scale using various methods (solution, melt and in situ polymerization), be processed into diverse forms (writing ink, fibers, films, and complex 3D architectures), and be used in a range of applications (anti-counterfeiting, information storage, and oxygen sensors). Plus their environmental (aqueous) stability makes the polymer-PAHs a promising option to expand the portfolio of organic RTPs.

mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity.

Developmental sevoflurane exposure leads to neuronal cell death, and subsequent learning and memory cognitive defects. The underlyi\ng mechanism remains to be elucidated. Gasdermin D (GSDMD)-mediated pyroptosis is a form of inflammatory cell death and participates in a variety of neurodegenerative diseases. Several studies illustrated that dysregulation of mTOR activity is involved in pyroptotic cell death. The current study was designed to interrogate the role of GSDMD-mediated pyroptosis and mTOR activity in developmental sevoflurane exposure. We found that inhibition of GSDMD pore formation with Disulfiram (DSF) or Necrosulfonamide (NSA) significantly attenuated sevoflurane neurotoxicity in vitro. In addition, treatment with DSF or NSA also mitigated damage-associated molecular patterns (DAMPs) release and subsequent plasma membrane rupture (PMR) induced by sevoflurane challenge. Further investigation showed that the overactivation of mTOR signaling is involved in sevoflurane induced pyroptosis both in vivo and in vitro. Intriguingly, we found that the DAMPs release and subsequent PMR triggered by developmental sevoflurane priming were compromised by knocking down the expression of mTORC1 component Raptor, but not mTORC2 component Rictor. Moreover, sevoflurane induced pyroptosis could also be restored by suppressing mTOR activity or knocking down the expressions of Ras-related small GTPases RagA or RagC. Finally, administration of DSF or NSA dramatically improved the spatial and emotional cognitive disorders without alternation of locomotor activity. Taken together, these results indicate that mTORC1-dependent and GSDMD-mediated pyroptosis contributes to the developmental sevoflurane neurotoxicity. Characterizing these processes may provide experimental evidence for the possible prevention of developmental sevoflurane neurotoxicity.

Receptor and Ionic Mechanism of Histamine on Mouse Dorsolateral Striatal Neurons.

The dorsolateral striatum (DLS) is the critical neural substrate that plays a role in motor control and motor learning. Our past study revealed a direct histaminergic projection from the tuberomammillary nucleus (TMN) of the hypothalamus to the rat striatum. However, the afferent of histaminergic fibers in the mouse DLS, the effect of histamine on DLS neurons, and the underlying receptor and ionic mechanisms remain unclear. Here, we demonstrated a direct histaminergic innervation from the TMN in the mouse DLS, and histamine excited both the direct-pathway spiny projection neurons (d-SPNs) and the indirect-pathway spiny projection neurons (i-SPNs) of DLS via activation of postsynaptic H1R and H2R, albeit activation of presynaptic H3R suppressed neuronal activity by inhibiting glutamatergic synaptic transmission on d-SPNs and i-SPNs in DLS. Moreover, sodium-calcium exchanger 3 (NCX3), potassium-leak channels linked to H1R, and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) coupled to H2R co-mediated the excitatory effect induced by histamine on d-SPNs and i-SPNs in DLS. These results demonstrated the pre- and postsynaptic receptors and their downstream multiple ionic mechanisms underlying the inhibitory and excitatory effects of histamine on d-SPNs and i-SPNs in DLS, suggesting a potential modulatory effect of the central histaminergic system on the DLS as well as its related motor control and motor learning.

Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

Effects of over-expression of E2F transcription factor 1 on radiosensitivity glioma U251 cells / 中华行为医学与脑科学杂志

Objective:To investigate the effects of over-expression of E2F transcription factor 1 (E2F1) on proliferation, invasion, apoptosis and radiosensitivity of glioma cell U251.Methods:Real-time quantitative PCR (qRT-PCR) were used to detect the differential expression of E2F1 mRNA in glioma cells LN18, SW1088, U251 and normal brain glial cells. The stable over-expression of E2F1 plasmid was constructed and transfected into U251 cells. qRT-PCR and Western blot test were used to detect the expression of E2F1, pituitary tumor transforming gene 1(PTTG1), C-Myc, B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax) mRNA and protein expression in the control group and E2F1 over-expression group.U251 cells were divided into control group(no X-ray irradiation), irradiation group(6 Gy dose of X-ray), and irradiation + E2F1 over-expression group(transfected with E2F1 first, then irradiated by 6 Gy of X-ray). Cell proliferation ability was detected by cell counting Kit-8(CCK-8) cell viability detection reagent, and cell invasion and migration ability were detected by Transwell chamber. Apoptosis and cell cycle were detected by flow cytometry.GraphPad Prism 8.0 was used for data analysis.The statistical methods were one-way ANOVA and independent sample t-test. Results:qRT-PCR showed that there was statistical difference in the mRNA levels of E2F1( F=201.92, P<0.05) in different cell lines.The expression levels of E2F1 mRNA in LN18(4.04±0.29), SW1088(3.19±0.16)and U251(4.66±0.20) cells were higher than those in HEB(1.02±0.07)cells ( q=27.00, 19.40, 32.52, all P<0.05). After successfully constructing U251 cells with stable over-expression of E2F1 plasmid, qRT-PCR and Western blot detection results showed that: the mRNA and protein levels of E2F1, PTTG1, C-Myc and Bcl-2 in E2F1 over-expression group were higher than those in control group ( t=77.16, 57.88, 4.63, 51.13, 7.50, 70.85, 8.38, 48.81, all P<0.05). Bax mRNA(0.20±0.01) and protein(0.66±0.01) levels were lower than those in control group((1.00±0.02), (0.94±0.01)), and the differences were statistically significant ( t=1.74, 54.65, both P<0.05). After X-ray irradiation (6 Gy), CCK8 detection results showed: the proliferation ability of the three groups at 24, 48, 72 and 96 h were significantly different ( F=95.41, 187.53, 1 158.49, 7 883.78, all P<0.05). The proliferation capacity of the irradiation group were lower than those of the control group at 24, 48, 72 and 96 h ( q=19.51, 27.20, 66.60, 174.9, all P<0.05). The proliferation capacity of irradiation + E2F1 over-expression group at 24, 48, 72 and 96 h were higher than those of irradiation group ( q=10.63, 10.81, 21.11, 60.90, all P<0.05). Transwell assay results showed that there were significant differences in cell invasion and migration ability among the three groups ( F=315.38, 681.10, both P<0.05). The invasion and migration ability of cells in the irradiation group were lower than those in the control group ( q=35.09, 12.76, both P<0.05), and the invasion and migration ability of cells in the irradiation + E2F1 over-expression group were higher than those in the irradiation group ( q=52.06, 22.81, both P<0.05). Flow cytometry showed that there were significant differences in apoptosis rate and percentage of cells in each cycle among the three groups ( F=667.63, 3 213.30, 3 011.26, 861.98, all P<0.05). The percentage of the apoptosis rate, S phase and G2 phase cells in the irradiation group were higher than those in the control group ( q=51.10, 89.39, 51.82, all P<0.05), while the percentage of G1 phase cells in the irradiation group was lower than that in the control group ( q=141.2, P<0.05). The apoptosis rate and percentage of S phase and G2 phase cells in the irradiation + E2F1 over-expression group were lower than those in the irradiation group ( q=18.87, 41.42, 29.31, all P<0.05), while the number of G1 phase cells in the irradiation + E2F1 over-expression group was lower than that in the irradiation group ( q=70.73, P<0.05). Conclusion:Over-expression of E2F1 can reduce the radiosensitivity of glioma U251 cells by regulating the expression of mRNA and protein of genes related to cell cycle and apoptosis, and E2F1 may be involved in the radioresistance of glioma cells.