Alzheimer’s disease(AD)is a neurodegenerative disorder associated with brain aging,and the accumulation ofβ-amyloid(Aβ)and hyperphosphorylated Tau proteins are key pathological features.Currently,drugs for the trea...Alzheimer’s disease(AD)is a neurodegenerative disorder associated with brain aging,and the accumulation ofβ-amyloid(Aβ)and hyperphosphorylated Tau proteins are key pathological features.Currently,drugs for the treatment of AD are mainly single-targeted,but the complex pathogenesis of AD makes it difficult to achieve the desired results.Therefore,the development of multitargeted therapies is crucial for future interventions.Rice bran oil(RBO)has been recognized as an edible oil with several health benefits,but its effects on AD caused by brain aging remain underexplored.In this study,the effects of RBO on memory dysfunction in D-galactose(D-gal)mice and its molecular mechanisms were investigated via in vivo and in silico methods from the perspective of AD pathologies.Our results suggested that compounds in RBO could modulate the activities of Aβprecursor protein cleaving enzyme 1(BACE1),mitogen-activated protein kinase 3(MAPK3),matrix metalloproteinase 3(MMP3),and intercellular adhesion molecule 1(ICAM1),leading to inhibition of Aβaccumulation and Tau protein hyperphosphorylation.Moreover,RBO reduced Aβ-induced oxidative stress by inhibiting the activity of mouse double minute 2 homolog(MDM2)and cyclic adenosine monophosphate(cAMP)response element binding protein binding protein(CREBBP),and attenuated neuroinflammation by inhibiting the activity of nitric oxide synthase 2(NOS2)and reducing Aβaccumulation and Tau protein hyperphosphorylation.Additionally,α-linolenic acid in RBO exhibited inhibitory effects on D-gal-induced apoptosis in PC12 cells through modulation of NOS2,MDM2,ICAM1,and phospho-extracellular signal-regulated kinase 1/2(p-ERK1/2).Similarly,stigmastanol inhibited apoptosis in D-gal-induced PC12 cells through the regulation of NOS2.Thus,RBO can be considered as a potential functional food to attenuate AD owing to its multicomponent and multitarget effects.展开更多
The article concluded that network pharmacology provides new ideas and insights into the molecular mechanism of traditional Chinese medicine(TCM)treatment of cancer.TCM is a new choice and hot spot in the field of can...The article concluded that network pharmacology provides new ideas and insights into the molecular mechanism of traditional Chinese medicine(TCM)treatment of cancer.TCM is a new choice and hot spot in the field of cancer treatment.We have also previously published studies on TCM and network pharmacology.In this letter,we summarize the new paradigm of network pharmacology in cancer treatment mechanisms.展开更多
An algorithm to track multiple sharply maneuvering targets without prior knowledge about new target birth is proposed. These targets are capable of achieving sharp maneuvers within a short period of time, such as dron...An algorithm to track multiple sharply maneuvering targets without prior knowledge about new target birth is proposed. These targets are capable of achieving sharp maneuvers within a short period of time, such as drones and agile missiles.The probability hypothesis density (PHD) filter, which propagates only the first-order statistical moment of the full target posterior, has been shown to be a computationally efficient solution to multitarget tracking problems. However, the standard PHD filter operates on the single dynamic model and requires prior information about target birth distribution, which leads to many limitations in terms of practical applications. In this paper,we introduce a nonzero mean, white noise turn rate dynamic model and generalize jump Markov systems to multitarget case to accommodate sharply maneuvering dynamics. Moreover, to adaptively estimate newborn targets’information, a measurement-driven method based on the recursive random sampling consensus (RANSAC) algorithm is proposed. Simulation results demonstrate that the proposed method achieves significant improvement in tracking multiple sharply maneuvering targets with adaptive birth estimation.展开更多
Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stre...Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stress,neuroinflammation,metabolic disorders,and massive neuronal loss.Due to its complex pathology,no effective cure for AD has been found to date.Therefore,there is an unmet clinical need for the development of new drugs against AD.Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents.Naringin,a naturally occurring flavanone glycoside,is predominantly found in citrus fruits and Chinese medicinal herbs.Mounting evidence shows that naringin and its aglycone,naringenin,have direct neuroprotective effects on AD,such as anti-amyloidogenic,antioxidant,anti-acetylcholinesterase,and anti-neuroinflammatory effects,as well as metal chelation.Furthermore,they are known to improve disordered glucose/lipid metabolism,which is a high risk factor for AD.In this review,we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology.Additionally,we provide an overview of the current clinical applications of naringin and naringenin.The novel delivery systems for naringin and naringenin,which can address their widespread pharmacokinetic limitations,are also discussed.The literature indicates that naringin and naringenin could be multilevel,multitargeted,and multifaceted for preventing and treating AD.展开更多
In this manuscript,we comment on the article by Liu et al published in the recent issue of the journal.Hyperuricemia(HUA)has become the second most common metabolic disease after type 2 diabetes mellitus and is the mo...In this manuscript,we comment on the article by Liu et al published in the recent issue of the journal.Hyperuricemia(HUA)has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout.This discussion focuses on the targets and clinical application value of traditional Chinese medicine(TCM)extracts in the treatment of HUA and gout,emphasizing the role of gut microbiota.Liu et al’s study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms,including inhibition of uric acid(UA)reabsorption,promotion of UA excretion,repair of intestinal barrier function,and regulation of gut microbiota and metabolome.Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat,which have clear and single targets,many TCMs have multi-target effects.However,the active components and mechanisms of TCMs are not fully understood,limiting their clinical application in the treatment of HUA and gout.Additionally,the role of gut microbiota in UA metabolic homeostasis needs to be further explored.展开更多
BACKGROUND Thymic carcinoid(TC)is a rare entity among anterior mediastinal malignancies.TCs are neuroendocrine carcinomas that constitute approximately 2%–5%of all thymic epithelial tumors.CASE SUMMARY The study repo...BACKGROUND Thymic carcinoid(TC)is a rare entity among anterior mediastinal malignancies.TCs are neuroendocrine carcinomas that constitute approximately 2%–5%of all thymic epithelial tumors.CASE SUMMARY The study reported a rare TC with multiple bone metastases.A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg.Magnetic resonance imaging scans revealed damage to the lumbar spine,sacrocaudal vertebrae and iliac crest,suggesting bone metastasis;computed tomography(CT)scan of the thorax showed a calcified anterior mediastinal mass;positron emission tomography-CT demonstrated multiple abnormal bone signals;and laboratory work-up showed no endocrine abnormalities.Fine-needle aspiration biopsy revealed predominantly single small,round to oval cells with scant cytoplasm and some loose clusters,suggesting endocrine manifestations.The pathological diagnosis was atypical carcinoid,which tend to originate from the thymus and was classified as intermediate-highly invasive.The patient underwent anlotinib-targeted therapy.Anlotinib(12 mg)was administered daily for 2 wk,after which the patient was allowed to rest for 21 d.Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29%after therapy.Treatment has a long stable disease benefit of more than 2.5 years.CONCLUSION These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.展开更多
Tebufenozide,an efficient insect growth regulator(IGR)against lepidopteran pests,presents a novel mode of action with minimal non-target impact.By competing with ecdysteroids for ecdysone receptor(EcR)binding,it regul...Tebufenozide,an efficient insect growth regulator(IGR)against lepidopteran pests,presents a novel mode of action with minimal non-target impact.By competing with ecdysteroids for ecdysone receptor(EcR)binding,it regulates insect growth precisely.This study explores tebufenozide's potential as a multitarget IGR,targeting both EcR and Ostrinia furnacalis chitinase I(OfChtI).The inhibitory activity against OfChtI is comparable to that of substrates(GlcNAc)5,with an IC50 of 45.77μM.Our computational findings indicate that tebufenozide binds at the subsite1 to t1 of OfChtI through various interactions.Notably,tebufenozide establishes a pi-pi interaction with the flipped sidechain of Trp107,enabling tebufenozide to deeply penetrate into the S1 pocket,thereby obstructing substrate binding to OfChtI.These insights highlight the potency of multitarget strategies,laying the groundwork for innovative IGR designs that offer comprehensive pest management solutions.展开更多
The quantization of circuits has received to be rather attractive in domains of solid state—molecular—and biophysics, since the quanta referred to as Q-bits play a significant role in the design of the quantum compu...The quantization of circuits has received to be rather attractive in domains of solid state—molecular—and biophysics, since the quanta referred to as Q-bits play a significant role in the design of the quantum computer and entangled structures. Quantized circuits cannot be applied without modifications, since the energy differences are not equidistant and the polarization of the excited states has to be accounted for having particular importance for the creation of virtual states. Applications of the presented theory are scanning methods in radiotherapy without multi-leaf collimators, which may be realized in tomo-scanning radiotherapy and in the keV domain, which provides a new design of CT. The problem of lateral scatter in the target and energy storage by heat production is significantly reduced by a multilayer system with focusing the impinging electrons at the walls and by a magnetic field. The verification of the Heisenberg-Euler scatter of crossing beams of 9 MV is a central problem of photon physics and can be solved by the new bremsstrahlung technique. A comparison with GEANT 4 Monte-Carlo data indicates that the presented method also works in the GeV domain, and a multi-target can improve the bremsstrahlung yield. GEANT 4 provides the spatial distribution, whereas the virtual oscillator states only show the created energy spectrum. In every case, the exploitation yield can be drastically improved by the superiority of the focused multitarget system compared to a single standard target, and the door to new technologies is opened.展开更多
This paper studies the dynamic estimation problem for multitarget tracking. A novel gat- ing strategy that is based on the measurement likelihood of the target state space is proposed to improve the overall effectiven...This paper studies the dynamic estimation problem for multitarget tracking. A novel gat- ing strategy that is based on the measurement likelihood of the target state space is proposed to improve the overall effectiveness of the probability hypothesis density （PHD） filter. Firstly, a measurement-driven mechanism based on this gating technique is designed to classify the measure- ments. In this mechanism, only the measurements for the existing targets are considered in the update step of the existing targets while the measurements of newborn targets are used for exploring newborn targets. Secondly, the gating strategy enables the development of a heuristic state estima- tion algorithm when sequential Monte Carlo （SMC） implementation of the PHD filter is investi- gated, where the measurements are used to drive the particle clustering within the space gate. The resulting PHD filter can achieve a more robust and accurate estimation of the existing targets by reducing the interference from clutter. Moreover, the target birth intensity can be adaptive to detect newborn targets, which is in accordance with the birth measurements. Simulation results demonstrate the computational efficiency and tracking performance of the proposed algorithm.展开更多
Multitarget stool DNA(mt-sDNA) testing was approved for average risk colorectal cancer(CRC) screening by the United States Food and Drug Administration and thereafter reimbursed for use by the Medicare program(2014).T...Multitarget stool DNA(mt-sDNA) testing was approved for average risk colorectal cancer(CRC) screening by the United States Food and Drug Administration and thereafter reimbursed for use by the Medicare program(2014).The United States Preventive Services Task Force(USPSTF) October 2015 draft recommendation for CRC screening included mt-s DNA as an "alternative" screening test that "may be useful in select clinical circumstances",despite its very high sensitivity for early stage CRC.The evidence supporting mt-s DNA for routine screening use is robust.The clinical efficacy of mt-s DNA as measured by sensitivity,specificity,life-years gained(LYG),and CRC deaths averted is similar to or exceeds that of the other more specifically recommended screening options included in the draft document,especially those requiring annual testing adherence.In a population with primarily irregular screening participation,tests with the highest point sensitivity and reasonable specificity are more likely to favorably impact CRC related morbidity and mortality than those depending on annual adherence.This paper reviews the evidence supporting mt-s DNA for routine screening and demonstrates,using USPSTF's modeling data,that mt-s DNA at three-year intervals provides significant clinical net benefits and fewer complications per LYG than annual fecal immunochemical testing,high sensitivity guaiac based fecal occult blood testing and 10-year colonoscopy screening.展开更多
AIM To determine the uptake of noninvasive multitarget stool DNA (mt-s DNA) in a cohort of colorectal cancer(CRC) screening non-compliant average-risk Medicare patients.METHODS This cross sectional primary care office...AIM To determine the uptake of noninvasive multitarget stool DNA (mt-s DNA) in a cohort of colorectal cancer(CRC) screening non-compliant average-risk Medicare patients.METHODS This cross sectional primary care office-based study examined mt-s DNA uptake in routine clinical practice among 393 colorectal cancer screening non-compliant Medicare patients ages 50-85 ordered by 77 physicians in a multispecialty group practice (USMD Physician Services, Dallas, TX) from October, 2014-September, 2015. Investigators performed a Health Insurance Portability and Accountability Act compliant retrospective review of electronic health records to identify mt-s DNA use in patients who were either > 10 years since last colonoscopy and/or > 1 year since last fecal occult blood test. Test positive patients were advised to get diagnostic colonoscopy and thereafter patients were characterized by the most clinically significant lesion documented on histopathology of biopsies or excisional tissue. Descriptive statistics were employed. Key outcome measures included mt-s DNA compliance and diagnostic colonoscopy compliance on positive cases.RESULTS Over 12 mo, 77 providers ordered 393 mt-sD NA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sD NA was negative in 85.3%(296/347) and positive in 14.7%(51/347). Follow-up colonoscopy was performed in 49 positive patients (96.1% colonoscopy compliance) with two patients lost to follow up. Index findings included: colon cancer(4/49, 8.2%), advanced adenomas (21/49, 42.9%), non-advanced adenomas(15/49, 30.6%), and negative results (9/49, 18.4%). The positive predictive value for advanced colorectal lesions was 51.0% and for any colorectal neoplasia was 81.6%. The mean age of patients with colorectal cancer was 70.3 and all CRC's were localized Stage Ⅰ(2) and Stage Ⅱ (2), three were located in the proximal colon and one was located in the distal colon.CONCLUSION Mt-s DNA provided medical benefit to screening noncompliant Medicare population. High compliance with mt-s DNA and subsequent follow-up diagnostic colonoscopy identified patients with clinically critical advanced colorectal neoplasia.展开更多
In radar systems of automatic detection, an estimate of background clutter power is used to set the detection threshold. An interference saturated environment is frequently encountered in these systems (multiple targe...In radar systems of automatic detection, an estimate of background clutter power is used to set the detection threshold. An interference saturated environment is frequently encountered in these systems (multiple target situations). Therefore, the detection of signals in such an environment becomes one of the most important problems to be solved. The double-threshold algorithm is one of the more interesting detectors used in these situations. While the first threshold operation ensures that the calculation of the detection (second) threshold is based on a set of samples which is free of strong interferers and is therefore much more representative of the noise level, the second threshold is used to declare the presence or the absence of the radar target. The object of the present paper is to analyze the performance of such type of CFAR schemes when the radar receiver contains a noncoherent integrator amongst its basic elements. It is found that the processor detectabil ity loss is very low and the performance degradation, caused by interferers is quite small even if the number of outlying targets is large, given that the first threshold is properly chosen.展开更多
A fast joint probabilistic data association （FJPDA） algorithm is proposed in tiffs paper. Cluster probability matrix is approximately calculated by a new method, whose elements βi^t（K） can be taken as evaluation ...A fast joint probabilistic data association （FJPDA） algorithm is proposed in tiffs paper. Cluster probability matrix is approximately calculated by a new method, whose elements βi^t（K） can be taken as evaluation functions. According to values of βi^t（K）, N events with larger joint probabilities can be searched out as the events with guiding joint probabilities, tiros, the number of searching nodes will be greatly reduced. As a result, this method effectively reduces the calculation load and nnkes it possible to be realized on real-thne, Theoretical ,analysis and Monte Carlo simulation results show that this method is efficient.展开更多
Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),p...Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),platelet-derived growth factor receptors,vascular endothelial growth factor receptors (VEGFR),etc.And tyrosine kinase inhibitor is involved in connection with the generation and progression of many kinds of cancer including lung cancer.Several studies have evaluated the effect of Sunitinib on non-small cell lung cancer (NSCLC),by single agent,continuous daily dosing or in combination with chemotherapeutics (with docetaxel or gemcitabine plus cisplatin),which all showed certain effect.The test of Sunitinib in combination with gemcitabine plus cisplatin for advanced NSCLC shown that at the maximum tolerated dose:oral Sunitinib 37.5 mg/day intermittently (Schedule 2/1:2 weeks on treatment,1 week off treatment) schedule with intravenous infusions of gemcitabine (1000 mg/m2 days 1,8) and cisplatin (80 mg/m2 day 1),administered in 3-week cycles,66.7% patients achieved partial responses.And adverse effects were mild to moderate in severity (grades 1 to 2).Therapy was generally well tolerated.In summary,all the evidence above suggests that Sunitinib may play an important role in the treating of NSCLC.展开更多
The yield of bremsstrahlung (BS) from collisions of fast electrons (energy at least 6 MeV) with a Tungsten target can be significantly improved by exploitation of Tungsten wall scatter in a multi-layered target. A sim...The yield of bremsstrahlung (BS) from collisions of fast electrons (energy at least 6 MeV) with a Tungsten target can be significantly improved by exploitation of Tungsten wall scatter in a multi-layered target. A simplified version of a previously developed principle is also able to focus on small angle scattered electrons by a Tungsten wall. It is necessary that the thickness of each Tungsten layer does not exceed 0.04 mm—a thickness of 0.03 mm is suitable for accelerators in medical physics. Further focusing of electrons results from suitable magnetic fields with field strength between 0.5 Tesla and 1.2 Tesla (if the cone with multi-layered targets is rather narrow). Linear accelerators in radiation therapy only need to be focused by wall scatter without further magnetic fields (a standard case: 31 plates with 0.03 mm thickness and 1 mm distance between the plates). We considered three cases with importance in medical physics: A very small cone with an additional magnetic field for focusing (the field diameter at 90 cm depth: 6 cm), a medium cone with an optional magnetic field (field diameter at 90 cm depth: 13 cm) and a broad cone without a magnetic field (the field diameter at 90 cm depth: 30 cm). All these cases can be positioned in a carousel. Measurements have been performed in the existing carousel positioned in the plane of the flattening filter and scatter foils for electrons.展开更多
For data association in multisensor and multitarget tracking, a novel parallel algorithm is developed to improve the efficiency and real-time performance of FGAs-based algorithm. One Cluster of Workstation （COW） wit...For data association in multisensor and multitarget tracking, a novel parallel algorithm is developed to improve the efficiency and real-time performance of FGAs-based algorithm. One Cluster of Workstation （COW） with Message Passing Interface （MPI） is built. The proposed Multi-Deme Parallel FGA （MDPFGA） is run on the platform. A serial of special MDPFGAs are used to determine the static and the dynamic solutions of generalized m-best S-D assignment problem respectively, as well as target states estimation in track management. Such an assignment-based parallel algorithm is demonstrated on simulated passive sensor track formation and maintenance problem. While illustrating the feasibility of the proposed algorithm in multisensor multitarget tracking, simulation results indicate that the MDPFGAs-based algorithm has greater efficiency and speed than the FGAs-based algorithm.展开更多
DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid...DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors.MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels,inducing hypomethylation of p16 and hyperacetylation of histones H_(3) K9 and H4 K8.Besides,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest.Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC.Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes.Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.展开更多
Multitarget insecticides are more likely to achieve comprehensive regulation of insects with a low risk of resistance.Insect chitinolytic enzymes,including GH18 chitinases and GH20β-N-acetyl-D-hexosaminidase,are attr...Multitarget insecticides are more likely to achieve comprehensive regulation of insects with a low risk of resistance.Insect chitinolytic enzymes,including GH18 chitinases and GH20β-N-acetyl-D-hexosaminidase,are attractive targets for multitarget insecticide design by virtue of their similar substrate binding mode and catalytic mechanism.On the other hand,natural products with diverse skeletal structures are potential repositories of chitinolytic enzyme inhibitors.This minireview first presents the theoretical basis of developing multitargeted inhibitors against insect chitinolytic enzymes and then focuses on the progress in developing multitarget inhibitors derived from natural products.These may provide ideas for the exploitation of novel pesticide leads from natural products by targeting multiple targets.展开更多
In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells p...In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.展开更多
基金supported by the Science and Technology Innovation Program of Hunan Province(2022RC1148)the Natural Science Foundation of Hunan Province(2022JJ31009,2022JJ50260)+4 种基金the Program for Science and Technology of Changsha,China(kh2301028)the Science and Technology Innovation Plan Project of Hunan Province(2023NK2033)the Innovation Leading Plan Project of Hunan Province(2021GK4022)the“Kemen Food”Graduate Science and Technology Innovation Project of Central South University of Forestry and Technology(2023KMCX02)the Graduate Science and Technology Innovation Fund Project of Hunan Province(QL20220182).
文摘Alzheimer’s disease(AD)is a neurodegenerative disorder associated with brain aging,and the accumulation ofβ-amyloid(Aβ)and hyperphosphorylated Tau proteins are key pathological features.Currently,drugs for the treatment of AD are mainly single-targeted,but the complex pathogenesis of AD makes it difficult to achieve the desired results.Therefore,the development of multitargeted therapies is crucial for future interventions.Rice bran oil(RBO)has been recognized as an edible oil with several health benefits,but its effects on AD caused by brain aging remain underexplored.In this study,the effects of RBO on memory dysfunction in D-galactose(D-gal)mice and its molecular mechanisms were investigated via in vivo and in silico methods from the perspective of AD pathologies.Our results suggested that compounds in RBO could modulate the activities of Aβprecursor protein cleaving enzyme 1(BACE1),mitogen-activated protein kinase 3(MAPK3),matrix metalloproteinase 3(MMP3),and intercellular adhesion molecule 1(ICAM1),leading to inhibition of Aβaccumulation and Tau protein hyperphosphorylation.Moreover,RBO reduced Aβ-induced oxidative stress by inhibiting the activity of mouse double minute 2 homolog(MDM2)and cyclic adenosine monophosphate(cAMP)response element binding protein binding protein(CREBBP),and attenuated neuroinflammation by inhibiting the activity of nitric oxide synthase 2(NOS2)and reducing Aβaccumulation and Tau protein hyperphosphorylation.Additionally,α-linolenic acid in RBO exhibited inhibitory effects on D-gal-induced apoptosis in PC12 cells through modulation of NOS2,MDM2,ICAM1,and phospho-extracellular signal-regulated kinase 1/2(p-ERK1/2).Similarly,stigmastanol inhibited apoptosis in D-gal-induced PC12 cells through the regulation of NOS2.Thus,RBO can be considered as a potential functional food to attenuate AD owing to its multicomponent and multitarget effects.
文摘The article concluded that network pharmacology provides new ideas and insights into the molecular mechanism of traditional Chinese medicine(TCM)treatment of cancer.TCM is a new choice and hot spot in the field of cancer treatment.We have also previously published studies on TCM and network pharmacology.In this letter,we summarize the new paradigm of network pharmacology in cancer treatment mechanisms.
基金supported by the National Natural Science Foundation of China (61773142)。
文摘An algorithm to track multiple sharply maneuvering targets without prior knowledge about new target birth is proposed. These targets are capable of achieving sharp maneuvers within a short period of time, such as drones and agile missiles.The probability hypothesis density (PHD) filter, which propagates only the first-order statistical moment of the full target posterior, has been shown to be a computationally efficient solution to multitarget tracking problems. However, the standard PHD filter operates on the single dynamic model and requires prior information about target birth distribution, which leads to many limitations in terms of practical applications. In this paper,we introduce a nonzero mean, white noise turn rate dynamic model and generalize jump Markov systems to multitarget case to accommodate sharply maneuvering dynamics. Moreover, to adaptively estimate newborn targets’information, a measurement-driven method based on the recursive random sampling consensus (RANSAC) algorithm is proposed. Simulation results demonstrate that the proposed method achieves significant improvement in tracking multiple sharply maneuvering targets with adaptive birth estimation.
基金supported by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.TGD23C050001)by National Natural Science Foundation of China(No.82074186).
文摘Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stress,neuroinflammation,metabolic disorders,and massive neuronal loss.Due to its complex pathology,no effective cure for AD has been found to date.Therefore,there is an unmet clinical need for the development of new drugs against AD.Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents.Naringin,a naturally occurring flavanone glycoside,is predominantly found in citrus fruits and Chinese medicinal herbs.Mounting evidence shows that naringin and its aglycone,naringenin,have direct neuroprotective effects on AD,such as anti-amyloidogenic,antioxidant,anti-acetylcholinesterase,and anti-neuroinflammatory effects,as well as metal chelation.Furthermore,they are known to improve disordered glucose/lipid metabolism,which is a high risk factor for AD.In this review,we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology.Additionally,we provide an overview of the current clinical applications of naringin and naringenin.The novel delivery systems for naringin and naringenin,which can address their widespread pharmacokinetic limitations,are also discussed.The literature indicates that naringin and naringenin could be multilevel,multitargeted,and multifaceted for preventing and treating AD.
基金Supported by Zhejiang Province Leading Geese Program,No.2024C03218Research Project of Jinan Microecological Biomedicine Shandong Laboratory,No.JNL-2023010Q.
文摘In this manuscript,we comment on the article by Liu et al published in the recent issue of the journal.Hyperuricemia(HUA)has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout.This discussion focuses on the targets and clinical application value of traditional Chinese medicine(TCM)extracts in the treatment of HUA and gout,emphasizing the role of gut microbiota.Liu et al’s study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms,including inhibition of uric acid(UA)reabsorption,promotion of UA excretion,repair of intestinal barrier function,and regulation of gut microbiota and metabolome.Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat,which have clear and single targets,many TCMs have multi-target effects.However,the active components and mechanisms of TCMs are not fully understood,limiting their clinical application in the treatment of HUA and gout.Additionally,the role of gut microbiota in UA metabolic homeostasis needs to be further explored.
基金Supported by Guangxi Guilin Science and Technology Fund,No.20190218-7-6.
文摘BACKGROUND Thymic carcinoid(TC)is a rare entity among anterior mediastinal malignancies.TCs are neuroendocrine carcinomas that constitute approximately 2%–5%of all thymic epithelial tumors.CASE SUMMARY The study reported a rare TC with multiple bone metastases.A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg.Magnetic resonance imaging scans revealed damage to the lumbar spine,sacrocaudal vertebrae and iliac crest,suggesting bone metastasis;computed tomography(CT)scan of the thorax showed a calcified anterior mediastinal mass;positron emission tomography-CT demonstrated multiple abnormal bone signals;and laboratory work-up showed no endocrine abnormalities.Fine-needle aspiration biopsy revealed predominantly single small,round to oval cells with scant cytoplasm and some loose clusters,suggesting endocrine manifestations.The pathological diagnosis was atypical carcinoid,which tend to originate from the thymus and was classified as intermediate-highly invasive.The patient underwent anlotinib-targeted therapy.Anlotinib(12 mg)was administered daily for 2 wk,after which the patient was allowed to rest for 21 d.Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29%after therapy.Treatment has a long stable disease benefit of more than 2.5 years.CONCLUSION These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.
基金financially supported by the National Natural Science Foundation of China(No.22177132 and 21977114).
文摘Tebufenozide,an efficient insect growth regulator(IGR)against lepidopteran pests,presents a novel mode of action with minimal non-target impact.By competing with ecdysteroids for ecdysone receptor(EcR)binding,it regulates insect growth precisely.This study explores tebufenozide's potential as a multitarget IGR,targeting both EcR and Ostrinia furnacalis chitinase I(OfChtI).The inhibitory activity against OfChtI is comparable to that of substrates(GlcNAc)5,with an IC50 of 45.77μM.Our computational findings indicate that tebufenozide binds at the subsite1 to t1 of OfChtI through various interactions.Notably,tebufenozide establishes a pi-pi interaction with the flipped sidechain of Trp107,enabling tebufenozide to deeply penetrate into the S1 pocket,thereby obstructing substrate binding to OfChtI.These insights highlight the potency of multitarget strategies,laying the groundwork for innovative IGR designs that offer comprehensive pest management solutions.
文摘The quantization of circuits has received to be rather attractive in domains of solid state—molecular—and biophysics, since the quanta referred to as Q-bits play a significant role in the design of the quantum computer and entangled structures. Quantized circuits cannot be applied without modifications, since the energy differences are not equidistant and the polarization of the excited states has to be accounted for having particular importance for the creation of virtual states. Applications of the presented theory are scanning methods in radiotherapy without multi-leaf collimators, which may be realized in tomo-scanning radiotherapy and in the keV domain, which provides a new design of CT. The problem of lateral scatter in the target and energy storage by heat production is significantly reduced by a multilayer system with focusing the impinging electrons at the walls and by a magnetic field. The verification of the Heisenberg-Euler scatter of crossing beams of 9 MV is a central problem of photon physics and can be solved by the new bremsstrahlung technique. A comparison with GEANT 4 Monte-Carlo data indicates that the presented method also works in the GeV domain, and a multi-target can improve the bremsstrahlung yield. GEANT 4 provides the spatial distribution, whereas the virtual oscillator states only show the created energy spectrum. In every case, the exploitation yield can be drastically improved by the superiority of the focused multitarget system compared to a single standard target, and the door to new technologies is opened.
基金supported by the Aeronautical Science Foundation of China(No.201401P6001)
文摘This paper studies the dynamic estimation problem for multitarget tracking. A novel gat- ing strategy that is based on the measurement likelihood of the target state space is proposed to improve the overall effectiveness of the probability hypothesis density （PHD） filter. Firstly, a measurement-driven mechanism based on this gating technique is designed to classify the measure- ments. In this mechanism, only the measurements for the existing targets are considered in the update step of the existing targets while the measurements of newborn targets are used for exploring newborn targets. Secondly, the gating strategy enables the development of a heuristic state estima- tion algorithm when sequential Monte Carlo （SMC） implementation of the PHD filter is investi- gated, where the measurements are used to drive the particle clustering within the space gate. The resulting PHD filter can achieve a more robust and accurate estimation of the existing targets by reducing the interference from clutter. Moreover, the target birth intensity can be adaptive to detect newborn targets, which is in accordance with the birth measurements. Simulation results demonstrate the computational efficiency and tracking performance of the proposed algorithm.
文摘Multitarget stool DNA(mt-sDNA) testing was approved for average risk colorectal cancer(CRC) screening by the United States Food and Drug Administration and thereafter reimbursed for use by the Medicare program(2014).The United States Preventive Services Task Force(USPSTF) October 2015 draft recommendation for CRC screening included mt-s DNA as an "alternative" screening test that "may be useful in select clinical circumstances",despite its very high sensitivity for early stage CRC.The evidence supporting mt-s DNA for routine screening use is robust.The clinical efficacy of mt-s DNA as measured by sensitivity,specificity,life-years gained(LYG),and CRC deaths averted is similar to or exceeds that of the other more specifically recommended screening options included in the draft document,especially those requiring annual testing adherence.In a population with primarily irregular screening participation,tests with the highest point sensitivity and reasonable specificity are more likely to favorably impact CRC related morbidity and mortality than those depending on annual adherence.This paper reviews the evidence supporting mt-s DNA for routine screening and demonstrates,using USPSTF's modeling data,that mt-s DNA at three-year intervals provides significant clinical net benefits and fewer complications per LYG than annual fecal immunochemical testing,high sensitivity guaiac based fecal occult blood testing and 10-year colonoscopy screening.
文摘AIM To determine the uptake of noninvasive multitarget stool DNA (mt-s DNA) in a cohort of colorectal cancer(CRC) screening non-compliant average-risk Medicare patients.METHODS This cross sectional primary care office-based study examined mt-s DNA uptake in routine clinical practice among 393 colorectal cancer screening non-compliant Medicare patients ages 50-85 ordered by 77 physicians in a multispecialty group practice (USMD Physician Services, Dallas, TX) from October, 2014-September, 2015. Investigators performed a Health Insurance Portability and Accountability Act compliant retrospective review of electronic health records to identify mt-s DNA use in patients who were either > 10 years since last colonoscopy and/or > 1 year since last fecal occult blood test. Test positive patients were advised to get diagnostic colonoscopy and thereafter patients were characterized by the most clinically significant lesion documented on histopathology of biopsies or excisional tissue. Descriptive statistics were employed. Key outcome measures included mt-s DNA compliance and diagnostic colonoscopy compliance on positive cases.RESULTS Over 12 mo, 77 providers ordered 393 mt-sD NA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sD NA was negative in 85.3%(296/347) and positive in 14.7%(51/347). Follow-up colonoscopy was performed in 49 positive patients (96.1% colonoscopy compliance) with two patients lost to follow up. Index findings included: colon cancer(4/49, 8.2%), advanced adenomas (21/49, 42.9%), non-advanced adenomas(15/49, 30.6%), and negative results (9/49, 18.4%). The positive predictive value for advanced colorectal lesions was 51.0% and for any colorectal neoplasia was 81.6%. The mean age of patients with colorectal cancer was 70.3 and all CRC's were localized Stage Ⅰ(2) and Stage Ⅱ (2), three were located in the proximal colon and one was located in the distal colon.CONCLUSION Mt-s DNA provided medical benefit to screening noncompliant Medicare population. High compliance with mt-s DNA and subsequent follow-up diagnostic colonoscopy identified patients with clinically critical advanced colorectal neoplasia.
文摘In radar systems of automatic detection, an estimate of background clutter power is used to set the detection threshold. An interference saturated environment is frequently encountered in these systems (multiple target situations). Therefore, the detection of signals in such an environment becomes one of the most important problems to be solved. The double-threshold algorithm is one of the more interesting detectors used in these situations. While the first threshold operation ensures that the calculation of the detection (second) threshold is based on a set of samples which is free of strong interferers and is therefore much more representative of the noise level, the second threshold is used to declare the presence or the absence of the radar target. The object of the present paper is to analyze the performance of such type of CFAR schemes when the radar receiver contains a noncoherent integrator amongst its basic elements. It is found that the processor detectabil ity loss is very low and the performance degradation, caused by interferers is quite small even if the number of outlying targets is large, given that the first threshold is properly chosen.
文摘A fast joint probabilistic data association （FJPDA） algorithm is proposed in tiffs paper. Cluster probability matrix is approximately calculated by a new method, whose elements βi^t（K） can be taken as evaluation functions. According to values of βi^t（K）, N events with larger joint probabilities can be searched out as the events with guiding joint probabilities, tiros, the number of searching nodes will be greatly reduced. As a result, this method effectively reduces the calculation load and nnkes it possible to be realized on real-thne, Theoretical ,analysis and Monte Carlo simulation results show that this method is efficient.
文摘Sunitinib malate is one of the multitargeted tyrosine kinase inhibitor,which are being used in clinic.It can inhibit more than 80 kinds of receptor`s tyrosine kinase,including epidermal growth factor receptor (EGFR),platelet-derived growth factor receptors,vascular endothelial growth factor receptors (VEGFR),etc.And tyrosine kinase inhibitor is involved in connection with the generation and progression of many kinds of cancer including lung cancer.Several studies have evaluated the effect of Sunitinib on non-small cell lung cancer (NSCLC),by single agent,continuous daily dosing or in combination with chemotherapeutics (with docetaxel or gemcitabine plus cisplatin),which all showed certain effect.The test of Sunitinib in combination with gemcitabine plus cisplatin for advanced NSCLC shown that at the maximum tolerated dose:oral Sunitinib 37.5 mg/day intermittently (Schedule 2/1:2 weeks on treatment,1 week off treatment) schedule with intravenous infusions of gemcitabine (1000 mg/m2 days 1,8) and cisplatin (80 mg/m2 day 1),administered in 3-week cycles,66.7% patients achieved partial responses.And adverse effects were mild to moderate in severity (grades 1 to 2).Therapy was generally well tolerated.In summary,all the evidence above suggests that Sunitinib may play an important role in the treating of NSCLC.
文摘The yield of bremsstrahlung (BS) from collisions of fast electrons (energy at least 6 MeV) with a Tungsten target can be significantly improved by exploitation of Tungsten wall scatter in a multi-layered target. A simplified version of a previously developed principle is also able to focus on small angle scattered electrons by a Tungsten wall. It is necessary that the thickness of each Tungsten layer does not exceed 0.04 mm—a thickness of 0.03 mm is suitable for accelerators in medical physics. Further focusing of electrons results from suitable magnetic fields with field strength between 0.5 Tesla and 1.2 Tesla (if the cone with multi-layered targets is rather narrow). Linear accelerators in radiation therapy only need to be focused by wall scatter without further magnetic fields (a standard case: 31 plates with 0.03 mm thickness and 1 mm distance between the plates). We considered three cases with importance in medical physics: A very small cone with an additional magnetic field for focusing (the field diameter at 90 cm depth: 6 cm), a medium cone with an optional magnetic field (field diameter at 90 cm depth: 13 cm) and a broad cone without a magnetic field (the field diameter at 90 cm depth: 30 cm). All these cases can be positioned in a carousel. Measurements have been performed in the existing carousel positioned in the plane of the flattening filter and scatter foils for electrons.
基金Supported by National Defence Scientific Research Foundation
文摘For data association in multisensor and multitarget tracking, a novel parallel algorithm is developed to improve the efficiency and real-time performance of FGAs-based algorithm. One Cluster of Workstation （COW） with Message Passing Interface （MPI） is built. The proposed Multi-Deme Parallel FGA （MDPFGA） is run on the platform. A serial of special MDPFGAs are used to determine the static and the dynamic solutions of generalized m-best S-D assignment problem respectively, as well as target states estimation in track management. Such an assignment-based parallel algorithm is demonstrated on simulated passive sensor track formation and maintenance problem. While illustrating the feasibility of the proposed algorithm in multisensor multitarget tracking, simulation results indicate that the MDPFGAs-based algorithm has greater efficiency and speed than the FGAs-based algorithm.
基金financial supports from China Postdoctoral Science Foundation (No.2018M631825)Shenzhen Development and Reform Committee (No.2019156)+2 种基金Shenzhen Science,Technology and Innovation Commission (No.JCYJ20180306174248782)Department of Science and Technology of Guangdong Province (No.2017B030314083)Shenzhen Bay Laboratory Open Funding (No.SZBL2019062801009)。
文摘DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors.MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels,inducing hypomethylation of p16 and hyperacetylation of histones H_(3) K9 and H4 K8.Besides,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest.Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC.Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes.Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.
基金supported by the National Key R&D Program of China(2022YFD1700200)the Project of Natural Science Foundation of Liaoning Province(2022-KF-15-02).
文摘Multitarget insecticides are more likely to achieve comprehensive regulation of insects with a low risk of resistance.Insect chitinolytic enzymes,including GH18 chitinases and GH20β-N-acetyl-D-hexosaminidase,are attractive targets for multitarget insecticide design by virtue of their similar substrate binding mode and catalytic mechanism.On the other hand,natural products with diverse skeletal structures are potential repositories of chitinolytic enzyme inhibitors.This minireview first presents the theoretical basis of developing multitargeted inhibitors against insect chitinolytic enzymes and then focuses on the progress in developing multitarget inhibitors derived from natural products.These may provide ideas for the exploitation of novel pesticide leads from natural products by targeting multiple targets.
基金financial supports from the Shenzhen Development and Reform Committee(Nos.20151961 and 2019156)Department of Science and Technology of Guangdong Province(No.2017B030314083)。
文摘In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.
