Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,includi...Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).展开更多
AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups ...AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups to assess pupillary responses under varying light intensities(100,250,500 lx)and pharmacological interventions(1%atropine,1%cyclopentolate,1%tropicamide,or 2%pilocarpine).Baseline pupil size and eccentricity were recorded using a non-contact Python-based imaging system integrating edge detection and pixel-to-distance conversion.Direct illumination effects were measured at sequential time points,followed by drug administration and longitudinal tracking of pupillary changes.The protocol was repeated at 12wk of age for developmental comparisons.Postexperiment,enucleated eyes were analyzed to evaluate in vitro vs in vivo differences.RESULTS:Significant age-dependent differences in pupil dynamics were observed.Both 2-and 12-week-old guinea pigs exhibited marked pupil constriction under direct illumination(P<0.001),with decreased eccentricity post-constriction(P<0.001).Indirect illumination caused inconsistent pupil size changes(2-week:P=0.68;12-week:P=0.49).Pharmacologically,atropine,cyclopentolate,and tropicamide induced pupil dilation(P<0.001),whereas pilocarpine caused constriction(P<0.001).All drug groups showed reduced eccentricity(P<0.001).In vivo/in vitro comparisons revealed significant structural differences.CONCLUSION:This study investigates pupillary responses in developing guinea pigs,revealing a direct pupillary light reflex(PLR)with light intensity-dependent responses,while indirect PLR was undetectable.The differential effects of muscarinic modulators on pupillary responses underscore the critical role of cholinergic signaling in ocular accommodation,with age-related variations in sensitivity.Additionally,a novel non-contact measurement methodology achieved a precision of 0.01 mm for pupillary quantification,enhancing accuracy in ocular studies.展开更多
Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly im...Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly implicated in the onset and progression of aging,neurodegenerative diseases,metabolic disorders,and tumors,thereby rendering mitochondria-targeted regulation,a vital strategy for disease prevention and treatment.The recently developed mitochondrial membrane chromatography(MMC)technique,which immobilizes mitochondrial proteins as a chromatographic separation medium,has shown great potential for efficiently screening mitochondria-targeted modulators from complex compound library.In contrast to traditional screening methods,MMC has no need to purify mitochondrial proteins and can preserve its in situ and physiological conformation.Consequently,it presents broader application prospects for screening mitochondrial modulators as well as investigating receptor-ligand interactions involving any target protein associated with mitochondria.This review aims to elucidate the critical role of mitochondria in the development and progression of major chronic diseases,discuss recent advancements and applications of MMC,and propose future directions for MMC in the identification of novel mitochondrial modulators.展开更多
Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer...Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.展开更多
Monolithic electro absorption modulated distributed feedback(DFB) lasers are proposed and fabricated by using a modified double stack active layer.The 38mA threshold,9dB extinction ratio (from 0 5V to 3 0V),and ab...Monolithic electro absorption modulated distributed feedback(DFB) lasers are proposed and fabricated by using a modified double stack active layer.The 38mA threshold,9dB extinction ratio (from 0 5V to 3 0V),and about 5mW output power at the 100mA operation current are achieved.Compared with other reported results (only 1 5mW at the same operation current) of the traditional stack active structure,the proposed structure improves the output power of devices.展开更多
Silicon-based high-speed electro-optical modulator is the key component of silicon photonics for future communiction and interconnection systems. In this paper, introduced are the optical mudulation mechanisms in sili...Silicon-based high-speed electro-optical modulator is the key component of silicon photonics for future communiction and interconnection systems. In this paper, introduced are the optical mudulation mechanisms in silicon, reviewed are some recent progresses in high-speed silicon modulators, and analyzed are advantages and shortages of the silicon modulators of different types.展开更多
Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic th...Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.展开更多
We propose a low-speed photonic sampling for independent high-frequency characterization of a Mach–Zehnder modulator(MZM)and a photodetector(PD)in an optical link.A low-speed mode-locked laser diode(MLLD)provides an ...We propose a low-speed photonic sampling for independent high-frequency characterization of a Mach–Zehnder modulator(MZM)and a photodetector(PD)in an optical link.A low-speed mode-locked laser diode(MLLD)provides an ultrawideband optical stimulus with scalable frequency range,working as the photonic sampling source of the link.The uneven spectrum lines of the MLLD are firstly characterized with symmetric modulation within the interesting frequency range.Then,the electro-optic modulated signals are down-converted to the first Nyquist frequency range,yielding the self-referenced extraction of modulation depth and half-wave voltage of the MZM without correcting the responsivity fluctuation of the PD in the link.Finally,the frequency responsivity of the PD is self-referenced measured under null modulation of the MZM.As frequency responses of the MZM and the PD can be independently obtained,our method allows self-referenced high-frequency measurement for a high-speed optical link.In the proof-of-concept experiment,a 96.9 MS/s MLLD is used for measuring a MZM and a PD within the frequency range up to 50 GHz.The consistency between our method and the conventional method verifies that the ultra-wideband and self-referenced high-frequency characterization of high-speed MZMs and PDs.展开更多
Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinet...Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators （SARMs） have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defined clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.展开更多
Spatial light modulators,as dynamic flat-panel optical devices,have witnessed rapid development over the past two decades,concomitant with the advancements in micro-and opto-electronic integration technology.In partic...Spatial light modulators,as dynamic flat-panel optical devices,have witnessed rapid development over the past two decades,concomitant with the advancements in micro-and opto-electronic integration technology.In particular,liquid-crystal spatial light modulator(LC-SLM)technologies have been regarded as versatile tools for generating arbitrary optical fields and tailoring all degrees of freedom beyond just phase and amplitude.These devices have gained significant interest in the nascent field of structured light in space and time,facilitated by their ease of use and real-time light manipulation,fueling both fundamental research and practical applications.Here we provide an overview of the key working principles of LC-SLMs and review the significant progress made to date in their deployment for various applications,covering topics as diverse as beam shaping and steering,holography,optical trapping and tweezers,measurement,wavefront coding,optical vortex,and quantum optics.Finally,we conclude with an outlook on the potential opportunities and technical challenges in this rapidly developing field.展开更多
Alternative splicing(AS), the process of removing introns from pre-m RNA and re-arrangement of exons to give several types of mature transcripts, has been described more than 40 years ago. However, until recently, it ...Alternative splicing(AS), the process of removing introns from pre-m RNA and re-arrangement of exons to give several types of mature transcripts, has been described more than 40 years ago. However, until recently, it has not been clear how extensive it is. Genome-wide studies have now conclusively shown that more than 90% of genes are alternatively spliced in humans. This makes AS one of the main drivers of proteomic diversity and, consequently, determinant of cellular function repertoire. Unsurprisingly, given its extent, numerous splice isoforms have been described to be associated with several dise-ases including cancer. Many of them have antagonistic functions, e.g., pro- and anti-angiogenic or pro- and anti-apoptotic. Additionally several splice factors have been recently described to have oncogene or tumour suppressors activities, like SF3B1 which is frequently mutated in myelodysplastic syndromes. Beside the implications for cancer pathogenesis, de-regulated AS is recognized as one of the novel areas of cell biology where therapeutic manipulations may be designed. This editorial discusses the possibilities of manipulation of AS for therapeutic benefit in cancer. Approaches involving the use of oligonucleotides as well as small molecule splicing modulators are presented as well as thoughts on how specificity might be accomplished in splicing therapeutics.展开更多
Graphene has been recognized as a promising candidate in developing tunable terahertz(THz)functional devices due to its excellent optical and electronic properties,such as high carrier mobility and tunable conductivit...Graphene has been recognized as a promising candidate in developing tunable terahertz(THz)functional devices due to its excellent optical and electronic properties,such as high carrier mobility and tunable conductivity.Here,we review graphene-based THz modulators we have recently developed.First,the optical properties of graphene are discussed.Then,graphene THz modulators realized by different methods,such as gate voltage,optical pump,and nonlinear response of graphene are presented.Finally,challenges and prospective of graphene THz modulators are also discussed.展开更多
Two different poling techniques-corona poling and contact poling in the backdrop of electro-optic （EO） polymer modulators are compared. A 3-layer structure EO polymer modulator is prepared for the poling. The poling...Two different poling techniques-corona poling and contact poling in the backdrop of electro-optic （EO） polymer modulators are compared. A 3-layer structure EO polymer modulator is prepared for the poling. The poling setups and procedures of these two different methods are given. It is found that a well-controlled precure step is very critical, otherwise it will result in either lower poling efficiency or damaged film. Experimental results show that contact poling does not create severe surface damage as corona poling and poling voltage is much lower, but corona poling provides higher EO effect than contact poling. Besides, contact poling can provide poling size as large as the substrate size.展开更多
A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expre...A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expressed in Xenopus ooctyes.Compound 4g as a positive allosteric modulator(PAM)showed better efficacy than lead compound 3(HZZ-A-11)with an EC50 value of 1.23±0.41μM.Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders,such as schizophrenia and Alzheimer’s disease.展开更多
Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have sh...Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.展开更多
Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery.Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin(IL...Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery.Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin(IL)-1β and IL-18 are initially produced in precursor form in response to toll-like receptor(TLR) ligands and undergo maturation by inflammasomes, which are cytosolic multi-protein complexes containing nucleotide-binding oligomerization domain(NOD)-containing protein 2-like receptors(NLRs). Immune modulators targeting inflammasomes have been investigated to control inflammatory diseases such as metabolic syndrome. However, most immune modulators possessing anti-inflammasome properties attenuate production of other cytokines, which are essential for host defense. In this review, we analyzed the effect of anti-inflammasome agents on the production of cytokines which are not regulated by inflammasome and involving in initial immune responses. As a result, the infiammasome inhibitors are put into three categories: non-effector, stimulator, or inhibitor of cytokine production. Even the stimulator of cytokine production ameliorated symptoms resulting from inflammasome activation in mouse models. Thus, we suggest ideal immune modulators targeting inflammasomes in order to enhance cytokine production while inhibiting cytokine maturation.展开更多
Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity,despite advances in treating cerebral aneurysms.There has been recent progress in the intensive care management and monitoring ...Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity,despite advances in treating cerebral aneurysms.There has been recent progress in the intensive care management and monitoring of patients with subarachnoid hemorrhage,but the results remain unsatisfactory.Microglia,the resident immune cells of the brain,are increasingly recognized as playing a significant role in neurological diseases,including subarachnoid hemorrhage.In early brain injury following subarachnoid hemorrhage,microglial activation and neuroinflammation have been implicated in the development of disease complications and recovery.To understand the disease processes following subarachnoid hemorrhage,it is important to focus on the modulators of microglial activation and the pro-inflammatory/anti-inflammatory cytokines and chemokines.In this review,we summarize research on the modulators of microglia-mediated inflammation in subarachnoid hemorrhage,including transcriptome changes and the neuroinflammatory signaling pathways.We also describe the latest developments in single-cell transcriptomics for microglia and summarize advances that have been made in the transcriptome-based classification of microglia and the implications for microglial activation and neuroinflammation.展开更多
基金supported by the Hellenic Foundation for Research and Innovation,HFRI,“2nd Call for HFRI Research Projects to support Faculty Members&Researchers”Project 02667 to GL.
文摘Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).
文摘AIM:To investigate the effects of different light intensities and various mydriatic and miotic drugs on pupil accommodation in guinea pigs.METHODS:Forty-two-week-old guinea pigs were randomly divided into four groups to assess pupillary responses under varying light intensities(100,250,500 lx)and pharmacological interventions(1%atropine,1%cyclopentolate,1%tropicamide,or 2%pilocarpine).Baseline pupil size and eccentricity were recorded using a non-contact Python-based imaging system integrating edge detection and pixel-to-distance conversion.Direct illumination effects were measured at sequential time points,followed by drug administration and longitudinal tracking of pupillary changes.The protocol was repeated at 12wk of age for developmental comparisons.Postexperiment,enucleated eyes were analyzed to evaluate in vitro vs in vivo differences.RESULTS:Significant age-dependent differences in pupil dynamics were observed.Both 2-and 12-week-old guinea pigs exhibited marked pupil constriction under direct illumination(P<0.001),with decreased eccentricity post-constriction(P<0.001).Indirect illumination caused inconsistent pupil size changes(2-week:P=0.68;12-week:P=0.49).Pharmacologically,atropine,cyclopentolate,and tropicamide induced pupil dilation(P<0.001),whereas pilocarpine caused constriction(P<0.001).All drug groups showed reduced eccentricity(P<0.001).In vivo/in vitro comparisons revealed significant structural differences.CONCLUSION:This study investigates pupillary responses in developing guinea pigs,revealing a direct pupillary light reflex(PLR)with light intensity-dependent responses,while indirect PLR was undetectable.The differential effects of muscarinic modulators on pupillary responses underscore the critical role of cholinergic signaling in ocular accommodation,with age-related variations in sensitivity.Additionally,a novel non-contact measurement methodology achieved a precision of 0.01 mm for pupillary quantification,enhancing accuracy in ocular studies.
基金financially supported by,the Space Medical Experiment Project of China Manned Space Program(Program No.:HYZHXM01023)the National Natural Science Foundation of China(Grant No.:31870848)+1 种基金the National foreign experts project(Grant No.:G2022170026L)Key R&D Program of Shaanxi Province(Grant Nos.:2021GXLH-Z-064&2024SF-ZDCYL-03-24).
文摘Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly implicated in the onset and progression of aging,neurodegenerative diseases,metabolic disorders,and tumors,thereby rendering mitochondria-targeted regulation,a vital strategy for disease prevention and treatment.The recently developed mitochondrial membrane chromatography(MMC)technique,which immobilizes mitochondrial proteins as a chromatographic separation medium,has shown great potential for efficiently screening mitochondria-targeted modulators from complex compound library.In contrast to traditional screening methods,MMC has no need to purify mitochondrial proteins and can preserve its in situ and physiological conformation.Consequently,it presents broader application prospects for screening mitochondrial modulators as well as investigating receptor-ligand interactions involving any target protein associated with mitochondria.This review aims to elucidate the critical role of mitochondria in the development and progression of major chronic diseases,discuss recent advancements and applications of MMC,and propose future directions for MMC in the identification of novel mitochondrial modulators.
基金supported by FIS/IMSS project No.FIS/IMSS/PROT/G13/1216CGA received Beca de Excelencia en Investigación by Fundación IMSS,ACS+1 种基金JJSU received financial support from CIS/IMSSCONACy T,RPA received financial support from USC-CONACYT Postdoctoral Scholars Program
文摘Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.
文摘Monolithic electro absorption modulated distributed feedback(DFB) lasers are proposed and fabricated by using a modified double stack active layer.The 38mA threshold,9dB extinction ratio (from 0 5V to 3 0V),and about 5mW output power at the 100mA operation current are achieved.Compared with other reported results (only 1 5mW at the same operation current) of the traditional stack active structure,the proposed structure improves the output power of devices.
基金National Basic Research Program of China("973"Project , 2007CB613405 and 2006CB302803)"863"National High Technology Programme of China(2006AA03Z424)
文摘Silicon-based high-speed electro-optical modulator is the key component of silicon photonics for future communiction and interconnection systems. In this paper, introduced are the optical mudulation mechanisms in silicon, reviewed are some recent progresses in high-speed silicon modulators, and analyzed are advantages and shortages of the silicon modulators of different types.
文摘Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.
基金the National Key Research and Development Program of China(2019YFB2203500)the National Natural Science Foundation of China(NSFC)(61927821)+1 种基金the Joint Research Fund of Ministry of Education of China(6141A02022436)the Fundamental Research Funds for the Central Universities(ZYGX2019Z011).
文摘We propose a low-speed photonic sampling for independent high-frequency characterization of a Mach–Zehnder modulator(MZM)and a photodetector(PD)in an optical link.A low-speed mode-locked laser diode(MLLD)provides an ultrawideband optical stimulus with scalable frequency range,working as the photonic sampling source of the link.The uneven spectrum lines of the MLLD are firstly characterized with symmetric modulation within the interesting frequency range.Then,the electro-optic modulated signals are down-converted to the first Nyquist frequency range,yielding the self-referenced extraction of modulation depth and half-wave voltage of the MZM without correcting the responsivity fluctuation of the PD in the link.Finally,the frequency responsivity of the PD is self-referenced measured under null modulation of the MZM.As frequency responses of the MZM and the PD can be independently obtained,our method allows self-referenced high-frequency measurement for a high-speed optical link.In the proof-of-concept experiment,a 96.9 MS/s MLLD is used for measuring a MZM and a PD within the frequency range up to 50 GHz.The consistency between our method and the conventional method verifies that the ultra-wideband and self-referenced high-frequency characterization of high-speed MZMs and PDs.
文摘Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators （SARMs） have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defined clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.
基金supports from National Natural Science Foundation of China (No.62235009).
文摘Spatial light modulators,as dynamic flat-panel optical devices,have witnessed rapid development over the past two decades,concomitant with the advancements in micro-and opto-electronic integration technology.In particular,liquid-crystal spatial light modulator(LC-SLM)technologies have been regarded as versatile tools for generating arbitrary optical fields and tailoring all degrees of freedom beyond just phase and amplitude.These devices have gained significant interest in the nascent field of structured light in space and time,facilitated by their ease of use and real-time light manipulation,fueling both fundamental research and practical applications.Here we provide an overview of the key working principles of LC-SLMs and review the significant progress made to date in their deployment for various applications,covering topics as diverse as beam shaping and steering,holography,optical trapping and tweezers,measurement,wavefront coding,optical vortex,and quantum optics.Finally,we conclude with an outlook on the potential opportunities and technical challenges in this rapidly developing field.
基金Supported by BBSRC(Biotechnology and Biological Sciences Research Council)United Kingdom and Richard Bright VEGF Research Trust
文摘Alternative splicing(AS), the process of removing introns from pre-m RNA and re-arrangement of exons to give several types of mature transcripts, has been described more than 40 years ago. However, until recently, it has not been clear how extensive it is. Genome-wide studies have now conclusively shown that more than 90% of genes are alternatively spliced in humans. This makes AS one of the main drivers of proteomic diversity and, consequently, determinant of cellular function repertoire. Unsurprisingly, given its extent, numerous splice isoforms have been described to be associated with several dise-ases including cancer. Many of them have antagonistic functions, e.g., pro- and anti-angiogenic or pro- and anti-apoptotic. Additionally several splice factors have been recently described to have oncogene or tumour suppressors activities, like SF3B1 which is frequently mutated in myelodysplastic syndromes. Beside the implications for cancer pathogenesis, de-regulated AS is recognized as one of the novel areas of cell biology where therapeutic manipulations may be designed. This editorial discusses the possibilities of manipulation of AS for therapeutic benefit in cancer. Approaches involving the use of oligonucleotides as well as small molecule splicing modulators are presented as well as thoughts on how specificity might be accomplished in splicing therapeutics.
基金Project supported by the National Key Research and Development Program of China(Grant No.2017YFA0701004)the National Natural Science Founda-tion of China(Grant Nos.61675145,61722509,61735012,and 61420106006).
文摘Graphene has been recognized as a promising candidate in developing tunable terahertz(THz)functional devices due to its excellent optical and electronic properties,such as high carrier mobility and tunable conductivity.Here,we review graphene-based THz modulators we have recently developed.First,the optical properties of graphene are discussed.Then,graphene THz modulators realized by different methods,such as gate voltage,optical pump,and nonlinear response of graphene are presented.Finally,challenges and prospective of graphene THz modulators are also discussed.
文摘Two different poling techniques-corona poling and contact poling in the backdrop of electro-optic （EO） polymer modulators are compared. A 3-layer structure EO polymer modulator is prepared for the poling. The poling setups and procedures of these two different methods are given. It is found that a well-controlled precure step is very critical, otherwise it will result in either lower poling efficiency or damaged film. Experimental results show that contact poling does not create severe surface damage as corona poling and poling voltage is much lower, but corona poling provides higher EO effect than contact poling. Besides, contact poling can provide poling size as large as the substrate size.
基金National Natural Science Foundation of China aw arded to Q.Sun(NSFC,Grant No.81973169,21572011)and K.W.Wang(NSFC,Grant No.81537410)the Ministry of Science and Technology of China to K.W.Wang(Grant No.2014ZX09507003-006-004)。
文摘A series of 2-arylamino-1,3,5-triazine derivatives(4a–4g),which were designed and synthesized via Sonogashira coupling reaction,were evaluated using two-electrode voltage clamp(TEVC)recordings of humanα7 nAChR expressed in Xenopus ooctyes.Compound 4g as a positive allosteric modulator(PAM)showed better efficacy than lead compound 3(HZZ-A-11)with an EC50 value of 1.23±0.41μM.Further pharmacological evaluation of compound 4g might lead to the developmental potential for therapy of cognitive deficits commonly shared by neuropsychiatric disorders,such as schizophrenia and Alzheimer’s disease.
文摘Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.
基金supported by 2015 Research Grant from Kangwon National University(No.520150280)
文摘Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery.Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin(IL)-1β and IL-18 are initially produced in precursor form in response to toll-like receptor(TLR) ligands and undergo maturation by inflammasomes, which are cytosolic multi-protein complexes containing nucleotide-binding oligomerization domain(NOD)-containing protein 2-like receptors(NLRs). Immune modulators targeting inflammasomes have been investigated to control inflammatory diseases such as metabolic syndrome. However, most immune modulators possessing anti-inflammasome properties attenuate production of other cytokines, which are essential for host defense. In this review, we analyzed the effect of anti-inflammasome agents on the production of cytokines which are not regulated by inflammasome and involving in initial immune responses. As a result, the infiammasome inhibitors are put into three categories: non-effector, stimulator, or inhibitor of cytokine production. Even the stimulator of cytokine production ameliorated symptoms resulting from inflammasome activation in mouse models. Thus, we suggest ideal immune modulators targeting inflammasomes in order to enhance cytokine production while inhibiting cytokine maturation.
文摘Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity,despite advances in treating cerebral aneurysms.There has been recent progress in the intensive care management and monitoring of patients with subarachnoid hemorrhage,but the results remain unsatisfactory.Microglia,the resident immune cells of the brain,are increasingly recognized as playing a significant role in neurological diseases,including subarachnoid hemorrhage.In early brain injury following subarachnoid hemorrhage,microglial activation and neuroinflammation have been implicated in the development of disease complications and recovery.To understand the disease processes following subarachnoid hemorrhage,it is important to focus on the modulators of microglial activation and the pro-inflammatory/anti-inflammatory cytokines and chemokines.In this review,we summarize research on the modulators of microglia-mediated inflammation in subarachnoid hemorrhage,including transcriptome changes and the neuroinflammatory signaling pathways.We also describe the latest developments in single-cell transcriptomics for microglia and summarize advances that have been made in the transcriptome-based classification of microglia and the implications for microglial activation and neuroinflammation.
