Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of l...Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.展开更多
OBJECTIVE:To evaluate the effect of electroacupuncture on chemotherapy-induced peripheral neuropathy(CIPN), quality of life and immune status of patients with malignant tumors.METHODS:From Jan, 2013 to May, 2014, 37 p...OBJECTIVE:To evaluate the effect of electroacupuncture on chemotherapy-induced peripheral neuropathy(CIPN), quality of life and immune status of patients with malignant tumors.METHODS:From Jan, 2013 to May, 2014, 37 patients with malignant tumors were included in this prospective single-blinded study, and randomized to receive either electroacupuncture or acupuncture treatment on basis of chemotherapy.The chemotherapy was continued for 2 courses as previous before the treatments, with 21 days as a course of treatment.Patients received acupuncture and electroacupuncture once per day starting at the day before chemotherapy for consecutive 7 days followed by 14 days off, with 21 days as a course of treatment, and continued for two courses of treatment.Then CIPN, traditional Chinese clinical symptoms,quality of life and immune status were all evaluated for each patient prior treatment and after two courses of treatment.RESULTS:The gender, age, cancer species as well as incidence(83.3% vs 84.2%) and grades of CIPN before treatments were all similar in patients receiving acupuncture or electroacupuncture(all P >0.05).After treatments, most patients with peripheral neuropathy were cured by two courses of electroacupuncture(84.2% vs 21.1%), whereas the other group of patients had similar incidences of peripheral neuropathy compared with prior-acupuncture(83.3% vs 72.2%).Besides, patients receiving electroacupuncture had lower incidence of peripheral neuropathy than those receiving acupuncture treatment(χ~2= 9.745, P = 0.002).The grades of peripheral neuropathy were significantly different in the two groups post-treatment(χ~2= 13.983, P =0.007).The total effective rates for traditional Chinese clinical symptoms were 16.7% and 84.2% in acupuncture and electroacupuncture groups, respectively(Z =-4.239, P < 0.001).The electroacupuncture treatment provided a more satisfactory life for patients compared with acupuncture(Z =-4.76, P < 0.001).Both electroacupuncture and acupuncture had no effects on immune function.CONCLUSION:展开更多
We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by...We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.展开更多
Biomimetic nanocarriers are emerging as efficient vehicles to facilitate dietary absorption of biomacromolecules. In this study, two vitamins, thiamine and niacin, are employed to decorate liposomes loaded with insuli...Biomimetic nanocarriers are emerging as efficient vehicles to facilitate dietary absorption of biomacromolecules. In this study, two vitamins, thiamine and niacin, are employed to decorate liposomes loaded with insulin, thus facilitating oral absorption via vitamin ligand–receptor interactions. Both vitamins are conjugated with stearamine, which works to anchor the ligands to the surface of liposomes.Liposomes prepared under optimum conditions have a mean particle size of 125–150 nm and an insulin entrapment efficiency of approximately 30%–36%. Encapsulation into liposomes helps to stabilize insulin due to improved resistance against enzymatic disruption, with 60% and 80% of the insulin left after 4 h when incubated in simulated gastric and intestinal fluids, respectively, whereas non-encapsulated insulin is broken down completely at 0.5 h. Preservation of insulin bioactivity against preparative stresses is validated by intra-peritoneal injection of insulin after release from various liposomes using the surfactant Triton X-100. In a diabetic rat model chemically induced by streptozotocin, both thiamine-and niacindecorated liposomes showed a comparable and sustained mild hypoglycemic effect. The superiority of decorated liposomes over conventional liposomes highlights the contribution of vitamin ligands. It is concluded that decoration of liposomes with thiamine or niacin facilitates interactions with gastrointestinal vitamin receptors and thereby facilitates oral absorption of insulin-loaded liposomes.展开更多
A methodology is proposed for predicting the effective thermal conductivity of dilute suspensions of nanoparticles （nanofluids） based on rheology. The methodology uses the rheological data to infer microstructures o...A methodology is proposed for predicting the effective thermal conductivity of dilute suspensions of nanoparticles （nanofluids） based on rheology. The methodology uses the rheological data to infer microstructures of nanoparticles quantitatively, which is then incorporated into the conventional Hamilton-Crosser equation to predict the effective thermal conductivity of nanofluids. The methodology is experimentally validated using four types of nanofluids made of titania nanoparticles and titanate nanotubes dispersed in water and ethylene glycol. And the modified Hamilton-Zrosser equation successfully predicted the effective thermal conductivity of the nanofluids.展开更多
The Circular Electron Positron Collider(CEPC)is a large scientific project initiated and hosted by China,fostered through extensive collaboration with international partners.The complex comprises four accelerators:a 3...The Circular Electron Positron Collider(CEPC)is a large scientific project initiated and hosted by China,fostered through extensive collaboration with international partners.The complex comprises four accelerators:a 30 GeV Linac,a 1.1 GeV Damping Ring,a Booster capable of achieving energies up to 180 GeV,and a Collider operating at varying energy modes(Z,W,H,and tt).The Linac and Damping Ring are situated on the surface,while the subterranean Booster and Collider are housed in a 100 km circumference underground tunnel,strategically accommodating future expansion with provisions for a potential Super Proton Proton Collider(SPPC).The CEPC primarily serves as a Higgs factory.In its baseline design with synchrotron radiation(SR)power of 30 MW per beam,it can achieve a luminosity of 5×10^(34)cm^(-2)s^(-1)per interaction point(IP),resulting in an integrated luminosity of 13 ab^(-1)for two IPs over a decade,producing 2.6 million Higgs bosons.Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons,facilitating precise measurements of Higgs coupling at sub-percent levels,exceeding the precision expected from the HL-LHC by an order of magnitude.This Technical Design Report(TDR)follows the Preliminary Conceptual Design Report(Pre-CDR,2015)and the Conceptual Design Report(CDR,2018),comprehensively detailing the machine's layout,performance metrics,physical design and analysis,technical systems design,R&D and prototyping efforts,and associated civil engineering aspects.Additionally,it includes a cost estimate and a preliminary construction timeline,establishing a framework for forthcoming engineering design phase and site selection procedures.Construction is anticipated to begin around 2027-2028,pending government approval,with an estimated duration of 8 years.The commencement of experiments and data collection could potentially be initiated in the mid-2030s.展开更多
The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex ...The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other micelles.All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles.The transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other groups.Moreover,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups.Thus,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups.In conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.展开更多
In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have neve...In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have never been accurately portrayed.The current practice of IVIVC has to resort to in vivo absorption fractions(Fa).In this proof-of-concept study,in vivo dissolution of a model poorly watersoluble drug fenofbrate(FNB)was investigated by fuorescence bioimaging.FNB crystals were frst labeled by near-infrared fuorophores with aggregation-caused quenching properties.The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media,enabling accurate monitoring of residual drug crystals.The linearity established between fuorescence and crystal concentration justifed reliable quantifcation of FNB crystals.In vitro dissolution was frst measured following pharmacopoeia monograph protocols with well-documented IVIVC.The synchronicity between fuorescence and in vitro dissolution of FNB supported using fuorescence as a measure for determination of dissolution.In vitro dissolution correlated well with in vivo dissolution,acquired by either live or ex vivo imaging.The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with Faobtained from pharmacokinetic data.展开更多
Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, in...Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.展开更多
Background There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms,while more studies demonstrate that depression negatively affects bone density and increases fracture risk.Aims To...Background There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms,while more studies demonstrate that depression negatively affects bone density and increases fracture risk.Aims To explore the relationship between major depressive disorder(MDD)and fracture risk.Methods We conducted a nested case-control analysis(32670 patients with fracture and 397017 individuals without fracture)and a matched cohort analysis(16496 patients with MDD and 435492 individuals without MDD)in the same prospective UK Biobank data set.Further,we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools.We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci.We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study.Results We found that MDD was associated with a 14%increase in fracture risk(hazard ratio(HR)1.14,95%CI 1.14 to 1.15,p<0.001)in the nested case-control analysis,while fracture was associated with a 72%increase in MDD risk(HR 1.72,95%CI 1.64 to 1.79,p<0.001)in the matched cohort analysis,suggesting a longitudinal and bidirectional relationship.Further,genetic summary data suggested a genetic overlap between MDD and fracture.Specifically,we identified four shared genomic loci,with the top signal(rs7554101)near SGIP1.The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling.We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa.In addition,we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD.Conclusions The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis.The shared genetic components(such as SGIP1)between the disea展开更多
This research aims to develop a non-invasive strategy for small interfering RNA(siRNA)nasal delivery based on ionic liquids(ILs)and cationic lipid(2,3-dioleoyloxy-propyl)-trimethylammonium-chloride(DOTAP).Other than t...This research aims to develop a non-invasive strategy for small interfering RNA(siRNA)nasal delivery based on ionic liquids(ILs)and cationic lipid(2,3-dioleoyloxy-propyl)-trimethylammonium-chloride(DOTAP).Other than the classical role of penetration enhancer,ILs also acted as superior solvents to simultaneously load siRNA and DOTAP,forming siRNA-DOTAP-ILs(siRNA-DILs)formulations.During nasal mucosa penetration,DOTAP and ILs components self-assembled into cationic lipid nanocomplexes to load siRNA for enhanced in situ transfection.The siRNA-DILs demonstrated resistance against RNase,significant mucosa penetration,prolonged nasal retention,and satisfying gene-silencing efficacy at lower dosage.Meanwhile,DILs were also able to deliver KCa3.1-targeted siRNA effectively for the treatment of allergic rhinitis in rat model by nasal route.Thus,DILs have great potentials to deliver biological macromolecules across nasal mucosa by in situ dynamic self-assembly.展开更多
Oral formulations are always preferred to injections due to the advantages of high patient compliance,no biohazardous needle waste,and low requirements for administration skills.However,the presence of multiple gastro...Oral formulations are always preferred to injections due to the advantages of high patient compliance,no biohazardous needle waste,and low requirements for administration skills.However,the presence of multiple gastrointestinal(GI)barriers,including extreme gastric acidity and a broad pH gradient,digestive enzymes,thick and variable mucus layers,and tight junctions in the enteric epithelia,restricts the rate and extent of oral absorption.Only active ingredients with favorable physicochemical properties.展开更多
The discrimination against nutritional fat emulsion injections was considered by imaging tools,which aims to elucidate the in vivo behaviors of nanoemulsions.In this study,20%nutritional fat emulsion injections were s...The discrimination against nutritional fat emulsion injections was considered by imaging tools,which aims to elucidate the in vivo behaviors of nanoemulsions.In this study,20%nutritional fat emulsion injections were selected from different company including original and generic products.Meanwhile,a water quenching fluorescent probe(P2)was used to label them by an incubation method.The fluorescent intensity analysis of blood-borne fluorescence reveals rapid clearance of nanoemulsion in all groups,which shows'L'-type blood kinetic profiles.However,these kinetic parameters do not have significant difference.Following intravenous administration,the nanoemulsions in all groups concomitantly accumulated in organs of reticulo-endothelial system(RES),such as liver and spleen,and were cleared from body circulation mostly after 12 h.AUC(0-t)of organs from different groups showed dissimilar results in some organs.These intuitional results are of significance in understa nding the in vivo behaviors of nanoemulsions,which can provide a new way to discriminate against nutritional fat emulsions.展开更多
Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete flu...Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete fluorescence quenching and significant re-illumination,which undermine bioimaging accuracy.Herein,through structural modifications to reinforce the hydrophobicity,planarity and rigidity of fluorophores with an aza-BODIPY framework,probes featuring absolute ACQ(aACQ)and negligible re-illumination are developed and evaluated in various nanocarriers.aACQ probes,FD-B21 and FD-C7,exhibit near-infrared emission,high quantum yield,photostability,water sensitivity,and negligible re-illumination in blood,plasma and 1%Tween-80 in contrast to ACQ probe P2 and conventional probe DiR.All nanocarriers can be labeled efficiently by the tested fluorophores.Polymeric micelles(PMs)labeled by different aACQ probes manifest similar biodistribution patterns,which however differ from that of DiR-labeled PMs and could be ascribed to the appreciable re-illumination of DiR.Significantly lower re-illumination is also found in aACQ probes(2%-3%)than DiR(20%-40%)in Caco-2,Hela,and Raw264.7 cells.Molecular dynamics simulations unravel the molecular mechanisms behind aggregation and re-illumination,supporting the hypothesis of planarity dependency.It is concluded that aACQ fluorophores demonstrate excellent water sensitivity and negligible fluorescence re-illumination,making themselves useful tools for more accurate bioimaging of nanocarriers.展开更多
Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor(GECAM)is a constellation with four instruments(launch date):GECAM-A/B(10 December 2020),GECAM-C(27 July 2022)and GECAM-D(13 March 2024),which ...Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor(GECAM)is a constellation with four instruments(launch date):GECAM-A/B(10 December 2020),GECAM-C(27 July 2022)and GECAM-D(13 March 2024),which are dedicated to monitoring gamma-ray transients in all-sky.The primary science objectives of GECAM include Gamma-Ray Bursts(GRBs),Soft Gamma-ray Repeaters(SGRs),high energy counterparts of Gravitation Wave(GW)and Fast Radio Burst(FRB),Solar Flares(SFLs),as well as Terrestrial Gamma-ray Flashes(TGFs)and Terrestrial Electron Beams(TEBs).A series of observations and research have been made since the launch of GECAM-A/B.GECAM observations provide new insights into these highenergy transients,demonstrating the unique role of GECAM in the“multi-wavelength,multi-messenger”era.展开更多
基金financially supported by National Natural Science Foundation of China (81573363 and 81690263)National Key Basic Research Program (2015CB931800)
文摘Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.
基金Supported by the Study of Electric Acupuncture in Preventing the Peripheral Neuritis Induced by Chemotherapy and Promoting the Immune Function in Cancer Patients from:Comprehensive and Integrative Medicine Institute,KoreaMechanism Study of Electric Acupuncture in Oxaliplatin-chemotherapy-induced Peripheral Neuropathy by SP-NMDAR Pathway from:Shanghai TCM-integrated Hospital+3 种基金Effect of Bushen-Jianpi Decoction on Postoperative Recurrence and Vasculogenic Mimicry Formation after Recurrence in Liver Cancer Tissues of Nude Mice with Transplanted Liver Cancer(No.2012J003A)Mechanism Study of Fuzheng Jianpi Decoction on Tumor Metastasis Inhibition by Protecting Intestinal Barrier and Regulating PI3K/AKT Signaling Pathway Expression in Colorectal Tumor Microenvironment(No.15ZR1438700)Effect of Jianpi-Guchang Decoction on the Gut Barrier Function and Immune Function in Lung or Colorectal Cancer Patients Treated by Chemotherapy Based on the Thought of "Same Treatment for Different Diseases"(No.15401930300)Effect of Jianpi-Guben Decoction on the Gut Barrier Function in Postoperative Colorectal Cancer Patients Treated by Chemotherapy to Balance the Gut Enviroment(No.Hongkou 1502-01)
文摘OBJECTIVE:To evaluate the effect of electroacupuncture on chemotherapy-induced peripheral neuropathy(CIPN), quality of life and immune status of patients with malignant tumors.METHODS:From Jan, 2013 to May, 2014, 37 patients with malignant tumors were included in this prospective single-blinded study, and randomized to receive either electroacupuncture or acupuncture treatment on basis of chemotherapy.The chemotherapy was continued for 2 courses as previous before the treatments, with 21 days as a course of treatment.Patients received acupuncture and electroacupuncture once per day starting at the day before chemotherapy for consecutive 7 days followed by 14 days off, with 21 days as a course of treatment, and continued for two courses of treatment.Then CIPN, traditional Chinese clinical symptoms,quality of life and immune status were all evaluated for each patient prior treatment and after two courses of treatment.RESULTS:The gender, age, cancer species as well as incidence(83.3% vs 84.2%) and grades of CIPN before treatments were all similar in patients receiving acupuncture or electroacupuncture(all P >0.05).After treatments, most patients with peripheral neuropathy were cured by two courses of electroacupuncture(84.2% vs 21.1%), whereas the other group of patients had similar incidences of peripheral neuropathy compared with prior-acupuncture(83.3% vs 72.2%).Besides, patients receiving electroacupuncture had lower incidence of peripheral neuropathy than those receiving acupuncture treatment(χ~2= 9.745, P = 0.002).The grades of peripheral neuropathy were significantly different in the two groups post-treatment(χ~2= 13.983, P =0.007).The total effective rates for traditional Chinese clinical symptoms were 16.7% and 84.2% in acupuncture and electroacupuncture groups, respectively(Z =-4.239, P < 0.001).The electroacupuncture treatment provided a more satisfactory life for patients compared with acupuncture(Z =-4.76, P < 0.001).Both electroacupuncture and acupuncture had no effects on immune function.CONCLUSION:
基金This work was supported by the National Key R&D Program of China(No.2020YFC0841400)Tongji Hospital Clinical Research Project(Nos.XXGZBDYJ009 and 2019YBKY019).
文摘We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.
基金financially supported by Shanghai Commission of Science and Technology (15ZR1403000)National Natural Science Foundation of China (81573363, 81690263, and 21372063)
文摘Biomimetic nanocarriers are emerging as efficient vehicles to facilitate dietary absorption of biomacromolecules. In this study, two vitamins, thiamine and niacin, are employed to decorate liposomes loaded with insulin, thus facilitating oral absorption via vitamin ligand–receptor interactions. Both vitamins are conjugated with stearamine, which works to anchor the ligands to the surface of liposomes.Liposomes prepared under optimum conditions have a mean particle size of 125–150 nm and an insulin entrapment efficiency of approximately 30%–36%. Encapsulation into liposomes helps to stabilize insulin due to improved resistance against enzymatic disruption, with 60% and 80% of the insulin left after 4 h when incubated in simulated gastric and intestinal fluids, respectively, whereas non-encapsulated insulin is broken down completely at 0.5 h. Preservation of insulin bioactivity against preparative stresses is validated by intra-peritoneal injection of insulin after release from various liposomes using the surfactant Triton X-100. In a diabetic rat model chemically induced by streptozotocin, both thiamine-and niacindecorated liposomes showed a comparable and sustained mild hypoglycemic effect. The superiority of decorated liposomes over conventional liposomes highlights the contribution of vitamin ligands. It is concluded that decoration of liposomes with thiamine or niacin facilitates interactions with gastrointestinal vitamin receptors and thereby facilitates oral absorption of insulin-loaded liposomes.
基金supported by the UK EPSRC under Grants EP/F027389/1,EP/F023014/1,EP/D000645/1 and EP/F000464/1The British Council PMI2 Scheme under Grant RC177
文摘A methodology is proposed for predicting the effective thermal conductivity of dilute suspensions of nanoparticles （nanofluids） based on rheology. The methodology uses the rheological data to infer microstructures of nanoparticles quantitatively, which is then incorporated into the conventional Hamilton-Crosser equation to predict the effective thermal conductivity of nanofluids. The methodology is experimentally validated using four types of nanofluids made of titania nanoparticles and titanate nanotubes dispersed in water and ethylene glycol. And the modified Hamilton-Zrosser equation successfully predicted the effective thermal conductivity of the nanofluids.
基金support from diverse funding sources,including the National Key Program for S&T Research and Development of the Ministry of Science and Technology(MOST),Yifang Wang's Science Studio of the Ten Thousand Talents Project,the CAS Key Foreign Cooperation Grant,the National Natural Science Foundation of China(NSFC)Beijing Municipal Science&Technology Commission,the CAS Focused Science Grant,the IHEP Innovation Grant,the CAS Lead Special Training Programthe CAS Center for Excellence in Particle Physics,the CAS International Partnership Program,and the CAS/SAFEA International Partnership Program for Creative Research Teams.
文摘The Circular Electron Positron Collider(CEPC)is a large scientific project initiated and hosted by China,fostered through extensive collaboration with international partners.The complex comprises four accelerators:a 30 GeV Linac,a 1.1 GeV Damping Ring,a Booster capable of achieving energies up to 180 GeV,and a Collider operating at varying energy modes(Z,W,H,and tt).The Linac and Damping Ring are situated on the surface,while the subterranean Booster and Collider are housed in a 100 km circumference underground tunnel,strategically accommodating future expansion with provisions for a potential Super Proton Proton Collider(SPPC).The CEPC primarily serves as a Higgs factory.In its baseline design with synchrotron radiation(SR)power of 30 MW per beam,it can achieve a luminosity of 5×10^(34)cm^(-2)s^(-1)per interaction point(IP),resulting in an integrated luminosity of 13 ab^(-1)for two IPs over a decade,producing 2.6 million Higgs bosons.Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons,facilitating precise measurements of Higgs coupling at sub-percent levels,exceeding the precision expected from the HL-LHC by an order of magnitude.This Technical Design Report(TDR)follows the Preliminary Conceptual Design Report(Pre-CDR,2015)and the Conceptual Design Report(CDR,2018),comprehensively detailing the machine's layout,performance metrics,physical design and analysis,technical systems design,R&D and prototyping efforts,and associated civil engineering aspects.Additionally,it includes a cost estimate and a preliminary construction timeline,establishing a framework for forthcoming engineering design phase and site selection procedures.Construction is anticipated to begin around 2027-2028,pending government approval,with an estimated duration of 8 years.The commencement of experiments and data collection could potentially be initiated in the mid-2030s.
基金supported by the National Natural Science Foundation of China(Nos.81872815,81872826,82030107,81690263)Science and Technology Commission of Shanghai Municipality(No.19XD1400300)。
文摘The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other micelles.All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles.The transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other groups.Moreover,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups.Thus,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups.In conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.
基金supported by the National Natural Science Foundation of China(Nos.81973247,81872815,81872826 and 81690263)Science and Technology Commission of Shanghai Municipality(19XD1400300,China)。
文摘In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have never been accurately portrayed.The current practice of IVIVC has to resort to in vivo absorption fractions(Fa).In this proof-of-concept study,in vivo dissolution of a model poorly watersoluble drug fenofbrate(FNB)was investigated by fuorescence bioimaging.FNB crystals were frst labeled by near-infrared fuorophores with aggregation-caused quenching properties.The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media,enabling accurate monitoring of residual drug crystals.The linearity established between fuorescence and crystal concentration justifed reliable quantifcation of FNB crystals.In vitro dissolution was frst measured following pharmacopoeia monograph protocols with well-documented IVIVC.The synchronicity between fuorescence and in vitro dissolution of FNB supported using fuorescence as a measure for determination of dissolution.In vitro dissolution correlated well with in vivo dissolution,acquired by either live or ex vivo imaging.The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with Faobtained from pharmacokinetic data.
基金funded by the Science and Technology Committee of Shanghai Municipality (Nos.19430741400, 23S11901500,23ZR1413100, and 21430760800)the National Natural Science Foundation of China (Nos.81973247 and 82030107)。
文摘Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.
基金supported by the‘Pioneer’and‘Leading Goose’R&D Program of Zhejiang(#2023C03164 and#2024SSYS0032)the National Natural Science Foundation of China(#82370887)+1 种基金the Chinese National Key Technology R&D Program,Ministry of Science and Technology(#2021YFC2501702)the funds from the Westlake Laboratory of Life Sciences and Biomedicine(#202208014).
文摘Background There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms,while more studies demonstrate that depression negatively affects bone density and increases fracture risk.Aims To explore the relationship between major depressive disorder(MDD)and fracture risk.Methods We conducted a nested case-control analysis(32670 patients with fracture and 397017 individuals without fracture)and a matched cohort analysis(16496 patients with MDD and 435492 individuals without MDD)in the same prospective UK Biobank data set.Further,we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools.We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci.We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study.Results We found that MDD was associated with a 14%increase in fracture risk(hazard ratio(HR)1.14,95%CI 1.14 to 1.15,p<0.001)in the nested case-control analysis,while fracture was associated with a 72%increase in MDD risk(HR 1.72,95%CI 1.64 to 1.79,p<0.001)in the matched cohort analysis,suggesting a longitudinal and bidirectional relationship.Further,genetic summary data suggested a genetic overlap between MDD and fracture.Specifically,we identified four shared genomic loci,with the top signal(rs7554101)near SGIP1.The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling.We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa.In addition,we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD.Conclusions The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis.The shared genetic components(such as SGIP1)between the disea
基金supported by National Natural Science Foundation of China(No.82073801)。
文摘This research aims to develop a non-invasive strategy for small interfering RNA(siRNA)nasal delivery based on ionic liquids(ILs)and cationic lipid(2,3-dioleoyloxy-propyl)-trimethylammonium-chloride(DOTAP).Other than the classical role of penetration enhancer,ILs also acted as superior solvents to simultaneously load siRNA and DOTAP,forming siRNA-DOTAP-ILs(siRNA-DILs)formulations.During nasal mucosa penetration,DOTAP and ILs components self-assembled into cationic lipid nanocomplexes to load siRNA for enhanced in situ transfection.The siRNA-DILs demonstrated resistance against RNase,significant mucosa penetration,prolonged nasal retention,and satisfying gene-silencing efficacy at lower dosage.Meanwhile,DILs were also able to deliver KCa3.1-targeted siRNA effectively for the treatment of allergic rhinitis in rat model by nasal route.Thus,DILs have great potentials to deliver biological macromolecules across nasal mucosa by in situ dynamic self-assembly.
文摘Oral formulations are always preferred to injections due to the advantages of high patient compliance,no biohazardous needle waste,and low requirements for administration skills.However,the presence of multiple gastrointestinal(GI)barriers,including extreme gastric acidity and a broad pH gradient,digestive enzymes,thick and variable mucus layers,and tight junctions in the enteric epithelia,restricts the rate and extent of oral absorption.Only active ingredients with favorable physicochemical properties.
基金financially supported by the National Natural Science Foundation of China(Nos.81872826,81573363,81690263)Science and Technology Commission of Shanghai Municipality(No.18ZR1404100)Shanghai Pujiang Program(No.18PJD001)。
文摘The discrimination against nutritional fat emulsion injections was considered by imaging tools,which aims to elucidate the in vivo behaviors of nanoemulsions.In this study,20%nutritional fat emulsion injections were selected from different company including original and generic products.Meanwhile,a water quenching fluorescent probe(P2)was used to label them by an incubation method.The fluorescent intensity analysis of blood-borne fluorescence reveals rapid clearance of nanoemulsion in all groups,which shows'L'-type blood kinetic profiles.However,these kinetic parameters do not have significant difference.Following intravenous administration,the nanoemulsions in all groups concomitantly accumulated in organs of reticulo-endothelial system(RES),such as liver and spleen,and were cleared from body circulation mostly after 12 h.AUC(0-t)of organs from different groups showed dissimilar results in some organs.These intuitional results are of significance in understa nding the in vivo behaviors of nanoemulsions,which can provide a new way to discriminate against nutritional fat emulsions.
基金Shanghai Municipal Commission of Science and Technology,Grant/Award Numbers:21430760800,19XD1400300National Natural Science Foundation of China,Grant/Award Numbers:81872826,81872815,81973247,82030107。
文摘Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete fluorescence quenching and significant re-illumination,which undermine bioimaging accuracy.Herein,through structural modifications to reinforce the hydrophobicity,planarity and rigidity of fluorophores with an aza-BODIPY framework,probes featuring absolute ACQ(aACQ)and negligible re-illumination are developed and evaluated in various nanocarriers.aACQ probes,FD-B21 and FD-C7,exhibit near-infrared emission,high quantum yield,photostability,water sensitivity,and negligible re-illumination in blood,plasma and 1%Tween-80 in contrast to ACQ probe P2 and conventional probe DiR.All nanocarriers can be labeled efficiently by the tested fluorophores.Polymeric micelles(PMs)labeled by different aACQ probes manifest similar biodistribution patterns,which however differ from that of DiR-labeled PMs and could be ascribed to the appreciable re-illumination of DiR.Significantly lower re-illumination is also found in aACQ probes(2%-3%)than DiR(20%-40%)in Caco-2,Hela,and Raw264.7 cells.Molecular dynamics simulations unravel the molecular mechanisms behind aggregation and re-illumination,supporting the hypothesis of planarity dependency.It is concluded that aACQ fluorophores demonstrate excellent water sensitivity and negligible fluorescence re-illumination,making themselves useful tools for more accurate bioimaging of nanocarriers.
文摘Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor(GECAM)is a constellation with four instruments(launch date):GECAM-A/B(10 December 2020),GECAM-C(27 July 2022)and GECAM-D(13 March 2024),which are dedicated to monitoring gamma-ray transients in all-sky.The primary science objectives of GECAM include Gamma-Ray Bursts(GRBs),Soft Gamma-ray Repeaters(SGRs),high energy counterparts of Gravitation Wave(GW)and Fast Radio Burst(FRB),Solar Flares(SFLs),as well as Terrestrial Gamma-ray Flashes(TGFs)and Terrestrial Electron Beams(TEBs).A series of observations and research have been made since the launch of GECAM-A/B.GECAM observations provide new insights into these highenergy transients,demonstrating the unique role of GECAM in the“multi-wavelength,multi-messenger”era.
