Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

In Vitro Propagation and Artificial Seed Production of Fritillaria cirrhosa D. Don, an Endangered Medicinal Plant

Fritillaria cirrhosa D.Don(Liliaceae)is an endangered perennial bulbous plant and its dry bulb is a valuable med-icinal material with antitussive and expectorant effects.Nevertheless,lack of resources and expensive prices make it difficult to meet clinical needs.This study presents a regeneration system aimed at overcoming the challenge of inadequate supply in F.cirrhosa,focusing on:(1)callus induction,(2)bulblets and adventitious bud induction,and(3)artificial seed production.Callus development was achieved in 84.93%on Murashige and Skoog(MS)medium fortified with 1.0 mg·L^(-1) picloram.The optimal medium for callus differentiation into regenerated bulb-lets was MS medium supplemented with 1.0 mg·L^(-1)6-benzyladenine(6-BA)and 0.2 mg·L^(-1)α-naphthaleneacetic acid(NAA).Subsequently,bulblets and adventitious buds were induced from regenerated bulblet sections cul-tured on MS medium fortified with 0.3 mg·L^(-1)6-BA+1.0 mg·L^(-1)2,4-dichlorophenoxyacetic acid(2,4-D),2.0 mg·L^(-1)6-BA+0.5 mg·L^(-1),and the induction rates were 88.17%and 84.24%,respectively.The regenerated bulblets were transplanted into a substrate of humus soil,river sand,and pearlite(1:1:1)after low-temperature treatment.The germination rate was 42.80%after culture for 30 days.Regenerated bulblets were used for encap-sulations in liquid MS medium containing 3%sucrose(w/v)+0.5 mg·L^(-1) NAA+2.0 mg·L^(-1)6-BA+3%sodium alginate(w/v)with a 10 min exposure to 2%CaCl_(2).Under non-aseptic conditions,the germination rate reached 81.67%,while the rooting rate was 20.56%after 45 days.The capsule added 1.0 g·L^(-1) carbendazim and 1.0 g·L^(-1) activated carbon was the best component of artificial seeds.This study successfully established an efficient regen-eration system for the rapid propagation of F.cirrhosa,involving in vitro bulblet regeneration and artificial seed production.This method introduces a novel approach for efficient breeding and germplasm preservation,making it suitable for large-scale industrial resource production.

Design of 50 MeV proton microbeam based on cyclotron accelerator

High-energy proton microbeam facilities are powerful tools in space science,biology and cancer therapy studies.The primary limitations of the 50 MeV proton microbeam system are the poor beam quality provided by the cyclotron and the problem of intense scattering in the slit position.Here,we present an optical design for a cyclotron-based 50 MeV high-energy proton microbeam system with a micron-sized resolution.The microbeam system,which has an Oxford triplet lens configuration,has relatively small spherical aberrations and is insensitive to changes in the beam divergence angle and momentum spread.In addition,the energy filtration included in the system can reduce the beam momentum spread from 1 to 0.02%.The effects of lens parasitic aberrations and the lens fringe field on the beam spot resolution are also discussed.In addition,owing to the severe scattering of 50 MeV protons in slit materials,a slit system model based on the Geant4 toolkit enables the quantitative analysis of scattered protons and secondary particles.For the slit system settings under a 10-micron final beam spot,very few scattered protons can enter the quadrupole lens system and affect the focusing performance of the microbeam system,but the secondary radiation of neutrons and gamma rays generated at the collimation system should be considered for the 50 MeV proton microbeam.These data demonstrate that a 50 MeV proton microbeam system with a micron-sized beam spot based on a cyclotron is feasible.

高糖条件下致钙信号改变的机制研究

目的探讨高糖对大鼠心房肌钙信号的影响及其机制。方法分离大鼠心房肌细胞,分成2部分:第1部分分左旋葡萄糖(LG)组、正常葡萄糖(NG)组、高葡萄糖(HG)组、HG+尿酸组;第2部分分过氧化亚硝基阴离子(ONOO^-)组、分解后ONOO^-(DC-ONOO^-)组、ONOO^-+尿酸组。观察钙瞬变、钙通道蛋白RYR2、钙调控蛋白FKBP12.6的变化。结果HG组的钙瞬变幅度较NG组高,ONOO^-增加钙释放,尿酸可以减弱其效应;HG组和ONOO^-组RYR2蛋白的表达降低,尿酸可抑制HG和ONOO^-导致的RYR2蛋白表达效应,高糖可调控RYR2蛋白上游调控分子FKBP12.6的表达。结论(1)高糖及ONOO^-增加钙释放,氧化应激抑制因子―尿酸减少钙释放;(2)高糖减少RYR2表达,尿酸可以抑制其效应;(3)高糖可以通过氧化应激调控RYR2上游信号通路分子FKBP12.6,从而调控钙信号。

A male-ABCD algorithm for hepatocellular carcinoma risk prediction in HBs Ag carriers

Objective: Hepatocellular carcinoma(HCC) development among hepatitis B surface antigen(HBs Ag) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBs Ag-positive male adults.Methods: HBs Ag-positive males of 35-69 years old(N=6,153) were included from a multi-center populationbased liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using Bultrasonography and α-fetoprotein(AFP). We used logistic regression models to determine potential risk factors,built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.Results: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT(γ-glutamyl-transpeptidase), counts of platelets, white cells,concentration of DCP(des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91(0.90-0.93), larger than existing models. At 1.5 points of risk score,26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk,with positive prediction value of 22.85% and 12.35%, respectively.Conclusions: Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.

Effects of carbohydrate supplements on exercise-induced menstrual dysfunction and ovarian subcellular structural changes in rats

Background： Exercise-associated menstrual dysfunction （EAMD） is a common health problem in female athletes as a part of female athlete triad （FAT）, a condition related to low energy availability. In this study, we explored the possibility that carbohydrate supplements can improve the status of EAMD and prevent exercise-induced ovarian injury in a FAT rat model. This research aimed to provide experimental evidence with regard to the relationship of energy intervention and EAMD. Methods： Forty-five female Sprague-Dawley rats （2 months old） were randomly divided into five experimental groups： control group （C）, 9-week exercise as model for EAMD （E）, post-EAMD recovery group （R）, oligosaccharide intervention group （O）, and glucose intervention group （G）. All rats were sacrificed at the end of 9 weeks. Serum samples were collected for measuring gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, 1713-estradiol and progesterone levels. The ovaries were taken for investigation of exercise- and carbohydrate-induced follicular subcellular structure changes. Results： Exercise induced irregular menstrual cycles and ovary subcellular structural damages, such as swollenness of mitochondria in rats from groups E and R. Both glucose and oligosaccharide supplements restored well-differentiated mitochondria in the ovarian follicular cells, and a significant improvement of endoplasmic reticulum and Golgi in swollenness in theca cells in groups O and G compared to groups C, E, and R. There was no difference in mitochondria subcellular structural changes between groups O and G. Group E showed attenuation of serum levels of 17β-estradiol and progesterone compared to C. There were no differences of 17β-estradiol serum levels among groups O, G, and R, while group G showed a lower level of progesterone than C. Conclusion： Female adult rats with 9-week continuous exercise can cause menstrual dysregulation as a model for EAMD. Post-EAMD intervention with glucose and oligosaccharide intake can normalize the menstrual cycle, restore the follicular subcellular structure, and reverse the exercise-induced reduction of ovary sex hormones. It suggests a positive feedback of hypothalamus-pituitary-ovary axis might be involved in the molecular mechanisms of energy intake in treating EAMD.

Seismic Data Recovery with Curvelet Bivariate Shrinkage Function Based on Compressed Sensing

Recovery of under-sampled seismic data is a critical problem,in oil and gas exploration,therefore recovery algorithms with iterative shrinkage based on compressed sensing have been recently proposed. However most of these algorithms usually adopt a soft shrinkage function,which assumes that all of the sparse coefficients are independent of each other in curvelet or other domains,little attention has so far been devoted to the inter-dependencies of coefficients. In this paper,the dependencies of parent-child curvelet coefficients of seismic data are exploited by Bayesian estimation,moreover the new seismic data recovery algorithm via curvelet-based bivariate shrinkage function is proposed. First the respective parent-child curvelet coefficients joint distribution models of fully-sampled seismic data and noise signal caused by missing traces are established,then the bivariate shrinkage function according to the Bayesian maximum posterior probability estimation is obtained,finally the Landweber iterative shrinkage algorithm is used in the recovery process.When compared with existing recovery algorithms,it is proved that the proposed algorithm can obtain higher PSNR performance,and maintains the texture details better in events of seismic data

Effect of intraocular lens implantation on visual field in glaucoma and comorbid cataracts

AIM: To investigate the effects of intraocular lens(IOL) implantation on visual field(VF) in patients with glaucoma and comorbid cataracts(G&C) with different disease severities.METHODS: Totally 56 eyes of 50 patients with primary G&C were included. All patients were divided into three groups based on the severity of the VF defect: the mild, moderate, and severe stage. Phacoemulsification was performed for cataract removal combined with IOL implantation. Visual acuity(VA) and VF tests were performed for all enrolled patients, up to 3 mo after surgery. Changes in VF threshold and global VF index in various groups were also recorded before and after surgery. The mean light sensitivity(MS) values and the changes following surgery(DMS) were compared between the three groups. Advanced Glaucoma Intervention Study(AGIS) scoring was analyzed on all VF results for analysis of changes in VF before and after surgery.RESULTS: Following surgery, the MS values of the three groups of G&C increased significantly, while the AGIS scores decreased statistically in all groups. The DMS values for the three zones in moderate and severe stage but not mild stage were statistically different between zones. The DMS value was significantly higher in zone I than those in zone II and III(zone I>zone II>zone III;P<0.05). The DMS was significantly higher in zone I than that in zone III in moderate stage patients(zone I>zone II>zone III;P<0.01), while the DMS values in the severe stage patients was significantly higher in zone I than those in zone II and III(zone I>zone II>zone III;P<0.01). CONCLUSION: The mean VF sensitivity of glaucoma patients increased significantly after cataract removal and IOL implantation. Variations in the severity and distribution of characteristics of VF defects result in differences in postoperative VF improvements after cataract surgery. The magnitude of increase in VF sensitivity is associated with VF defect characteristic in glaucoma.

Malnutrition predicts poor outcomes in diabetic COVID-19 patients in Huangshi,Hubei

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has spread throughout the world,which becomes a global public health emergency.Undernourishment prolongs its convalescence and has an adverse effect on its prognosis,especially in diabetic patients.The purpose of this study was to evaluate the prevalence and characteristics of undernourishment and to determine how it is related to the prognostic outcomes in the diabetic patients with coronavirus disease 2019(COVID-19).A retrospective,multicenter study was conducted in 85 diabetic COVID-19 patients from three hospitals in Hubei Province.All patients were assessed using the European Nutritional Risk Screening 2002(NRS-2002)and other nutritional assessments when admitted.Of them,35(41.18%)were at risk of malnutrition(NRS score≥3).Severe COVID-19 patients had a significantly lower level of serum albumin and prealbumin and higher NRS score than non-severe patients.Multivariate logistic regression analysis showed that serum prealbumin and NRS score increased the likelihood of progression into severe status(P<0.05).Meanwhile,single factor and multivariate analysis determined that grade of illness severity was an independent predictor for malnutrition.Furthermore,prealbumin and NRS score could well predict severe status for COVID-19 patients.The malnutrition group(NRS score≥3)had more severe illness than the normal nutritional(NRS score<3)group(P<0.001),and had a longer length of in-hospital stay and higher mortality.Malnutrition is highly prevalent among COVID-19 patients with diabetes.It is associated with severely ill status and poor prognosis.Evaluation of nutritional status should be strengthened,especially the indicators of NRS-2002 and the level of serum prealbumin.

Synergistic asymmetric diarylation of tethered alkenes via C–H functionalization of simple(hetero)arenes

By virtue of the atom-and step-economy, utilization of simple arenes as a supplant of pre-prepared aryl metal species or aryl halides for the synthesis of arylated chiral molecules has attracted great attention from the synthetic community. While transition-metal-catalyzed enantioselective diarylation of tethered alkenes has been employed to prepare important chiral cyclic compounds, the direct use of simple arenes as aryl precursors is still underdeveloped, probably due to the difficulties in the effective control of the reactivity, site-selectivity and/or enantioselectivity. Herein we report an asymmetric Pd/Ag dual metal catalytic system for the non-directed, site-and enantioselective domino Heck/intermolecular C–H functionalization of arenes.Mechanistic studies showed that Pd and Ag act in cooperation in the catalysis and the chiral bisphosphine ligand plays a bifunctional role, i.e., assisting the silver species in the cleavage of the aryl C–H bond, while inducing the enantioselectivity on direct complexation with palladium. This method provides an efficient approach to the corresponding chiral oxindoles with good enantiomeric excesses from a broad scope of arenes, including fluoroarenes, heteroarenes and several complex products derived from medicines or natural products.

Polarization-maintaining few mode fiber composed of a central circular-hole and an elliptical-ring core

We propose a novel waveguide design of polarization-maintaining few mode fiber(PM-FMF) supporting ≥10non-degenerate modes, utilizing a central circular air hole and a circumjacent elliptical-ring core. The structure endows a new degree of freedom to adjust the birefringence of all the guided modes, including the fundamental polarization mode. Numerical simulations demonstrate that, by optimizing the air hole and elliptical-ring core,a PM-FMF supporting 10 distinctive polarization modes has been achieved, and the effective index difference Δn_(eff) between the adjacent guided modes could be kept larger than 1.32 × 10^(-4) over the whole C +L band. The proposed fiber structure can flexibly tailored to support an even larger number of modes in PM-FMF(14-mode PM-FMF has been demonstrated as an example), which can be readily applicable to a scalable mode division multiplexing system.

Distributed Brillouin frequency shift extraction via a convolutional neural network

Distributed optical fiber Brillouin sensors detect the temperature and strain along a fiber according to the local Brillouin frequency shift(BFS),which is usually calculated by the measured Brillouin spectrum using Lorentzian curve fitting.In addition,cross-correlation,principal component analysis,and machine learning methods have been proposed for the more efficient extraction of BFS.However,existing methods only process the Brillouin spectrum individually,ignoring the correlation in the time domain,indicating that there is still room for improvement.Here,we propose and experimentally demonstrate a BFS extraction convolutional neural network(BFSCNN)to retrieve the distributed BFS directly from the measured two-dimensional data.Simulated ideal Brillouin spectra with various parameters are used to train the BFSCNN.Both the simulation and experimental results show that the extraction accuracy of the BFSCNN is better than that of the traditional curve fitting algorithm with a much shorter processing time.The BFSCNN has good universality and robustness and can effectively improve the performances of existing Brillouin sensors.

Chronic spinal cord injury repair by NT3-chitosan only occurs after clearance of the lesion scar

Spinal cord injury(SCI)is a severe damage usually leading to limb dysesthesia,motor dysfunction,and other physiological disability.We have previously shown that NT3-chitosan could trigger an acute SCI repairment in rats and non-human primates.Due to the negative effect of inhibitory molecules in glial scar on axonal regeneration,however,the role of NT3-chitosan in the treatment of chronic SCI remains unclear.Compared with the fresh wound of acute SCI,how to handle the lesion core and glial scars is a major issue related to chronic-SCI repair.Here we report,in a chronic complete SCI rat model,establishment of magnetic resonancediffusion tensor imaging(MR-DTI)methods to monitor spatial and temporal changes of the lesion area,which matched well with anatomical analyses.Clearance of the lesion core via suction of cystic tissues and trimming of solid scar tissues before introducing NT3-chitosan using either a rigid tubular scaffold or a soft gel form led to robust neural regeneration,which interconnected the severed ascending and descending axons and accompanied with electrophysiological and motor functional recovery.In contrast,cystic tissue extraction without scar trimming followed by NT3-chitosan injection,resulted in little,if any regeneration.Taken together,after lesion core clearance,NT3-chitosan can be used to enable chronic-SCI repair and MR-DTI-based mapping of lesion area and monitoring of ongoing regeneration can potentially be implemented in clinical studies for subacute/chronic-SCI repair.

Distributed curvature sensing based on a bending loss-resistant ring-core fiber

A theoretical and experimental study on curvature sensing using a Brillouin optical time-domain analyzer based on the ring-core fiber(RCF)is reported.The Brillouin gain spectrum of the RCF is investigated,and the Brillouin frequency shift(BFS)dependence on temperature and strain is calibrated.We theoretically analyze the fiber bending-induced BFS and peak Brillouin gain variation for the RCF through a numerical simulation method,and the RCF is revealed to have a high curvature sensitivity.Distributed curvature sensing is successfully demonstrated,with the bending radius ranging from 0.5 to 1.5 cm,corresponding to a BFS variation from 32.90 to7.81 MHz.The RCF takes advantage of great bending loss resistance,and the maximum macrobending loss at the extreme bending radius of 0.5 cm is less than 0.01 d B/turn.Besides,the peak Brillouin gain of the RCF is discovered to vary significantly in response to fiber bending,which is expected to be another parameter for distributed curvature determination.The results imply that the RCF is a promising candidate for highly sensitive distributed curvature measurement,especially in sharp bending circumstances.