Hepatocytes direct the formation of a pro-metastatic niche in the liver.

The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Radiomics using CT images for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma: a multi-centric study.

OBJECTIVES: To develop a CT-based radiomics model for preoperative prediction of lymph node (LN) metastasis in perihilar cholangiocarcinoma (pCCA). METHODS: The study enrolled consecutive pCCA patients from three independent Chinese medical centers. The Boruta algorithm was applied to build the radiomics signature for the primary tumor and LN. The k-means algorithm was employed to cluster the selected LNs based on the radiomics signature LN. Support vector machines were used to construct the prediction models. The diagnostic efficiency was measured by the area under the receiver operating characteristic curve (AUC). The optimal model was evaluated in terms of calibration, clinical usefulness, and prognostic value. RESULTS: A total of 214 patients were included in the study (mean age: 61.6 years ± 9.4; 130 male). The selected LNs were classified into two clusters, which were significantly correlated with LN metastasis in all cohorts (p < 0.001). The model incorporated the clinical risk factors, radiomics signature primary tumor, and the LN cluster obtained the best discrimination, with AUC values of 0.981 (95% CI: 0.962-1), 0.896 (95% CI: 0.810-0.982), and 0.865 (95% CI: 0.768-0.961) in the training, internal validation, and external validation cohorts, respectively. High-risk patients predicted by the optimal model had shorter overall survival than low-risk patients (median, 13.7 vs. 27.3 months, p < 0.001). CONCLUSIONS: The study proposed a radiomics model with good performance to predict LN metastasis in pCCA. As a noninvasive preoperative prediction tool, this model may help in patient risk stratification and personalized treatment. CLINICAL RELEVANCE STATEMENT: A CT-based radiomics model accurately predicts lymph node metastasis in perihilar cholangiocarcinoma patients. This noninvasive preoperative tool can aid in patient risk stratification and personalized treatment, potentially improving patient outcomes. KEY POINTS: • The radiomics model based on contrast-enhanced CT is a useful tool for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma. • Radiomics features extracted from lymph nodes show great potential for predicting lymph node metastasis. • The study is the first to identify a lymph node phenotype with a high probability of metastasis based on radiomics.

Isolation, antibacterial characterization, and alternating tangential flow-based preparation of viable cells of Lacticaseibacillus paracasei XLK 401: Potential application in milk preservation.

It is desirable to obtain high levels of viable Lacticaseibacillus paracasei, a widely used food probiotic whose antibacterial activity and potential application in milk remain largely uninvestigated. Here, we isolated and purified the L. paracasei strain XLK 401 from food-grade blueberry ferments and found that it exhibited strong antibacterial activity against both gram-positive and gram-negative foodborne pathogens, including Staphylococcus aureus, Salmonella paratyphi B, Escherichia coli O157, and Shigella flexneri. Then, we applied alternating tangential flow (ATF) technology to produce viable L. paracasei XLK 401 cells and its cell-free supernatant (CFS). Compared with the conventional fed-batch method, 22 h of ATF-based processing markedly increased the number of viable cells of L. paracasei XLK 401 to 12.14 ± 0.13 log cfu/mL. Additionally, the CFS exhibited good thermal stability and pH tolerance, inhibiting biofilm formation in the abovementioned foodborne pathogens. According to liquid chromatography-mass spectrometry analysis, organic acids were the main antibacterial components of XLK 401 CFS, accounting for its inhibition activity. Moreover, the CFS of L. paracasei XLK 401 effectively inhibited the growth of multidrug-resistant gram-positive Staph. aureus and gram-negative E. coli O157 pathogens in milk, and caused a reduction in the pathogenic cell counts by 6 to 7 log cfu/mL compared with untreated control, thus considerably maintaining the safety of milk samples. For the first time to our knowledge, ATF-based technology was employed to obtain viable L. paracasei on a large scale, and its CFS could serve as a broad-spectrum biopreservative for potential application against foodborne pathogens in milk products.

MRTF-A alleviates myocardial ischemia reperfusion injury by inhibiting the inflammatory response and inducing autophagy.

Myocardin-related transcription factor A (MRTF-A) has an inhibitory effect on myocardial infarction; however, the mechanism is not clear. This study reveals the mechanism by which MRTF-A regulates autophagy to alleviate myocardial infarct-mediated inflammation, and the effect of silent information regulator 1 (SIRT1) on the myocardial protective effect of MRTF-A was also verified. MRTF-A significantly decreased cardiac damage induced by myocardial ischemia. In addition, MRTF-A decreased NLRP3 inflammasome activity, and significantly increased the expression of autophagy protein in myocardial ischemia tissue. Lipopolysaccharide (LPS) and 3-methyladenine (3-MA) eliminated the protective effects of MRTF-A. Furthermore, simultaneous overexpression of MRTF-A and SIRT1 effectively reduced the injury caused by myocardial ischemia; this was associated with downregulation of inflammatory factor proteins and when upregulation of autophagy-related proteins. Inhibition of SIRT1 activity partially suppressed these MRTF-A-induced cardioprotective effects. SIRT1 has a synergistic effect with MRTF-A to inhibit myocardial ischemia injury through reducing the inflammation response and inducing autophagy.

Multifunctional Covalent Organic Framework-Based Microneedle Patch for Melanoma Treatment.

Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-Fe3O4@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-Fe3O4@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of Fe3O4@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-Fe3O4@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-Fe3O4@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.

Ethanol Embolization of Chest Wall Arteriovenous Malformations: Four-Year Findings.

OBJECTIVES: To summarize the clinical characteristics and investigate the efficacy of ethanol embolotherapy in the treatment of chest well arteriovenous malformation (AVM). Treatment-associated complications were also explored. MATERIALS AND METHODS: Between March 2017 and August 2021, 32 consecutive patients (mean age, 23.7 years; age range, 5-54 years) who underwent ethanol embolotherapy for chest well AVMs under general anesthesia were included in this study. Embolization was performed through a direct puncture, transarterial catheterization, or a combination of the 2 procedures. The mean follow-up duration after the last treatment was 18.0 months (range, 3-42 months). The degree of devascularization on follow-up (assessed using angiography or computed tomography), and the clinical signs and symptoms of AVMs were evaluated as the therapeutic outcomes. The major and minor complications associated with the procedures were recorded. RESULTS: A total of 103 embolization procedures (mean, 3.2; range, 2-7) comprising 101 ethanol embolization and 2 coil embolizations were performed on 32 patients with chest wall AVMs. The AVM nidus was accessed through the transarterial approach alone in 4 patients, by direct puncture in 11, and a combined procedure in 17 patients. Overall, more than 80% of the procedures were performed using the combined approach. Complete AVM devascularization was achieved in 12 (37.5%) patients. Moreover, 76% to 99% AVM was achieved in 18 patients (56.3%), and 50% to 75% in 2 patients (6.3%). Bleeding, pain, heart failure, and cosmetic deformities were the indications for treatment. For 3 patients (3/32, 9.4%) who had bleeding, the treatment stopped the hemorrhage. Complete pain relief was reported in 8 patients (8/32, 25.0%), whereas complete relief from congestive heart failure post-embolization was observed in 5 of the 6 patients with congestive heart failure (5/6, 83.3%). Complete correction of cosmesis deformities after embolization was achieved in 10 patients (10/32, 31.3%). Two patients who underwent surgery to correct persistent deformity after embolization only showed insignificant improvement. In addition, 6 (18.8%) patients developed 13 complications including blister, necrosis, hemothorax, transient hemoglobinuria, and transient pulmonary artery hypertension. CONCLUSIONS: Ethanol embolotherapy is a safe and effective procedure for chest well AVMs. Surgery is required for some patients with residual cosmesis deformity. CLINICAL IMPACT: Currently, there is no standard treatment for chest well AVMs due to their rarity and high heterogeneity. The present study shows that thanol embolotherapy is a safe and clinically effective treatment procedure for the chest well AVMs. Transarterial embolization in combination with direct puncture embolization can reach the AVM nidus. Ethanol embolotherapy can achieve complete obliteration of the AVM nidus in the majority of patients. Surgery may still be needed to correct cosmetic deformity after embolization. The present study provides valuable evidence to inform clinical decision-making.

[Lianmei Qiwu Decoction relieves diabetic cardiac autonomic neuropathy by regulating AMPK/TrkA/TRPM7 signaling pathway].

This study investigated the effect of Lianmei Qiwu Decoction(LMQWD) on the improvement of cardiac autonomic nerve remodeling in the diabetic rat model induced by the high-fat diet and explored the underlying mechanism of LMQWD through the AMP-activated protein kinase(AMPK)/tropomyosin receptor kinase A(TrkA)/transient receptor potential melastatin 7(TRPM7) signaling pathway. The diabetic rats were randomly divided into a model group, an LMQWD group, an AMPK agonist group, an unloaded TRPM7 adenovirus group(TRPM7-N), an overexpressed TRPM7 adenovirus group(TRPM7), an LMQWD + unloaded TRPM7 adenovirus group(LMQWD+TRPM7-N), an LMQWD + overexpressed TRPM7 adenovirus group(LMQWD+TRPM7), and a TRPM7 channel inhibitor group(TRPM7 inhibitor). After four weeks of treatment, programmed electrical stimulation(PES) was employed to detect the arrhythmia susceptibility of rats. The myocardial cell structure and myocardial tissue fibrosis of myocardial and ganglion samples in diabetic rats were observed by hematoxylin-eosin(HE) staining and Masson staining. The immunohistochemistry, immunofluorescence, real-time quantitative polymerase chain reaction(RT-PCR), and Western blot were adopted to detect the distribution and expression of TRPM7, tyrosine hydroxylase(TH), choline acetyltransferase(ChAT), growth associated protein-43(GAP-43), nerve growth factor(NGF), p-AMPK/AMPK, and other genes and related neural markers. The results showed that LMQWD could significantly reduce the arrhythmia susceptibility and the degree of fibrosis in myocardial tissues, decrease the levels of TH, ChAT, and GAP-43 in the myocardium and ganglion, increase NGF, inhibit the expression of TRPM7, and up-regulate p-AMPK/AMPK and p-TrkA/TrkA levels. This study indicated that LMQWD could attenuate cardiac autonomic nerve remodeling in the diabetic state, and its mechanism was associated with the activation of AMPK, further phosphorylation of TrkA, and inhibition of TRPM7 expression.

Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver.

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

1,7-Di-tert-butyl-Substituted aza-BODIPYs by Low-Barrier Rotation to Enhance a Photothermal-Photodynamic Effect.

1,7-Di-tert-butyl-substituted aza-BODIPYs (tBu-azaBDP) were successfully obtained for the first time. The structures of tBu-azaBDP and Ph-azaBDP were confirmed by X-ray crystal analysis, and tBu-azaBDP 2 is more twisted than Ph-azaBDP 5. tBu-azaBDPs have significant photo-stability and enhanced water solubility. tBu-azaBDPs possess excellent optical properties, such as high molar extinction coefficients, broad full width half maxima, and large Stokes shifts, which is comparable to those of the parent dye Ph-azaBDP. Although the low-barrier rotation of the distal -tBu groups in tBu-azaBDPs results in low quantum yield, photothermal conversion efficiency and singlet oxygen generation ability of tBu-azaBDPs are more effective than those of Ph-azaBDP, which is highly desirable for a photothermal-photodynamic therapy agent.

Evaluation of Nanoparticle Stability under Blood Flow Shear.

The stability of drug-loaded nanoparticles in vivo is related to the success of the drug delivery, which is investigated as a deficiency due to the limitation of traditional experimental methods. In this study, dissipative particle dynamics (DPD), a simulation method suitable for soft matter and fluids, was used to study the stability of amphiphilic nanoparticles in the blood microenvironment. By comparing the morphology alteration of nanoparticles with various molecular topologies in the shear fluid field, we have found that branch degree and geometric symmetry would be the key factors in maintaining the nanoparticle's stability. This research could provide more theoretical guidance for drug delivery system design.

Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil.

To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aß 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.

MRI monitoring of transplanted neonatal porcine islets labeled with polyvinylpyrrolidone-coated superparamagnetic iron oxide nanoparticles in a mouse model.

Islet transplantation is a potential treatment option for certain patients with type 1 diabetes; however, it still faces barriers to widespread use, including the lack of tools to monitor islet grafts post-transplantation. This study investigates whether labeling neonatal porcine islets (NPI) with polyvinylpyrrolidone-coated superparamagnetic iron oxide nanoparticles (PVP-SPIO) affects their function, and whether this nanoparticle can be utilized to monitor NPI xenografts with magnetic resonance imaging (MRI) in a mouse model. In vitro, PVP-SPIO-labeled NPI in an agarose gel was visualized clearly by MRI. PVP-SPIO-labeled islets were then transplanted under the kidney capsules of immunodeficient nondiabetic and diabetic mice. All diabetic mice that received transplantation of PVP-SPIO-labeled islets reached normoglycemia. Grafts appeared as hypo-intense areas on MRI and were distinguishable from the surrounding tissues. Following injection of spleen cells from immunocompetent mice, normoglycemic recipient mice became diabetic and islet grafts showed an increase in volume, accompanied by a mixed signal on MRI. Overall, this study demonstrates that PVP-SPIO did not affect the function of NPI that PVP-SPIO-labeled islets were easily seen on MRI, and changes in MRI signals following rejection suggest a potential use of PVP-SPIO-labeled islets to monitor graft viability.

Absolute Ethanol Embolization of Lip Arteriovenous Malformations: Observational Results from 10 Years of Experience.

PURPOSE: To evaluate the safety and efficacy of ethanol embolization of lip arteriovenous malformations (AVMs). MATERIALS AND METHODS: Seventy-six patients with lip AVMs were treated with 173 ethanol embolization procedures. Lip AVMs were treated with direct puncture alone in 21 patients (35 procedures, 20.2%), transarterial embolization alone in 13 patients (18 procedures, 10.4 %), and a combination of both in 60 patients (120 procedures, 69.3%). Adjunctive surgical resection was performed after embolization for cosmetic purposes based on the patient's request, including patient preference, functional impairment, and skin necrosis. The mean duration of follow-up was 30.9 months ± 27.6. The follow-up included clinic visits and telephonic questionnaires to evaluate the clinical signs and symptoms of AVMs as well as quality of life measures. RESULTS: Of 76 patients, 51 showed 100% devascularization of AVMs, as determined using arteriography, followed by 23 with 76%-99% devascularization and 2 with 50%-75% devascularization. Of the 76 patients, 40 achieved complete symptom relief and 25 achieved major improvements in cosmetic deformity after embolization. Additionally, 54 patients achieved satisfactory function and aesthetic improvement with ethanol embolotherapy alone, whereas 22 achieved similar outcomes with a combination of ethanol embolotherapy and surgical intervention. Thirty-three adverse events (including 1 major) were documented. CONCLUSIONS: Ethanol embolization of lip AVMs, as a mainstay, is efficacious in managing these lesions, with acceptable complications. Surgical resection after embolization may improve function and cosmesis in a subset of patients.

Automatic digital optical heterodyne phase locking loop in the milliradian domain for spaceborne laser interferometry.

We developed a digital optical phase locking loop (OPLL) with three advantages, including high precision of phase locking, high control bandwidth up to 2.8 MHz, and automatic laser locking strategy. Spaceborne laser interferometers will be used to measure tiny displacements caused by gravitational waves in millions of kilometers range. A slave laser will be heterodyne phase locked to the incoming weak light at the end of an arm, emitting a higher power light back to the other satellite to measure pathlength variations at the picometer level. Such accuracy requires extremely precise OPLL. We report an experiment to demonstrate a digital OPLL that can automatically lock two independent free-running Nd:YAG lasers with residual phase error below 1mrad/Hz above 0.01 Hz, which is the best performance recorded for digital servos, to our knowledge. Such performance tested under a normal laboratory environment will be highly improved in a vacuum environment with temperature and vibration well controlled. Both the digital OPLL and the automatic strategy were implemented on a field programmable gate array that could be potentially used for future gravitational-wave detection. Our experiment might change the thinking of scientists who study phasemeters of gravitational-wave detection because we are aware that the digital phase locking loop used for "optical phase tracking" is differently designed from "optical phase locking."

Trans-ophthalmic arterial ethanol embolotherapy for arteriovenous malformations: a single-center experience.

Arteriovenous malformation (AVM)-derived ophthalmic artery (OphA) branches are not common, and their management is very challenging. We evaluated the safety and efficacy of Trans OphA ethanol embolotherapy for these lesions. We retrospectively reviewed 26 patients with AVMs fed by OphA, who underwent transOphA embolization using ethanol from February, 2015 to December, 2019. Sixty-six transOphA embolotherapy procedures (range, 1-4 procedures; mean, 2.5 procedures) were performed. Devascularization degree, visual field, visual acuity, and quality-of-life outcomes were compared and analyzed at follow up (mean, 32.6 months; month range 10-60). Complications were recorded. Twenty-five of the 26 patients (96%) reported complete or > 90% AVM devascularization while one patient (4%) showed > 70% devascularization. Eleven patients (42%) presented with visual acuity impairments; among them, 6 had improvements while 4 were completely relieved. Eight patients (30.7%) presented visual field defects, 3 had improvements while 4 were completely relieved. Ten patients (38.4%) presented with diplopia and exophthalmos with 2 being completely relieved while 6 had major improvements. Bleeding was controlled in all cases (100%). All patients (100%) exhibited cosmetic deformities with 17 being completely relieved. Moreover, all patients (100%) exhibited impaired daily life, which was resolved in 21 patients with 5 patients reporting major improvements. After endovascular treatment, there was no vision loss, death, or permanent disability in any patient. TransOphA ethanol embolotherapy is efficacious and safe for symptomatic resolution or improvement of AVMs fed by OphA with acceptable complications without the risk of visual impairment.

Sweep frequency method with variance weight probability for temperature extraction of the Brillouin gain spectrum based on an artificial neural network.

The development of optical fiber sensors has led to the possibility of accumulating vast, real-time databases of acoustic and other measurements throughout fiber networks, which brings even more widespread concern on improving the sampling effectiveness. In this paper, we present two kinds of sweep frequency methods based on using a neural network to extract temperature from the Brillouin gain spectrum (BGS). Gauss centralization and variance weight probability methods are proposed to compare with the uniform sweep frequency method. By analyzing formulas of the ideal BGS model, we find the gain near the peak of Brillouin gain spectrum has greater correlation with temperature extraction than other positions. Therefore, the Gaussian centralized sweep method is proposed. We further investigate the variation of the weights in the neural network and Brillouin data distribution in different positions and find that the variance is positively correlated with the weights in hidden layers. So, we propose the sweep frequency method based on variance weight probability and make a complement to interpret the rationality of this method in neural network. In all the aforementioned approaches, 281 points are obtained between the 9.07 GHz to 9.35 GHz range under the same condition. The data of each method is trained ten times and tested through the same neural network structure. All the RMSE of each test stage covers all data collecting the passage. The result shows that the RMSE of variance weight probability sweep frequency method is 0.5277, which is superior to the Gauss centralization sweep frequency method that was 0.6864 and the uniform sweep frequency method that was 0.9140.

An Update on the Routes for the Delivery of Donepezil.

Dementia is a significant public health problem in the 21st century. Alzheimer's disease (AD) is an essential factor in dementia. Currently, the drugs used for the treatment of AD are mainly acetylcholine inhibitors (AChEIs). As an AChEI, donepezil (DP) can improve patients' cognitive ability with low side effects and has been accepted by most patients and doctors. For AD patients, the dosage regimen is also crucial due to aging and diseases. Although there are DP oral tablets on the market, there are still many problems to be solved. At present, more and more research is conducted to optimize the route of administration of DP to improve the self-administration of patients. The research fields of DP administration include oral administration, injection administration, intranasal administration, and transdermal administration. This Review is to present the development of different DP administrations and evaluates the advantages and limitations of those works, hoping to optimize the DP dosage regimen for AD patients.

Stability and Diffusion Properties of Insulin in Dissolvable Microneedles: A Multiscale Simulation Study.

Microneedle (MN) technology has been proven to be promising to become an effective drug delivery route of insulin for diabetes treatment, with the advantages of high delivery efficiency, convenient management, and minimal risk of infection. However, efforts are still required to verify the insulin activity in MNs for further clinical application. Moreover, it is also essential to study the diffusion properties of insulin to understand the ability of various MN materials to control insulin release. Herein, we have combined all-atom molecular dynamics simulation and coarse-grained dissipative particle dynamics to systematically study insulin's structural stability and diffusion coefficient in polyvinyl alcohol and hyaluronic acid solutions. The all-atom simulation reveals the dissimilarities in the interaction mode between insulin and the two polymers. It also points out that the presence of the two polymers would not irreversibly impact the secondary structure of insulin, thereby ensuring regular insulin expression in vivo. Mesoscopic simulation results manifest that the diffusion coefficient of insulin in hyaluronic acid (HA) solution is greater than that of the polyvinyl alcohol (PVA) system. Meanwhile, through the study of insulin centroid trajectory, we have claimed two different diffusion mechanisms of insulin in polymer solution: The movement of insulin in the HA and water solution follows the Brownian motion rule. In comparison, the hopping effect of insulin has been observed in the PVA solution due to poor intermolecular affinity as well as lower polymer water solubility. By summarizing different diffusion mechanisms, this study can provide theoretical guidance for preparing insulin-loaded dissolvable MNs.

Mesoscopic Simulation for the Effect of Cross-Linking Reactions on the Drug Diffusion Properties in Microneedles.

The drug diffusion issue in microneedles is the focus of its medical application. It will not only affect the distribution of drugs in the needle body but will also have an impact on the drug release performance of the microneedle. The utilization of cross-linked polymer materials to obtain the drug diffusion control has been experimentally verified as a feasible method. However, the mechanism research on the molecular level is still incomplete. In this study, the dissipative particle dynamics (DPD) simulation has been applied to study the effect of the cross-linking reaction on drug diffusion in hyaluronic acid microneedles. We have discovered that when the cross-linking degree reaches 90%, the diffusion coefficient of the drug is 6.45 times lower than that of the uncross-linked system. The main reason for the decline in drug diffusion ability is that the cross-linking reaction varies the conformation of the polymer. The amplification in the cross-linking degree makes the polymer coils more compact and approach each other, finally forming a continuously distributed cross-linked network, which reduces its degradation rate in the body. Simultaneously, these cross-linked networks can also hinder the interaction of soluble drugs with water, thereby preventing the premature release of drugs. The simulation results are consistent with the data collected in the previous microneedle experiment. This work will be an extension of DPD simulation in the application of biological materials.

Quantum teleportation of multiple degrees of freedom of a single photon.

Quantum teleportation provides a 'disembodied' way to transfer quantum states from one object to another at a distant location, assisted by previously shared entangled states and a classical communication channel. As well as being of fundamental interest, teleportation has been recognized as an important element in long-distance quantum communication, distributed quantum networks and measurement-based quantum computation. There have been numerous demonstrations of teleportation in different physical systems such as photons, atoms, ions, electrons and superconducting circuits. All the previous experiments were limited to the teleportation of one degree of freedom only. However, a single quantum particle can naturally possess various degrees of freedom--internal and external--and with coherent coupling among them. A fundamental open challenge is to teleport multiple degrees of freedom simultaneously, which is necessary to describe a quantum particle fully and, therefore, to teleport it intact. Here we demonstrate quantum teleportation of the composite quantum states of a single photon encoded in both spin and orbital angular momentum. We use photon pairs entangled in both degrees of freedom (that is, hyper-entangled) as the quantum channel for teleportation, and develop a method to project and discriminate hyper-entangled Bell states by exploiting probabilistic quantum non-demolition measurement, which can be extended to more degrees of freedom. We verify the teleportation for both spin-orbit product states and hybrid entangled states, and achieve a teleportation fidelity ranging from 0.57 to 0.68, above the classical limit. Our work is a step towards the teleportation of more complex quantum systems, and demonstrates an increase in our technical control of scalable quantum technologies.