Exosomes are lipid bilayer membrane vesicles and are emerging as competent nanocarriers for drug delivery. The clinical translation of exosomes faces many challenges such as massive production, ...standard isolation, drug loading, stability and quality control. In recent years, artificial exosomes are emerging based on nanobiotechnology to overcome the limitations of natural exosomes. Major types of artificial exosomes include 'nanovesicles (NVs)', 'exosome-mimetic (EM)' and 'hybrid exosomes (HEs)', which are obtained by top-down, bottom-up and biohybrid strategies, respectively. Artificial exosomes are powerful alternatives to natural exosomes for drug delivery. Here, we outline recent advances in artificial exosomes through nanobiotechnology and discuss their strengths, limitations and future perspectives. The development of artificial exosomes holds great values for translational nanomedicine.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern ...globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans.
We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed.
Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor.
A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.
Extracellular vesicles (EVs) are nanovesicles involved in multiple biological functions. Small EVs (sEVs) are emerging as therapeutics and drug delivery systems for their contents, natural carrier ...properties, and nanoscale size. Despite various clinical application potentials, little is known about the effects of storage conditions on sEVs for functional analysis and therapeutic use. In this study, we evaluated the stability of sEVs stored at 4 °C, −20 °C, and −80 °C up to 28 days and compared them to fresh sEVs. Also, the effect of freeze-thawing circles on the quantity of sEVs was assessed. We found that different storage temperatures, along with shelf life, impact the stability of sEVs when compared to freshly isolated sEVs. Storage changes the size distribution, decreases quantity and contents, and impacts cellular uptake and biodistribution of sEVs. For functional studies, isolated sEVs are suggested to be analyzed freshly or stored at 4 °C or −20 °C for short-term preservation depending on study design; but −80 °C condition would be more preferable for long-term preservation of sEVs for therapeutic application.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In recent years, person re-identification (ReID) has received much attention since it is a fundamental task in intelligent surveillance systems and has widespread application prospects in numerous ...fields. Given an image of a pedestrian captured from one camera, the task is to identify this pedestrian from the gallery set captured by other multiple cameras. It is a challenging issue since the appearance of a pedestrian may suffer great changes across different cameras. The task has been greatly boosted by deep learning technology. There are mainly six types of deep learning-based methods designed for this issue, i.e. identification deep model, verification deep model, distance metric-based deep model, part-based deep model, video-based deep model and data augmentation-based deep model. In this paper, we first give a comprehensive review of current six types of deep learning methods. Second, we present the detailed descriptions of existing person ReID datasets. Then, some state-of-the-art performances of methods over recent years on several representative ReID datasets are summarized. Finally, we conclude this paper and discuss the future directions of the person ReID.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To help doctors and patients evaluate lumbar intervertebral disc degeneration (IVDD) accurately and efficiently, we propose a segmentation network and a quantitation method for IVDD from T2MRI. A ...semantic segmentation network (BianqueNet) composed of three innovative modules achieves high-precision segmentation of IVDD-related regions. A quantitative method is used to calculate the signal intensity and geometric features of IVDD. Manual measurements have excellent agreement with automatic calculations, but the latter have better repeatability and efficiency. We investigate the relationship between IVDD parameters and demographic information (age, gender, position and IVDD grade) in a large population. Considering these parameters present strong correlation with IVDD grade, we establish a quantitative criterion for IVDD. This fully automated quantitation system for IVDD may provide more precise information for clinical practice, clinical trials, and mechanism investigation. It also would increase the number of patients that can be monitored.
Pancreatic cancer remains one of the most highly lethal diseases with very poor prognosis. Gemcitabine (GEM) is the first-line chemotherapeutic drug for pancreatic cancer treatment but is associated ...with significant side effects when administered systemically. Exosomes have emerged as attractive candidates for drug delivery for their high delivery efficiency and biocompatibility. Here, GEM was loaded into autologous exosomes to formulate ExoGEM for targeted chemotherapy of pancreatic cancer. Autologous exosomes facilitate cellular uptake of GEM and contributed to significantly increased cytotoxic effect of GEM, while heterologous cellular uptake showed less efficiency. Autologous exosomes showed targeting ability to pancreatic cancer in biodistribution study, and GEM concentration in tumor site was increased via ExoGEM delivery. ExoGEM treatment, in tumor-bearing mice, significantly suppressed tumor growth, with prolonged survival in a dose-response manner, but caused minimal damage to normal tissues. More importantly, tumors in several mice treated with ExoGEM were disappeared without recurrence. Autologous exosomes are safe and effective vehicles for targeted delivery of GEM against pancreatic cancer. This delivery strategy may have implications for personalized chemotherapy of pancreatic cancer.
Exosomes are efficient delivery vehicles in intracellular communication. Moreover, potential tropism of autologous exosomes to the tumor microenvironment make them competitive delivery vehicles. The use of cancer-derived exosomes for drug delivery and superior targeting efficacy and enhanced anticancer efficacy of therapeutics have been evidenced. Gemcitabine is a mainstay for pancreatic treatment. However, poor cellular uptake and low targeting effects of gemcitabine often lead to severe systemic toxicity. Therefore, to overcome this limitation, we herein loaded gemcitabine into autologous pancreatic cancer-derived exosomes for the targeted chemotherapy of pancreatic cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Targeted drug delivery to the glioblastoma (GBM) overcoming blood-brain barrier (BBB) has been challenging. Exosomes are promising vehicles for brain tumor drug delivery, but the production and ...purification hinder its application for nanomedicine. Besides, the formation of protein corona (PC) may affect the behaviour of nanocarriers. Here, multifunctional exosomes-mimetics (EM) are developed and decorated with angiopep-2 (Ang) for enhancing GBM drug delivery by manipulating PC. Docetaxel (DTX)-loaded EM with Ang modification (DTX@Ang-EM) show less absorption of serum proteins and phagocytosis by macrophages. Ang-EM show enhanced BBB penetration ability and targeting ability to the GBM. Ang-EM-mediated delivery increase the concentration of DTX in the tumor area. The multifunctional DTX@Ang-EM exhibits significant inhibition effects on orthotopic GBM growth with reduced side effects of the chemotherapeutic. Findings from this study indicate that the developed DTX@Ang-EM provide a new strategy for targeted brain drug delivery and GBM therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Dense extracellular matrix (ECM) in the tumor stroma has been a challenge for drug penetration and cytotoxic T lymphocyte (CTL) infiltration. Neutrophil elastase (NE), in surface‐bound form, can ...destruct ECM rapidly, may be used for remodeling tumor ECM, and overcoming tumor stromal barrier. Focusing on elastosis in triple‐negative breast tumor, biomimetic liposomes with chimeric cell membrane proteins (LMP) are developed and for the first time, it is demonstrated that LMP with surface‐bound elastase (NE‐LMP) can target and degrade ECM effectively in tumor stroma, with minimal toxicity to normal tissues. The pretreatment of NE‐LMP increases the accumulation of chemotherapeutics at the tumor site and enhances antitumor effects. Also, NE‐LMP facilitates CTL infiltration in tumors and exhibits enhanced chemo‐immunotherapy in combination of PD‐1 immune checkpoint blockade treatment in orthotopic 4T1 tumor‐bearing mice, with significantly prolonged survival. Moreover, the remodeling of the tumor ECM by NE‐LMP shows inhibiting effects on metastasis in the lung. Findings from this study suggest that NE‐LMP holds promise for enhancing deep penetration of drug and infiltration of CTL in desmoplastic tumor by effective degrading ECM in the tumor stroma.
The dense ECM in stroma of triple‐negative breast tumors limits penetration of chemotherapeutics and infiltration of cytotoxic T lymphocytes into the tumor. In this study, biomimetic liposomes with membrane proteins and surface‐bound elastase (NE‐LMP) are developed for targeted remodeling of tumor ECM. The combined treatment of NE‐LMPs with chemotherapeutics and PD‐1 immune checkpoint blockade exhibit enhanced tumor chemo‐immunotherapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Previous studies reveal that hydrogen sulphide (H2S) exerts neuroprotection against neurotoxin‐induced Parkinson's disease (PD), but the underlying mechanism remains elusive. The present study was ...aimed to investigate whether H2S inhibits neuronal apoptosis of substantia nigra with the involvement of autophagy via promoting leptin signalling in 6‐hydroxydopamine (6‐OHDA)‐induced PD rats. In this study, neuronal apoptosis was analysed by TUNEL staining, the activity of caspase‐3 was measured by Caspase‐3 fluorometric assay kit, the expressions of Bax, Bcl‐2, Beclin‐1, LC3II, P62 and leptin were determined by Western blot analysis, and the numbers of autophagosomes and autolysosomes were assessed by transmission electron microscopy. Results showed that NaHS, a donor of exogenous H2S, mitigates 6‐OHDA‐induced the increases in the numbers of TUNEL‐positive cells, the activity of caspase‐3 and the expression of Bax, and attenuates 6‐OHDA‐induced a decrease in the expression of Bcl‐2 in substantia nigra of rats. In addition, 6‐OHDA enhanced the expressions of Beclin‐1, LC3‐II and P62, increased the number of autophagosomes, and decreased the number of autolysosomes in the substantia nigra, which were also blocked by administration of NaHS. Furthermore, NaHS reversed 6‐OHDA‐induced the down‐regulation of leptin expression in the substantia nigra, and treatment with leptin‐OBR, a blocking antibody of leptin receptor, attenuated the inhibition of NaHS on neuronal apoptosis and the improvement of NaHS on the blocked autophagic flux in substantia nigra of 6‐OHDA‐treated rats. Taken together, these results demonstrated that H2S attenuates neuronal apoptosis of substantia nigra depending on restoring impaired autophagic flux through up‐regulating leptin signalling in PD.
H2S alleviates the neuronal apoptosis of substantia nigra by restoring impaired autophagy flux in 6‐OHDA‐subjected PD rats, while the down‐regulation the expression of leptin by leptin‐OBR, a blocking antibody, remarkably reversed the protective role of H2S on neuronal apoptosis by blocking the restorative effect of H2S on impaired autophagy flux in the substantia nigra of 6‐OHDA‐subjected PD rats.
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DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
China faces the greatest challenge from stroke in the world. According to results from the Global Burden of Disease Study 2019, there were 3.94 million new stroke cases, 28.76 million prevalent cases ...and 2.19 million deaths due to stroke in China in 2019. Furthermore, stroke is also the leading cause of disability-adjusted life-year (DALY) in China, the number of DALYs reached 45.9 million in 2019. Several recent large-scale epidemiological surveys have updated the data on pre-existing conditions contributed to stroke. The age-adjusted prevalence of overweight among Chinese adults aged 18–69 years was 34.4%, and the prevalence of obesity was 16.8% in 2018. 50.9% of Chinese adults ≥18 years of age without history of hypertension had prehypertension in 2018. The weighted prevalence of hypertension in adults was 27.5% in 2018. The weighted prevalence of total diabetes and pre-diabetes diagnosed by the American Diabetes Association criteria were 12.8% and 35.2%, respectively, among Chinese adults ≥18 years of age in 2017. The weighted atrial fibrillation prevalence was 1.8% among Chinese adults ≥45 years of age and equates to being present in an estimated 7.9 million people in China. Data from 1672 tertiary public hospitals in the Hospital Quality Monitoring System (HQMS) showed that 3 411 168 stroke cases were admitted during 2019. Of those, 2 818 875 (82.6%) were ischaemic strokes (ISs), 485 474 (14.2%) were intracerebral haemorrhages (ICHs), 106 819 (3.1%) were subarachnoid haemorrhages (SAHs). The average age was 66 years old, and 59.6% were male. A total of 1379 (<0.1%), 2604 (0.5%), 1250 (1.2%) paediatric strokes (age <18 years) were identified among IS, ICH and SAH, respectively. Over one-third (1 231 519 (36.1%)) of the stroke cases were covered by urban resident basic medical insurance, followed by urban employee basic medical insurance (891 103 (26.1%)) and new rural cooperative medical schema (543 108 (15.9%)). The leading risk factor was hypertension (57.3% for IS, 69.9% for ICH and 44.1% for SAH), and the leading comorbidity was pneumonia or pulmonary infection (10.4% for IS, 34.6% for ICH and 29.7% for SAH). In-hospital death/discharge against medical advice rate was 8.5%, ranging from 6.0% for IS to 20.6% for SAH. The median and IQR of length of stay was 9.0 (6.0–13.0) days, ranging from 10.0 (7.0–13.0) in IS to 14.0 (8.0–22.0) in ICH. Similar data from 2847 secondary public hospitals or private hospitals in the HQMS were also reported. Data from HQMS showed that higher proportions of interprovincial admission to other provinces were seen in Inner Mongolia, Anhui, Tibet and Beijing. Higher proportions of interprovincial admission from other provinces were seen in Beijng, Tianjin, Shanghai and Ningxia. Data from 323 601 strokes from 1337 hospitals in the Chinese Stroke Center Alliance during 2019 demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS, ICH and SAH were 0.78±0.20, 0.69±0.27 and 0.60±0.31, respectively.
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