Unimolecular Self-Assembled Hemicyanine-Oleic Acid Conjugate Acts as a Novel Succinate Dehydrogenase Inhibitor to Amplify Photodynamic Therapy and Eliminate Cancer Stem Cells

Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells(CSCs).However,the innate drawbacks,including short lifetime and diffusion distance of reactive oxygen species and hypoxia within solid tumors,have become bottlenecks for clinical applications of photodynamic therapy.Here,we develop a mitochondria-targeting hemicyanine-oleic acid conjugate(CyOA),which can self-assemble into supramolecular nanoparticles(NPs)without any exogenous excipients.CyOA is also shown for targeting the mitochondrial complex II protein succinate dehydrogenase to inhibit oxidative phosphorylation and reverse tumor hypoxia,resulting in 50.4-fold higher phototoxicity against breast cancer stem cells(BCSCs)compared to SO_(3)-CyOA NPs that cannot target to mitochondria.In 4T1 and BCSC tumor models,CyOA NPs achieve higher tumor inhibition and less lung metastasis nodules compared to the clinically used photosensitizer Hiporfin.This study develops a self-assembled small molecule that can serve as both oxidative phosphorylation inhibitor and photosensitizer for eradication of CSCs and treatment of solid tumors.

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.

What makes residents participate in the rural toilet revolution?

Recent data reveals a staggering reality:as of 2020,approximately 3.6 billion individuals across the globe remain devoid of proper sanitation services[1].Worldwide governmental and nongovernmental organisations are dedicatedly engaged in the arduous task of ameliorating living standards by providing secure sanitation facilities.Nevertheless,a recurring challenge persists,with these initiatives frequently encountering setbacks,especially in rural areas.

Utilization of MSWI fly ash as partial cement or sand substitute with focus on cementing efficiency and health risk assessment

The strength of cement substituted mortar decreases with the increase in fly ash amount,whereas the strength increases when the fly ash is blended as sand substitute.A mortar with highest strength(compressive strength=30.2 Mpa;flexural strength=7.0 Mpa)was obtained when the sand replacement ratio was 0.75%.The k value(cementing efficiency)of fly ash varied between 0.36 and 0.15 for the fly ash fraction in binder between 5%and 25%.The k values of fly ash used for sand replacement were all significantly above that used for cement substitution.The macropores assigned to the gaps between particles decreased when the fly ash was used as sand replacement,providing an explanation for the strength enhancement.The waste-extraction procedure(toxicity-sulphuric acid and nitric acid method(HJ/T 299-2007))was used to evaluate metal leaching,indicating the reuse possibility of fly ash blended mortar.For the mortar with the mass ratio of fly ash to binder of 0.5%,the carcinogenic risks(CR)and non-carcinogenic hazard quotient(HQ)in sensitive scenario for blended mortar utilization were 9.66 x 10 and 0.06,respectively;these results were both lower than the threshold values,showing an acceptable health risk.The CR(9.89 x 105)and HQ(3.89)of the nonsensitive scenario for fly ash treatment exceeded the acceptable threshold values,indicating health risks to onsite workers.The main contributor to the carcinogenic and non-carcinogenic risk is Cr and Cd,respectively.The CR and HQ from inhalation was the main route of heavy metal exposure.

Assessment of metals in dry-toilet collected matters from suburban areas of Ulaanbaatar, Mongolia, using biosolids quality guidelines and potential ecological risk index

Dry-toilet collected matter （DCM） from traditional dry-toilet pits are a potential health and ecological risk in suburban areas. In this study, the characteristics of metals in DCMs from suburban areas of Ulaanbaatar were surveyed. The results indicate that DCMs contain a high percentage of organic matter and nutrients, while heavy metals are at low levels, which shows good agricultural potential. The concentration ranges of Cr, Cu, Hg, Ni, Pb, and Zn were 11±5, 46±9, 0.08±0.05, 9±3, 17±9, and 338±86mg·kg^-1, respectively. The concentration of Cd was below 0.5 mg.kgl, and a high positive relation was shown between chromium and nickel concentrations. The heavy metals in DCMs were safe for land application but Zn in DCMs was close to the effects range median （ERM）, which is toxic in some cases, such as amphipod bioassays. Because it is mandatory to treat DCMs to reduce pathogens, in the case of heavy metal enrichment and agricultural reuse, composting or pyrolysis are better choices than incinera- tion. Compared with global soil background values, the heavy metals in DCMs showed a low level of ecological risk, but a medium level when compared with Mongolian soil background values. The ecological risk of six heavy metals was in the descending order Hg 〉 Cu 〉 Zn 〉 Pb 〉 Ni 〉 Cr and the contribution rate of Hg exceeded 60%.

Bibliometric analysis of China’s contribution to the knowledge system of cerebrovascular intervention

Background:Cerebrovascular disease has become the leading cause of death in China.The purpose of this article is to analyze China’s contribution to the interventional treatment of cerebrovascular diseases.Methods:Bibliometric analysis was used for evaluating the quantity,quality,research hotspots,and cooperation network of publications regarding interventional treatment of cerebrovascular diseases from China.These articles were searched from the database of Web of Science Core Collection.The authors,publication years,citation times,regions,and source journals of retrieved articles were recorded.Network analysis and visualization were performed on Citespace5.6.Results:From 1991 to 2019,a total of 5052 articles regarding cerebrovascular intervention were contributed by Chinese researchers.The number of publications from China grew fastest annually in the latest 5 years among countries.These publications were cited 61,216 times,with 12.12 average citations per item.The h-index was 82.Affiliated hospitals of Capital Medical University contributed most articles.Cerebral ischemia and intracranial aneurysm were the most popular keywords over the three decades.The timeline view of keywords indicated that cerebral ischemia always was a hot spot.Stent techniques were the main treatment tools and still had a strong developing trend.Neural regeneration and neuroprotection were the hot topics of basic researches related to cerebrovascular intervention.Conclusions:The number of researches grows rapidly in China over the decades,but the quality still needs further improvement.The increasing contributions of Chinese researchers to the global knowledge system of cerebrovascular intervention are promising.

Development of fusiform aneurysms induced by topical application of elastase in a rabbit model

Background: Research on the etiology and pathophysiology of fusiform aneurysm has been impeded due to the inability to collect fusiform aneurysm specimens. We aim to resolve this through the development of a novel fusiform aneurysm model in rabbits.Methods: Sixty New Zealand White rabbits were divided into ten groups (n = 6 per group): groups A, B, C, D, E and groups a, b, c, d, e. Elastase, at a concentration of 0, 0.5, 1, 2.5 and 5 U/μL respectively was administered to each rabbit to incubate their carotid arteries. Three weeks later, angiography, histomorphometry,immunohistochemistry and immunofluorescent were performed.Results: Heparin administration is indispensable. No thrombosis was observed in groups A, B, C, D and E, whereas,increased thromboembolism occurred in groups a, b, c, d and e. Based on the size and wall thickness of aneurysms specimens, 5 U/μL was the optimal concentration of elastase to induce fusiform aneurysms. At 5 U/μL, the intraluminal carotid diameter increased significantly from 2.50 ± 0.32 mm to 3.11 ± 0.55 mm (p < 0.01). The wall thickness significantly reduced from 176.0 ± 39.8 μm to 39.7 ± 14.6 μm (p < 0.01) post aneurysm induction. The histolopathological evaluation revealed the elastic lamina and the smooth muscle cell''''s lamina were markedly attenuated and the intimal endothelial lamina became thin or even absent.Conclusions: Our research demonstrates that intracranial fusiform aneurysm could be modeled in rabbit carotid artery adventitia incubation by porcine pancreatic elastase.

Targeting cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy

Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on CAFs.After systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and photothermal-therapies.Thus,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their survival.As a result,the tumor growth was significantly inhibited in 4T1 tumors.The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.