Dual stimuli-activatable versatile nanoplatform for photodynamic therapy and chemotherapy of triple-negative breast cancer

Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.

Defective arginine metabolism impairs mitochondrial homeostasis in Caenorhabditis elegans

Arginine catabolism involves enzyme-dependent reactions in both mitochondria and the cytosol,defects in which may lead to hyperargininemia,a devastating developmental disorder.It is largely unknown if defective arginine catabolism has any effects on mitochondria.Here we report that normal arginine catabolism is essential for mitochondrial homeostasis in Caenorhabditis elegans.Mutations of the arginase gene argn-1 lead to abnormal mitochondrial enlargement and reduced adenosine triphosphate(ATP)production in C elegans hypodermal cells.ARGN-1 localizes to mitochondria and its loss causes arginine accumulation,which disrupts mitochondrial dynamics.Heterologous expression of human ARGl or ARG2 rescued the mitochondrial defects of argn-1 mutants.Importantly,genetic inactivation of the mitochondrial basic amino acid transporter SLC-25A29 or the mitochondrial glutamate transporter SLC-25A18.1 fully suppressed the mitochondrial defects caused by argn-1 mutations.These findings suggest that mitochondrial damage probably contributes to the pathogenesis of hyperargininemia and provide clues for developing therapeutic treatments for hyperargininemia.

A pair of transporters controls mitochondrial Zn^(2+) levels to maintain mitochondrial homeostasis

Zn^(2+)is required for the activity of many mitochondrial proteins,which regulate mitochondrial dynamics,apoptosis and mitophagy.However,it is not understood how the proper mitochondrial Zn^(2+)level is achieved to maintain mitochondrial homeostasis.Using Caenorhabditis elegans,we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn^(2+).We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn^(2+)exporter.Loss of SLC-30A9 leads to mitochondrial Zn^(2+)accumulation,which damages mitochondria,impairs animal development and shortens the life span.We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn^(2+)import.Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn^(2+)accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9.Moreover,we reveal that the endoplasmic reticulum contains the Zn^(2+)pool from which mitochondrial Zn^(2+)is imported.These findings establish the molecular basis for controlling the correct mitochondrial levels for normal mitochondrial structure and functions.

Mercury mass flow in iron and steel production process and its implications for mercury emission control

The iron and steel production process is one of the predominant anthropogenic sources of atmospheric mercury emissions worldwide. In this study, field tests were conducted to study mercury emission characteristics and mass flows at two iron and steel plants in China. It was found that low-sulfur flue gas from sintering machines could contribute up to41% of the total atmospheric mercury emissions, and desulfurization devices could remarkably help reduce the emissions. Coal gas burning accounted for 17%–49% of the total mercury emissions, and therefore the mercury control of coal gas burning, specifically for the power plant burning coal gas to generate electricity, was significantly important. The emissions from limestone and dolomite production and electric furnaces can contribute29.3% and 4.2% of the total mercury emissions from iron and steel production. More attention should be paid to mercury emissions from these two processes. Blast furnace dust accounted for 27%–36% of the total mercury output for the whole iron and steel production process. The recycling of blast furnace dust could greatly increase the atmospheric mercury emissions and should not be conducted. The mercury emission factors for the coke oven,sintering machine and blast furnace were 0.039–0.047 g Hg/ton steel, and for the electric furnace it was 0.021 g Hg/ton steel. The predominant emission species was oxidized mercury, accounting for 59%–73% of total mercury emissions to air.

A hydroxyl radical detection system using gas expansion and fast gating laser-induced fluorescence techniques

An OH radical measurement instrument based on Fluorescence Assay by Gas Expansion（FAGE）has been developed in our laboratory.Ambient air is introduced into a low-pressure fluorescence cell through a pinhole aperture and irradiated by a dye laser at a high repetition rate of 8.5 k Hz.The OH radical is both excited and detected at 308 nm using A-X（0,0）band.To satisfy the high efficiency needs of fluorescence collection and detection,a 4-lens optical system and a self-designed gated photomultiplier（PMT）is used,and gating is actualized by switching the voltage applied on the PMT dynodes.A micro channel photomultiplier（MCP）is also prepared for fluorescence detection.Then the weak signal is accumulated by a photon counter in a specific timing.The OH radical excitation spectrum range in the wavelength of 307.82–308.2 nm is detected and the excited line for OH detection is determined to be Q1（2）line.The calibration of the FAGE system is researched by using simultaneous photolysis of H2O and O2.The minimum detection limit of the instrument using gated PMT is determined to be 9.4×10~5molecules/cm^3,and the sensitivity is 9.5×10^（-7）cps/（OH·cm^（-3））,with a signal-to-noise ratio of 2 and an integration time of 60 sec,while OH detection limit and the detection sensitivity using MCP is calculated to be 1.6×10~5molecules/cm^3and 2.3×10^（-6）cps/（OH·cm^（-3））.The laboratory OH radical measurement is carried out and results show that the proposed system can be used for atmospheric OH radical measurement.

Measurement of tropospheric HO_(2) radical using fluorescence assay by gas expansion with low interferences

An instrument to detect atmospheric HO_(2) radicals using fluorescence assay by gas expansion(FAGE)technique has been developed.HO_(2) is measured by reaction with NO to form OH and subsequent detection of OH by laser-induced fluorescence at low pressure.The system performance has been improved by optimizing the expansion distance and pressure,the influence factors of HO_(2) conversion efficiency are also studied.The interferences of RO_(2) radicals were investigated by determining the conversion efficiency of RO_(2) to OH during the measurement of HO_(2).The dependence of the conversion of HO_(2) on NO concentration was investigated,and low HO_(2) conversion efficiency was selected to realize the ambient HO_(2) measurement,where the conversion efficiency of RO_(2) derived by propane,ethene,isoprene and methanol to OH has been reduced to less than 6%in the atmosphere.Furthermore,no significant interferences from PM_(2.5) and NO were found in the ambient HO_(2) measurement.The detection limits for HO_(2)(S/N=2)are estimated to 4.8×10^5 cm^-3 and 1.1×10^6 cm^-3(ρHO_(2)=20%)under night and noon conditions,with 60 sec signal integration time.The instrument was successfully deployed during STORM-2018 field campaign at Shenzhen graduate school of Peking University.The concentration of atmospheric HOx radical and the good correlation of OH with j(O1D)was obtained here.The diurnal variation of HOx concentration shows that the OH maximum concentration of those days is about 5.3×10^6 cm^-3 appearing around 12:00,while the HO_(2) maximum concentration is about 4.2×10^8 cm^-3 appearing around 13:30.