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Sensitive probing of temperature variations on nanometre scales is an outstanding challenge in many areas of modern science and technology. In particular, a thermometer capable of subdegree temperature resolution over a large range of temperatures as well as integration within a living system could provide a powerful new tool in many areas of biological, physical and chemical research. Possibilities range from the temperature-induced control of gene expression and tumour metabolism to the cell-selective treatment of disease and the study of heat dissipation in integrated circuits. By combining local light-induced heat sources with sensitive nanoscale thermometry, it may also be possible to engineer biological processes at the subcellular level. Here we demonstrate a new approach to nanoscale thermometry that uses coherent manipulation of the electronic spin associated with nitrogen-vacancy colour centres in diamond. Our technique makes it possible to detect temperature variations as small as 1.8 mK (a sensitivity of 9 mK Hz(-1/2)) in an ultrapure bulk diamond sample. Using nitrogen-vacancy centres in diamond nanocrystals (nanodiamonds), we directly measure the local thermal environment on length scales as short as 200 nanometres. Finally, by introducing both nanodiamonds and gold nanoparticles into a single human embryonic fibroblast, we demonstrate temperature-gradient control and mapping at the subcellular level, enabling unique potential applications in life sciences.

This feature article delves into the realm of α-L-threose nucleic acid (TNA), an artificial nucleic acid analog characterized by a backbone comprising an unconventional four-carbon sugar, α-L-threose, with phosphodiester linkages connecting at the 2' and 3' vicinal positions of the sugar ring. Within this article, we encapsulate the potential, progress, current state of the art, and persisting challenges within TNA research. Kicking off with a historical overview of xeno nucleic acids (XNAs), the discussion transitions to the compelling attributes and structure-property relationships of TNAs as advanced tools when contrasted with natural nucleic acids. Noteworthy aspects such as their advantageous spatial arrangements of functional groups around the sugar ring, stable Watson-Crick base pairing, high binding affinity, biostability, biocompatibility, and in vivo bio-safety are highlighted. Moreover, the narrative unfolds the latest advancements in chemical and biological methodologies for TNA synthesis, spanning from monomer and oligomer synthesis to polymerization, alongside cutting-edge developments in enzyme engineering aimed at bolstering large-scale TNA synthesis for in vitro selection initiatives. The article sheds light on the evolution of TNA aptamers over time, expounding on the tools and selection techniques engineered to unearth superior binding aptamers and TNA catalysts. Furthermore, the article accentuates the recent applications of TNAs across diverse domains such as molecular detection, immunotherapy, gene therapy, synthetic biology, and molecular computing. In conclusion, we summarize the key aspects of recent TNA research, address persisting gaps and challenges, and provide crucial insights and future perspectives in the dynamic domain of TNA research.

Triple-negative breast cancer (TNBC) remains a significant challenge in terms of treatment, with limited efficacy of chemotherapy due to side effects and acquired drug resistance. In this study, a threose nucleic acid (TNA)-mediated antisense approach is employed to target therapeutic Akt genes for TNBC therapy. Specifically, two new TNA strands (anti-Akt2 and anti-Akt3) are designed and synthesized that specifically target Akt2 and Akt3 mRNAs. These TNAs exhibit exceptional enzymatic resistance, high specificity, enhance binding affinity with their target RNA molecules, and improve cellular uptake efficiency compared to natural nucleic acids. In both 2D and 3D TNBC cell models, the TNAs effectively inhibit the expression of their target mRNA and protein, surpassing the effects of scrambled TNAs. Moreover, when administered to TNBC-bearing animals in combination with lipid nanoparticles, the targeted anti-Akt TNAs lead to reduced tumor sizes and decreased target protein expression compared to control groups. Silencing the corresponding Akt genes also promotes apoptotic responses in TNBC and suppresses tumor cell proliferation in vivo. This study introduces a novel approach to TNBC therapy utilizing TNA polymers as antisense materials. Compared to conventional miRNA- and siRNA-based treatments, the TNA system holds promise as a cost-effective and scalable platform for TNBC treatment, owing to its remarkable enzymatic resistance, inexpensive synthetic reagents, and simple production procedures. It is anticipated that this TNA-based polymeric system, which targets anti-apoptotic proteins involved in breast tumor development and progression, can represent a significant advancement in the clinical development of effective antisense materials for TNBC, a cancer type that lacks effective targeted therapy., (© 2024 The Author(s). Small Methods published by Wiley‐VCH GmbH.)

Nanodiamonds (NDs) are considered promising delivery platforms, but inaccurate and uncontrolled release of drugs at target sites is the biggest challenge of NDs in precision medicine. This study presents the development of phototriggerable ND-based drug delivery systems, utilizing ortho -nitrobenzyl ( o -NB) molecules as photocleavable linkers between drugs and nanocarriers. UV irradiation specifically cleaved o -NB molecules and then was followed by releasing antisense oligonucleotides from ND-based carriers in both buffer and cellular environments. This ND system carried cell nonpermeable therapeutic agents for bypassing lysosomal trapping and degradation. The presence of fluorescent nitrogen-vacancy centers also allowed NDs to serve as biological probes for tracing in cells. We successfully demonstrated phototriggered release of antisense oligonucleotides from ND-based nanocarriers, reactivating their antisense functions. This highlights the potential of NDs, photocleavable linkers, and light stimuli to create advanced drug delivery systems for controlled drug release in disease therapy, opening possibilities for targeted and personalized treatments.

The human genome's nucleotide sequence variation, such as single nucleotide mutations, can cause numerous genetic diseases. However, detecting nucleic acids accurately and rapidly in complex biological samples remains a major challenge. While natural deoxyribonucleic acid (DNA) has been used as biorecognition probes, it has limitations like poor specificity, reproducibility, nuclease-induced enzymatic degradation, and reduced bioactivity on solid surfaces. To address these issues, we introduce a stable and reliable biosensor called graphene oxide (GO)- threose nucleic acid (TNA). It comprises chemically modified TNA capture probes on GO for detecting and imaging target nucleic acids in vitro and in vivo, distinguishing single nucleobase mismatches, and monitoring dynamic changes in target microRNA (miRNA). By loading TNA capture probes onto the GO substrate, the GO-TNA sensing platform for nucleic acid detection demonstrates a significant 88-fold improvement in the detection limit compared to TNA probes alone. This platform offers a straightforward preparation method without the need for costly and labor-intensive isolation procedures or complex chemical reactions, enabling real-time analysis. The stable TNA-based GO sensing nanoplatform holds promise for disease diagnosis, enabling rapid and accurate detection and imaging of various disease-related nucleic acid molecules at the in vivo level. STATEMENT OF SIGNIFICANCE: The study's significance lies in the development of the GO-TNA biosensor, which addresses limitations in nucleic acid detection. By utilizing chemically modified nucleic acid analogues, the biosensor offers improved reliability and specificity, distinguishing single nucleobase mismatches and avoiding false signals. Additionally, its ability to detect and image target nucleic acids in vivo facilitates studying disease mechanisms. The simplified preparation process enhances practicality and accessibility, enabling real-time analysis. The biosensor's potential applications extend beyond healthcare, contributing to environmental analysis and food safety. Overall, this study's findings have substantial implications for disease diagnosis, biomedical research, and diverse applications, advancing nucleic acid detection and its impact on various fields., Competing Interests: Declaration of competing interest Pik Kwan Lo, Pan Li, Ling Sum Liu and Fei Wang are listed as inventors on a U. S. patent application by City University of Hong Kong describing the construction of GO-TNA biosensors and their application in biomolecule detection. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The neuroinflammatory responses following ischemic stroke cause irreversible nerve cell death. Cell free-double strand DNA (dsDNA) segments from ischemic tissue debris are engulfed by microglia and sensed by their cyclic GMP-AMP synthase (cGAS), which triggers robust activation of the innate immune stimulator of interferon genes (STING) pathway and initiate the chronic inflammatory cascade. The decomposition of immunogenic dsDNA and inhibition of the innate immune STING are synergistic immunologic targets for ameliorating neuroinflammation. To combine the anti-inflammatory strategies of STING inhibition and dsDNA elimination, we constructed a DNase-mimetic artificial enzyme loaded with C-176. Nanoparticles are self-assembled by amphiphilic copolymers (P[CL 35 - b -(OEGMA 20.7 - co -NTAMA 14.3 )]), C-176, and Ce 4+ which is coordinated with nitrilotriacetic acid (NTA) group to form corresponding catalytic structures. Our work developed a new nano-drug that balances the cGAS-STING axis to enhance the therapeutic impact of stroke by combining the DNase-memetic Ce 4+ enzyme and STING inhibitor synergistically. In conclusion, it is a novel approach to modulating central nervus system (CNS) inflammatory signaling pathways and improving stroke prognosis., Competing Interests: The authors affirm that they have no known financial or interpersonal conflicts that could have appeared to have an impact on the research presented in this study., (© 2023 The Authors.)

Nanodiamonds (NDs) are a remarkable class of carbon-based nanoparticles in nanomedicine which have recently become a hot topic of research due to their unique features including functionalization versatility, tunable opto-magnetic properties, chemical stability, minimal cytotoxicity, high affinity to biomolecules and biocompatibility. These attractive features make NDs versatile tools for a wide range of biologically relevant applications. In this feature article, we discuss the opto-magnetic properties of negatively charged nitrogen vacancy (NV - ) centres in NDs as fluorescence probes. We further discuss the frequently used chemical methods for surface chemistry modification of NDs which are relevant for biomedical applications. The in vitro and in vivo biocompatibility of modified NDs is also highlighted. Subsequently, we give an overview of recent state-of-the-art biomedical applications of NDs as versatile tools for bioimaging and detection, and as targeting nanocarriers for chemotherapy, photodynamic therapy, gene therapy, antimicrobial and antiviral therapy, and bone tissue engineering. Finally, we pinpoint the main challenges for NDs in biomedical applications which lie ahead and discuss perspectives on future directions in advancing the field for practical applications and clinical translations.

In this study, we synthesized two phosphoramidites based on 2,7-bis-{4-nitro-8-[3-(2-propyl)-styryl]}-9,9-bis-[1-(3,6-dioxaheptyl)]-fluorene (BNSF) and 4,4'-bis-{8-[4-nitro-3-(2-propyl)-styryl]}-3,3'-di-methoxybiphenyl (BNSMB) structures as visible light-cleavable linkers for oligonucleotide conjugation. In addition to the commercial ultraviolet (UV) photocleavable (PC) linker, the BNSMB linker was further applied as a building component to construct photoregulated DNA devices as duplex structures, which are functionalized with fluorophores and quenchers. Selective cleavage of PC and BNSMB is achieved in response to ultraviolet (UV) and visible light irradiations as two inputs, respectively. This leads to controllable dissociation of pieces of DNA fragments, which is followed by changes of fluorescence emission as signal outputs of the system. By tuning the number and position of the photocleavable molecules, fluorophores, and quenchers, various DNA devices were developed, which mimic the functions of Boolean logic gates and achieve logic operations in AND, OR, NOR, and NAND gates in response to two different wavelengths of light inputs. By sequence design, the photolysis products can be precisely programmed in DNA devices and triggered to release in a selective and/or sequential manner. Thus, this photoregulated DNA device shows potential as a wavelength-dependent drug delivery system for selective control over the release of multiple individual therapeutic oligonucleotide-based drugs. We believe that our work not only enriches the library of photocleavable phosphoramidites available for bioconjugation but also paves the way for developing spatiotemporal-controlled, orthogonal-regulated DNA-based logic devices for a range of applications in materials science, polymers, chemistry, and biology.

Compared with siRNAs or other antisense oligonucleotides (ASOs), the chemical simplicity, DNA/RNA binding capability, folding ability of tertiary structure, and excellent physiological stability of threose nucleic acid (TNA) motivate scientists to explore it as a novel molecular tool in biomedical applications. Although ASOs reach the target cells/tumors, insufficient tissue penetration and distribution of ASOs result in poor therapeutic efficacy. Therefore, the study of the time course of drug absorption, biodistribution, metabolism, and excretion is of significantly importance. In this work, the pharmacokinetics and biosafety of TNAs in living organisms are investigated. We found that synthetic TNAs exhibited excellent biological stability, low cytotoxicity, and substantial uptake in living cells without transfection. Using U87 three-dimensional (3D) multicellular spheroids to mimic the in vivo tumor microenvironment, TNAs showed their ability to penetrate efficiently throughout the whole multicellular spheroid as a function of incubation time and concentration when the size of the spheroid is relatively small. Additionally, TNAs could be safely administrated into Balb/c mice and most of them distributed in the kidneys where they supposed to excrete from the body through the renal filtration system. We found that accumulation of TNAs in kidneys induced no pathological changes, and no acute structural and functional damage in renal systems. The favourable biocompatibility of TNA makes it attractive as a safe and effective nucleic acid-based therapeutic agent for practical biological applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Nucleic acids are emerging as powerful and functional biomaterials due to their molecular recognition ability, programmability, and ease of synthesis and chemical modification. Various types of nucleic acids have been used as gene regulation tools or therapeutic agents for the treatment of human diseases with genetic disorders. Nucleic acids can also be used to develop sensing platforms for detecting ions, small molecules, proteins, and cells. Their performance can be improved through integration with other organic or inorganic nanomaterials. To further enhance their biological properties, various chemically modified nucleic acid analogues can be generated by modifying their phosphodiester backbone, sugar moiety, nucleobase, or combined sites. Alternatively, using nucleic acids as building blocks for self-assembly of highly ordered nanostructures would enhance their biological stability and cellular uptake efficiency. In this review, we will focus on the development and biomedical applications of structural and functional natural nucleic acids, as well as the chemically modified nucleic acid analogues over the past ten years. The recent progress in the development of functional nanomaterials based on self-assembled DNA-based platforms for gene regulation, biosensing, drug delivery, and therapy will also be presented. We will then summarize with a discussion on the advanced development of nucleic acid research, highlight some of the challenges faced and propose suggestions for further improvement.

We successfully fabricated threose nucleic acid (TNA)-based probes for real-time monitoring of target miRNA levels in cells. Our TNA probe is comprised of a fluorophore-labeled TNA reporter strand by partially hybridizing to a quencher-labeled TNA that is designed to be antisense to a target RNA transcript; this results in effective quenching of its fluorescence. In the presence of RNA targets, the antisense capture sequence of the TNA binds to targeted transcripts to form longer, thermodynamic stable duplexes. This binding event displaces the reporter strand from the quencher resulting in a discrete "turning-on" of the fluorescence. Our TNA probe is highly specific and selective toward target miRNA and is able to distinguish one to two base mismatches in the target RNA. Compared with DNA probes, our TNA probes exhibited favorable nuclease stability, thermal stability, and exceptional storage ability for long-term cellular studies. Our TNA probes are efficiently taken up by cells with negligible cytotoxicity for dynamic detection of target miRNAs and can also differentiate the distinct target miRNA expression levels in different cell lines. This work illuminates for using TNA as a building component to construct a biocompatible probe for miRNA detection that offers alternative molecular reagents for miRNA-related diagnostics., Competing Interests: P.K.L., F.W., and L.S.L. are listed as inventors on a US patent application by the City University of Hong Kong describing the preparation and use of TNA-based probes. The other authors declare no competing financial interests., (© 2022 The Author(s).)

Photoacoustic imaging (PAI)-guided photothermal therapy (PTT) has drawn considerable attention due to the deeper tissue penetration and higher maximum permissible exposure. However, current phototheranostic agents are greatly restricted by weak absorption in the second near-infrared (NIR-II, 1000-1700 nm) window, long-term toxicity, and poor photostability. In this report, novel organic NIR-II conjugated polymer nanoparticles (CPNs) based on narrow bandgap donor-acceptor BDT-TBZ polymers were developed for effective cancer PAI and PTT. Characterization data confirmed the high photothermal conversion efficiency, good photostability, excellent PAI performance, and superior biocompatibility of as-obtained CPNs. In addition, in vitro and in vivo tests demonstrated the efficient PTT effect of CPNs in ablating cancer cells and inhibiting tumor growth under 1064 nm laser irradiation. More importantly, the CPNs exhibited rapid clearance capability through the biliary pathway and negligible systematic toxicity. Thus, this work provides a novel organic theranostic nanoplatform for NIR-II PAI-guided PTT, which advances the future clinical translation of biocompatible and metabolizable conjugated nanomaterials in cancer diagnosis and therapy.

Aptamers are exciting smart molecular probes for specific recognition of disease biomarkers. A number of strategies have been developed to convert target-aptamer binding into physically detectable signals. Since the aptamer sequence was first discovered, a large variety of aptamer-based biosensors have been developed, with considerable attention paid to their potential applications in clinical diagnostics. So far, a variety of techniques in combination with a wide range of functional nanomaterials have been used for the design of aptasensors to further improve the sensitivity and detection limit of target determination. In this paper, the advantages of aptamers over traditional antibodies as the molecular recognition components in biosensors for high-throughput screening target molecules are highlighted. Aptamer-target pairing configurations are predominantly single- or dual-site binding; the design of recognition modes of each aptamer-target pairing configuration is described. Furthermore, signal transduction strategies including optical, electrical, mechanical, and mass-sensitive modes are clearly explained together with examples. Finally, we summarize the recent progress in the development of aptamer-based biosensors for clinical diagnosis, including detection of cancer and disease biomarkers and in vivo molecular imaging. We then conclude with a discussion on the advanced development and challenges of aptasensors.

Short circulation lifetime, poor blood-brain barrier (BBB) permeability and low targeting specificity limit nanovehicles from crossing the vascular barrier and reaching the tumor site. Consequently, the precise diagnosis of malignant brain tumors remains a great challenge. This study demonstrates the imaging of photostable biopolymer-coated nanodiamonds (NDs) with tumor targeting properties inside the brain. NDs are labeled with PEGylated denatured bovine serum albumin (BSA) and tumor vasculature targeting tripeptides RGD. The modified NDs show high colloidal stability in different buffer systems. Moreover, it is found that discrete dcBSA-PEG-NDs cross the in vitro BBB model more effectively than aggregated NDs. Importantly, compared with the non-targeting NDs, RGD-dcBSA-PEG-NDs can selectively target the tumor site in U-87 MG bearing mice after systemic injection. Overall, this discrete ND system enables efficacious brain tumor visualization with minimal toxicity to other major organs, and is worthy of further investigation into the applications as a unique platform for noninvasive theragnostics and/or thermometry at different stages of human diseases in the brain.

Metal oxo (M[double bond, length as m-dash]O) complexes are common oxidants in chemical and biological systems. The use of Lewis acids to activate metal oxo species has attracted great interest in recent years, especially after the discovery of the CaMn 4 O 5 cluster in the oxygen-evolving centre of photosystem II. Strong Lewis acids such as Sc 3+ and BF 3 , as well as strong Brønsted acids such as H 2 SO 4 and CF 3 SO 3 H, are commonly used to activate metal oxo species. In this work, we demonstrate that relatively weak Lewis acids such as Ca 2+ and other group 2 metal ions, as well as weak Brønsted acids such as CH 3 CO 2 H, can readily activate the stable RuO 4 - complex towards the oxidation of alkanes. Notably, the use of Ca 2+ and CH 3 CO 2 H together produces a remarkable cooperative effect on RuO 4 - , resulting in a much more efficient oxidant. DFT calculations show that Ca 2+ and CH 3 CO 2 H can bind to two oxo ligands to form a chelate ring. This results in substantial lowering of the barrier for hydrogen atom abstraction from cyclohexane., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In this study, the differences on the physico-chemical parameters, lignocellulose degradation, dynamic succession of microbial community, gene expression of carbohydrate-active enzymes and antibiotics resistance genes were compared during composting systems of bagasse pith/pig manure (BP) and manioc waste/pig manure (MW). The results revealed that biodegradation rates of organic matter, cellulose, hemicellulose and lignin (29.14%, 17.53%,45.36% and 36.48%) in BP were higher than those (15.59%, 16.74%, 41.23% and 29.77%) in MW. In addition, the relative abundance of Bacillus, Luteimonas, Clostridium, Pseudomonas, Streptomyces and expression of genes encoding carbohydrate- active enzymes in BP were higher than those in MW based on metagenomics sequencing. During composting, antibiotics and antibiotic resistance genes were substantially reduced, but the removal efficiency was divergent in the both samples. Taken together, metagenomics analysis was a potential method for evaluating lignocellulose's biodegradation process and determining the elimination of antibiotic and antibiotic resistance genes from different composting sources of biomass., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Clinical and experimental studies have shown that obesity increases the development and progression of breast cancer. The impact of obesity on the tumor microenvironment plays an important role in tumorigenesis, yet the precise mechanisms underlying obesity-mediated effects on cell-to-cell communication within the tumor microenvironment have been difficult to define. In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1-/-; p53+/- mice, an animal breast cancer model. Hierarchical clustering and gene pathway enrichment analyses of scRNA-seq data showed that five different subtypes of stromal fibroblasts existed in mouse Brca1 -mutated mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes ( Col3a1 , Col6a3 , Eln , and Sparc ) and downregulated expression of immunoregulatory genes ( Iigp1 and Cxcl10 ) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal fibroblasts. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands. Our studies provide new insight into a mechanistic paradigm wherein obesity modulates the functions of stromal and immune cells to create the tumorigenic microenvironment for promoting breast tumorigenesis.

The development of biocompatible drug delivery vehicles for cancer therapy in the brain remains a big challenge. In this study, we designed self-assembled DNA nanocages functionalized with or without blood-brain barrier (BBB)-targeting ligands, d and we investigated their penetration across the BBB. Our DNA nanocages were not cytotoxic and they were substantially taken up in brain capillary endothelial cells and Uppsala 87 malignant glioma (U-87 MG) cells. We found that ligand modification is not essential for this DNA system as the ligand-free DNA nanocages (LF-NCs) could still cross the BBB by endocytosis in in vitro and in vivo models. Our spherical DNA nanocages were more permeable across the BBB compared with tubular DNA nanotubes. Remarkably, in vivo studies revealed that DNA nanocages could carry anticancer drugs across the BBB and inhibit the tumor growth in a U-87 MG xenograft mouse model. This is the first example showing the potential of DNA nanocages as innovative delivery vehicles to the brain for cancer therapy. Unlike other delivery systems, our work suggest that a DNA nanocage-based platform provides a safe and cost-effective tool for targeted delivery to the brain and therapy for brain tumors.

The endothelial lipase LIPG possesses serine phospholipase activity and is involved in lipoprotein metabolism. Our previous studies have revealed that LIPG overexpression is required for tumor formation and metastasis of human basal-like triple-negative breast cancer (TNBC). We also demonstrated that LIPG differentially regulates TNBC malignancy through its enzymatic and non-enzymatic functions. The present studies were aimed at determining how XEN445, a specific inhibitor targeting LIPG phospholipase activity, impacts on TNBC tumor formation and malignant features. We established a cell-based LIPG enzymatic assay system to measure the inhibitory effect of XEN445 on LIPG phospholipase activity and determine its IC50. We found that XEN445 preferentially inhibited the proliferation of LIPG-expressing TNBC cells but not LIPG-negative luminal breast cancer cells. XEN445 inhibited the self-renewal of cancer stem cells (CSCs) in vitro and TNBC tumor formation in vivo. However, XEN445 had no inhibitory effect on the invasiveness and CSC stemness of TNBC cells. Our studies suggest that targeting both LIPG enzymatic and non-enzymatic functions is an important strategy for the treatment of TNBC.

A ubiquitously expressed transcription factor, specificity protein 1 (Sp1), interacts with the amyloid precursor protein (APP) promoter and likely mediates APP expression. Promoter-interaction strengths variably regulate the level of APP expression. Here, we examined the interactions of finger 3 of Sp1 (Sp1-f3) with a DNA fragment containing the APP promoter in different ionic solutions using atomic force microscope (AFM) spectroscopy. Sp1-f3 molecules immobilized on an Si substrate were bound to the APP promoter, which was linked to the AFM tips via covalent bonds. The interactions were strongly influenced by Pb 2+ , considering that substituting Zn 2+ with Pb 2+ increased the binding affinity of Sp1 for the APP promoter. The results revealed that the enhanced interaction force facilitated APP expression and that APP overexpression could confer a high-risk for disease incidence. An increased interaction force between Sp1-f3 and the APP promoter in Pb 2+ solutions was consistent with a lower binding free energy, as determined by computer-assisted analysis. The impact of Pb 2+ on cell morphology and related mechanical properties were also detected by AFM. The overexpression of APP caused by the enhanced interaction force triggered actin reorganization and further resulted in an increased Young's modulus and viscosity. The correlation with single-force measurements revealed that altered cellular activities could result from alternation of Sp1-APP promoter interaction. Our AFM findings offer a new approach in understanding Pb 2+ associated neurodegeneration., Competing Interests: Declaration of competing interest The authors report no declarations of interest., (Copyright © 2020. Published by Elsevier Inc.)

G-quadruplex structures are becoming useful alternative interaction modules for the assembly of DNA nanomaterials because of their unique inducibility by cations. In this study, we demonstrated a new strategy for the assembly of polymeric DNA nanoarchitectures in the presence of cations, such as K + and Na + , by employing G-quartet toeholds at the edges of discrete mini-square DNA building blocks as adhesive units. In comparison with the Watson-Crick base-paired duplex linkers, G-quadruplex arrays embedded in the self-assembled DNA system exhibit higher thermal stability. The morphology of these doughnut-shaped or spherical-shaped DNA nanostructures is highly regulated by the orientation of the folded G-quadruplexes either in parallel or antiparallel orientation in response to different cations. Furthermore, this G-quadruplex-mediated assembly strategy is able to manipulate the cycling of DNA assemblies between discrete and polymeric states by means of introducing cations and chelating agents sequentially. This property enables the reversible manipulation of the DNA-based nanosystems for at least 4 cycles. The G-quadruplex array embedded in this self-assembled DNA system can become a scaffold for functional molecules, as a number of organic molecules and proteins exhibit specific binding to these G-quadruplex structures. Besides, embedded G-quadruplexes are also considered as functional components of nanoscale electronic materials due to their electron transport through the stacked orientation of the G-quartet. Therefore, this work is an important step towards obtaining reversible, responsive G-quadruplex-induced DNA-based nanomaterials with versatile functionalities which will be highly useful in further electronic, biomedical and drug-delivery applications.

We design and synthesize a sequence-defined α-l-threose nucleic acid (TNA) polymer, which is complementary to certain nucleotide sites of target anti-apoptotic proteins, BcL-2 involving in development and progression of tumors. Compared to scramble TNA, anti-BcL-2 TNA significantly suppresses target mRNA and protein expression in cancerous cells and shows antitumor activity in carcinoma xenografts, resulting in suppression of tumor cell growth and induction of tumor cell death. Together with good biocompatibility, very low toxicity, excellent specificity features, and strong binding affinity toward the complementary target RNAs, TNAs become new useful biomaterials and effective alternatives to traditional antisense oligonucleotides including locked nucleic acids, morpholino oligomers, and peptide nucleic acids in antisense therapy. Compared to conventional cancer therapy such as radiotherapy, surgery, and chemotherapy, we anticipate that this TNA-based polymeric system will work effectively in antisense cancer therapy and shortly start to play an important role in practical application.

Targeted transcriptional modulation in the central nervous system (CNS) can be achieved by adeno-associated virus (AAV) delivery of CRISPR activation (CRISPRa) and interference (CRISPRi) transgenes. To enable AAV packaging, we constructed minimal CRISPRa and CRISPRi transgenes by fusing catalytically inactive Staphylococcus aureus Cas9 (dSaCas9) to the transcriptional activator (VP64 and VP160) and repressor (KRAB and SID4X) domains along with truncated regulatory elements. We then evaluated the performance of these constructs in two reporter assays (bioluminescent and fluorescent), five endogenous genes (Camk2a, Mycn, Nrf2, Keap1, and PDGFRA), and two cell lines (neuro-2a [N2a] and U87) by targeting the promoter and/or enhancer regions. To enable systemic delivery of AAVs to the CNS, we have also generated an AAV1-PHP.B by inserting a 7-mer PHP.B peptide on AAV1 capsid. We showed that AAV1-PHP.B can efficiently cross the blood-brain barrier (BBB) and be taken up by the brain tissue upon lateral tail vein injection in mice. Importantly, a single-dose intravenous administration of AAV1-PHP.B expressing CRISPRa was shown to achieve targeted transgene activation in the mouse brain. This proof-of-concept study will contribute to the development of a non-invasive, specific and potent AAV-CRISPR system for correcting transcriptional misregulation in broad brain areas and multiple neuroanatomical structures., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Photoresponsive DNA nanomaterials represent a new class of remarkable functional materials. By adjusting the irradiation wavelength, light intensity, and exposure time, various photocontrolled DNA-based systems can be reversibly or irreversibly regulated in respect of their size, shape, conformation, movement, and dissociation/association. This Review introduces the most updated progress in the development of photoresponsive DNA-based system and emphasizes their advantages over other stimuli-responsive systems. Their design and mechanisms to trigger the photoresponses are shown and discussed. The potential application of these photon-responsive DNA nanomaterials in biology, biomedicine, materials science, nanophotonic and nanoelectronic are also covered and described. The challenges faced and further directions of the development of photocontrolled DNA-based systems are also highlighted., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nanodiamond-gold nanoparticle (ND-AuNP) dimers constitute a potent tool for controlled thermal heating of biological systems on the nanoscale, by combining a local light-induced heat source with a sensitive local thermometer. Unfortunately, previous solution-based strategies to build ND-AuNP conjugates resulted in large nanoclusters or a broad population of multimers with limited separation efficiency. Here, we describe a new strategy to synthesize discrete ND-AuNP dimers via the synthesis of biotin-labeled DNA-AuNPs through thiol chemistry and its immobilization onto the magnetic bead (MB) surface, followed by reacting with streptavidin-labeled NDs. The dimers can be easily released from MB via a strand displacement reaction and separated magnetically. Our method is facile, convenient, and scalable, ensuring high-throughput formation of very stable dimer structures. This ligand-induced self-assembly approach enables the preparation of a wide variety of dimers of designated sizes and compositions, thus opening up the possibility that they can be deployed in many biological actuation and sensing applications.

Chromatin assembly factor 1 (CAF1), a histone chaperone that mediates the deposition of histone H3/H4 onto newly synthesized DNA, is involved in Notch signaling activation during Drosophila wing imaginal disc development. Here, we report another side of CAF1, wherein the subunits CAF1-p105 and CAF1-p180 (also known as CAF1-105 and CAF1-180, respectively) inhibit expression of Notch target genes and show this is required for proliferation of Drosophila ovarian follicle cells. Loss-of-function of either CAF1-p105 or CAF1-p180 caused premature activation of Notch signaling reporters and early expression of the Notch target Hindsight (Hnt, also known as Pebbled), leading to Cut downregulation and inhibition of follicle cell mitosis. Our studies further show Notch is functionally responsible for these phenotypes observed in both the CAF1-p105- and CAF1-p180-deficient follicle cells. Moreover, we reveal that CAF1-p105- and CAF1-p180-dependent Cut expression is essential for inhibiting Hnt expression in follicle cells during their mitotic stage. These findings together indicate a novel negative-feedback regulatory loop between Cut and Hnt underlying CAF1-p105 and CAF-p180 regulation, which is crucial for follicle cell differentiation. In conclusion, our studies suggest CAF1 plays a dual role to sustain cell proliferation by positively or negatively regulating Drosophila Notch signaling in a tissue-context-dependent manner., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

A DNA tetrahedron as the most classical and simplest three-dimensional DNA nanostructure has been widely utilized in biomedicine and biosensing. However, the existing assembly approaches usually require harsh thermal annealing conditions, involve the formation of unwanted by-products, and have poor size control. Herein, a facile strategy to fabricate a discrete DNA tetrahedron as a single, thermodynamically stable product in a quantitative yield at room temperature is reported. This system does not require a DNA trigger or thermal annealing treatment to initiate self-assembly. This DNA tetrahedron was made of three chemically ligated triangular-shaped DNAs in unconventional ladder-like arrangements, with measured heights of ∼4.16 ± 0.04 nm, showing extra protections for enzymatic degradation in biological environment. They show substantial cellular uptake in different cell lines via temperature, energy-dependent and clathrin-mediated endocytosis pathways. These characteristics allow our DNA tetrahedron to be used as vehicles for the delivery of very small and temperature-sensitive cargos. This novel assembly strategy developed for DNA tetrahedra could potentially be extended to other highly complex polyhedra; this indicated its generalizability., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The kinetics of water oxidation by K 2 FeO 4 has been reinvestigated by UV/Vis spectrophotometry from pH 7-9 in 0.2 m phosphate buffer. The rate of reaction was found to be second-order in both [FeO 4 2- ] and [H + ]. These results are consistent with a proposed mechanism in which the first step involves the initial equilibrium protonation of FeO 4 2- to give FeO 3 (OH) - , which then undergoes rate-limiting O-O bond formation. Analysis of the O 2 isotopic composition for the reaction in H 2 18 O suggests that the predominant pathway for water oxidation by ferrate is intramolecular O-O coupling. DFT calculations have also been performed, which support the proposed mechanism., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: We have previously shown that loss of miR-140 has a pro-fibrotic effect in the mammary gland. This study aims to investigate whether miR-140 loss and obesity act synergistically to promote non-alcoholic fatty liver disease (NAFLD), and to identify the underlying mechanisms., Methods and Results: Liver tissues were isolated from lean-fat-diet and high-fat-diet fed wild-type and miR-140 knockout mice. Using molecular staining and immunohistochemistry techniques, increased development of NAFLD and fibrotic indicators in miR-140 knockout mice were identified. Utilizing an in vitro model system, miR-140 was demonstrated to target TLR-4, and miR-140 overexpression was shown to be sufficient to inhibit palmitic acid signaling through the TLR-4/NFκB pathway., Conclusion: These findings demonstrate that loss of miR-140 results in increased expression of TLR-4, sensitizing cells to palmitic acid signaling and in increased inflammatory activity through the TLR4/NFκB pathway. This signaling axis promotes NAFLD development in a high-fat diet context and indicates the potential utility of miR-140 rescue as a therapeutic strategy in NAFLD., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have developed a reversible photoswitching platform based on 3D DNA nanotubes by integrating photoisomerizable azobenzene molecules along the edges. This would allow the reversible conformational changes of the nanotubes between linear and bent features and the switchable patterning of gold nanoparticles in response to UV/Vis irradiation. This work provides a new strategy to create reversibly reconfigurable transformative nanomaterials for potential applications in the fields of renewable energy, sensing, nanorobotics and nanomedicine.

Because of the chemical simplicity of α-l-threose nucleic acid (TNA) and its ability to exchange genetic information between itself and RNA, it has attracted significant interest as the RNA ancestor. We herein explore the biological properties and evaluate the potency of sequence-designed TNA polymers to suppress the gene expression in living environments. We found that sequence-specific TNA macromolecules exhibit strong affinity and specificity toward the complementary RNA targets, are highly biocompatible and nontoxic in a living cell system, and readily enter a number of cell lines without using transfecting agents. Particularly, TNA exhibited much stronger enzymatic resistance toward fetal bovine serum or human serum as compared to traditional antisense oligonucleotides, which means that the intrinsic structure of TNA is thoroughly resistant to biological degradation. Importantly, the efficacy of the TNA molecule with green fluorescent protein (GFP) target sequence (anti-GFP TNAs) as antisense agents was first demonstrated in living cells in which these polymers revealed high antisense activity in terms of the degree of inhibition of GFP gene expression. The GFP gene inhibition studies in HeLa and HEK293 cells characterize sequence-controlled TNA as a functional biomaterial and a valuable alternative to traditional antisense oligonucleotides such as peptide nucleic acids, phosphorodiamidate morpholino oligomers, and locked nucleic acids for a wide range of applications in drug discovery and life science research. Additionally, we also first reported the cost-efficient approach to synthesize the four TNA phosphoramidite monomers using 2-cyanoethyl N, N, N', N'-tetraisopropylphosphoramidite as a key reagent. Furthermore, by increasing the frequency of the deblocking and coupling reactions together with extending their reaction time in each synthesis cycle, sequence-controlled TNAs can be easily synthesized in a quantitative yield and high purity.

Current understanding of aggressive human basal-like triple-negative breast cancer (TNBC) remains incomplete. In this study, we show endothelial lipase (LIPG) is aberrantly overexpressed in basal-like TNBCs. We demonstrate that LIPG is required for in vivo tumorigenicity and metastasis of TNBC cells. LIPG possesses a lipase-dependent function that supports cancer cell proliferation and a lipase-independent function that promotes invasiveness, stemness and basal/epithelial-mesenchymal transition features of TNBC. Mechanistically, LIPG executes its oncogenic function through its involvement in interferon-related DTX3L-ISG15 signaling, which regulates protein function and stability by ISGylation. We show that DTX3L, an E3-ubiquitin ligase, is required for maintaining LIPG protein levels in TNBC cells by inhibiting proteasome-mediated LIPG degradation. Inactivation of LIPG impairs DTX3L-ISG15 signaling, indicating the existence of DTX3L-LIPG-ISG15 signaling. We further reveal LIPG-ISG15 signaling is lipase-independent. We demonstrate that DTX3L-LIPG-ISG15 signaling is essential for malignancies of TNBC cells. Targeting this pathway provides a novel strategy for basal-like TNBC therapy., Competing Interests: PL, YY, JL, YZ, WH, MK, QZ No competing interests declared, (© 2018, Lo et al.)

The state of activated sludge wastewater treatment process (AS WWTP) is conventionally identified by physico-chemical measurements which are costly, time-consuming and have associated environmental hazards. Image processing and analysis-based linear regression modeling has been used to monitor the AS WWTP. But it is plant- and state-specific in the sense that it cannot be generalized to multiple plants and states. Generalized classification modeling for state identification is the main objective of this work. By generalized classification, we mean that the identification model does not require any prior information about the state of the plant, and the resultant identification is valid for any plant in any state. In this paper, the generalized classification model for the AS process is proposed based on features extracted using morphological parameters of flocs. The images of the AS samples, collected from aeration tanks of nine plants, are acquired through bright-field microscopy. Feature-selection is performed in context of classification using sequential feature selection and least absolute shrinkage and selection operator. A support vector machine (SVM)-based state identification strategy was proposed with a new agreement solver module for imbalanced data of the states of AS plants. The classification results were compared with state-of-the-art multiclass SVMs (one-vs.-one and one-vs.-all), and ensemble classifiers using the performance metrics: accuracy, recall, specificity, precision, F measure and kappa coefficient (κ). The proposed strategy exhibits better results by identification of different states of different plants with accuracy 0.9423, and κ 0.6681 for the minority class data of bulking.

Epigenomics encompasses studies of the chemical modifications of genomic DNA and associated histones, interactions between genomic DNA sequences and proteins, the dynamics of the chromosomal conformation, the functional relationships between these epigenetic events, and the regulatory impacts of these epigenetic events on gene expression in cells. In comparison to current techniques that are only capable of characterizing average epigenomic features across bulk cell ensembles, single-cell epigenomic methodologies are emerging as powerful new techniques to study cellular plasticity and heterogeneity, as seen in stem cells and cancer. Here we summarize available techniques for studies of single-cell epigenomics, review their current applications to cancer research, and discuss future possibilities. This review also highlights that the full potential of single-cell epigenetic studies will be comprehended through integrating the multi-omics information of genomics, epigenomics and transcriptomics., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Forkhead box F2 (FOXF2) functions as a transcription factor and is critically involved in programming organogenesis and regulating epithelial-to-mesenchymal transition (EMT) and cell proliferation. We recently have revealed that FOXF2 can exert distinct functional effects on different molecular subtypes of breast cancer. We found that FOXF2 expression is epigenetically silenced in luminal breast cancers due to its tumor-suppressive role in DNA replication regulation. In contrast, FOXF2 is overexpressed in basal-like triple-negative breast cancers (TNBCs) due to its oncogenic role in promoting EMT. Although our and other studies have shown that FOXF2 dysregulation is critical for tumorigenesis of various tissue types, the role of FOXF2 in metabolic rewiring of cancer remains unknown. In this study, we analyzed our previous microarray data to understand the metabolic role of FOXF2 in non-cancerous and cancerous breast epithelial cells. Our studies showed that in non-cancerous breast epithelial cells FOXF2 can also play a dual role either in tumor suppression or in tumor promotion through regulating expression of tumor-suppressive and oncogenic metabolic genes. Furthermore, we found that FOXF2-regulated metabolic genes are not conserved between non-cancerous and cancerous breast epithelial cells and FOXF2 is involved in metabolic rewiring in breast cancer cells. This is the first report to explore the metabolic function of FOXF2 in breast cancer., Competing Interests: Conflict of Interest The author declares no conflict of interest.

The ferrate(vi) ion, [FeO 4 ] 2- , has attracted much interest in recent years because of its potential use as a green oxidant in organic synthesis and water treatment. Although there have been several reports on the use of ferrate(vi) for the oxidation of alcohols to the corresponding carbonyl compounds, the mechanism remains unclear. In this work, the kinetics of the oxidation of a series of alcohols with α-C-H bond dissociation energies ranging from 81 to 95 kcal mol -1 have been studied by UV/Vis spectrophotometry. The reactions are first-order in both [FeO 4 ] 2- and [alcohol]. The deuterium isotope effects for the oxidation of methanol/d 4 -methanol, ethanol/d 6 -ethanol and benzyl alcohol/d 7 -benzyl alcohol are 18.0 ± 0.1, 4.1 ± 0.1 and 11.2 ± 0.1, respectively. A linear correlation is found between the second-order rate constants and the α-C-H bond dissociation energies (BDEs) of the alcohols, consistent with a hydrogen atom transfer (HAT) mechanism. The proposed HAT mechanism is supported by DFT calculations.

It was found that the operational temperature and the incorporation of microbial fuel cell (MFC) into anaerobic membrane bioreactor (AnMBR) have significant effect on AnMBRs' filtration performance. This paper addresses two issues (i) effect of temperature on AnMBR; and (ii) effect of MFC on AnMBRs' performance. The highest COD removal efficiency was observed in mesophilic condition (45°C). It was observed that the bioreactors operated at 45°C had the highest filtration resistance compared to others, albeit the excellent performance in removing the organic pollutant. Next, MFC was combined with AnMBR where the MFC acted as a pre-treatment unit prior to AnMBR and it was fed directly with palm oil mill effluent (POME). The supernatant from MFC was further treated by AnMBR. Noticeable improvement in filtration performance was observed in the combined system. Decrease in polysaccharide amount was observed in combined system which in turn suggested that the better filtration performance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We have previously reported that the oxidation of SO 3 2- to SO 4 2- by a trans-dioxoruthenium(VI) complex, [Ru VI (TMC)(O) 2 )] 2+ (Ru VI ; TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazcyclotetradecane) in aqueous solutions occurs via an O-atom transfer mechanism. In this work, we have reinvestigated the effects of the pH on the oxidation of S IV by Ru VI in more detail in order to obtain kinetic data for the HSO 3 - pathway. The HSO 3 - pathway exhibits a deuterium isotope effect of 17.4, which indicates that O-H bond breaking occurs in the rate-limiting step. Density functional theory calculations have been performed that suggest that the oxidation of HSO 3 - by Ru VI may occur via a concerted or stepwise proton-coupled O-atom transfer mechanism.

This study reports biosensing using graphene field-effect transistors with the aid of pyrene-tagged DNA aptamers, which exhibit excellent selectivity, affinity, and stability for Escherichia coli (E. coli) detection. The aptamer is employed as the sensing probe due to its advantages such as high stability and high affinity toward small molecules and even whole cells. The change of the carrier density in the probe-modified graphene due to the attachment of E. coli is discussed theoretically for the first time and also verified experimentally. The conformational change of the aptamer due to the binding of E. coli brings the negatively charged E. coli close to the graphene surface, increasing the hole carrier density efficiently in graphene and achieving electrical detection. The binding of negatively charged E. coli induces holes in graphene, which are pumped into the graphene channel from the contact electrodes. The carrier mobility, which correlates the gate voltage to the electrical signal of the APG-FETs, is analyzed and optimized here. The excellent sensing performance such as low detection limit, high sensitivity, outstanding selectivity and stability of the graphene biosensor for E. coli detection paves the way to develop graphene biosensors for bacterial detection., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Os VI nitrido complex, Os VI (N)(quin) 2 (OTs) (1, quin=2-quinaldinate, OTs=tosylate), is a highly selective and efficient catalyst for the ring hydroxylation of alkylbenzenes with H 2 O 2 at room temperature. Oxidation of various alkylbenzenes occurs with ring/chain oxidation ratios ranging from 96.7/3.3 to 99.9/0.1, and total product yields from 93 % to 98 %. Moreover, turnover numbers up to 6360, 5670, and 3880 can be achieved for the oxidation of p-xylene, ethylbenzene, and mesitylene, respectively. Density functional theory calculations suggest that the active intermediate is an Os VIII nitrido oxo species., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three different sizes of powdered activated carbon (PAC) were added in hybrid anaerobic membrane bioreactors (AnMBRs) and their performance was compared with a conventional AnMBR without PAC in treating palm oil mill effluent. Their working volume was 1 L each. From the result, AnMBRs with PAC performed better than the AnMBR without PAC. It was also found that adding a relatively smaller size of PAC (approximately 100 μm) enhanced the chemical oxygen demand removal efficiency to 78.53 ± 0.66%, while the concentration of mixed liquor suspended solid and mixed liquor volatile suspended solid were 8,050 and 6,850 mg/L, respectively. The smaller size of PAC could also enhance the biofloc formation and biogas production. In addition, the smaller particle sizes of PAC incorporated into polyethersulfone membrane resulted in higher performance of membrane fouling control and produced better quality of effluent as compared to the membrane without the addition of PAC.

The normal myoepithelium has a tumor-suppressing nature and inhibits the progression of ductal carcinoma in situ (DCIS) into invasive ductal carcinoma (IDC). Conversely, a growing number of studies have shown that tumor-associated myoepithelial cells have a tumor-promoting effect. Moreover, the exact role of tumor-associated myoepithelial cells in the DCIS-to-IDC development remains undefined. To address this, we explored the role of tumor-associated myoepithelial cells in the DCIS-to-IDC progression. We developed a direct coculture system to study the cell-cell interactions between DCIS cells and tumor-associated myoepithelial cells. Coculture studies indicated that tumor-associated myoepithelial cells promoted the invasive progression of a DCIS cell model in vitro , and mechanistic studies revealed that the interaction with DCIS cells stimulated tumor-associated myoepithelial cells to secrete TGFβ1, which subsequently contributed to activating the TGFβ/Smads pathway in DCIS cells. We noted that activation of the TGFβ signaling pathway promoted the epithelial-mesenchymal transition, basal-like phenotypes, stemness, and invasiveness of DCIS cells. Importantly, xenograft studies further demonstrated that tumor-associated myoepithelial cells enhanced the DCIS-to-IDC progression in vivo Furthermore, we found that TGFβ-mediated induction of oncogenic miR-10b-5p expression and down-regulation of RB1CC1 , a miR-10b-5p-targeted tumor-suppressor gene, contributed to the invasive progression of DCIS. Our findings provide the first experimental evidence to directly support the paradigm that altered DCIS-associated myoepithelial cells promote the invasive progression of DCIS into IDC via TGFβ signaling activation., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

We report detailed absolute integral cross sections (σ's) for the quantum-rovibrational-state-selected ion-molecule reaction in the center-of-mass collision energy (E cm ) range of 0.05-10.00 eV, where (vvv) = (000), (100), and (020), and . Three product channels, HCO + + OH, HOCO + + H, and CO + + H 2 O, are identified. The measured σ(HCO + ) curve [σ(HCO + ) versus E cm plot] supports the hypothesis that the formation of the HCO + + OH channel follows an exothermic pathway with no potential energy barriers. Although the HOCO + + H channel is the most exothermic, the σ(HOCO + ) is found to be significantly lower than the σ(HCO + ). The σ(HOCO + ) curve is bimodal, indicating two distinct mechanisms for the formation of HOCO + . The σ(HOCO + ) is strongly inhibited at E cm < 0.4 eV, but is enhanced at E cm > 0.4 eV by (100) vibrational excitation. The E cm onsets of σ(CO + ) determined for the (000) and (100) vibrational states are in excellent agreement with the known thermochemical thresholds. This observation, along with the comparison of the σ(CO + ) curves for the (100) and (000) states, shows that kinetic and vibrational energies are equally effective in promoting the CO + channel. We have also performed high-level ab initio quantum calculations on the potential energy surface, intermediates, and transition state structures for the titled reaction. The calculations reveal potential barriers of ≈0.5-0.6 eV for the formation of HOCO + , and thus account for the low σ(HOCO + ) and its bimodal profile observed. The E cm enhancement for σ(HOCO + ) at E cm ≈ 0.5-5.0 eV can be attributed to the direct collision mechanism, whereas the formation of HOCO + at low E cm < 0.4 eV may involve a complex mechanism, which is mediated by the formation of a loosely sticking complex between HCO + and OH. The direct collision and complex mechanisms proposed also allow the rationalization of the vibrational inhibition at low E cm and the vibrational enhancement at high E cm observed for the σ(HOCO + ).

We demonstrate a nanotechnology approach for the development of cancer-cell-specific subcellular organelle-targeted drug nanocarriers based on photostable nanodiamonds (ND) functionalized with folic acid and mitochondrial localizing sequence (MLS) peptides. We showed that these multifunctional NDs not only distinguish between cancer cells and normal cells, and transport the loaded drugs across the plasma membrane of cancer cells, but also selectively deliver them to mitochondria and induce significant cytotoxicity and cell death compared with free Dox localized in lysosomes. Importantly, the cellular uptake of Dox was dramatically increased in a resistant model of MCF-7 cells, which contributed to the significant circumvention of P-glycoprotein-mediated drug resistance. Our work provides a novel method of designing nanodiamond-based carriers for targeted delivery and for circumventing drug resistance in doxorubicin-resistant human breast adenocarcinoma cancer cells.

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp 3 -carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac) 3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.

Ruthenium(II) tris(bipyridyl) cationic complex (Ru(bpy) 3 2+ ) incorporated UiO-67 (Universitetet i Oslo) nanoscale metal-organic frameworks (NMOFs) with an average diameter of ∼92 nm were developed as theranostic nanoplatform for in vitro two-photon fluorescence imaging and photodynamic therapy. After incorporation into porous UiO-67 nanoparticles, the quantum yield, luminescence lifetime, and two-photon fluorescence intensity of Ru(bpy) 3 2+ guest molecules were much improved owing to the steric confinement effect of MOF pores. Benefiting from these merits, the as-synthesized nanoparticles managed to be internalized by A549 cells while providing excellent red fluorescence in cytoplasm upon excitation with 880 nm irradiation. Photodynamic therapeutic application of the Ru(bpy) 3 2+ -incorporated UiO-67 NMOFs was investigated in vitro. The Ru(bpy) 3 2+ -incorporated UiO-67 NMOFs exhibited good biocompatibility without irradiation while having good cell-killing rates upon irradiation. In view of these facts, the developed Ru(bpy) 3 2+ -incorporated NMOFs give a new potential pathway to achieve enhanced two-photon fluorescence imaging and photodynamic therapy.