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This article investigates the Linder hypothesis for foreign direct investment (FDI) within the three‐way gravity framework, utilizing a newly compiled and extensive dataset encompassing greenfield and brownfield investment activities across diverse sectors from 2003 to 2018. The Linder hypothesis posits that multinational firms invest in countries with comparable income levels to their home country. Our primary findings affirm the relevance of the Linder hypothesis in the context of horizontal FDI. The influence of the Linder effect varies among sectors, with the service sector exhibiting the most pronounced effect, while no detectable effect is observable for the manufacturing sector. We also find that the Linder effect depends on the sector's position within the value chain and the degree of quality differentiation. Sectors closer to final consumer demand and those characterized by higher product differentiation exhibit greater exposure to the Linder effect. Additionally, our analysis reveals that the Linder effect is subject to variations based on the income levels of the host country and highlights the significance of consumer preferences in shaping FDI patterns. Our article underscores the pivotal role of industry dynamics, product quality considerations, and value chain positioning in influencing the Linder effect on FDI. [ABSTRACT FROM AUTHOR]

Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30–200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic. [ABSTRACT FROM AUTHOR]

A stroke is a serious life-threatening condition and a leading cause of death and disability that happens when the blood vessels to part of the brain are blocked or burst. While major advances in the understanding of the ischemic cascade in stroke was made over several decades, limited therapeutic options and high mortality and disability have caused researchers to extend the focus toward peripheral changes beyond brain. The largest proportion of microbes in human body reside in the gut and the interaction between host and microbiota in health and disease is well known. Our study aimed to explore the gut microbiota in patients with stroke with comparison to control group. Fecal samples were obtained from 51 subjects: 25 stroke patients (18 hemorrhagic, 7 ischemic) and 26 healthy control subjects. The variable region V3–V4 of the 16S rRNA gene was sequenced using the Illumina MiSeq platform. PICRUSt2 was used for prediction of metagenomics functions. Our results show taxonomic dysbiosis in stroke patients in parallel with functional dysbiosis. Here, we show that stroke patients have (1) increased Parabacteroides and Escherichia_Shigella, but decreased Prevotella and Fecalibacterium; (2) higher transposase and peptide/nickel transport system substrate-binding protein, but lower RNA polymerase sigma-70 factor and methyl-accepting chemotaxis protein, which are suggestive of malnutrition. Nutrients are essential regulators of both host and microbial physiology and function as key coordinators of host–microbe interactions. Manipulation of nutrition is expected to alleviate gut dysbiosis and prognosis and improve disability and mortality in the management of stroke. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA" published in Molecular Cancer. The correction addresses two errors in the original paper. The first error is the presentation of incorrect primer sequences for GAPDH in the Supplemental Methods. The correct primer sequences for GAPDH are provided in the correction. The second error is a misplaced western blot image for the loading control β-actin in Figure 4e. The correct image for β-actin bands is identified in the correction. These errors are minor and do not affect the conclusion of the article. The authors apologize for any inconvenience caused and request an opportunity to publish this correction. [Extracted from the article]

The Mormon cricket, Anabrus simplex , is a flightless katydid, one of the major devastating rangeland pests in several states of the western United States. During the past few years, their sudden and periodic outbreaks into massive migratory bands caused significant economic losses to the rangeland forage and agricultural crops, particularly grain crops. Current population management methods rely heavily on broad-spectrum chemical insecticides, which could be toxic to nontargets, and even the targeted species might develop resistance in the long run. Therefore, we assessed the potential of RNA interference (RNAi)-based alternative management strategies that could supplement the current methods. In insects, RNAi efficiency varies with the method of double-stranded RNA (dsRNA) delivery. We tested 2 different methods of dsRNA delivery: injection and oral feeding of dsRNA. The results showed that Mormon crickets are sensitive to injection of dsRNA in a dose-dependent manner, but refractory to the oral feeding of dsRNA. Further, we confirmed the high nuclease activity in the insect midgut. In order to protect the dsRNA from the dsRNase activity and facilitate its uptake in the midgut, we encapsulated dsRNA inside poly lactic-co-glycolic acid (PLGA) nanoparticles and studied its release kinetics and RNAi efficiency by oral feeding. The release kinetics clearly suggested that the PLGA nanoparticle permeates from the insect digestive system to the hemolymph; however, it failed to induce an efficient RNAi response of the targeted genes. In conclusion, our findings suggest the different responses to dsRNA delivery methods in Mormon crickets, and further investigations involving dsRNA stability and its uptake mechanism are required to use RNAi as an alternative Mormon cricket population management strategy. [ABSTRACT FROM AUTHOR]

Exosomes, a subtype of extracellular vesicles, ranging from 50 to 200 nm in diameter, and mediate cell-to-cell communication in normal biological and pathological processes. Exosomes derived from tumors have multiple functions in cancer progression, resistance, and metastasis through cancer exosome-derived tropism. However, there is no quantitative information on cancer exosome-derived tropism. Such data would be highly beneficial to guide cancer therapy by inhibiting exosome release and/or uptake. Using two fluorescent protein (mKate2) transfected ovarian cancer cell lines (OVCA4 and OVCA8), cancer exosome tropism was quantified by measuring the released exosome from ovarian cancer cells and determining the uptake of exosomes into parental ovarian cancer cells, 3D spheroids, and tumors in tumor-bearing mice. The OVCA4 cells release 50 to 200 exosomes per cell, and the OVCA8 cells do 300 to 560 per cell. The uptake of exosomes by parental ovarian cancer cells is many-fold higher than by non-parental cells. In tumor-bearing mice, most exosomes are homing to the parent cancer rather than other tissues. We successfully quantified exosome release and uptake by the parent cancer cells, further proving the tropism of cancer cell-derived exosomes. The results implied that cancer exosome tropism could provide useful information for future cancer therapeutic applications. [ABSTRACT FROM AUTHOR]

This paper provides an ex‐post impact assessment of the Russian invasion of Ukraine on international grain and oilseed trade. We use a commodity‐level empirical model to assess the counterfactual trade effects and evaluate the region‐specific global trade reallocation effects. We find that grain and oilseed imports from Ukraine were 78.2% below the counterfactual between February and July 2022. The Russia–Ukraine war caused substantial trade diversion, mainly benefiting countries in North America and Europe. The adjustment of global grain and oilseed trade operates primarily through price adjustments, with considerable heterogeneity across commodity groups. Our ex‐ante analysis demonstrates that the Ukraine–Russia war had substantial trade implications for the directly involved countries but only limited ones for the global grain and oilseed markets in terms of traded quantity. [ABSTRACT FROM AUTHOR]

Purpose: To assess the transretinal penetration of intravitreally injected retinal multicell-derived exosomes and to develop exosome-based active targeting of choroidal neovascularization (CNV) by bioengineering with ASL, which is composed of a membrane Anchor (BODIPY), Spacer (PEG), and targeting Ligands (cyclic RGD peptide). Methods: Retinal multicell-derived exosomes were recovered from a whole mouse retina using differential ultracentrifugation. Their size, number, and morphology were characterized using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Exosome markers were confirmed using an exosome detection antibody array. Intravitreal injection of fluorescent (PKH-26)-labeled or engineered ASL exosomes (1 × 106 exosomes/μL) were given to the wild-type mouse or laser-induced CNV mouse model. Retinal uptake of exosomes was assessed by in vivo retinal imaging microscopy and histological staining with DAPI, GSA, and anti-integrin αv for retinal sections or choroid/RPE flat mounts. Active targeting of CNV was assessed by comparing retinal uptake between areas with and without CNV and by colocalization analysis of ASL exosomes with integrin αv within CNV. Staining with anti-F4/80, anti-ICAM-1, and anti-GFAP antibodies on retinal sections were performed to identify intracellular uptake of exosomes and immediate reactive retinal gliosis after exosome treatment. Results: An average of 2.1 × 109 particles/mL with a peak size of 140 nm exosomes were recovered. Rapid retinal penetration of intravitreally injected exosomes was confirmed by retinal imaging microscopy at 3 and 24 h post-injection. Intravitreally delivered PKH-26-labeled exosomes reached inner and outer retinal layers including IPL, INL, OPL, and ONL at 1 and 7 days post-injection. Intravitreally injected ASL exosomes were predominantly delivered to the area of CNV including ONL, RPE, and choroid in laser-induced CNV mouse models with 89.5% of colocalization with integrin αv. Part of exosomes was also taken intracellularly to vascular endothelial cells and macrophages. After intravitreal injection, neither naive exosomes nor ASL exosomes induced immediate reactive gliosis. Conclusions: Intravitreally delivered retinal multicell-derived exosomes have good retinal penetration, and ASL modification of exosomes actively targets CNV with no immediate reactive gliosis. ASL exosomes have a great potential to serve as an intraocular drug delivery vehicle, allowing an active targeting strategy. [ABSTRACT FROM AUTHOR]

Vaccine coverage is severely limited in developing countries due to inefficient protection of vaccine functionality as well as lack of patient compliance to receive the additional booster doses. Thus, there is an urgent need to design a thermostable vaccine delivery platform that also enables release of the bolus after predetermined time. Here, the formation of injectable and light‐activatable polybubbles for vaccine delivery is reported. In vitro studies show that polybubbles enable delayed burst release, irrespective of cargo types, namely small molecule and antigen. The extracorporeal activation of polybubbles is achieved by incorporating near‐infrared (NIR)‐sensitive gold nanorods (AuNRs). Interestingly, light‐activatable polybubbles can be used for on‐demand burst release of cargo. In vitro, ex vivo, and in vivo studies demonstrate successful activation of AuNR‐loaded polybubbles. Overall, the light‐activatable polybubble technology can be used for on‐demand delivery of various therapeutics including small molecule drugs, immunologically relevant protein, peptide antigens, and nucleic acids. [ABSTRACT FROM AUTHOR]

Despite various therapeutic or diagnostic developments, cancer is still one of the most lethal diseases due to insufficiently adequate treatments and the delay of the early stage of disease detection. An image-guided drug delivery system (IGDDS), as a real-time noninvasive imaging assessment of therapeutic response, has the strong potential to improve the diagnosis and treatment of cancer because its imaging property offers the quantification of nanomedicine at the intended disease sites, the possible assurance of adequate treatment and elimination of undesirable delay of early-stage diagnosis due to low resolution. One of potential modality that overcomes these challenges could be the nanoconfinement of gold (Au) nanoparticles within other nanoparticles called "Particle-in-Particle (PIP)", which is a strong candidate of cancer treatment because of its "theranostic (therapy + diagnostics)" advantages including imaging (e.g., CT) and therapeutic hyperthermia application. In this review, we will elaborate on the current application of theranostic by nanoconfinement. Then, we will narrow down the gold nanoparticle-mediated theranostic application and its nanoconfinement advantages. Finally, the future direction for maximum nanoconfinement mediated cancer therapy will be included. [ABSTRACT FROM AUTHOR]

In this brief, time-domain arithmetic circuits, such as time adder, time subtractor, and time integrator, are proposed. The concept of these time-domain circuits are explained and their non-idealities are analyzed. Using the proposed time-domain arithmetic circuits, a prototype second-order $\Delta \Sigma $ -time-to-digital converter is implemented in a 65 nm standard CMOS process. The fabricated chip achieves 1.44 psrms of integrated noise in 1-MHz bandwidth while consuming 3.5 mW at 50 MS/s. [ABSTRACT FROM AUTHOR]

Formic acid (FA, HCOOH) using carbon dioxide (CO2) as a feedstock is sufficient to be synthesized on an industrial scale because it can be used as a carrier of hydrogen (H2) and as a precursor chemical in many chemical processes. Utilizing CO2 as an alternative carbon feedstock for FA production comes from reduction methods for greenhouse gas emission and fossil resource depletion. This study compares life cycle assessments (LCAs) to produce FA using CO obtained from fossil fuels (the conventional method), and using CO2 obtained using the carbon capture and utilization (CCU) method. The simulation compares supply energy (heat, electricity), and feedstock usage (CO, CO2, H2), and environmental impacts of FA production by the two processes in the Jeollanam-do industrial sector of Korea. The largest contributors to climate change (CC) were CO (71%) and heat (24%) in the fossil-based conventional process and H2 (76%) and electricity (9%) in the CCU process. The largest contributors to fossil resource depletion (FD) were CO (79%) and heat (18%) in the fossil-based conventional process and H2 (70%) and electricity (18%) in the CCU process. A case study showed that the lowest environmental impact was obtained using a combination of heat generation by burning wood chip, and electricity generation using hydropower. These results suggest that the use of captured CO2 for FA production can mitigate greenhouse gas emissions and fossil resource depletion. [ABSTRACT FROM AUTHOR]

In this brief, we propose a hybrid phase locked loop (PLL) which employs a coarse resolution gated ring oscillator time-to-digital converter in the digital integral (I) path and a switched RC circuit in the analog proportional (P) path, which provide lower in-band noise than a bang-bang phase detector-based hybrid PLL (BB-HPLL). We also present noise analysis of the proposed PLL which shows that in-band noise can be further reduced by increasing the integral path gain, which is contrary to conventional design of BB-HPLLs where I path gain is minimized. A prototype chip fabricated in the 65-nm CMOS achieves 13-dB improvement of in-band phase noise compared to a conventional hybrid PLL and 2.08 psrms jitter at 4.8 GHz, while consuming 2.22 mW from a 1.0-V supply. [ABSTRACT FROM AUTHOR]

SN-38 (7-ethyl-10-hydroxy-camptothecin) is an active metabolite of irinotecan (CPT-11) and the most potent camptothecin analogue. In this study, 2,4-dinitrobenzene sulfonyl (DNS) was covalently conjugated as a GSH-sensitive trigger to 10’–OH of SN-38 to yield a GSH-sensitive prodrug, denoted as DNS-SN38, with virtually quenched fluorescence due to donor-excited photo-induced electron transfer (d-PeT). By investigating DNS-SN38's activation properties upon fluorescence restoration and cytotoxic potency against ovarian cancer cell lines (A2780 and m-Cherry + OCSC1-F2), its potential applicability as a useful chemotherapeutic agent was demonstrated. [ABSTRACT FROM AUTHOR]

Formulation optimization from the early steps plays an important role in the success of drug delivery system development. To optimize nano-sized micelles based on poly(ethylene glycol)- b-poly(lactide)- b-poly(ethylene glycol) (PEG-PLA-PEG) triblock copolymers, the effect of PLA composition on the physicochemical properties of micelles was studied. Doxorubicin (DOX) was used to be encapsulated into micelles. In vitro studies on the safety of triblock copolymers and cytotoxicity of DOX-loaded micelles compared to free DOX were done, using MDA-MB-231 cells. Critical micelle concentration and micelle size were found to be linearly dependent on the PLA molecular weight (MW). In addition, it was shown that long PLA-containing micelles had low stability. The sizes of DOX-loaded micelles were bigger than those of empty micelles. The loading amount of DOX into micelles as well as the release rate of DOX from micelles depended on the PLA MW. Triblock copolymers themselves did not show any toxicity over a wide range of concentration. DOX-loaded micelles killed more tumor cells than free DOX. In summary, difference in hydrophobicity can be a critical factor to determine the physicochemical properties of micelles composed of PEG-PLA-PEG, and thus, it can affect the drug delivery efficacy of micelles. After considering all related factors, PEG-PLA-PEG 2 kDa-6 kDa-2 kDa seemed to be the best polymer for further studies. [ABSTRACT FROM AUTHOR]

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

We developed novel photosensitizing drug-carrying worm-like micelles using a pH-sensitiveAB2 miktoarm block copolymer consisting of one methoxy-poly(ethylene glycol) (mPEG) block (A) and two 3-diethylaminopropylated poly(L-lysine) [poly(Lys-DEAP)] blocks (B2). In particular, the Y-shaped AB2 miktoarm block copolymer structure mimicking the phospholipid structure enabled the facile preparation of worm-like micelles. The unique feature of pH-responsive DEAP as a hydrophobic moiety (non-protonated DEAP) at pH 7.4 and as a hydrophilic moiety (protonated DEAP) at pH 6.8 modulated acidic pH-activated micellar disintegration. These worm-like micelles serve as a basic transformer whose assembled conformation disintegrates in the acidic milieu (~pH 6.8) of solid tumors, resulting in improved phototoxicity due to triggered drug release from disintegrated micelles at acidic tumor sites and high-yield generation of cytotoxic singlet oxygen from the photosensitizing drug. As a result, the tumor volume in the nude mice treated with these worm-like micelles was approximately 5.2 times smaller than those treated with free drug. We anticipate that this system will provide great potential for tumor therapy. [ABSTRACT FROM AUTHOR]

Clinical translation of cell therapies requires strategies that can manufacture cells efficiently and economically. One promising way to reproducibly expand T cells for cancer therapy is by attaching the stimuli for T cells onto artificial substrates with high surface area. Here, we show that a carbon nanotube-polymer composite can act as an artificial antigen-presenting cell to efficiently expand the number of T cells isolated from mice. We attach antigens onto bundled carbon nanotubes and combined this complex with polymer nanoparticles containing magnetite and the T-cell growth factor interleukin-2 (IL-2). The number of T cells obtained was comparable to clinical standards using a thousand-fold less soluble IL-2. T cells obtained from this expansion were able to delay tumour growth in a murine model for melanoma. Our results show that this composite is a useful platform for generating large numbers of cytotoxic T cells for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

A new class of pH-responsive multivalent host–guest interactions to manipulate polypeptide-based nano-vehicles was developed. Poly(l-lysine) (poly(Lys)) grafted with β-cyclodextrin and 2,3-dimethylmaleic acid was coupled with oleic acid. This new polymer was utilized to fabricate pH-responsive nano-vehicles for antitumor drug doxorubicin delivery. The host–guest (zipping) interaction between β-cyclodextrin and 2,3-dimethylmaleic acid moieties and the hydrophobic interaction between the oleic acid molecules contributed to form self-assembled nano-vehicles. 2,3-Dimethylmaleic acid moieties were highly degradable at a slightly acidic pH (~pH 6.8). These nano-vehicles increased the release of the encapsulated doxorubicin content (by the unzipping interaction between β-cyclodextrin and degraded 2,3-dimethylmaleic acid moieties) when the pH of the solution decreased to 6.8. This event caused a significant increase in the efficiency of cellular doxorubicin uptake and in vitro tumor inhibition. [ABSTRACT FROM AUTHOR]

Purpose Combined therapeutic and diagnostic agents, 'theranostics' are emerging valuable tools for noninvasive imaging and drug delivery. Here, we report on a solid biodegradable multifunctional nanoparticle that combines both features. Methods Poly(lactide- co-glycolide) nanoparticles were engineered to confine superparamagnetic iron oxide contrast for magnetic resonance imaging while enabling controlled drug delivery and targeting to specific cells. To achieve this dual modality, fatty acids were used as anchors for surface ligands and for encapsulated iron oxide in the polymer matrix. Results We demonstrate that fatty acid modified iron oxide prolonged retention of the contrast agent in the polymer matrix during degradative release of drug. Antibody-fatty acid surface modification facilitated cellular targeting and subsequent internalization in cells while inducing clustering of encapsulated fatty-acid modified superparamagnetic iron oxide during particle formulation. This induced clustered confinement led to an aggregation within the nanoparticle and, hence, higher transverse relaxivity, r2, (294 mM−1 s−1) compared with nanoparticles without fatty-acid ligands (160 mM−1 s−1) and higher than commercially available superparamagnetic iron oxide nanoparticles (89 mM−1 s−1). Conclusion Clustering of superparamagnetic iron oxide in poly(lactide- co-glycolide) did not affect the controlled release of encapsulated drugs such as methotrexate or clodronate and their subsequent pharmacological activity, thus highlighting the full theranostic capability of our system. Magn Reson Med 70:1748-1760, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this study, a novel drug-carrying micelle composed of methoxy poly(ethylene glycol) (mPEG)- b-poly(L-lactic acid) (PLLA) with gas-forming carbonate linkage was fabricated. Here, the gas-forming carbonate linkage was formed by the chemical coupling of the terminal hydroxyl group of the PLLA block and benzyl chloroformate (BC). mPEG- b-PLLA-BC was self-organized in aqueous solution: the PEG block on the hydrophilic outer shell and the PLLA-BC block in the hydrophoboic innor core. The cleavage of carbonate linkage by hydrolysis and formation of carbon dioxide nanobubbles in the micellar core enabled an accelerated release of the encapsulated anticancer drug (doxorubicin: DOX) from the mPEG- b-PLLA-BC micelles. The amount of drug (DOX) released from the mPEG- b-PLLA-BC micelle was higher than that from the conventional mPEG- b-PLLA micelle, which allowed for increased in vitro toxicity against KB tumor cells. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The diagnosis of bacterial infections remains a major challenge in medicine. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Here, we present a family of contrast agents, termed maltodextrin-based imaging probes (MDPs), which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism that is independent of host response and secondary pathologies. MDPs are composed of a fluorescent dye conjugated to maltohexaose, and are rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the MDPs with a unique combination of high sensitivity and specificity for bacteria. Here, we show that MDPs selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, we demonstrate that MDPs can image as few as 105 colony-forming units in vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria. [ABSTRACT FROM AUTHOR]

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion. [ABSTRACT FROM AUTHOR]

New biodegradable and pH-sensitive block copolymers were prepared by grafting 1-(3-aminopropyl) imidazole onto a backbone polymer formed via condensation polymerization between l-cystine and EDTA-dianhydride. The copolymer with a graft ratio of 79% exhibited a good buffering capacity and pH sensitivity. These are attributed to protonation-deprotonation of the imidazole ring at around pH 7. The copolymers with less imidazole content did not show any apparent responses to changes in pH. The particle size of the copolymer aggregate formed under basic conditions was around 200 nm and increased with decreasing pH. The critical aggregation values at pH 6.0 and 8.0, derived from the changes of intensity ratios ( I1/ I3) in the emission spectrums of pyrene, were approximately 0.17 and 0.05 mg/ml, respectively. The surface charge of the aggregates increased with the decreasing pH as a result of the increase in protonation of imidazole and the tertiary amine in the polymer chain. The microviscosity of hydrophobic domains was estimated using 1,6-diphenyl-1,3,5-hexatriene. The decrease of the anisotropy value under acidic conditions reflects a disruption of hydrophobic interaction. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients. [ABSTRACT FROM AUTHOR]

In this study, we report the hyaluronate dot (dHA) with multiligand targeting ability and a photosensitizing antitumor model drug for treating metastatic bone tumors. Here, the dHA was chemically conjugated with alendronate (ALN, as a specific ligand to bone), cyclic arginine-glycine-aspartic acid (cRGD, as a specific ligand to tumor integrin αvβ3), and photosensitizing chlorin e6 (Ce6, for photodynamic tumor therapy), denoted as (ALN/cRGD)@dHA-Ce6. These dots thus prepared (≈10 nm in diameter) enabled extensive cellular interactions such as hyaluronate (HA)-mediated CD44 receptor binding, ALN-mediated bone targeting, and cRGD-mediated tumor integrin αvβ3 binding, thus improving their tumor targeting efficiency, especially for metastasized MDA-MB-231 tumors. As a result, these dots improved the tumor targeting efficiency and tumor cell permeability in a metastatic in vivo tumor model. Indeed, we demonstrated that (ALN/cRGD)@dHA-Ce6 considerably increased photodynamic tumor ablation, the extent of which is superior to that of the tumor ablation of dot systems with single or double ligands. These results indicate that dHA with multiligand can provide an effective treatment strategy for metastatic bone tumors. [ABSTRACT FROM AUTHOR]

In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host–guest interaction between γCDP and TPT. More importantly, the γCDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (~6.0) resulting from the chemical detachment of DMA from γCDP, which is followed by extensive TPT release. We demonstrated that γCDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that γCDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery. [ABSTRACT FROM AUTHOR]

Background: Very few proteins encoded by the presumed non-coding RNA transcripts have been identified. Their cellular functions remain largely unknown. This study identifies the tumor-suppressor function of a novel microprotein encoded by the precursor of miR-34a. It consists of 133 amino acid residues, thereby named as miPEP133 (pri-microRNA encoded peptide 133). Methods: We overexpressed miPEP133 in nasopharyngeal carcinoma (NPC), ovarian cancer and cervical cancer cell lines to determine its effects on cell growth, apoptosis, migration, or invasion. Its impact on tumor growth was evaluated in a xenograft NPC model. Its prognostic value was analyzed using NPC clinical samples. We also conducted western blot, immunoprecipitation, mass spectrometry, confocal microscopy and flow cytometry to determine the underlying mechanisms of miPEP133 function and regulation. Results: miPEP133 was expressed in normal human colon, stomach, ovary, uterus and pharynx. It was downregulated in cancer cell lines and tumors. miPEP133 overexpression induced apoptosis in cancer cells and inhibited their migration and invasion. miPEP133 inhibited tumor growth in vivo. Low miPEP133 expression was an unfavorable prognostic marker associated with advanced metastatic NPC. Wild-type p53 but not mutant p53 induced miPEP133 expression. miPEP133 enhanced p53 transcriptional activation and miR-34a expression. miPEP133 localized in the mitochondria to interact with mitochondrial heat shock protein 70kD (HSPA9) and prevent HSPA9 from interacting with its binding partners, leading to the decrease of mitochondrial membrane potential and mitochondrial mass. Conclusion: miPEP133 is a tumor suppressor localized in the mitochondria. It is a potential prognostic marker and therapeutic target for multiple types of cancers. [ABSTRACT FROM AUTHOR]

In this study, the synthesis of a novel catalyst WO3/MoCl5 was carried out by the thermal method. The method gave an entirely different product compared to previous studies that doped Mo on the surface of semiconductor metal oxides. The degradation reaction of crystal violet (CV) and rhodamine B (RB) dye were done without any energy source. The results showed an incomparably superior result for degradation, with a reaction rate constant of 1.74 s−1 for 30 ppm CV, 1.08 s−1 for 30 ppm RB, and a higher value than 1 s−1 for both cases of 50 ppm dye solution. To the author's knowledge, this catalyst has the highest reaction rate compared to other studies that targeted CV and RB, with an immense reaction rate increase of more than 100 times. Reusability of the three trials was verified, and the only process required was washing the catalyst after the reaction. One of the drawbacks of the advanced oxidation process (AOP), which has a degradation percent limit, has been solved, since 100% mineralization of the dye was available using this catalyst. FT-IR spectroscopy revealed that W-O-Mo linkage was successfully processed while Mo-Cl linkage has retained. 1H-NMR spectroscopy results confirmed that the degradation product of the dye treated by simple MoCl5 and WO3/MoCl5 was different. Deep inspection of specific regions of NMR fields gave necessary information about the degradation product using WO3/MoCl5. [ABSTRACT FROM AUTHOR]

Patients with epithelial ovarian cancer have the best overall survival when maximal surgical effort is accomplished. However, despite numerous technological advances, surgery still relies primarily on white-light reflectance and the surgeon's vision. As such, micrometastases are usually missed and most patients clinically classified as a complete responder eventually recur and succumb to the disease. Our objective is to develop optical enhancers which can aid in the visualization of ovarian cancer micrometastasis. To this end we developed a nanoparticle (NP) platform, which is specifically targeted to the tumor microenvironment. Targeting is achieved by coating FDA-approved PLGA-PEG NP with the peptide sequence RGD, which binds with high affinity to αVβ3 integrins present in both the tumor-associated neovasculature and on the surface of ovarian cancer cells. Administration of the NP platform carrying fluorescent dyes to mice bearing intraperitoneal ovarian cancer allowed visualization of tumor-associated vasculature and its contrast against normal blood vessels. More importantly, we demonstrate the visualization of intraperitoneal ovarian cancer micrometastasis as small as 100 μm with optimal resolution. Finally, we demonstrate that the fluorescent dye cargo was able to penetrate intra-tumorally. Such modality could be used to allow microscopic surgical debulking to assure maximal surgical effort. [ABSTRACT FROM AUTHOR]

A correction to the article "A carbon nanotube?polymer composite for T-cell therapy" that was published in the 2014 issue is presented.