DNA-Templated Nanofabrication of CdS-Au Nanoscale Schottky Contacts and Electrical Characterization.

DNA-templated nanofabrication presents an innovative approach to creating self-assembled nanoscale metal-semiconductor-based Schottky contacts, which can advance nanoelectronics. Herein, we report the successful fabrication of metal-semiconductor Schottky contacts using a DNA origami scaffold. The scaffold, consisting of DNA strands organized into a specific linear architecture, facilitates the competitive arrangement of Au and CdS nanorods, forming heterojunctions, and addresses previous limitations in low electrical conductance making DNA-templated electronics with semiconductor nanomaterials. Electroless gold plating extends the Au nanorods and makes the necessary electrical contacts. Tungsten electrical connection lines are further created by electron beam-induced deposition. Electrical characterization reveals nonlinear Schottky barrier behavior, with electrical conductance ranging from 0.5 × 10-4 to 1.7 × 10-4 S. The conductance of these DNA-templated junctions is several million times higher than with our prior Schottky contacts. Our research establishes an innovative self-assembly approach with applicable metal and semiconductor materials for making highly conductive nanoscale Schottky contacts, paving the way for the future development of DNA-based nanoscale electronics.

Immunogenic Treatment of Metastatic Breast Cancer Using Targeted Carbon Nanotube Mediated Photothermal Therapy in Combination with Anti-Programmed Cell Death Protein-1.

The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single-walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anticancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45°C). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-programmed cell death protein-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. SIGNIFICANCE STATEMENT: This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-programmed cell death protein-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45°C and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.

Implementation of the national antimicrobial stewardship competencies for UK undergraduate healthcare professional education within undergraduate pharmacy programmes: a survey of UK schools of pharmacy.

Background: Pharmacists play a key role in antimicrobial stewardship (AMS). Consensus-based national AMS competencies for undergraduate healthcare professionals in the UK reflect the increasing emphasis on competency-based healthcare professional education. However, the extent to which these are included within undergraduate pharmacy education programmes in the UK is unknown. Objectives: To explore which of the AMS competencies are delivered, including when and at which level, within UK undergraduate MPharm programmes. Methods: A cross-sectional online questionnaire captured the level of study of the MPharm programme in which each competency was taught, the method of delivery and assessment of AMS education, and examples of student feedback. Results: Ten institutions completed the survey (33% response rate). No institution reported covering all 54 AMS competencies and 5 of these were taught at half or fewer of the institutions. Key gaps were identified around taking samples, communication, outpatient parenteral antimicrobial therapy and surgical prophylaxis. The minimum time dedicated to AMS teaching differed between institutions (range 9-119 h), teaching was generally through didactic methods, and assessment was generally through knowledge recall and objective structured clinical examinations. Feedback from students suggests they find AMS and antimicrobial resistance (AMR) to be complex yet important topics. Conclusions: UK schools of pharmacy should utilize the competency framework to identify gaps in their AMS, AMR and infection teaching. To prepare newly qualified pharmacists to be effective at delivering AMS and prescribing antimicrobials, schools of pharmacy should utilize more simulated environments and clinical placements for education and assessment of AMS.

Education of the public health workforce and the Sustainable Development Goals: An analysis of existing competency sets.

Objectives: This paper describes a project designed to quantify the extent to which existing competency frameworks used for educating the public health workforce contribute to achieving the Sustainable Development Goals (SDGs) directly relevant to public health. Study design: This was a qualitative study involving a content and thematic analysis and mapping of nine available public health competency sets against the World Federation of Public Health Association's Global Charter for the Public's Health and the SDGs. Methods: First, the SDG targets directly relevant to public health were selected, then mapped against the elements of the Global Charter to illustrate their alignment with aspects of public health practice. Next, competencies from each respective framework were mapped against the SDG targets, and the results quantified as to the coverage of the SDG targets by each of the frameworks. Results: Overall, very few competencies directly or fully covered the SDG targets in question, however, there were more competencies partially covering the targets. Except for one framework, many issues found in the SDG targets were not explicitly addressed by the competencies in most of the frameworks, namely, migration, human rights, violence, and food and water scarcity. Conclusions: Overall, urgent action is required to ensure public health competency frameworks are more in line with the SDGs and include public health issues that disproportionally affect low- and middle-income countries.

A qualitative investigation of perceptions towards antibiotics by members of the public after choosing to pledge as an Antibiotic Guardian.

INTRODUCTION: Antimicrobial resistance is one of the biggest threats facing global humanity. In 2014, Public Health England (now the UK Health Security Agency) launched the Antibiotic Guardian (AG) campaign as a national health promotion initiative to increase public and health professionals' commitment to reducing the threat of antibiotic resistance (ABR). The aim of this research study was to gain a snapshot of public AG attitudes towards antibiotic use, the AG campaign and illness postpledge. METHODOLOGY: This research used an exploratory study design using thematic and framework analysis of semistructured, in-depth interviews. A purposive convenience sampling strategy was used to recruit 10 participants; adults in the general population who had registered with and chosen an AG pledge via the AG online platform during November 2020 were eligible for inclusion. Interviews were conducted via Zoom. RESULTS: Six main themes were identified: campaign awareness, motivators to pledge (uncertainty about the future of ABR, personal gratification, personal responsibility, moral obligation and COVID-19), perceptions of personal responsibility (and patient perspectives of moral obligation in clinicians), the impact of the campaign and campaign promotion. Pledging appeared to solidify existing perceptions AGs held. Behavioural motivations for responsible antibiotic behaviours stemmed from perceptions of personal responsibility, moral obligation and concerns about ABR. AGs attributed responsibility to variable patterns in overprescribing. Perceptions towards COVID-19, coinciding with the previously established study period, appeared mixed. AGs were keen to promote responsible perceptions in relation to antibiotics, resistance and the AG campaign. However, poor social acceptability of ABR concern was raised as a barrier to campaign promotion. DISCUSSION: The AGs' longstanding commitment to antimicrobial resistance demonstrates the importance of a pre-existing interest in the public's self-reported judicious behaviours and decision to pledge to an ABR-focused campaign. Presenting the local and global threat to human mortality and morbidity in a more relatable format in public messaging should be considered in future strategies promoting ABR awareness and shifts in public perceptions. More frequent messaging to existing AGs is further recommended to propagate positive behaviour change among a wider audience. PATIENT OR PUBLIC CONTRIBUTION: This study was based on interviews with adult members of the public who had pledged to be AGs via the website www.AntibioticGuardian.com. Interviews were based on the public's perceptions of the AG campaign, antibiotic use and ABR.

Simulation and experimental verification of ambient neutron doses in a pencil beam scanning proton therapy room as a function of treatment plan parameters.

Out-of-field patient doses in proton therapy are dominated by neutrons. Currently, they are not taken into account by treatment planning systems. There is an increasing need to include out-of-field doses in the dose calculation, especially when treating children, pregnant patients, and patients with implants. In response to this demand, this work presents the first steps towards a tool for the prediction of out-of-field neutron doses in pencil beam scanning proton therapy facilities. As a first step, a general Monte Carlo radiation transport model for simulation of out-of-field neutron doses was set up and successfully verified by comparison of simulated and measured ambient neutron dose equivalent and neutron fluence energy spectra around a solid water phantom irradiated with a variation of different treatment plan parameters. Simulations with the verified model enabled a detailed study of the variation of the neutron ambient dose equivalent with field size, range, modulation width, use of a range shifter, and position inside the treatment room. For future work, it is planned to use this verified model to simulate out-of-field neutron doses inside the phantom and to verify the simulation results by comparison with previous in-phantom measurement campaigns. Eventually, these verified simulations will be used to build a library and a corresponding tool to allow assessment of out-of-field neutron doses at pencil beam scanning proton therapy facilities.

Controlling Nanoparticle Uptake in Innate Immune Cells with Heparosan Polysaccharides.

We used heparosan (HEP) polysaccharides for controlling nanoparticle delivery to innate immune cells. Our results show that HEP-coated nanoparticles were endocytosed in a time-dependent manner by innate immune cells via both clathrin-mediated and macropinocytosis pathways. Upon endocytosis, we observed HEP-coated nanoparticles in intracellular vesicles and the cytoplasm, demonstrating the potential for nanoparticle escape from intracellular vesicles. Competition with other glycosaminoglycan types inhibited the endocytosis of HEP-coated nanoparticles only partially. We further found that nanoparticle uptake into innate immune cells can be controlled by more than 3 orders of magnitude via systematically varying the HEP surface density. Our results suggest a substantial potential for HEP-coated nanoparticles to target innate immune cells for efficient intracellular delivery, including into the cytoplasm. This HEP nanoparticle surface engineering technology may be broadly used to develop efficient nanoscale devices for drug and gene delivery as well as possibly for gene editing and immuno-engineering applications.

Neutron Radiation Dose Measurements in a Scanning Proton Therapy Room: Can Parents Remain Near Their Children During Treatment?

Purpose: This study aims to characterize the neutron radiation field inside a scanning proton therapy treatment room including the impact of different pediatric patient sizes. Materials and Methods: Working Group 9 of the European Radiation Dosimetry Group (EURADOS) has performed a comprehensive measurement campaign to measure neutron ambient dose equivalent, H*(10), at eight different positions around 1-, 5-, and 10-year-old pediatric anthropomorphic phantoms irradiated with a simulated brain tumor treatment. Several active detector systems were used. Results: The neutron dose mapping within the gantry room showed that H*(10) values significantly decreased with distance and angular deviation with respect to the beam axis. A maximum value of about 19.5 µSv/Gy was measured along the beam axis at 1 m from the isocenter for a 10-year-old pediatric phantom at 270° gantry angle. A minimum value of 0.1 µSv/Gy was measured at a distance of 2.25 m perpendicular to the beam axis for a 1-year-old pediatric phantom at 140° gantry angle.The H*(10) dependence on the size of the pediatric patient was observed. At 270° gantry position, the measured neutron H*(10) values for the 10-year-old pediatric phantom were up to 20% higher than those measured for the 5-year-old and up to 410% higher than for the 1-year-old phantom, respectively. Conclusions: Using active neutron detectors, secondary neutron mapping was performed to characterize the neutron field generated during proton therapy of pediatric patients. It is shown that the neutron ambient dose equivalent H*(10) significantly decreases with distance and angle with respect to the beam axis. It is reported that the total neutron exposure of a person staying at a position perpendicular to the beam axis at a distance greater than 2 m from the isocenter remains well below the dose limit of 1 mSv per year for the general public (recommended by the International Commission on Radiological Protection) during the entire treatment course with a target dose of up to 60 Gy. This comprehensive analysis is key for general neutron shielding issues, for example, the safe operation of anesthetic equipment. However, it also enables the evaluation of whether it is safe for parents to remain near their children during treatment to bring them comfort. Currently, radiation protection protocols prohibit the occupancy of the treatment room during beam delivery.

Out-of-Field Doses Produced by a Proton Scanning Beam Inside Pediatric Anthropomorphic Phantoms and Their Comparison With Different Photon Modalities.

Since 2010, EURADOS Working Group 9 (Radiation Dosimetry in Radiotherapy) has been involved in the investigation of secondary and scattered radiation doses in X-ray and proton therapy, especially in the case of pediatric patients. The main goal of this paper is to analyze and compare out-of-field neutron and non-neutron organ doses inside 5- and 10-year-old pediatric anthropomorphic phantoms for the treatment of a 5-cm-diameter brain tumor. Proton irradiations were carried out at the Cyclotron Centre Bronowice in IFJ PAN Krakow Poland using a pencil beam scanning technique (PBS) at a gantry with a dedicated scanning nozzle (IBA Proton Therapy System, Proteus 235). Thermoluminescent and radiophotoluminescent dosimeters were used for non-neutron dose measurements while secondary neutrons were measured with track-etched detectors. Out-of-field doses measured using intensity-modulated proton therapy (IMPT) were compared with previous measurements performed within a WG9 for three different photon radiotherapy techniques: 1) intensity-modulated radiation therapy (IMRT), 2) three-dimensional conformal radiation therapy (3D CDRT) performed on a Varian Clinac 2300 linear accelerator (LINAC) in the Centre of Oncology, Krakow, Poland, and 3) Gamma Knife surgery performed on the Leksell Gamma Knife (GK) at the University Hospital Centre Zagreb, Croatia. Phantoms and detectors used in experiments as well as the target location were the same for both photon and proton modalities. The total organ dose equivalent expressed as the sum of neutron and non-neutron components in IMPT was found to be significantly lower (two to three orders of magnitude) in comparison with the different photon radiotherapy techniques for the same delivered tumor dose. For IMPT, neutron doses are lower than non-neutron doses close to the target but become larger than non-neutron doses further away from the target. Results of WG9 studies have provided out-of-field dose levels required for an extensive set of radiotherapy techniques, including proton therapy, and involving a complete description of organ doses of pediatric patients. Such studies are needed for validating mathematical models and Monte Carlo simulation tools for out-of-field dosimetry which is essential for dedicated epidemiological studies which evaluate the risk of second cancers and other late effects for pediatric patients treated with radiotherapy.

Evaluating UK Pharmacy Workers' Knowledge, Attitudes and Behaviour towards Antimicrobial Stewardship and Assessing the Impact of Training in Community Pharmacy.

The Antibiotic Guardian (AG) campaign, developed in 2014 is an online 'pledge' approach to engage health workers and the public about antimicrobial resistance. It is underpinned by models of science communication and behaviour change. Since its launch until the end of 2021, more than 140,000 individuals pledged. A service evaluation was conducted to determine the impact of the campaign upon UK pharmacy workers, in response to national training introduced in 2020. Pledged pharmacy workers were sent an online questionnaire collating demographics, self-reported behaviour and opportunity to support prudent antibiotic use. It also investigated respondents' daily practice and antimicrobial stewardship (AMS) efforts, and motivations for pledging. Capability was measured with a set of knowledge questions. Awareness of changes to the Community Pharmacy Quality Scheme in England to include incentivized training on antimicrobial resistance (AMR) was explored. Of the 5344 pharmacy workers invited to participate, 783 (14.6%) responded to the survey. There was a statistically significant difference between job roles and capability score. Pharmacists, including Academic and Hospital Pharmacists and Pharmacy Technicians reported higher confidence and capability scores than Dispensers and Pharmacy Assistants (F = 13.776, p = 0.0002). Respondents reported strong knowledge on antimicrobial resistance and high confidence in fulfilling their AG stewardship pledge within daily practices (92.7% of all respondents answered all capability questions, as measured by knowledge, correctly). Two thirds of respondents (61.6% (423/693)) agreed or strongly agreed that they had access to and were able to utilise local antibiotic prescribing guidance and a similar proportion of responding community pharmacists (60%) were aware of the content of their workplace AMS plans. No statistically significant relationships were found between motivations for pledging and subsequent behaviour; pledging due to mandatory requirements of work-place training was the most common answer in both 2019 (42%) and 2020 (54%) cohorts. This evaluation supports the value of the AG pledge-based approach to engage and educate pharmacy workers. Reflections show its impact on increasing evidence-based stewardship for pharmacy workers and their response to mandatory training requirement by employers highlights the effectiveness of the AG campaign to promote AMS within pharmacy teams.

Annexin A5 as a targeting agent for cancer treatment.

Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly regulated and is an "eat me" signal for phagocytosis in healthy cells. Although cancer cells and vasculature express high levels of externalized PS, they do not undergo apoptosis, making them a promising biomarker for cancer treatment. Annexin A5 (ANXA5) is the native binding partner of PS and can actively target and deliver chemotherapies to the tumor microenvironment (TME) via PS expression. ANXA5 acts as a bridge between the innate and adaptive immune systems and contributes to an immunostimulatory profile in the TME. ANXA5-enzyme prodrug therapies allow for systemic delivery of prodrugs and targeted killing at the tumor site. ANXA5-carbon nanotube conjugates have been used to physically ablate tumors via photothermal therapy. This review aims to explore the expression of PS in cancer cells and how ANXA5 has been used as a chemotherapeutic and targeting agent for cancer.

Out-of-field doses in pediatric craniospinal irradiations with 3D-CRT, VMAT, and scanning proton radiotherapy: A phantom study.

PURPOSE: Craniospinal irradiation (CSI) has greatly increased survival rates for patients with a diagnosis of medulloblastoma and other primitive neuroectodermal tumors. However, as it includes exposure of a large volume of healthy tissue to unwanted doses, there is a strong concern about the complications of the treatment, especially for the children. To estimate the risk of second cancers and other unwanted effects, out-of-field dose assessment is necessary. The purpose of this study is to evaluate and compare out-of-field doses in pediatric CSI treatment using conventional and advanced photon radiotherapy (RT) and advanced proton therapy. To our knowledge, it is the first such comparison based on in-phantom measurements. Additionally, for out-of-field doses during photon RT in this and other studies, comparisons were made using analytical modeling. METHODS: In order to describe the out-of-field doses absorbed in a pediatric patient during actual clinical treatment, an anthropomorphic phantom, which mimics the 10-year-old child, was used. Photon 3D-conformal RT (3D-CRT) and two advanced, highly conformal techniques: photon volumetric-modulated arc therapy (VMAT) and active pencil beam scanning (PBS) proton RT were used for CSI treatment. Radiophotoluminescent and poly-allyl-diglycol-carbonate nuclear track detectors were used for photon and neutron dosimetry in the phantom, respectively. Out-of-field doses from neutrons were expressed in terms of dose equivalent. A two-Gaussian model was implemented for out-of-field doses during photon RT. RESULTS: The mean VMAT photon doses per target dose to all organs in this study were under 50% of the target dose (i.e., <500 mGy/Gy), while the mean 3D-CRT photon dose to oesophagus, gall bladder, and thyroid, exceeded that value. However, for 3D-CRT, better sparing was achieved for eyes and lungs. The mean PBS photon doses for all organs were up to three orders of magnitude lower compared to VMAT and 3D-CRT and exceeded 10 mGy/Gy only for the oesophagus, intestine, and lungs. The mean neutron dose equivalent during PBS for eight organs of interest (thyroid, breasts, lungs, liver, stomach, gall bladder, bladder, prostate) ranged from 1.2 mSv/Gy for bladder to 23.1 mSv/Gy for breasts. Comparison of out-of-field doses in this and other phantom studies found in the literature showed that a simple and fast two-Gaussian model for out-of-field doses as a function of distance from the field edge can be applied in a CSI using photon RT techniques. CONCLUSIONS: PBS is the most promising technique for out-of-field dose reduction in comparison to photon techniques. Among photon techniques, VMAT is a preferred choice for most of out-of-field organs and especially for the thyroid, while doses for eyes, breasts, and lungs are lower for 3D-CRT. For organs outside the field edge, a simple analytical model can be helpful for clinicians involved in treatment planning using photon RT but also for retrospective data analysis for cancer risk estimates and epidemiology in general.

A General Public Study on Preferences and Welfare Impacts of Antimicrobial Resistance in the United Kingdom.

BACKGROUND: Antibiotics have led to considerable increases in life expectancy. However, over time, antimicrobial resistance has accelerated and is now a significant global public health concern. Understanding societal preferences for the use of antibiotics as well as eliciting the willingness to pay for future research is crucial. OBJECTIVE: To investigate preferences for different strategies to optimize antibiotic use and to understand the willingness to pay for future research in antimicrobial resistance and antimicrobial drug development. METHODS: A discrete-choice experiment was administered to a sample of the UK general population. Respondents were asked to make nine choices, each offering three options-two hypothetical "doctor and antibiotics" and one "no doctor-no antibiotics"-defined by five attributes: treatment, days needed to recover, risk of bacterial infection that needs antibiotics, risk of common side effects, and risk of antimicrobial resistance by 2050. Data were analyzed using random parameters logit models. A double-bounded contingent valuation was also included in the survey to explore the willingness to pay for policies to contain antimicrobial resistance. RESULTS: Among the 2579 respondents who completed the survey, 1151 always selected "no doctor-no antibiotics" and 57 never varied their choices; therefore, 1371 responses were used in the analysis. Risk of antimicrobial resistance by 2050 was the most important attribute and the "treatment" was the least important attribute, although this was sensitive to a higher risk of bacterial infection. The aggregate annual willingness to pay for containing antimicrobial resistance was approximately £8.35 billion (~£5-£10 billion). CONCLUSIONS: The antimicrobial resistance risk is relevant and important to the general public. The high willingness to pay suggests that large investments in policies or interventions to combat antimicrobial resistance are justified.

Risk factors associated with albuminuria in Rwanda: results from a STEPS survey.

BACKGROUND: Non-communicable diseases (NCDs) are a growing burden which affects every part of the world, including developing countries. Chronic kidney disease (CKD) has varied etiology which can result from or complicate other NCDs such as diabetes and cardiovascular diseases. The growing prevalence of NCDs coupled with the increasing age in most developing countries, has seen a marked increase of CKD in these settings. CKD has been described as "the most neglected NCD" and greatly affects the quality of life of patients. It also places a huge economic burden on societies. However, few epidemiological data exist, particularly in sub-Saharan Africa. Assessment of the prevalence of albuminuria as a marker of kidney damage and CKD progression and its main risk factors was thus needed in Rwanda. METHODS: This study analyzed data collected during the first STEPwise approach to NCD risk factor Surveillance (STEPS) survey in Rwanda, conducted from 2012 to 2013, to assess the prevalence of albuminuria. A multistage cluster sampling allowed to select a representative sample of the general population. Furthermore, descriptive, as well as univariable analyses and multiple logistic regression were performed to respond to the research question. RESULTS: This survey brought a representative sample of 6,998 participants, among which 4,384 (62.65%) were female. Median age was 33 years (interquartile range, IQR 26-44), and over three quarters (78.45%) lived in rural areas. The albuminuria prevalence was 105.9 per 1,000 population. Overall, semi-urban and urban residency were associated with lower odds of CKD (odds ratio, OR 0.36, CI 0.23-0.56, p<0.001 and OR 0.34, CI 0.23-0.50, p<0.001, respectively) than rural status. Being married or living with a partner had higher odds (OR 1.44 (CI 1.03-2.02, p=0.031) and OR 1.62 (CI 1.06-2.48, p=0.026), respectively) of CKD than being single. Odds of positive albuminuria were also greater among participants living with human immunodeficiency virus (HIV) (OR 1.64, CI 1.09- 2.47, p=0.018). Gender, age group, smoking status and vegetable consumption, body mass index (BMI) and hypertension were not associated with albuminuria. CONCLUSION: The albuminuria prevalence was estimated at 105.9 per 1,000 in Rwanda. Rural residence, partnered status and HIV positivity were identified as main risk factors for albuminuria. Increased early screening of albuminuria to prevent CKD among high-risk groups, especially HIV patients, is therefore recommended.

A selective fluorescence sensor for hypochlorite used for the detection of hypochlorite in zebrafish.

Hypochlorite is used as a water disinfectant and it is also produced by biological organisms. Its detection and quantification is important and could lead to its mechanism of reactivity in cells. We have synthesized a new fluorescence sensor for hypochlorite based on bithiophene and furan-carbohydrazide. The sensor shows increased fluorescence as a function of hypochlorite and is selective for hypochlorite. Fluorescence enhancement due to hypochlorite is observed when the sensor is used in aqueous solutions at neutral pH values. Using the sensor, the detection limit for hypochlorite is 4.2 µM, making the sensor practical to determine hypochlorite in water. Applying the sensor to aide in the detection of hypochlorite in zebrafish, showed localization of ClO-/HClO in the air bladders and eyes of zebrafish.

Targeted Single-Walled Carbon Nanotubes for Photothermal Therapy Combined with Immune Checkpoint Inhibition for the Treatment of Metastatic Breast Cancer.

The greatest contributors to cancer mortality are metastasis and the consequences of its treatment. Here, we present a novel treatment of metastatic breast cancer that combines photothermal therapy with targeted single-walled carbon nanotubes (SWCNTs) and immunostimulation with a checkpoint inhibitor. We find that the selective near-infrared photothermal ablation of primary orthotopic EMT6 breast tumors in syngeneic BALB/cJ mice using an annexin A5 (ANXA5) functionalized SWCNT bioconjugate synergistically enhances an anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)-dependent abscopal response, resulting in an increased survival (55%) at 100 days after tumor inoculation. In comparison, there was no survival at 100 days for either photothermal therapy by itself or immunostimulation by itself. Prior to photothermal therapy, the SWCNT-ANXA5 bioconjugate was administered systemically at a relatively low dose of 1.2 mg/kg, where it then accumulated in tumor vasculature via ANXA5-dependent binding. During photothermal therapy, the average maximum temperature in the tumor reached 54 °C (duration 175 s). The mechanism of prolonged survival resulting from combinatorial photothermal ablation and immune stimulation was evaluated by flow cytometric quantification of splenic antitumoral immune effector cells and serum cytokine quantification.

Mechanism and Kinetics of Copper Complexes Binding to the Influenza A M2 S31N and S31N/G34E Channels.

Copper(II) is known to bind in the influenza virus His37 cluster in the homotetrameric M2 proton channel and block the proton current needed for uncoating. Copper complexes based on iminodiacetate also block the M2 proton channel and show reduced cytotoxicity and zebrafish-embryo toxicity. In voltage-clamp oocyte studies using the ubiquitous amantadine-insensitive M2 S31N variant, the current block showed fast and slow phases, in contrast to the single phase found for amantadine block of wild-type M2. Here, we evaluate the mechanism of block by copper adamantyl iminodiacitate and copper cyclooctyl iminodiacitate complexes and address whether the complexes can coordinate with one or more of the His37 imidazoles. The current traces were fitted to parametrized master equations. The energetics of binding and the rate constants suggest that the first step is copper complex binding within the channel, and the slow step in the current block is the formation of a Cu-histidine coordination complex. Solution-phase isothermal titration calorimetry and density functional theory (DFT) calculations indicate that imidazole binds to the copper complexes. Structural optimization using DFT reveals that the complexes fit inside the channel and project the Cu(II) toward the His37 cluster, allowing one imidazole to form a coordination complex with Cu(II). Electrophysiology and DFT studies also show that the complexes block the G34E amantadine-resistant mutant despite some crowding in the binding site by the glutamates.