Structure Guided Discovery of Novel Pan Metallo-ß-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.

Quantifying refractive error in companion dogs with and without nuclear sclerosis: 229 eyes from 118 dogs.

OBJECTIVE: To evaluate the relationship between nuclear sclerosis (NS) and refractive error in companion dogs. ANIMALS STUDIED: One hundred and eighteen companion dogs. PROCEDURES: Dogs were examined and found to be free of significant ocular abnormalities aside from NS. NS was graded from 0 (absent) to 3 (severe) using a scale developed by the investigators. Manual refraction was performed. The effect of NS grade on refractive error was measured using a linear mixed effects analysis adjusted for age. The proportion of eyes with >1.5 D myopia in each NS grade was evaluated using a chi-square test. Visual impairment score (VIS) was obtained for a subset of dogs and compared against age, refractive error, and NS grade. RESULTS: Age was strongly correlated with NS grade (p < .0001). Age-adjusted analysis of NS grade relative to refraction showed a mild but not statistically significant increase in myopia with increasing NS grade, with eyes with grade 3 NS averaging 0.58-0.88 D greater myopia than eyes without NS. However, the myopia of >1.5 D was documented in 4/58 (6.9%) eyes with grade 0 NS, 12/91 (13.2%) eyes with grade 1 NS, 13/57 (22.8%) eyes with grade 2 NS, and 7/23 (30.4%) eyes with grade 3 NS. Risk of myopia >1.5 D was significantly associated with increasing NS grade (p = .02). VIS was associated weakly with refractive error, moderately with age, and significantly with NS grade. CONCLUSIONS: NS is associated with visual deficits in some dogs but is only weakly associated with myopia. More work is needed to characterize vision in aging dogs.

Sustained Release of Dexamethasone from 3D-Printed Scaffolds Modulates Macrophage Activation and Enhances Osteogenic Differentiation.

Enhancing osteogenesis via modulating immune cells is emerging as a new approach to address the current challenges in repairing bone defects and fractures. However, much remains unknown about the crosstalk between immune cells and osteolineage cells during bone formation. Moreover, biomaterial scaffold-based approaches to effectively modulate this crosstalk to favor bone healing are also lacking. This study is the first to investigate the interactions between macrophages and mesenchymal stem cells (MSCs) in co-cultures with the sustained release of an anti-inflammatory and pro-osteogenesis drug (dexamethasone) from three-dimensional (3D)-printed scaffolds. We successfully achieved the sustained release of dexamethasone from polycaprolactone (PCL) by adding the excipient-sucrose acetate isobutyrate (SAIB). Dexamethasone was released over 35 days in the 17-163 nM range. The osteogenic differentiation of MSCs was enhanced by M1 macrophages at early time points. The late-stage mineralization was dominated by dexamethasone, with little contribution from the macrophages. Besides confirming BMP-2 whose secretion was promoted by both dexamethasone and M1 macrophages as a soluble mediator for enhanced osteogenesis, IL-6 was found to be a possible new soluble factor that mediated osteogenesis in macrophage-MSC co-cultures. The phenotype switching from M1 to M2 was drastically enhanced by the scaffold-released dexamethasone but only marginally by the co-cultured MSCs. Our results offer new insight into macrophage-MSC crosstalk and demonstrate the potential of using drug-release scaffolds to both modulate inflammation and enhance bone regeneration.

Assessing the effect of adverse economic events on severity of hunger among food pantry clients.

This study assessed relationship between adverse economic events (AEE) and hunger level (i.e., little to no, moderate, severe). A cross-sectional survey was conducted from June to August 2018 in 10 food pantries with 616 food pantry users. Hunger level was assessed by the Household Hunger Scale. AEE were evaluated over the past 3 months. Participants (60.55%) experienced unexpected or increased medical expenses (17.69%), job loss (13.64%), pay reduction (11.85%), and death of a family member (9.09%). Pay reduction (OR = 1.87, 95% CI: 1.12, 3.14) and increased debt (OR = 2.71, 95% CI: 1.92, 3.84) were associated with moderate hunger; death of a family member (OR = 2.43, 95% CI: 1.21, 4.90), pay reduction (OR = 2.95, 95% CI: 1.24, 7.04), and increased debt (OR = 3.46, 95% CI: 1.98, 6.04) were associated with severe hunger. Awareness of AEE can inform public health programs and policies for people in need of additional resources, which is essential in times of increased economic instability.

Socio-demographic factors associated with hunger among food pantry users in Eastern Massachusetts.

To assess the determinants of hunger among food pantry users, the present study used a cross-sectional survey that included a modified Household Hunger Scale to quantify hunger. Mixed-effects logistic regression models were used to assess the relationship between hunger categories and various household socio-demographic and economic characteristics, such as age, race, household size, marital status and experience of any economic hardship. The survey was administered to food pantry users from June 2018 to August 2018 at various food pantries across Eastern Massachusetts with 611 food pantry users completing the questionnaire at any of the 10 food pantry sites. One-fifth (20⋅13 %) of food pantry users experienced moderate hunger and 19⋅14 % experienced severe hunger. Food pantry users who were single, divorced or separated; had less than a high school education; working part-time, unemployed or retired; or, who earned incomes less than $1000 per month were most likely to experience severe or moderate hunger. Pantry users who experienced any economic hardship had 4⋅78 the adjusted odds of severe hunger (95 % CI 2⋅49, 9⋅19), which was much larger than the odds of moderate hunger (AOR 1⋅95; 95 % CI 1⋅10, 3⋅48). Younger age and participation in WIC (AOR 0⋅20; 95 % CI 0⋅05-0⋅78) and SNAP (AOR 0⋅53; 95 % CI 0⋅32-0⋅88) were protective against severe hunger. The present study illustrates factors affecting hunger in food pantry users, which can help inform public health programmes and policies for people in need of additional resources. This is essential particularly in times of increasing economic hardships recently exacerbated by the COVID-19 pandemic.

Comparing COVID-19-related Morbidity and Mortality Between Patients With and Without Substance Use Disorders: A Retrospective Cohort Study.

Objectives: People with substance use disorders (SUD) are suggested to have higher risk of hospitalization, intubation, or death from coronavirus disease 2019 (COVID-19), although data are mixed. Little is known about other COVID-19-related complications in this group. We compared morbidity and mortality among individuals with and without SUD who were admitted to an urban safety net hospital with COVID-19 early in the pandemic, contemporaneous to other published studies on this subject. Methods: We performed a retrospective study of patients ⩾18 years old admitted with COVID-19 from March 16th to April 8th, 2020. SUD included alcohol, opioid, cocaine, amphetamine, and benzodiazepine use disorders and was identified using diagnostic codes, free text clinical documentation, and urine drug screens. The primary outcome was inpatient mortality. Secondary outcomes included clinical complications (eg, secondary infections, venous thromboembolism) and resource utilization (eg, mechanical ventilation, length of stay). We used multivariable regression to assess the relationship between SUD and mortality. Results: Of 409 patients, the mean age was 56 years and 13.7% had SUD. Those with SUD were more likely to be male, have experienced homelessness, have pulmonary disease or hepatitis C, or use tobacco or cannabis. After multivariable analysis, SUD was not associated with mortality (aOR 1.03; 95% CI, 0.31-3.10). Secondary outcomes were also similar between groups. Conclusions: Our findings suggest that persons with and without SUD have similar COVID-19-related outcomes. Previously reported increased COVID-19 complications may be from medical comorbidities.

Comparison of echocardiography, biomarkers and taurine concentrations in cats eating high- or low-pulse diets.

OBJECTIVES: There are ongoing investigations into diet-associated dilated cardiomyopathy in dogs, but there has been minimal investigation into possible diet-associated dilated cardiomyopathy in cats. The objective of this study was to compare cardiac size and function, cardiac biomarkers and taurine concentrations in healthy cats eating high- vs low-pulse diets. We hypothesized that cats eating high-pulse diets would have larger hearts, lower systolic function and higher biomarker concentrations than cats eating low-pulse diets and that there would be no difference in taurine concentrations between the diet groups. METHODS: Echocardiographic measurements, cardiac biomarkers, and plasma and whole-blood taurine concentrations were compared between cats eating high- and low-pulse commercial dry diets in a cross-sectional study. RESULTS: There were no differences between the high- (n = 21) and low-pulse (n = 31) diet groups with regard to age, sex and breed, but more cats in the high-pulse group were overweight or obese (67% vs 39%; P = 0.05). Diet duration was not different in the groups, but the range was wide (6-120 months). No differences were found between the diet groups for key cardiac measurements, biomarker concentrations, or plasma or whole-blood taurine concentrations. However, there were significant negative correlations between diet duration and measures of left ventricular wall thickness in the high-pulse, but not the low-pulse, diet group. CONCLUSIONS AND RELEVANCE: This study did not detect significant associations between high-pulse diets and cardiac size, function and biomarkers, but the secondary observation of significant negative correlations between time on high-pulse diets and left ventricular wall thickness warrants further evaluation.

Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.

Understanding the impacts of COVID-19 on the determinants of food insecurity: A state-specific examination.

This paper examines risk factors influencing food insecurity during the first year of the COVID-19 pandemic in a state in the U.S. heavily impacted by it and offers recommendations for multi-sector intervention. The U.S. Census Bureau Household Pulse Survey was analyzed to evaluate the impacts of COVID-19 on food security in Massachusetts from April 2020 through March 2021 using a study sample of 57,678 participants. Food security was defined as a categorical variable (food security, marginal food security, low food security, very low food security) and binary variable (food security and food insecurity). Known or suspected factors that contribute to it, such as childcare, education, employment, housing, and transportation were examined in multivariate logistic regression models. Data imputation methods accounted for missing data. Sociodemographic characteristics, including lower education level and living in a household with children, were determinants of food insecurity. Another factor that influenced food insecurity was economic hardships, such as unemployment, being laid off due to COVID-19, not working due to concerns about contracting or spreading COVID-19, or not having enough money to buy food. A third factor influencing food insecurity was food environment, such as lack of geographic access to healthy foods. Some of these factors have been exacerbated by the pandemic and will continue to impact food security. These should be addressed through a comprehensive approach with public health efforts considering all levels of the social ecological model and the context created by the pandemic.

A mixed methods study to inform and evaluate a longitudinal nurse practitioner/community health worker intervention to address social determinants of health and chronic obstructive pulmonary disease self-management.

BACKGROUND: Individuals with low socioeconomic status experience higher prevalence and worse outcomes of chronic obstructive pulmonary disease (COPD). We undertook a quality improvement initiative at our safety net hospital in which a nurse practitioner (NP)/community health worker (CHW) team followed patients with COPD, frequent admissions, and unmet SDOH needs from hospitalization through one month post-discharge. We report our mixed methods approach to inform development and preliminary evaluation of this intervention. METHODS: We first assessed characteristics of patients admitted with COPD in 2018 (n = 1811), performing multivariable logistic regression to identify factors associated with ≥ 2 admissions per year. We then tested a standardized tool to screen for unmet SDOH needs in a convenience sample of 51 frequently hospitalized patients with COPD. From January-July 2019, we pilot tested the NP/CHW intervention with 57 patients, reviewed NP/CHW logs, and conducted qualitative interviews with 16 patient participants to explore impressions of the intervention. RESULTS: Patients with Medicaid insurance, mental health disorders, cardiac disease, and substance use disorder had increased odds of having ≥ 2 admissions. COPD severity, comorbidities, and unmet SDOH needs made COPD self-management challenging. Seventy-four percent of frequently admitted patients with COPD completing SDOH screening had unmet SDOH needs. Patients perceived that the NP/CHW intervention addressed these barriers by connecting them to resources and providing emotional support. CONCLUSIONS: Many patients with COPD admitted at our safety-net hospital experience unmet SDOH needs that impede COPD self-management. A longitudinal NP/CHW intervention to address unmet SDOH needs following discharge appears feasible and acceptable.

How Do Medicaid Agencies Improve Substance Use Treatment Benefits? Lessons from Three States' 1115 Waiver Experiences.

CONTEXT: In 2015, the Centers for Medicare and Medicaid Services (CMS) urged state Medicaid programs to use 1115 waiver demonstrations to expand substance use treatment benefits. We analyzed four critical points in states' decision-making processes before expanding benefits. METHODS: We conducted qualitative cross-case comparison of three states that were early adopters of the 1115 waiver request. We conducted 44 interviews with key informants from CMS, Medicaid, and other state agencies, providers, and managed care organizations. FINDINGS: Policy makers expanded substance use treatment in response to "fragmented" care systems and unsustainable funding streams. Medicaid staff had mixed preferences for implementing new benefits via 1115 waivers or state plan amendments. The 1115 waiver process enabled states to provide coverage for residential benefits, but state plan amendments made other services permanent parts of the benefit. Medicaid agencies relied on interorganizational networks to identify evidence-based practices. Medicaid staff secured legislative support for reform by focusing on program integrity concerns and downstream effects of substance use rather than Medicaid beneficiaries' needs. CONCLUSIONS: Decision-making processes were influenced by Medicaid agency characteristics and interorganizational partnerships, not federal executive branch influence. Lessons from early-adopter states provide a road map for other state Medicaid agencies considering similar reform.

Translating Medicaid policy into practice: policy implementation strategies from three US states' experiences enhancing substance use disorder treatment.

BACKGROUND: Despite the important upstream impact policy has on population health outcomes, few studies in implementation science in health have examined implementation processes and strategies used to translate state and federal policies into accessible services in the community. This study examines the policy implementation strategies and experiences of Medicaid programs in three US states that responded to a federal prompt to improve access to evidence-based practice (EBP) substance use disorder (SUD) treatment. METHODS: Three US state Medicaid programs implementing American Society of Addiction Medicine (ASAM) Criteria-driven SUD services under Section 1115 waiver authority were used as cases. We conducted 44 semi-structured interviews with Medicaid staff, providers and health systems partners in California, Virginia, and West Virginia. Interviews were triangulated with document review of state readiness and implementation plans. The Exploration, Preparation, Implementation, Sustainment Framework (EPIS) guided qualitative theme analysis. The Expert Recommendations for Implementing Change and Specify It criteria were used to create a taxonomy of policy implementation strategies used by policymakers to promote providers' uptake of statewide EBP SUD care continuums. RESULTS: Four themes describe states' experiences and outcomes implementing a complex EBP SUD treatment policy directive: (1) Medicaid agencies adapted their inner/outer contexts to align with EBPs and adapted EBPs to fit their local context; (2) enhanced financial reimbursement arrangements were inadequate bridging factors to achieve statewide adoption of new SUD services; (3) despite trainings, service providers and managed care organizations demonstrated poor fidelity to the ASAM Criteria; and (4) successful policy adoption at the state level did not guarantee service providers' uptake of EBPs. States used 29 implementation strategies to implement EBP SUD care continuums. Implementation strategies were used in the Exploration (n=6), Preparation (n=10), Implementation (n=19), and Sustainment (n=6) phases, and primarily focused on developing stakeholder interrelationships, evaluative and iterative approaches, and financing. CONCLUSIONS: This study enhances our understanding of statewide policy implementation outcomes in low-resource, public healthcare settings. Themes highlight the need for additional pre-implementation and sustainment focused implementation strategies. The taxonomy of detailed policy implementation strategies employed by policymakers across states should be tested in future policy implementation research.

Predicting longitudinal service use for individuals with substance use disorders: A latent profile analysis.

INTRODUCTION: Substance use disorders (SUD) are chronic conditions that often warrant coordinated medical care throughout a relapsing and remitting course. However, SUD treatment is frequently measured as a binary outcome, where individuals either receive or do not receive care following the immediate treatment seeking event. This study aimed to describe longitudinal treatment seeking behaviors by assessing service use patterns among individuals with diagnosed SUDs in a safety net hospital that offers a "no wrong door" care model. This study also examined whether certain patient subgroups were more likely to transition to service use patterns that support recovery or treatment disengagement over time. METHODS: The team conducted a retrospective cohort study using electronic health record data from adult patients diagnosed with SUDs (n = 1157) who regularly accessed services at a safety net hospital over a five-year period. The study used latent class analysis (LCA) and latent profile analysis to empirically identify distinct treatment utilization profiles of individuals with SUDs. We used multinomial logistic regression to evaluate predictors of class membership and transitions over a five-year period. RESULTS: The research team identified five distinct service use classes, including patients who disengaged from services (42.4%), or those who predominantly used outpatient substance use services (7.0%), mental health services (13.0%), primary care services (24.7%), or other specialty care services (13.1%). Being female and an older adult were statistically significant predictors for membership in any service use-driven status. Black patients had increased odds for "substance use service" and "primary care" service statuses over time. CONCLUSION: LCA and latent transition analysis (LTA) methods are novel approaches for identifying profiles of patients with higher risk for health services disengagement. SUD treatment engagement strategies are needed to reach males, young adults, and individuals with non-opioid SUDs.

Electric Field Induced Biomimetic Transmembrane Electron Transport Using Carbon Nanotube Porins.

Cells modulate their homeostasis through the control of redox reactions via transmembrane electron transport systems. These are largely mediated via oxidoreductase enzymes. Their use in biology has been linked to a host of systems including reprogramming for energy requirements in cancer. Consequently, the ability to modulate membrane redox systems may give rise to opportunities to modulate underlying biology. The current work aims to develop a wireless bipolar electrochemical approach to form on-demand electron transfer across biological membranes. To achieve this goal, it is shown that by using membrane inserted carbon nanotube porins (CNTPs) that can act as bipolar nanoelectrodes, one can control electron flow with externally applied electric fields across membranes. Before this work, bipolar electrochemistry has been thought to require high applied voltages not compatible with biological systems. It is shown that bipolar electrochemical reaction via gold reduction at the nanotubes can be modulated at low cell-friendly voltages, providing an opportunity to use bipolar electrodes to control electron flux across membranes. The authors provide new mechanistic insight into this newly describe phenomena at the nanoscale. The results presented give rise to a new method using CNTPs to modulate cell behavior via wireless control of membrane electron transfer.

Membrane fusion and drug delivery with carbon nanotube porins.

Drug delivery mitigates toxic side effects and poor pharmacokinetics of life-saving therapeutics and enhances treatment efficacy. However, direct cytoplasmic delivery of drugs and vaccines into cells has remained out of reach. We find that liposomes studded with 0.8-nm-wide carbon nanotube porins (CNTPs) function as efficient vehicles for direct cytoplasmic drug delivery by facilitating fusion of lipid membranes and complete mixing of the membrane material and vesicle interior content. Fusion kinetics data and coarse-grained molecular dynamics simulations reveal an unusual mechanism where CNTP dimers tether the vesicles, pull the membranes into proximity, and then fuse their outer and inner leaflets. Liposomes containing CNTPs in their membranes and loaded with an anticancer drug, doxorubicin, were effective in delivering the drug to cancer cells, killing up to 90% of them. Our results open an avenue for designing efficient drug delivery carriers compatible with a wide range of therapeutics.

The Association of Zygomaticomaxillary Complex Fractures with Naso-Orbitoethmoid Fractures in Pediatric Populations.

BACKGROUND: Naso-orbitoethmoid fractures associated with ipsilateral zygomaticomaxillary complex fractures are more challenging injuries than zygomaticomaxillary complex fractures alone. However, there is a paucity of information on this complex fracture pattern in the pediatric population. This study investigated the cause, treatment, and outcomes of combined zygomaticomaxillary complex and naso-orbitoethmoid fractures versus isolated zygomaticomaxillary complex fractures in pediatric patients. METHODS: This was a 25-year retrospective cohort study of pediatric patients who presented to a single institution with zygomaticomaxillary complex fractures. Baseline patient demographics and clinical information, and concomitant injuries, treatment/operative management, and postoperative complications/deformities were recorded and compared between patients with combined zygomaticomaxillary complex and naso-orbitoethmoid fractures and patients with isolated zygomaticomaxillary complex fractures. RESULTS: Forty-nine patients were identified to have had zygomaticomaxillary complex fractures in the authors' 25-year study period, of whom 46 had adequate clinical documentation and follow-up. Seventeen patients had combined zygomaticomaxillary complex-naso-orbitoethmoid fractures, of whom six had panfacial fractures. Both patient groups (zygomaticomaxillary complex only and combined zygomaticomaxillary complex-naso-orbitoethmoid fractures) were similar in terms of demographics. However, a significantly greater proportion of combined fracture patients experienced postoperative complications compared to isolated zygomaticomaxillary complex fracture patients, even after excluding those with panfacial fractures (87.5 percent versus 35.3 percent; p < 0.001). Enophthalmos (37.5 percent) and midface growth restriction (37.5 percent) were the two most common complications/deformities in all combined fracture patients. CONCLUSIONS: High-impact trauma can lead to zygomaticomaxillary complex fractures with associated naso-orbitoethmoid fractures in children. This injury pattern was found to cause significantly greater postoperative morbidity than isolated zygomaticomaxillary complex fractures alone. Thus, pediatric patients presenting with this complex facial fracture pattern should be closely monitored. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Discovery of a new class of integrin antibodies for fibrosis.

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab's yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFß activation. In IPF patient lung fibroblasts, TGFß treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFß action though mechanisms beyond the inhibition of latent TGFß activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.

Toward nanobioelectronic medicine: Unlocking new applications using nanotechnology.

Bioelectronic medicine aims to interface electronic technology with biological components and design more effective therapeutic and diagnostic tools. Advances in nanotechnology have moved the field forward improving the seamless interaction between biological and electronic components. In the lab many of these nanobioelectronic devices have the potential to improve current treatment approaches, including those for cancer, cardiovascular disorders, and disease underpinned by malfunctions in neuronal electrical communication. While promising, many of these devices and technologies require further development before they can be successfully applied in a clinical setting. Here, we highlight recent work which is close to achieving this goal, including discussion of nanoparticles, carbon nanotubes, and nanowires for medical applications. We also look forward toward the next decade to determine how current developments in nanotechnology could shape the growing field of bioelectronic medicine. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Biosensing.

Modulating the biological function of protein by tailoring the adsorption orientation on nanoparticles.

Protein orientation in nanoparticle-protein conjugates plays a crucial role in binding to cell receptors and ultimately, defines their targeting efficiency. Therefore, understanding fundamental aspects of the role of protein orientation upon adsorption on the surface of nanoparticles (NPs) is vital for the development of clinically important protein-based nanomedicines. In this work, new insights on the effect of the different orientation of cytochrome c (cyt c) bound to gold nanoparticles (GNPs) using various ligands on its apoptotic activity is reported. Time-of-Flight Secondary-Ion Mass Spectrometry (ToF-SIMS), electrochemical and circular dichroism (CD) analyses are used to investigate the characteristics of cyt c orientation and structure on functionalized GNPs. These studies indicate that the orientation and position of the heme ring inside the cyt c structure can be altered by changing the surface chemistry on the GNPs. A difference in the apoptosis inducing capability because of different orientation of cyt c bound to the GNPs is observed. These findings indicate that the biological activity of a protein can be modulated on the surface of NPs by varying its adsorption orientation. This study will impact on the rational design of new nanoscale biosensors, bioelectronics, and nanoparticle-protein based drugs.

Mammalian-Cell-Driven Polymerisation of Pyrrole.

A model cancer cell line was used to initiate polymerisation of pyrrole to form the conducting material polypyrrole. The polymerisation was shown to occur through the action of cytosolic exudates rather than that of the membrane redox sites that normally control the oxidation state of iron as ferricyanide or ferrocyanide. The data demonstrate for the first time that mammalian cells can be used to initiate synthesis of conducting polymers and suggest a possible route to detection of cell damage and/or transcellular processes through in situ and amplifiable signal generation.