A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease.

Biocompatible Cobalt Oxide Nanoparticles for X-ray Fluorescence Microscopy.

The synthesis of water-soluble nanoparticles is a well-developed field for ferrite-based nanoparticles with the majority consisting of iron oxide or mixed metal iron oxide nanoparticles. However, the synthesis of non-agglomerated non-ferrite metal/metal oxide NPs is not as well established. The synthesis and characterization of uniform 20 nm, biologically compatible cobalt oxide (CoO) nanoparticles (NPs) is described. These nanoparticles have two principle components: 1) a CoO core of suitable size to contain enough cobalt atoms to be visualized by X-ray fluorescence microscopy (XFM) and 2) a robust coating that inhibits NP aggregation as well as renders them water-soluble and biocompatible (i.e. stealth coatings). Stable cobalt oxide NPs are obtained with octadecyl amine coatings as reported by Bhattacharjee. Two strategies for solubilizing these NPs in water were investigated with varying degrees of success. Exchanging the octadecyl amine coating for a nitrodopamine anchored PEG coating yielded the desired water-soluble NPs but in very low yield. Alternately, leaving the octadecyl amine coating on the NP and interdigitating this with a maleic anhydride-vinyl copolymer with different hydrophobic sidechains followed by opening the maleic anhydride ring with amine substituted PEG polymers (the water solubilizing component), yielded the desired water soluble NPS were obtained in good yield. Characterization data for the nanoparticles and the components of the coatings required for bioorthogonal reactions to ligate them with biotargeting agents are also described.

Social and structural drivers of HIV vulnerability among a respondent-driven sample of feminine and non-feminine presenting transgender women who have sex with men in Zimbabwe.

INTRODUCTION: We sought to characterize social and structural drivers of HIV vulnerability for transgender women (TGW) in Zimbabwe, where TGW are not legally recognized, and explore differences in vulnerability by feminine presentation. METHODS: A secondary analysis was conducted with a sub-sample of participants recruited from a 2019 respondent-driven sampling survey that comprised men who have sex with men, TGW and genderqueer individuals assigned male sex at birth, from two cities in Zimbabwe. Survey questionnaires captured information related to socio-demographics, sexual and substance use behaviours, and social and structural barriers to HIV services. Secondary analyses were restricted to participants who identified as female, transfemale or transwomen (236/1538) and were unweighted. Descriptive statistics were used to calculate sample estimates and chi-square and Fisher's exact tests were used to assess differences in vulnerability by feminine presentation. RESULTS: Among 236 TGW, almost half (45.3%) presented as feminine in the 6 months preceding the survey and 8.5% had ever used hormones to affirm their gender identities. Median age among TGW was 23 years (interquartile range: 20-26). Feminine presenting TGW in our sample had higher prevalence of arrest (15.9% vs. 3.9%), rejection by family/friends (38.3% vs. 14.0%), employment termination (11.2% vs. 3.9%), employment refusal (14.0% vs. 3.9%), denial of healthcare (16.8% vs. 2.3%), physical, sexual or verbal harassment or abuse (59.8% vs. 34.1%), alcohol dependence (32.7% vs. 12.4%), recent transactional sex with a male or TGW partner (30.8% vs. 13.3%) and recent non-injection drug use (38.3% vs. 20.2%) than non-feminine presenting TGW (all p-value <0.05). CONCLUSIONS: Findings suggest that TGW, particularly feminine presenting TGW, experience social and structural inequities which may contribute to HIV vulnerability. Interventions aimed at addressing inequities, including trans competency training for providers and gender-affirming, psychosocial and legal support services for TGW, might mitigate risk.

Hepatitis B virus infection (HBV) and HIV-HBV coinfection among men who have sex with men, transgender women, and genderqueer individuals in Harare and Bulawayo Zimbabwe, 2019.

Objectives: To measure HIV and Hepatitis B virus (HBV) prevalence and associated risk behaviors among men who have sex with men (MSM) and transgender women/genderqueer individuals (TGW/GQ) in Zimbabwe. Methods: We conducted a biobehavioral survey using respondent-driven sampling (RDS) among adult MSM and TGW/GQ in Harare and Bulawayo, Zimbabwe in 2019. Participants completed a questionnaire and underwent testing for HIV and HBV. Results: Overall, 1,510 (Harare: 694, Bulawayo 816) participants were enrolled and consented to testing; 3.8 % (58) tested positive for HBV, 22.5 % (339) tested positive for HIV, and 2.2 % (33) tested positive for both HIV and HBV. HBV prevalence was higher among participants with HIV compared to HIV-negative participants (9.7 % vs. 2.1 %, p < 0.0001). Overall, HBV prevalence was not statistically different between MSM and TGW/GQ (3.7 % vs 4.5 %, p = 0.49) nor between Harare and Bulawayo (3.3 % vs 4.3 %, p = 0.33). Conclusions: Our survey demonstrates the prevalence of HBV among MSM and TGW/GQ is lower than other estimates of HBV among MSM in Africa but remains high among our survey population living with HIV highlighting the need to expand HBV testing and treatment services, especially among people with HIV in Zimbabwe.

Draft genome of co-cultured Melainabacteria sp. 17Bon1m.

We report the 7.6 Mb draft genome sequence of Melainabacteria sp. strain 17Bon1, which was sequenced from a co-culture with the diatom Rhopalodia gibba collected from the Clark Fork River in Bonita, MT.

Factors Associated with Having both Male and Female Recent Sexual Partnerships Among Men Who Have Sex with Men in Harare and Bulawayo, Zimbabwe.

To better understand male and female sexual partnerships among men who have sex with men (MSM), we used data from a 2019 biobehavioral survey among MSM in Harare and Bulawayo, Zimbabwe to conduct bivariate analyses and multivariable logistic regression to determine whether sociodemographic characteristics and HIV-related factors were associated with having both male and female sexual partnerships within the last 6 months. Of included MSM (N = 1143), 31% reported both male and female partnerships in the last 6 months. Being married/cohabiting (adjusted odds ratio (aOR) = 8.58, 95% confidence interval (CI) = 4.92-14.95) or separated/divorced/widowed (aOR = 1.96, 95% CI = 1.24-3.08) vs. being single, and hazardous alcohol consumption (aOR = 1.58, 95% CI 1.19-2.09) were associated with higher odds of having both male and female recent partnerships. Being aged 35 + vs. 18-24 (aOR = 0.50, 95% CI = 0.31-0.81), condomless receptive anal intercourse at last sex with the main male partner (aOR = 0.43, 95% CI = 0.26-0.74), and positive HIV status (aOR = 0.46, 95% CI = 0.31-0.67) were associated with lower odds of recent male and female partnerships. MSM in Harare who reported harassment/abuse (aOR = 3.16, 95% CI = 1.72-5.79) had higher odds of both male and female partnerships than MSM in Bulawayo reporting harassment/abuse. The prevalence of both male and female recent partnerships (31%) was lower among MSM in this survey than in other biobehavioral surveys of MSM in sub-Saharan Africa. Findings suggest that MSM with recent male and female partnerships compared to MSM with only male recent partners have lower odds of positive HIV status and participate in behaviors that lower HIV risk; however, the direction of these relationships cannot be determined due to the cross-sectional nature of the data. The findings also suggest a possible connection between experiences of stigma of MSM behavior and not having both male and female partnerships that warrants further exploration. Accessible, stigma-free HIV testing and education programming that considers the potential overlap between the MSM and general populations via both male and female partnerships and the associated behaviors could be a key component of HIV elimination in Zimbabwe.

Fiber Integrated Metal-Organic Frameworks as Functional Components in Smart Textiles.

Owing to high modularity and synthetic tunability, metal-organic frameworks (MOFs) on textiles are poised to contribute to the development of state-of-the-art wearable systems with multifunctional performance. While these composite materials have demonstrated promising functions in sensing, filtration, detoxification, and biomedicine, their applicability in multifunctional systems is only beginning to materialize. This review highlights the multifunctionality and versatility of MOF-integrated textile systems. It summarizes the operational goals of MOF@textile composites, encompassing sensing, filtration, detoxification, drug delivery, UV protection, and photocatalysis. Building upon these recent advances, this review concludes with an outlook on emerging opportunities for the diverse applications of MOF@textile systems in the realm of smart wearables.

Stigma, Social Cohesion, and HIV Risk Among Sexual and Gender Minorities in Two Cities in Zimbabwe.

Though stigma is a recognized contributor to the disproportionate HIV burden among sexual and gender minorities (SGM) in sub-Saharan Africa, data describing this association among Zimbabwean SGM are limited. We examined relationships between SGM stigma and HIV and the potential for social cohesion to moderate the association among Zimbabwean men who have sex with men, transgender women, and genderqueer individuals. Consenting participants (n = 1511) recruited through respondent-driven sampling for a biobehavioral survey in Harare and Bulawayo completed structured interviews and received HIV testing. Reported SGM stigma was common (68.9% in Harare and 65.3% in Bulawayo) and associated with HIV infection in Harare (adjusted prevalence ratio [aPR] = 1.82, 95% confidence interval [CI] = 1.27-2.62) and Bulawayo (aPR = 1.51, 95% CI = 1.15-2.00) in relative risk regression. Social cohesion did not moderate these relationships. Findings demonstrate stigma's association with HIV vulnerability among Zimbabwean SGM, highlighting the need for stigma-mitigation to reduce HIV transmission in this population.

HIV care cascade and associated factors among men who have sex with men, transgender women, and genderqueer individuals in Zimbabwe: findings from a biobehavioural survey using respondent-driven sampling.

BACKGROUND: Globally, men who have sex with men (MSM), transgender women, and genderqueer individuals are at greater risk for HIV than the general population although little data are available from these groups in Zimbabwe, a country with a national adult HIV prevalence of 12·9%. We aimed to examine progress towards the UNAIDS 90-90-90 treatment targets and factors associated with meeting the targets among a sample of MSM, transgender women, and genderqueer individuals in Zimbabwe. METHODS: In this cross-sectional survey in 2019, we used respondent-driven sampling to identify MSM, transgender women, and genderqueer individuals aged at least 18 years to participate in a biobehavioural survey in Harare and Bulawayo, Zimbabwe. Participants were eligible to participate if they were assigned male at birth; had engaged in anal or oral sex with a man in the past 12 months; resided in Harare or Bulawayo for at least 1 month; spoke English, Shona, or Ndebele; provided written informed consent; and were in possession of a valid recruitment coupon if applicable. Enrolled participants completed a questionnaire and underwent HIV testing, and off-site viral load testing was done on all HIV-positive samples. Unweighted bivariate analyses and multivariable logistic regression models were used to evaluate the association of sociodemographic, behavioural, and other factors with HIV-positive status awareness among MSM, transgender women, and genderqueer individuals, and with viral load suppression among MSM. Analyses were done firstly using self-reported information and then by classifying those with a viral load of less than 200 copies per mL as being aware of their status and on treatment (viral load recategorisation). FINDINGS: Among MSM, 248 (21%; 95% CI 19-24) of 1176 tested positive for HIV. Of those who tested positive, based on self-report, 119 (48%; 95% CI 42-54) reported knowing their HIV status, of whom 112 (94%; 88-98) reported using antiretroviral therapy (ART), of whom 89 (79%; 71-87) had viral load suppression. Based on viral load recategorisation, 180 (73%; 67-78) of 248 MSM testing HIV positive reported knowing their HIV status, of whom 174 (97%; 93-99) reported using ART, of whom 151 (87%; 81-91) had viral load suppression. 92 (28%; 23-33) of 335 transgender women and genderqueer individuals tested positive for HIV. Based on self-reports from these individuals 34 (37%; 27-48) of 92 participants reported knowing their HIV status, of whom 31 (91%; 76-98) reported using ART, of whom 27 (87%; 70-96%) had viral load suppression. Based on viral load recategorisation of data from transgender women and genderqueer participants, 53 (58%; 47-58) of 92 reported awareness of their HIV status, of whom 50 (94%; 84-99) reported using ART, of whom 46 (92%; 81-98) had viral load suppression. HIV-positive MSM aged 18-24 years had lower odds of being aware of their status than those aged at least 35 years (adjusted odds ratio [aOR] 0·34; 95% CI 0·13-0·92), as did HIV-positive MSM aged 25-34 years (aOR 0·26; 0·12-0·56). HIV-positive MSM aged 18-24 years also had a lower odds of having viral load suppression than those aged 35 years and older (aOR 0·35; 0·16-0·78), as did those aged 25-34 years (aOR 0·36; 0·19-0·67). No factors were significantly associated with awareness among transgender women and genderqueer individuals in multivariable models. INTERPRETATION: Our survey showed that HIV prevalence was high and the largest difference between our results and the 90-90-90 treatment targets was in HIV status awareness, indicating the need for improvements in engaging MSM (especially young MSM), transgender women, and genderqueer individuals in HIV testing services. FUNDING: US President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention.

Characterizing acceptable and appropriate implementation strategies of a biobehavioral survey among men who have sex with men and others assigned male who have sex with men in Zimbabwe.

Key populations including men who have sex with men (MSM), female sex workers, people who inject drugs, transgender persons, and prisoners account for nearly 50% of new HIV infections globally. To inform the HIV response and monitor trends in HIV prevalence and incidence among key populations, countries have increased efforts to implement biobehavioral surveys (BBS) with these groups as part of routine surveillance. Yet the marginalized nature of populations participating in a BBS requires contextually acceptable and appropriate strategies for effective implementation. We conducted a formative assessment to inform the first BBS conducted with MSM and others assigned male who have sex with men (OAMSM) in Zimbabwe, where same-sex sexual behaviors are illegal and highly stigmatized and describe applications of our findings. Qualitative data were collected through four focus groups with 32 MSM/OAMSM and 25 in-depth interviews (15 MSM/OAMSM, 10 service providers/gatekeepers) from December 2018 to January 2019. Rapid assessment techniques were employed including rapid identification of themes from audio recordings and review of detailed field notes and memos to identify key themes. Findings from this assessment included contextually relevant considerations including behaviors and terminology to avoid when working with MSM/OAMSM in Zimbabwe, appropriate compensation amounts for survey participation, proposed data collection sites, and differences in sexual openness, marital status, and networks among younger and older MSM/OAMSM. Participants also reported strong network ties suggesting respondent-driven sampling-a peer chain referral approach-to be an appropriate recruitment method in this context. Taken together, these findings highlighted key considerations and strategies for implementation to ensure the subsequent BBS in Zimbabwe was both acceptable and appropriate. These results and applications of these results are important for informing surveillance efforts and broader HIV-related engagement efforts among MSM/OAMSM in Zimbabwe as well as in other contextually similar countries in Southern Africa.

High Burden of Active Syphilis and Human Immunodeficiency Virus/Syphilis Coinfection Among Men Who Have Sex With Men, Transwomen, and Genderqueer Individuals in Zimbabwe.

BACKGROUND: Syphilis increases human immunodeficiency virus (HIV) acquisition risk and impacts the immunologic and virologic response among people living with HIV (PLHIV). We assessed the prevalence of active or current syphilis and HIV/syphilis and their correlates among men who have sex with men (MSM), transwomen, and genderqueer (TGW/GQ) individuals in Zimbabwe. METHODS: Among a respondent-driven sample of MSM and TGW/GQ who were tested for HIV and syphilis in Harare and Bulawayo, Zimbabwe in 2019 (n = 1511), multiple logistic regression was used to assess correlates of active syphilis. Unadjusted logistic regression was used among PLHIV (n = 340) due to small sample size. All analyses were unweighted as data did not reach convergence for HIV. RESULTS: Prevalence of active syphilis overall and among PLHIV was 5.5% and 10.1%, respectively, in Harare, and 5.6% and 11.0%, respectively, in Bulawayo. Participants were more likely to have active syphilis if they were PLHIV (adjusted odds ratio [aOR], 2.2; 95% confidence interval [CI], 1.4-3.6), aged 25-34 years (aOR, 2.2 years; 95% CI, 1.3-3.8 years; reference, 18-24 years), or self-report sexually transmitted infection symptoms (aOR, 1.8; 95% CI, 1.1-3.0). Compared with Bulawayo TGW/GQ, MSM in Harare (aOR, 0.2; 95% CI, 0.1-0.5) and Bulawayo (aOR, 0.2; 95% CI, 0.1-0.4), and TGW/GQ in Harare (aOR, 0.2; 95% CI, 0.1-0.6) were less likely to have active syphilis. Among PLHIV, coinfection was 13.0% among TGW/GQ and 9.7% among MSM. Odds of coinfection were higher for those aged 25 to 34 years (OR, 3.7 years; 95% CI, 1.2-11.1 years) and lower among Harare MSM (OR, 0.2; 95% CI, 0.1-0.7), Bulawayo MSM (OR, 0.1; 95% CI, 0.0-0.4), and Harare TGW/GQ (OR, 0.1; 95% CI, 0.0-0.4) compared with Bulawayo TGW/GQ. CONCLUSIONS: Findings highlight a high burden of syphilis among MSM and TGW/GQ and underscore the importance of HIV/syphilis detection and improved service delivery for these groups.

Large Isotope Effects in Organometallic Chemistry.

The kinetic isotope effect (KIE) is key to understanding reaction mechanisms in many areas of chemistry and chemical biology, including organometallic chemistry. This ratio of rate constants, kH /kD , typically falls between 1-7. However, KIEs up to 105 have been reported, and can even be so large that reactivity with deuterium is unobserved. We collect here examples of large KIEs across organometallic chemistry, in catalytic and stoichiometric reactions, along with their mechanistic interpretations. Large KIEs occur in proton transfer reactions such as protonation of organometallic complexes and clusters, protonolysis of metal-carbon bonds, and dihydrogen reactivity. C-H activation reactions with large KIEs occur with late and early transition metals, photogenerated intermediates, and abstraction by metal-oxo complexes. We categorize the mechanistic interpretations of large KIEs into the following three types: (a) proton tunneling, (b) compound effects from multiple steps, and (c) semi-classical effects on a single step. This comprehensive collection of large KIEs in organometallics provides context for future mechanistic interpretation.

The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development.

During heart development, epicardial cells residing within the outer layer undergo epithelial-mesenchymal transition (EMT) and migrate into the underlying myocardium to support organ growth and morphogenesis. Disruption of epicardial EMT results in embryonic lethality, yet its regulation is poorly understood. Here, we report epicardial EMT within the mesothelial layer of the mouse embryonic heart at ultra-high resolution using scanning electron microscopy combined with immunofluorescence analyses. We identified morphologically active EMT regions that associated with key components of the extracellular matrix, including the basement membrane-associated proteoglycan agrin. Deletion of agrin resulted in impaired EMT and compromised development of the epicardium, accompanied by downregulation of Wilms' tumor 1. Agrin enhanced EMT in human embryonic stem cell-derived epicardial-like cells by decreasing ß-catenin and promoting pFAK localization at focal adhesions, and promoted the aggregation of dystroglycan within the Golgi apparatus in murine epicardial cells. Loss of agrin resulted in dispersal of dystroglycan in vivo, disrupting basement membrane integrity and impairing EMT. Our results provide new insights into the role of the extracellular matrix in heart development and implicate agrin as a crucial regulator of epicardial EMT.

Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable human cardiac cells to be studied in vitro, although they use glucose as their primary metabolic substrate and do not recapitulate the properties of adult cardiomyocytes. Here, we have explored the interplay between maturation by stimulation of fatty acid oxidation and by culture in 3D. We have investigated substrate metabolism in hiPSC-CMs grown as a monolayer and in 3D, in porous collagen-derived scaffolds and in engineered heart tissue (EHT), by measuring rates of glycolysis and glucose and fatty acid oxidation (FAO), and changes in gene expression and mitochondrial oxygen consumption. FAO was stimulated by activation of peroxisome proliferator-activated receptor alpha (PPARα), using oleate and the agonist WY-14643, which induced an increase in FAO in monolayer hiPSC-CMs. hiPSC-CMs grown in 3D on collagen-derived scaffolds showed reduced glycolysis and increased FAO compared with monolayer cells. Activation of PPARα further increased FAO in cells on collagen/elastin scaffolds but not collagen or collagen/chondroitin-4-sulphate scaffolds. In EHT, FAO was significantly higher than in monolayer cells or those on static scaffolds and could be further increased by culture with oleate and WY-14643. In conclusion, a more mature metabolic phenotype can be induced by culture in 3D and FAO can be incremented by pharmacological stimulation.

Use of artificial intelligence to enhance phenotypic drug discovery.

Research and development (R&D) productivity across the pharmaceutical industry has received close scrutiny over the past two decades, especially taking into consideration reports of attrition rates and the colossal cost for drug development. The respective merits of the two main drug discovery approaches, phenotypic and target based, have divided opinion across the research community, because each hold different advantages for identifying novel molecular entities with a successful path to the market. Nevertheless, both have low translatability in the clinic. Artificial intelligence (AI) and adoption of machine learning (ML) tools offer the promise of revolutionising drug development, and overcoming obstacles in the drug discovery pipeline. Here, we assess the potential of target-driven and phenotypic-based approaches and offer a holistic description of the current state of the field, from both a scientific and industry perspective. With the emerging partnerships between AI/ML and pharma still in their relative infancy, we investigate the potential and current limitations with a particular focus on phenotypic drug discovery. Finally, we emphasise the value of public-private partnerships (PPPs) and cross-disciplinary collaborations to foster innovation and facilitate efficient drug discovery programmes.

Metabolic flux analyses to assess the differentiation of adult cardiac progenitors after fatty acid supplementation.

Myocardial infarction is the most prevalent of cardiovascular diseases and pharmacological interventions do not lead to restoration of the lost cardiomyocytes. Despite extensive stem cell therapy studies, clinical trials using cardiac progenitor cells have shown moderate results. Furthermore, differentiation of endogenous progenitors to mature cardiomyocytes is rarely reported. A metabolic switch from glucose to fatty acid oxidation occurs during cardiac development and cardiomyocyte maturation, however in vitro differentiation protocols do not consider the lack of fatty acids in cell culture media. The aim of this study was to assess the effect of this metabolic switch on control and differentiated adult cardiac progenitors, by fatty acid supplementation. Addition of oleic acid stimulated the peroxisome proliferator-activated receptor alpha pathway and led to maturation of the cardiac progenitors, both before and after transforming growth factor-beta 1 differentiation. Addition of oleic acid following differentiation increased expression of myosin heavy chain 7 and connexin 43. Also, total glycolytic metabolism increased, as did mitochondrial membrane potential and glucose and fatty acid transporter expression. This work provides new insights into the importance of fatty acids, and of peroxisome proliferator-activated receptor alpha, in cardiac progenitor differentiation. Harnessing the oxidative metabolic switch induced maturation of differentiated endogenous stem cells. (200 words).

Are solo infections of the diphyllobothriidean cestode Schistocephalus solidus more virulent than multiple infections?

We performed a long-term natural experiment investigating the impact of the diphyllobotriidean cestode Schistocephalus solidus on the body condition and clutch size (CS) of threespine stickleback Gasterosteus aculeatus, its second intermediate host, and the growth of larval parasites in host fish. We tested the hypothesis that single S. solidus infections were more virulent than multiple infections. We also asked whether the metrics of mean and total parasite mass (proxies for individual and total volume, respectively) were consistent with predictions of the resource constraints or the life history strategy (LHS) hypothesis for the growth of, hence exploitation by, larval helminths in intermediate hosts. The samples were drawn from Walby Lake, Alaska in eight of 11 years. Host body condition and CS (egg number per spawning bout) decreased significantly with intensity after adjustments for host size and parasite index. Thus, infections have an increasingly negative impact on measures of host fitness with greater intensity, in contrast to the hypothesis that single infections are more harmful than multiple infections. We also found that mean parasite mass decreased with intensity while total parasite mass increased with intensity as predicted by the LHS hypothesis.

Changing Metabolism in Differentiating Cardiac Progenitor Cells-Can Stem Cells Become Metabolically Flexible Cardiomyocytes?

The heart is a metabolic omnivore and the adult heart selects the substrate best suited for each circumstance, with fatty acid oxidation preferred in order to fulfill the high energy demand of the contracting myocardium. The fetal heart exists in an hypoxic environment and obtains the bulk of its energy via glycolysis. After birth, the "fetal switch" to oxidative metabolism of glucose and fatty acids has been linked to the loss of the regenerative phenotype. Various stem cell types have been used in differentiation studies, but most are cultured in high glucose media. This does not change in the majority of cardiac differentiation protocols. Despite the fact that metabolic state affects marker expression and cellular function and activity, the substrate composition is currently being overlooked. In this review we discuss changes in cardiac metabolism during development, the various protocols used to differentiate progenitor cells to cardiomyocytes, what is known about stem cell metabolism and how consideration of metabolism can contribute toward maturation of stem cell-derived cardiomyocytes.

Care coordination at a pediatric accountable care organization (ACO): A qualitative analysis.

OBJECTIVE: Care coordinators may help manage care for children with chronic illness. Their role in pediatric epilepsy care is understudied. We aimed to qualitatively describe the content of a care coordination intervention for children with epilepsy. METHODS: We conducted nine semi-structured interviews and one focus group with care coordinators at a pediatric accountable care organization (ACO) in Ohio. The care coordinators used a modified version of a published care coordination checklist for children with epilepsy (Patel AD, 2014). We analyzed transcripts using thematic analysis. We focused on (1) the content of the intervention; and (2) perceptions of facilitators and barriers to improve outcomes, with an emphasis on epilepsy specific facilitators and barriers. RESULTS: Care coordinators interacted with children and families in multiple contexts (phone calls, physician visits, home visits), and included relationship building (developing rapport and trust between families and the health system), communication (transmission of information between the child, family, physician, and other care providers), and service (help with housing, transportation, scheduling, liaison with community resources, etc.). Facilitators and barriers of care coordination included factors related to parents, physicians, health system, payers, and community. Epilepsy-specific barriers included stigma (felt & enacted) and the anxiety associated with clinical uncertainty. Epilepsy related facilitators included a seizure action plan, written educational materials, and an epilepsy specific care coordination checklist. CONCLUSION: In addition to facilitators and barriers common to many care coordination programs, pediatric epilepsy care coordinators should be particularly aware of epilepsy stigma and clinical uncertainty. A care coordination checklist and epilepsy focused educational materials written to accommodate people with low health literacy may provide additional benefit. Further research is required to understand the effect of care coordination on costs, use of health services, seizure control, and quality of life for children with epilepsy.

Stem Cell Therapy for the Heart: Blind Alley or Magic Bullet?

When stressed by ageing or disease, the adult human heart is unable to regenerate, leading to scarring and hypertrophy and eventually heart failure. As a result, stem cell therapy has been proposed as an ultimate therapeutic strategy, as stem cells could limit adverse remodelling and give rise to new cardiomyocytes and vasculature. Unfortunately, the results from clinical trials to date have been largely disappointing. In this review, we discuss the current status of the field and describe various limitations and how future work may attempt to resolve these to make way to successful clinical translation.