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Green hydrogen, generated through the electrolysis of water using renewable energy sources, is recognized as a highly promising alternative to fossil fuels in the pursuit of net-zero carbon emissions. Electrocatalysts are crucial for reducing overpotentials and enhancing the efficiency of the hydrogen evolution reaction (HER) for the production of green hydrogen. Homogeneous HER serves as a primary method to assess the activity and mechanisms of novel non-precious molecular electrocatalysts in pursuit of replacing precious platinum standards. However, these catalysts can sometimes exhibit instability under reductive and acidic conditions during homogeneous HER. Thus, it is also essential to evaluate catalysts through heterogeneous HER for initial assessment and practical application. In this study, we examine a series of structurally related N 2 S 2 chelated Ni(II) complexes, which are tailored to optimize the basicity of the catalyst for heterogeneous HER activity. These complexes are insoluble in 0.5 M H 2 SO 4 , and the films formed after catalyst deposition on glassy carbon electrodes (GCEs) exhibit catalytic currents during HER, demonstrating moderate to good overpotentials, Tafel slopes, and charge transfer resistance. Furthermore, we observe the anticipated structure-activity relationship that arises from tuning the catalyst structure. The complexes maintain stability over extended reductive cycling, as confirmed by various surface characterization techniques, including SEM, EDX, XPS, and XRD. This study highlights the potential of utilizing catalyst basicity to develop efficient and robust heterogeneous HER catalysts.

Competing Interests: AME reports advisory board participation for GSK, Gilead, and Bit Bio and honoraria (speaker fees) from Gilead. LA reports being a member of the National Institute for Health and Care Research BASIS trial drug monitoring committee. SF reports being the British Association for Sexual Health and HIV and Bloodborne Virus Special Interest Group chair from 2020 to 2024, being the British HIV Association Guidelines Subcommittee chair from 2023 to the present day, honoraria from MSD, Gilead Sciences and Viiv Healthcare, and a research grant from Gilead (to the British HIV Association). AD is a drug monitoring committee member for the BASIS trial. All other authors declare no competing interests. This work was funded by NIHR (National Institute of Health Research grants: NIHR154762, NIHR15330, NIHR154191 and NIHR154359). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. KG-O and RMB are joint first authors.

Background and Aims: The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end-stage renal disease (ESRD) risk in SLD., Methods: 234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI-proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB-4 score > 2.67) was determined using FIB-4 scores. eGFR < 60 mL/min/1.73 m 2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively., Results: 102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB-4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35-1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06-3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75-2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36-5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow-up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19-2.43)., Conclusions: In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Aims: To explore the views and attitudes of professionals, patients and the public to a role for community pharmacists in the identification of alcohol-related liver disease (ArLD)., Methods: Semi-structured interviews were conducted with a purposive sample of patients with ArLD, members of the public, pharmacy staff, and clinicians managing patients with ArLD across the Wessex region of south England. The interviews explored experiences of alcohol, ArLD and health advice in pharmacies and elicited views of what a pharmacist role in identifying ArLD could entail and factors influencing this. Transcripts were analysed using reflexive thematic analysis., Results: Twenty-six participants were interviewed and three themes were generated: (i) acknowledging, seeking help and engaging with a hidden problem; (ii) professional roles, boundaries and attributes; (iii) communication, relationships, collaboration and support. Participants reported key challenges to identifying people at-risk of ArLD. Offering testing for ArLD was perceived to motivate engagement but there were concerns about pharmacists performing this. A role was mostly seen to be finding people at-risk and engaging them with further care such as referral to liver services. This was perceived to require developing interprofessional collaborations, remuneration and training for pharmacy staff, and community-based liver testing., Conclusions: Professionals, patient and public participants recognized a role for pharmacists in the identification of ArLD. This was envisaged to incorporate educating pharmacy users about ArLD risk, and identifying and directly engaging those at-risk with liver and support services through development of interprofessional collaborations. The findings of this study support and can inform future work to develop this role., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press.)

Objectives: This aimed to develop a blueprint for an effective community pharmacy Hepatitis C virus (HCV) testing service by producing a consensus statement., Study Design: This was a modified Delphi process., Methods: We recruited a heterogenous panel of experts (who had been involved in the setup or delivery of a community pharmacy HCV testing service) by purposive and chain referral methods. We had three rounds of a modified Delphi process. The first was a series of questions with free text responses and was analysed using thematic analysis, and the second and third were statements for the respondents to rate using a 7-point Likert scale. Consensus was predefined in a published protocol, and the results were reviewed by a public and patient involvement panel before the statement was finalised., Results: We had 24 participants, including community and hospital-based pharmacists, local pharmaceutical committee members, charity representatives (Hepatitis C Trust), local clinical service lead, nurse specialists and doctors. The response rate of the first, second and third rounds were 100%, 96% and 88%, respectively. After the third round, we had 60 statements that reached consensus. We discussed the accepted statements with a patient and public involvement group. We used these statements to produce the I-COPTIC statement and a graphical summary., Conclusions: We developed a blueprint for the design of a gold standard community pharmacy HCV testing service. We believe this will support the successful implementation of community pharmacy testing for HCV. Community pharmacy testing is an important service to help achieve and maintain HCV elimination., (Copyright © 2024. Published by Elsevier Ltd.)

A series of thiosemicarbazonato-hydrazinatopyridine zinc(II) complexes were evaluated as direct air CO 2 capture agents. The complexes sequester CO 2 in a methanol solution as a metal-coordinated methylcarbonate. The reaction is reversible upon sparging of solutions with an inert gas (N 2 or Ar). The capture process involves metal-ligand cooperativity with the noncoordinating nitrogen of the hydrazinatopyridine functional group serving as a Brønsted-Lowry base and the zinc acting as a Lewis acid. In this study, the pendent amine of the thiosemicarbazonato group was varied to include 4-phenyl (ZnL 5 ), 4-(trifluoromethyl)phenyl (ZnL 6 ), 4-cyanophenyl (ZnL 7 ), 4-tolyl (ZnL 8 ), and 4-naphthyl (ZnL 9 ). Hyperconjugation between the pendent group and the ligand core resulted in modulation of the metal ion acidity, as quantified by ligand exchange equilibrium constants ( K 3 = 193-511) and ligand basicity (p K a,MeOH = 11.09-11.94). Variations in electronic structure that decreased ligand basicity were more than offset by increases in Lewis acidity. The equilibrium constant ( K 1 ) for CO 2 capture varied from 46300 to 73700. Overall, the value of K 1 was directly related to the relative Lewis acidity of the complexes ( K 3 ). Notably, there was an overall inverse relationship between K 1 and the ligand basicity. The results provide insights into ligand design to further improve CO 2 capture.

A series of isomeric bis(alkylthiocarbamate) copper complexes have been synthesized, characterized, and evaluated for antiproliferation activity. The complexes were derived from ligand isomers with 3-methylpentyl (H 2 L 2 ) and cyclohexyl (H 2 L 3 ) backbone substituents, which each yield a pair of linkage isomers. The thermodynamic products CuL 2a/3a have two imino N and two S donors resulting in three five-member chelate rings (555 isomers). The kinetic isomers CuL 2b/3b have one imino and one hydrazino N donor and two S donors resulting in four-, six-, and five-member rings (465 isomers). The 555 isomers have more accessible Cu II/I potentials (E 1/2 = -811/-768 mV vs. ferrocenium/ferrocene) and lower energy charge transfer bands than their 465 counterparts (E 1/2 = -923/-854 mV). Antiproliferation activities were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL 2a was potent ( A549 EC 50 = 0.080 μM) and selective ( IMR-90 EC 50 / A549 EC 50 = 25) for A549. Its linkage isomer CuL 2b had equivalent A549 activity, but lower selectivity ( IMR-90 EC 50 / A549 EC 50 = 12.5). The isomers CuL 3a and CuL 3b were less potent with A549 EC 50 values of 1.9 and 0.19 μM and less selective with IMR-90 EC 50 / A549 EC 50 ratios of 2.3 and 2.65, respectively. There was no correlation between reduction potential and A549 antiproliferation activity/selectivity., Competing Interests: The authors declare the following competing financial interest(s): Complexes described in this manuscript are included in an issued US patent (US-11208379-B2) entitled “Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds.” A portion of the results described in this manuscript are included in the dissertation Alkylthiocarbamate metal complexes with antiproliferation activity by Kritika Bajaj, University of Louisville.[21]

Background and Aims: The World Health Assembly recommends integration of palliative care into treatment of patients with any life-limiting condition, yet patients with non-malignant disease are less likely to receive specialist palliative care (SPC). This study compares SPC offered to patients with hepatocellular carcinoma (HCC) versus patients with chronic liver disease without HCC (CLD without HCC)., Methods: Patients who died from CLD or HCC over 5 years (2013-2017) in England were identified using a dataset linking national data on all hospital admissions (Hospital Episode Statistics - HES) with national mortality data from the Office for National Statistics (HES - ONS). The primary outcome was the proportion of patients who received inpatient SPC in their last year of life (LYOL). Secondary outcomes were (1) early inpatient SPC input and (2) the proportion dying in a hospice. The outcomes were compared between patients with HCC and CLD without HCC., Results: 29 669 patients were identified, 8143 of whom had HCC. Patients with HCC were significantly more likely to receive inpatient SPC input-adjusted OR 3.74 (95% CI 3.52-3.97) and early inpatient SPC input-adjusted OR 7.26 (95% CI 6.38-8.25) and die in a hospice OR 8.23 (95% CI 7.33-9.24) than patients with CLD without HCC., Conclusions: These data highlight the stark inequity in access to SPC services between patients with HCC and patients with CLD without HCC in England. Addressing these inequities will improve end-of-life care for patients with CLD., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

A series of hybrid thiosemicarbazone-alkylthiocarbamate copper complexes with similar electronic environments but distinct physical structures have been prepared, characterized, and evaluated for antiproliferation activity. The complexes include the constitutional isomers (1-phenylpropane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL 1 ) and (1-phenylpropane-1-one-(N-methylthiosemicarbazonato)-2-imine-(O-ethylthiocarbamato))copper(II) (CuL 2 ) along with (1-propane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL 3 ). Complexes CuL 1 and CuL 2 differ in the positions of the pendent thiosemicarbazone (TSC) and alkylthiocarbamate (ATC) moieties on the 1-phenylpropane backbone. Complex CuL 3 employs a propane backbone with the TSC in the 2-position as in CuL 1 . The isomer pair CuL 1 and CuL 2 have equivalent electronic environments with indistinguishable Cu II/I potentials (E 1/2 = -0.86 V vs. ferrocenium/ferrocene) and electron paramagnetic resonance (EPR) spectra (g ∥ = 2.26, g ⊥ = 2.08). The electronic structure of CuL 3 has a similar E 1/2 of -0.84 V and identical EPR parameters to CuL 1, 2 . Single crystal X-ray diffraction studies confirm a consistent donor environment with no substantial variation in the CuN or CuS bond distances and angles between the complexes. The antiproliferation activities of the CuL 1-3 were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL 1 had the highest A549 activity ( A549 EC 50 = 0.065 μM) and selectivity ( IMR-90 EC 50 / A549 EC 50 = 20). The constitutional isomer CuL 2 displayed decreased A549 activity (0.18 μM) and selectivity (10.6). The complex CuL 3 displayed activity (0.009 μM) similar to CuL 1 but with a lack of selectivity (1.0). Cellular copper loading determined by ICP-MS was consistent with the activity and selectivity trends. The complexes CuL 1-3 did not induce reactive oxygen species (ROS) generation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Craig Grapperhaus reports financial support was provided by National Science Foundation CHE-1955268. Robert Buchanan reports financial support was provided by National Science Foundation CHE-1800245. Paula Bates reports financial support was provided by National Institutes of Health U01 HL127518. Mark Mashuta reports financial support was provided by Department of Energy (DEFG02-08CH11538) and the Kentucky Research Challenge Trust Fund. Results described in this manuscript are included in an issued US patent (US-11,208,379) entitled “Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds” issued to None., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Liver fibrosis is a key risk factor for cirrhosis, hepatocellular carcinoma and end stage liver failure. The National Institute for Health and Care Excellence guidelines for assessment for advanced (≥F3) liver fibrosis in people with nonalcoholic fatty liver disease recommend the use of enhanced liver fibrosis (ELF) test, followed by vibration-controlled transient elastography (VCTE). Performance of ELF at predicting significant (≥F2) fibrosis in real-world practice is uncertain. To assess the accuracy of ELF using VCTE; investigate the optimum ELF cutoff value to identify ≥F2 and ≥F3; and develop a simple algorithm, with and without ELF score, for detecting ≥F2., Methods: Retrospective evaluation of patients referred to a Community Liver Service for VCTE, Jan-Dec 2020. Assessment included: body mass index (BMI), diabetes status, alanine aminotransferase (ALT) levels, ELF score and biopsy-validated fibrosis stages according to VCTE., Results: Data from 273 patients were available. n =110 patients had diabetes. ELF showed fair performance for ≥F2 and ≥F3, area under the curve (AUC) = 0.70, 95% confidence interval (CI) 0.64-0.76 and AUC=0.72, 95% CI: 0.65-0.79 respectively. For ≥F2 Youden's index for ELF=9.85 and for ≥F3, ELF=9.95. Combining ALT, BMI, and HbA1c (ALBA algorithm) to predict ≥F2 showed good performance (AUC=0.80, 95% CI: 0.69-0.92), adding ALBA to ELF improved performance (AUC=0.82, 95% CI: 0.77-0.88). Results were independently validated., Conclusions: Optimal ELF cutoff for ≥F2 is 9.85 and 9.95 for ≥F3. ALT, BMI, and HbA1c (ALBA algorithm) can stratify patients at risk of ≥F2. ELF performance is improved by adding ALBA., Competing Interests: The authors have no conflict of interests related to this publication., (© 2023 Authors.)

Research developing and testing interventions that address the social determinants of liver disease are urgently needed; however, this cannot be achieved using conventional clinical research designs. A different approach is needed to conduct widely applicable, inclusive, and community-based research that addresses upstream factors driving liver morbidity. Natural experimental studies encompass a well-established field of research methodology that is less familiar to clinical hepatologists than conventional research methods such as the randomized control trial. The key strength of natural experiments is that, when robustly designed, they can be used to imply causality from routinely collected data. As such, they are well placed to test the impact of community interventions that aim to address social determinants of liver disease that cannot feasibly be assessed in a randomized control trial. In this review, we define natural experiments and their potential utility. We then work through examples of where they have already been used in clinical hepatology to highlight a range of research designs, analytical approaches, and best practices regarding their conduct and reporting. In doing so, we hope to equip clinical hepatologists with another tool to ensure the hepatology community can meet the global liver disease epidemic with evidence-based interventions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Little is known about the level of testing required to sustain elimination of hepatitis C (HCV), once achieved. In this study, we model the testing coverage required to maintain HCV elimination in an injecting network of people who inject drugs (PWID). We test the hypothesis that network-based strategies are a superior approach to deliver testing. We created a dynamic injecting network structure connecting 689 PWID based on empirical data. The primary outcome was the testing coverage required per month to maintain prevalence at the elimination threshold over 5 years. We compared four testing strategies. Without any testing or treatment provision, the prevalence of HCV increased from the elimination threshold (11.68%) to a mean of 25.4% (SD 2.96%) over the 5-year period. To maintain elimination with random testing, on average, 4.96% (SD 0.83%) of the injecting network needs to be tested per month. However, with a 'bring your friends' strategy, this was reduced to 3.79% (SD 0.64%) of the network (p < .001). The addition of contact tracing improved the efficiency of both strategies. In conclusion, we report that network-based approaches to testing such as 'bring a friend' initiatives and contact tracing lower the level of testing coverage required to maintain elimination., (© 2022 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

In this study, a series of thiosemicarbazonato-hydrazinatopyridine metal complexes were evaluated as CO 2 capture agents. The complexes incorporate a non-coordinating, basic hydrazinatopyridine nitrogen in close proximity to a Lewis acidic metal ion allowing for metal-ligand cooperativity. The coordination of various metal ions with (diacetyl-2-(4-methyl-thiosemicarbazone)-3-(2-hydrazinopyridine) (H 2 L 1 ) yielded ML 1 (M = Ni(II), Pd(II)), ML 1 (CH 3 OH) (M = Cu(II), Zn(II)), and [ML 1 (PPh 3 ) 2 ]BF 4 (M = Co(III)) complexes. The ML 1 (CH 3 OH) complexes reversibly capture CO 2 with equilibrium constants of 88 ± 9 and 6900 ± 180 for Cu(II) and Zn(II), respectively. Ligand effects were evaluated with Zn(II) through variation of the 4-methyl-thiosemicarbazone with 4-ethyl (H 2 L 2 ), 4-phenethyl (H 2 L 3 ), and 4-benzyl (H 2 L 4 ) derivatives. The equilibrium constant for CO 2 capture increased to 11,700 ± 300, 15,000 ± 400, and 35,000 ± 200 for ZnL 2 (MeOH), ZnL 3 (MeOH), and ZnL 4 (MeOH), respectively. Quantification of ligand basicity and metal ion Lewis acidity shows that changes in CO 2 capture affinity are largely associated with ligand basicity upon substitution of Cu(II) with Zn(II), while variation of the thiosemicarbazone ligand enhances CO 2 affinity by tuning the metal ion Lewis acidity. Overall, the Zn(II) complexes effectively capture CO 2 from dilute sources with up to 90%, 86%, and 65% CO 2 capture efficiency from 400, 1000, and 2500 ppm CO 2 streams.

In the last 20 years, noninvasive serum biomarkers to identify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) have been developed, validated against liver biopsy (the gold standard for determining the presence of liver fibrosis) and made available for clinicians to use to identify ≥F3 liver fibrosis. The aim of this review is firstly to focus on the current use of widely available biomarkers and their performance for identifying ≥F3. Secondly, we discuss whether noninvasive biomarkers have a role in identifying F2, a stage of fibrosis that is now known to be a risk factor for cirrhosis and overall mortality. We also consider whether machine learning algorithms offer a better alternative for identifying individuals with ≥F2 fibrosis. Thirdly, we summarise the utility of noninvasive serum biomarkers for predicting liver related outcomes (e.g., ascites and hepatocellular carcinoma) and non-liver related outcomes (e.g., cardiovascular-related mortality and extra hepatic cancers). Finally, we examine whether serial measurement of biomarkers can be used to monitor liver disease, and whether the use of noninvasive biomarkers in drug trials for non-alcoholic steatohepatitis can accurately, compared to liver histology, monitor liver fibrosis progression/regression. We conclude by offering our perspective on the future of serum biomarkers for the detection and monitoring of liver fibrosis in NAFLD.

In this study, we report a pair of electrocatalysts for the hydrogen evolution reaction (HER) based on the noninnocent ligand diacetyl-2-(4-methyl-3-thiosemicarbazone)-3-(2-pyridinehydrazone) (H 2 DMTH, H 2 L 1 ). The neutral complexes NiL 1 and PdL 1 were synthesized and characterized by spectroscopic and electrochemical methods. The complexes contain a non-coordinating, basic hydrazino nitrogen that is protonated during the HER. The p K a of this nitrogen was determined by spectrophotometric titration in acetonitrile to be 12.71 for NiL 1 and 13.03 for PdL 1 . Cyclic voltammograms of both NiL 1 and PdL 1 in acetonitrile exhibit diffusion-controlled, reversible ligand-centered events at -1.83 and -1.79 V (vs ferrocenium/ferrocene) for NiL 1 and PdL 1 , respectively. A quasi-reversible, ligand-centered event is observed at -2.43 and -2.34 V for NiL 1 and PdL 1 , respectively. The HER activity in acetonitrile was evaluated using a series of neutral and cationic acids for each catalyst. Kinetic isotope effect (KIE) studies suggest that the precatalytic event observed is associated with a proton-coupled electron transfer step. The highest turnover frequency values observed were 6150 s -1 at an overpotential of 0.74 V for NiL 1 and 8280 s -1 at an overpotential of 0.44 V for PdL 1 . Density functional theory (DFT) computations suggest both complexes follow a ligand-centered HER mechanism where the metals remain in the +2 oxidation state.

Linkage isomers are coordination compounds with the same composition but different donor atoms, resulting in distinct physical and electronic structures. A pair of linkage isomers, CuL 555 and CuL 465 , derived from phenylglyoxal bis(ethylthiocarbamate) were synthesized, isolated, and characterized by structural, electrochemical, and spectroscopic methods. The isomers are stable in solution under ambient conditions, but CuL 465 converts to CuL 555 in acid, consistent with quantum-chemical calculations. The complexes were screened against a lung adenocarcinoma cell line (A549) and a nonmalignant lung fibroblast cell line (IMR-90) to evaluate the antiproliferation activity. CuL 555 and CuL 465 possessed EC 50 values of 0.113 ± 0.030 and 0.115 ± 0.038 μM for A549 and 1.87 ± 0.29 and 0.77 ± 0.22 μM for IMR-90, respectively.

Fungi are ubiquitous in nature, and typically cause little or no environmental or pathogenic damage to their plant, animal, and human hosts. However, a small but growing number of pathogenic fungi are spreading world-wide at an alarming rate threatening global ecosystem health and proliferation. Many of these emerging pathogens have developed multi-drug resistance to front line therapeutics increasing the urgency for the development of new antifungal agents. This review examines the development of thiosemicarbazones, bis(thiosemicarbazones), and their metal complexes as potential antifungal agents against more than 65 different fungal strains. The fungistatic activity of the compounds are quantified based on the zone of inhibition, minimum inhibitory concentration, or growth inhibition percentage. In this review, reported activities were standardized based on molar concentrations to simplify comparisons between different compounds. Of all the fungal strains reported in the review, A. niger in particular was very resistant towards a majority of tested compounds. Our analysis of the data shows that metal complexes are typically more active than non-coordinated ligands with copper(II) and zinc(II) complexes generally displaying the highest activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Transmission of Hepatitis C (HCV) continues via sharing of injection equipment between people who inject drugs (PWID). Network-based modelling studies have produced conflicting results about whether random treatment is preferable to targeting treatment at PWID with multiple partners. We hypothesise that differences in the modelled injecting network structure produce this heterogeneity. The study aimed to test how changing network structure affects HCV transmission and treatment effects. We created three dynamic injecting network structures connecting 689 PWID (UK-net, AUS-net and USA-net) based on published empirical data. We modelled HCV in the networks and at 5 years compared prevalence of HCV 1) with no treatment, 2) with randomly targeted treatment and 3) with treatment targeted at PWID with the most injecting partnerships (degree-based treatment). HCV prevalence at 5 years without treatment differed significantly between the three networks (UK-net (42.8%) vs. AUS-net (38.2%), p < 0.0001 and vs. USA-net (54.0%), p < 0.0001). In the treatment scenarios UK-net and AUS-net showed a benefit of degree-based treatment with a 5-year prevalence of 1.0% vs. 9.6% p < 0.0001 and 0.15% vs. 0.44%, p < 0.0001. USA-net showed no significant difference (29.3% vs. 29.2%, p = 0.0681). Degree-based treatment was optimised with low prevalence, moderate treatment coverage conditions whereas random treatment was optimised in low treatment coverage, high prevalence conditions. In conclusion, injecting network structure determines the transmission rate of HCV and the most efficient treatment strategy. In real-world injecting network structures, the benefit of targeting HCV treatment at individuals with multiple injecting partnerships may have been underestimated., (© 2021 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

As atmospheric levels of carbon dioxide (CO 2 ) continue to increase, there is an immediate need to balance the carbon cycle. Current approaches require multiple processes to fix CO 2 from the atmosphere or flue gas and then reduce it to value-added products. The zinc(II) catalyst Zn(DMTH) (DMTH = diacetyl-2-(4-methyl-3-thiosemicarbazonate)-3-(2-pyridinehydrazonato)) reduces CO 2 from air to formate with a faradaic efficiency of 15.1% based on total charge. The catalyst utilizes metal-ligand cooperativity and redox-active ligands to fix, activate, and reduce CO 2 . This approach provides a new strategy that incorporates sustainable earth-abundant metals that are oxygen and water tolerant.

A series of hybrid ligands ( H 2 L 1 - H 2 L 3 ) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O -alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper ( 4 - 6 ), nickel ( 7 - 9 ), and zinc ( 10 - 12 ) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the Cu II/I reduction potential of ∼160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates 4 - 12 were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives 4 and 6 were found to have potent and cancer-selective antiproliferative effects, with GI 50 values less than 100 nM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 nonmalignant lung fibroblasts. In comparison, the nickel complexes were much less active and had little cancer-selectivity. Varying by ligand, the zinc complexes were less potent or had comparable activity compared to that of the corresponding copper complex. UV-visible spectroscopy indicated that zinc complex 10 was transmetalated in the presence of equimolar copper, whereas nickel complex 7 was not. Copper complexes 4 and 6 were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, 4 and 6 were substantially more active against A549 cancer cells than Cu(ATSM) and were more cancer-selective (for A549 compared to IMR-90) than Cu(GTSM). Our results suggest that hybrid thiosemicarbazone-alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

The zinc(II) complex of diacetyl-2-(4-methyl-3-thiosemicarbazone)-3-(2-hydrazonepyridine), ZnL 1 ( 1 ), was prepared and evaluated as a precatalyst for the hydrogen evolution reaction (HER) under homogeneous conditions in acetonitrile. Complex 1 is protonated on the noncoordinating nitrogen of the hydrazonepyridine moiety to yield the active catalyst Zn(HL 1 )OAc ( 2 ) upon addition of acetic acid. Addition of methyl iodide to 1 yields the corresponding methylated derivative ZnL 2 I ( 3 ). In solution, partial dissociation of the coordinated iodide yields the cationic derivative 3' . Complexes 1 - 3 were characterized by 1 H NMR, FT-IR, and UV-visible spectroscopies. The solid-state structures of 2 and 3 were determined by single crystal X-ray diffraction. HER studies conducted in acetonitrile with acetic acid as the proton source yield a turnover frequency (TOF) of 7700 s -1 for solutions of 1 at an overpotential of 1.27 V and a TOF of 6700 s -1 for solutions of 3 at an overpotential of 0.56 V. For both complexes, the required potential for catalysis, E cat/2 , is larger than the thermodynamic reduction potential, E 1/2 , indicative of a kinetic barrier attributed to intramolecular proton rearrangement. The effect is larger for solutions of 1 (+440 mV) than for solutions of 3 (+160 mV). Controlled potential coulometry studies were used to determine faradaic efficiencies of 71 and 89% for solutions of 1 and 3 , respectively. For both catalysts, extensive cycling of potential under catalytic conditions results in the deposition of a film on the glassy carbon electrode surface that is active as an HER catalyst. Analysis of the film of 3 by X-ray photoelectron spectroscopy indicates the complex remains intact upon deposition. A proposed ligand-centered HER mechanism with 1 as a precatalyst to 2 is supported computationally using density functional theory (DFT). All catalytic intermediates in the mechanism were structurally and energetically characterized with the DFT/B3LYP/6-311g(d,p) in solution phase using a polarizable continuum model (PCM). The thermodynamic feasibility of the mechanism is supported by calculation of equilibrium constants or reduction potentials for each proposed step.

A series of crystalline nickel(II) complexes ( 1 - 3 ) based on inexpensive bis(thiosemicarbazone) ligands diacetylbis(4-methyl-3-thiosemicarbazone) (H 2 ATSM), diacetylbis(4,4-dimethyl-3-thiosemicarbazone) (H 2 ATSDM), and diacetylbis[4-(2,2,2-trifluoroethyl)-3-thiosemicarbazone] (H 2 ATSM-F 6 ) were synthesized and characterized by single-crystal X-ray diffraction and NMR, UV-visible, and Fourier transform infrared spectroscopies. Modified electrodes GC-1 - GC-3 were prepared with films of 1 - 3 deposited on glassy carbon and evaluated as potential hydrogen evolution reaction (HER) catalysts. HER studies in 0.5 M aqueous H 2 SO 4 (10 mA cm -2 ) revealed dramatic shifts in the overpotential from 0.740 to 0.450 V after extended cycling for 1 and 2 . The charge-transfer resistances for GC-1 - GC-3 were determined to be 270, 160, and 630 Ω, respectively. Characterization of the modified surfaces for GC-1 and GC-2 by scanning electron microscopy and Raman spectroscopy revealed similar crystalline coatings before HER that changed to surface-modified crystallites after conditioning. The surface of GC-3 had an initial glasslike appearance before HER that delaminated after HER. The differences in the surface morphology and the effect of conditioning are correlated with crystal-packing effects. Complexes 1 and 2 pack as columns of interacting complexes in the crystallographic a direction with short interplanar spacings between 3.37 and 3.54 Å. Complex 3 packs as columns of isolated molecules in the crystallographic b direction with long-range interplanar spacings of 9.40 Å.

The molecular catalyst diacetyl-bis(N-4-methyl-3-thiosemi-carbazonato)nickel(ii) (NiATSM) was integrated with Si for light-driven hydrogen evolution from water. Compared to an equivalent loading of Ni metal, the NiATSM/p-Si electrode performed better. Durability of the surface-bound catalyst under operation in acid was achieved without covalent attachment by using Nafion binding.

In this study, we report the electrocatalytic behavior of the neutral, monomeric Ni(II) complex of diacetyl-bis( N-4-methyl-3-thiosemicarbazonato), NiL 1 , for ligand-assisted metal-centered hydrogen evolution in acetonitrile (ACN) and dimethylformamide (DMF). Using foot-of-the-wave analysis (FOWA), NiL 1 displays a maximum turnover frequency (TOF) of 4200 and 1200 s -1 for acetic acid (CH 3 COOH) in ACN and DMF, whereas for trifluoroacetic acid (CF 3 COOH) the TOFs are 1300 and 120 s -1 in ACN and DMF, respectively. In ACN, the overpotentials are 0.53 and 0.67 V for CH 3 COOH and CF 3 COOH, respectively. In DMF, the overpotential is 0.85 V for CH 3 COOH. First-order dependence with respect to the catalyst is established. NiL 1 displays a minimum Faradaic efficiency of 87% from controlled potential electrolysis. Gas analysis from controlled potential electrolysis in both ACN and DMF using CH 3 COOH and CF 3 COOH confirms NiL 1 as an electrocatalyst to produce H 2 . In ACN, TONs of 48 and 24 were obtained for CH 3 COOH and CF 3 COOH, respectively in 4 h. In DMF, TONs of 13 and 3 were obtained for CH 3 COOH and CF 3 COOH, respectively. The H 2 evolution reaction was evaluated using deuterated acid, demonstrating an inverse kinetic isotope, which is consistent with formation of a metal hydride intermediate. A proposed ligand-assisted metal-centered mechanism for HER is supported by computational investigations. All catalytic intermediates in the proposed mechanism were structurally and energetically characterized using density functional theory (DFT), with the B3LYP/6-311g(d,p) and BP86/TZV/P in solution modeled via polarizable continuum model. The final step of catalysis involves the reaction of [HNi(L 1 ·)] - with H + generating H 2 . The correctness of proposed mechanism was confirmed by location of corresponding transition state (TS) having single imaginary frequency ( i1786 cm -1 ).

Background: Blood transfusion can be lifesaving for patients with hemorrhage; however, transfusion requirements for victims of gun violence are poorly understood., Study Design and Methods: In an urban, Level 1 trauma center, 23,422 trauma patients were analyzed in a retrospective cohort study. Patients with gunshot wounds (GSWs) (n = 2,672; 11.4% of trauma patients) were compared to those with non-GSW traumatic injuries from 2005 to 2017, to assess blood utilization., Results: The GSW cohort was approximately five times more likely to require transfusion (538 of 2672 [20.1%] vs. 798 of 20,750 [3.9%]; p < 0.0001), and the number of blood component units transfused per patient was approximately 10 times greater (3.3 ± 13.5 vs. 0.31 ± 3.8 units/patient; p < 0.0001), compared to the non-GSW cohort. The risk-adjusted likelihood of requiring high-dose transfusion was greater in the GSW cohort (odds ratio, 2.38; 95% confidence interval, 1.14-5.80), and requirements were increased for all four blood components (red blood cells, platelets, plasma, and cryoprecipitate). Patients with GSWs had approximately 14 times greater overall mortality (653 of 2672 [24.4%] vs. 352 of 20,750 [1.7%]; p < 0.0001]. Compared to non-GSW penetrating injuries (e.g., stab wounds), those with GSWs had approximately four times higher transfusion requirements (3.3 ± 13.5 vs. 0.80 ± 3.8 units/patient; p < 0.0001), and approximately eight times greater overall mortality (653 of 2672 [24.4%] vs. 28 of 956 [2.9%]; p < 0.0001)., Conclusions: Compared to other traumatic injuries, GSW injuries are associated with substantially greater blood utilization and mortality. Trauma centers treating GSW injuries should have ready access to all blood components and ability to implement massive transfusions., (© 2018 AABB.)

In this study, we report the electrocatalytic behavior of the neutral, monomeric Cu(II) complex of diacetyl-bis(N-4-methyl-3-thiosemicarbazonato), CuL 1 , for metal-assisted ligand-centered hydrogen evolution in acetonitrile and dimethylformamide. CuL 1 displays a maximum turnover frequency (TOF) of 10 000 s -1 in acetonitrile and 5100 s -1 in dimethylformamide at an overpotential of 0.80 and 0.76 V, respectively. The rate law is first-order in catalyst and second-order in proton concentration. Gas analysis from controlled potential electrolysis confirms CuL 1 as an electrocatalyst to produce H 2 with a minimum Faradaic efficiency of 81% and turnover numbers as high as 73 while showing no sign of degradation over 23 h. The H 2 evolution reaction (HER) was probed using deuterated acid, demonstrating a kinetic isotope effect of 7.54. A proton inventory study suggests one proton is involved in the rate-determining step. Catalytic intermediates were identified using 1 H NMR, X-ray photoelectron, and UV-visible spectroscopies. All catalytic intermediates in the proposed mechanism were successfully optimized using density functional theory calculations with the B3LYP functional and the 6-311g(d,p) basis set and support the proposed mechanism.

The homogeneous, nonaqueous catalytic activity of the rhenium-thiolate complex ReL 3 (L = diphenylphosphinobenzenethiolate) for the hydrogen evolution reaction (HER) has been transferred from nonaqueous homogeneous to aqueous heterogeneous conditions by immobilization on a glassy carbon electrode surface. A series of modified electrodes based on ReL 3 and its oxidized precursor [ReL 3 ][PF 6 ] were fabricated by drop-cast methods, yielding catalytically active species with HER overpotentials for a current density of 10 mA/cm 2 , ranging from 357 to 919 mV. The overpotential correlates with film resistance as measured by electrochemical impedance spectroscopy and film morphology as determined by scanning and transmission electron microscopy. The lowest overpotential was for films based on the ionic [ReL 3 ][PF 6 ] precursor with the inclusion of carbon black. Stability measurements indicate a 2 to 3 h conditioning period in which the overpotential increases, after which no change in activity is observed within 24 h or upon reimmersion in fresh aqueous, acidic solution. Electronic spectroscopy results are consistent with ReL 3 as the active species on the electrode surface; however, the presence of an undetected quantity of catalytically active degradation species cannot be excluded. The HER mechanism was evaluated by Tafel slope analysis, which is consistent with a novel Volmer-Heyrovsky-Tafel-like mechanism that parallels the proposed homogeneous HER pathway. Proposed mechanisms involving traditional metal-hydride processes vs ligand-centered reactivity were examined by density functional theory, including identification and characterization of relevant transition states. The ligand-centered path is energetically favored with protonation of cis-sulfur sites culminating in homolytic S-H bond cleavage with H 2 evolution via H atom coupling.

The function of the heart valve interstitial cells (VICs) is intimately connected to heart valve tissue remodeling and repair, as well as the onset and progression of valvular pathological processes. There is yet only very limited knowledge and extant models for the complex three-dimensional VIC internal stress-bearing structures, the associated cell-level biomechanical behaviors, and how they change under varying activation levels. Importantly, VICs are known to exist and function within the highly dynamic valve tissue environment, including very high physiological loading rates. Yet we have no knowledge on how these factors affect VIC function. To this end, we extended our previous VIC computational continuum mechanics model (Sakamoto, et al., 2016, "On Intrinsic Stress Fiber Contractile Forces in Semilunar Heart Valve Interstitial Cells Using a Continuum Mixture Model," J. Mech. Behav. Biomed. Mater., 54(244-258)). to incorporate realistic stress-fiber geometries, force-length relations (Hill model for active contraction), explicit α-smooth muscle actin (α-SMA) and F-actin expression levels, and strain rate. Novel micro-indentation measurements were then performed using cytochalasin D (CytoD), variable KCl molar concentrations, both alone and with transforming growth factor β1 (TGF-β1) (which emulates certain valvular pathological processes) to explore how α-SMA and F-actin expression levels influenced stress fiber responses under quasi-static and physiological loading rates. Simulation results indicated that both F-actin and α-SMA contributed substantially to stress fiber force generation, with the highest activation state (90 mM KCL + TGF-β1) inducing the largest α-SMA levels and associated force generation. Validation was performed by comparisons to traction force microscopy studies, which showed very good agreement. Interestingly, only in the highest activation state was strain rate sensitivity observed, which was captured successfully in the simulations. These unique findings demonstrated that only VICs with high levels of αSMA expression exhibited significant viscoelastic effects. Implications of this study include greater insight into the functional role of α-SMA and F-actin in VIC stress fiber function, and the potential for strain rate-dependent effects in pathological states where high levels of α-SMA occur, which appear to be unique to the valvular cellular in vivo microenvironment.

The catalytic aerobic oxidation of benzylic alcohols to corresponding aldehydes has been investigated employing a tetradentate copper(ii) complex that incorporates N-methyl imidazole (NMI) as an integral part of an N 4 -ligand framework. The complex [L 3 -Cu] 2+ [(L 3 = 1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl(2-ethyl)amine] has been synthesized, characterized by spectroscopic and structural techniques, and its catalytic activity towards the aerobic oxidation of benzylic alcohols studied under ambient conditions. Catalytic turnover required addition of the nitroxyl radical initiator TEMPO. No oxidation was observed with hydroxyl radical initiators H 2 O 2 or tetrabutylammonium hydroperoxide. Additional NMI enhanced turnover with yields up to 99% within 4 hours. The relative quantities of substrate, catalyst, TEMPO, and NMI were systematically varied in a series of experiments to determine optimal conditions. The effect of oxygen at various flow rates as an alternate to ambient aerobic conditions was also investigated.

The reversible methanolysis of an azomethine C[double bond, length as m-dash]N in a series of copper(ii) Schiff base complexes has been investigated through combined spectroscopic, structural, and kinetic studies. Pentadentate copper(ii) complexes [L 1 -Cu(X)]Y (L 1 = 1,2-bis[(1-methyl-2-imidazolyl)methyleneamino]ethane; X = Y = ClO 4 - (1); X = Y = TfO - (2); X = Y = BF 4 - (3); X = H 2 O, Y = (ClO 4 - ) 2 (4) spontaneously add methanol in a ligand centered reaction to yield stable, isolable hemiaminal ether product complexes 5-8. In methanol free solution, 5-8 spontaneously release alcohol to regenerate 1-4. The methanol addition reaction is first-order in methanol and first-order in complex with second-order rate constants varying from 1.1 × 10 -4 to 187 × 10 -4 M -1 s -1 dependent on the donor ability of the axial ligand. Rate constants for methanol elimination vary from 0.67 to 3.7 × 10 -4 s -1 with dependence on the counterion and water content of the solvent. Equilibrium constants for methanolysis range from 1.5 to 51 M -1 . Structural comparisons of the Schiff base complexes 1-4 and the hemiaminal ether complexes 5-8 suggest methanol addition is favored by the release of ligand strain associated with three planar five-membered chelates in 1-4.

A new pathway for homogeneous electrocatalytic H2 evolution and H2 oxidation has been developed using a redox active thiosemicarbazone and its zinc complex as seminal metal-free and transition-metal-free examples. Diacetyl-bis(N-4-methyl-3-thiosemicarbazone) and zinc diacetyl-bis(N-4-methyl-3-thiosemicarbazide) display the highest reported TOFs of any homogeneous ligand-centered H2 evolution catalyst, 1320 and 1170 s(-1), respectively, while the zinc complex also displays one of the highest reported TOF values for H2 oxidation, 72 s(-1), of any homogeneous catalyst. Catalysis proceeds via ligand-centered proton-transfer and electron-transfer events while avoiding traditional metal-hydride intermediates. The unique mechanism is consistent with electrochemical results and is further supported by density functional theory. The results identify a new direction for the design of electrocatalysts for H2 evolution and H2 oxidation that are not reliant on metal-hydride intermediates.

Heart valve interstitial cells (VICs) play a critical role in the maintenance and pathophysiology of heart valve tissues. Normally quiescent in the adult, VICs can become activated in periods of growth and disease. When activated, VICs exhibit increased levels of cytokines and extracellular matrix (ECM) synthesis, and upregulated expression and strong contraction of α-smooth muscle actin (α-SMA) fibers. However, it remains unknown how expression and contraction of the α-SMA fibers, which vary among different VIC types, contribute to the overall VIC mechanical responses, including the nucleus and cytoskeleton contributions. In the present study, we developed a novel solid-mixture model for VIC biomechanical behavior that incorporated 1) the underlying cytoskeletal network, 2) the oriented α-SMA stress fibers with passive elastic and active contractile responses, 3) a finite deformable elastic nucleus. We implemented the model in a full 3D finite element simulation of a VIC based on known geometry. Moreover, we examined the respective mechanical responses of aortic and pulmonary VICs (AVICs and PVICs, respectively), which are known to have different levels of α-SMA expression levels and contractile behaviors. To calibrate the model, we simulated the combined mechanical responses of VICs in both micropipette aspiration (MA) and atomic force microscopy (AFM) experiments. These two states were chosen as the VICs were under significantly different mechanical loading conditions and activation states, with the α-SMA fibers inactivated in the MA studies while fully activated in the AFM studies. We also used the AFM to study the mechanical property of the nucleus. Our model predicted that the substantial differences found in stiffening of the AVIC compared to the PVICs was due to a 9 to 16 times stronger intrinsic AVIC α-SMA stress fiber contractile force. Model validation was done by simulating a traction force microscopy experiment to estimate the forces the VICs exert on the underlying substrate, and found good agreement with reported traction force microscopy results. Further, estimated nuclear stiffness for both AVICs and PVICs were similar and comparable to the literature, and were both unaffected by VIC activation level. These results suggest substantial functional differences between AVICs and PVICs at the subcellular level. Moreover, this first VIC computational biomechanical model is but a first step in developing a comprehensive, integrated view of the VIC pathophysiology and interactions with the valve ECM micro-environment based on simulation technologies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: We previously determined that newborn piglets orally gavaged with Ovalbumin (OVA) responded to systemic OVA re-exposure with tolerance; if adjuvants were included in oral vaccine, piglets responded with antibody-mediated immunity (Vet Immunol Immunopathol 161(3-4):211-21, 2014). Here, we will investigate whether newborn piglets gavaged with a vaccine comprised of OVA plus unmethylated CpG oligodeoxynucleotides (CpG; soluble component; OVA/CpG) combined with OVA plus CpG encapsulated within polyphosphazene microparticles (MP; particulate component) responded with systemic and mucosal immunity. To monitor the response to systemic antigen re-exposure, piglets were i.p.-immunized with OVA plus Incomplete Freund's Adjuvant (IFA) one month later., Results: Newborn piglets (n = 5/group) were gavaged with a combined soluble and particulate vaccine consisting of OVA (0.5-0.05 mg) plus 50 μg CpG and 0.5 mg OVA plus 50 μg CpG encapsulated within a polyphosphazene MP (0.5 mg) referred to as OVA/CpG + MP. Control piglets were gavaged with saline alone. Piglets were i.p. immunized with 10 mg OVA (or saline) in IFA at four weeks of age and then euthanized at eight weeks of age. We observed significantly higher titres of serum anti-OVA immunoglobulin (Ig) IgM, IgA, IgG, IgG1, IgG2 and IgG in piglets immunized with 0.05 mg OVA/CpG + MP relative to saline control animals. Thus, a single oral exposure at birth to a combined soluble and particulate OVA vaccine including adjuvants can circumvent induction of oral tolerance which impacts response to i.p. vaccination in later life. Further, piglets gavaged with 0.05 mg OVA/CpG + MP generated significant anti-OVA IgG and IgG1 titres in lung compared to saline control piglets but results were comparable to titres measured in parenteral control piglets. Peripheral blood mononuclear cells (PBMCs) ex vivo-stimulated with OVA showed markedly decreased production of IL-10 cytokine after 72 hours relative to animal-matched cells incubated with media alone. No production of IFN-γ was observed from any groups., Conclusion: Newborn piglets gavaged with low dose soluble and particulate OVA plus CpG ODN and polyphosphazene adjuvants produced antigen-specific antibodies in serum and lung after systemic re-exposure in later life. These data indicate circumvention of oral tolerance but not induction of oral immunity.

While the mechanical behaviors of the fibrosa and ventricularis layers of the aortic valve (AV) leaflet are understood, little information exists on their mechanical interactions mediated by the GAG-rich central spongiosa layer. Parametric simulations of the interlayer interactions of the AV leaflets in flexure utilized a tri-layered finite element (FE) model of circumferentially oriented tissue sections to investigate inter-layer sliding hypothesized to occur. Simulation results indicated that the leaflet tissue functions as a tightly bonded structure when the spongiosa effective modulus was at least 25 % that of the fibrosa and ventricularis layers. Novel studies that directly measured transmural strain in flexure of AV leaflet tissue specimens validated these findings. Interestingly, a smooth transmural strain distribution indicated that the layers of the leaflet indeed act as a bonded unit, consistent with our previous observations (Stella and Sacks in J Biomech Eng 129:757-766, 2007) of a large number of transverse collagen fibers interconnecting the fibrosa and ventricularis layers. Additionally, when the tri-layered FE model was refined to match the transmural deformations, a layer-specific bimodular material model (resulting in four total moduli) accurately matched the transmural strain and moment-curvature relations simultaneously. Collectively, these results provide evidence, contrary to previous assumptions, that the valve layers function as a bonded structure in the low-strain flexure deformation mode. Most likely, this results directly from the transverse collagen fibers that bind the layers together to disable physical sliding and maintain layer residual stresses. Further, the spongiosa may function as a general dampening layer while the AV leaflets deforms as a homogenous structure despite its heterogeneous architecture.

Background: Previous investigations in newborn lambs determined that adenovirus-mediated expression of antigen to a localized region of the gut induced antigen-specific mucosal and systemic immunity. These experiments were limited in that the localized region of the gut to which antigen was introduced was sterile and the influence of colostrum on the antigen was not assessed but they do suggest that mucosal vaccines may be an effective vaccination strategy to protect neonatal lambs. We propose that persistent oral antigen exposure introduced in extreme early life can induce immunity in lambs, despite the presence of commensal bacteria and colostrum., Results: To test this hypothesis, conventionally raised newborn lambs (n = 4 per group) were gavaged with ovalbumin (OVA) starting the day after birth for either a single day (2.27 g), every day for 3 days (0.23 g/day), or every day for 3 days then every second day until nine days of age (0.023 g/day). Lambs gavaged with OVA for 3 to 9 days developed significant serum anti-OVA IgG titres (p < 0.05), but not IgA titres, relative to control lambs (n = 4) after 3 and 4 weeks. At 4 weeks of age, lambs were immunized with OVA in Incomplete Freund's Adjuvant via intraperitoneal (i.p.) injection then lambs were euthanized at 7 weeks. Serum anti-OVA IgG titres were further augmented after i.p. immunization indicating immunity persisted and tolerance was not induced. Serum IgA titres remained low regardless of treatment. It is known that i.p. priming of sheep with antigen in Freund's complete adjuvant leads to an enhanced number of IgA and IgG antibody containing cells in the respiratory mucosa (Immunology 53(2):375-384, 1984). Lambs gavaged with a single bolus of 2.27 g OVA prior to i.p. immunization showed very low titres of anti-OVA IgA in the lung lavage. These data suggest that a single, high dose exposure to OVA can promote tolerance which impacts response to systemic vaccination in later life. Lambs gavaged with 0.023 g OVA for 9 days (Group C) generated significant anti-OVA IgA titres in lung (p < 0.001) compared to negative control lambs but no additive effect was observed compared to parenteral control lambs. When splenocytes were re-stimulated with OVA ex vivo, all groups failed to show increased lymphocyte proliferation or interferon (IFN)-γ production relative to the parenteral control group., Conclusions: In agreement with our hypothesis, persistent low dose antigen exposure primes humoral antibody production in serum in conventionally raised newborn lambs. In contrast, a single high dose bolus of antigen triggered oral tolerance which negatively impacted the quality and magnitude of the immune response to i.p. immunization in later life. These tangential responses are important as they indicate that the dose and/or repeated oral exposure to antigen, such as that which may be found in the neonate's environment, may promote immunity or alternatively it may negatively impact responses to parenteral vaccination.

Antimicrobial/host defense peptides (A/HDP) are natural compounds that are found in leucocyte cells and on the skin and bodily fluids of birds, reptiles, and mammals. Not only do they possess antibacterial, antiviral, and antiparasitic characteristics but they also stimulate the host immune system to combat infectious diseases and may play a role in the promotion of wound repair. Gamma-amino butyric acid (GABA) is an amino acid-based inhibitory neurotransmitter in the brain that has also been shown to promote wound healing on skin. The objective of this study was to establish a therapeutic cocktail that protects birds against Escherichia coli-related disease and lesions in broilers. We injected a cocktail of six A/HDPs with or without GABA into 3-wk-old broilers by a subcutaneous or intramuscular route followed 24 hr later by challenge with a field isolate of serogroup O2 E. coli. Birds were examined for 5-6 days post-E. coli challenge and clinical, pathologic, and bacteriologic assessments were conducted. Birds that were subcutaneously injected with an A/HDP plus GABA cocktail had significantly higher survival rates and lower levels of bacteremia (P < 0.05), but a similar percentage of the surviving birds had large cellulitis lesions compared to the surviving phosphate-buffered saline-injected control birds. When this cocktail was administered intramuscularly, there was a trend towards protection against E. coli-related death, although the results were not statistically significant and there was no reduction in bacteremia. A significant number of birds had a reduced bacterial load on cellulitis lesions but no reduction in lesion size, which suggests that when the cocktail was administered intramuscularly it failed to protect against cellulitis. These results suggest that the route of administration of the cocktail influences disease outcome. Gene expression analysis was performed to investigate whether the cocktail induced immunomodulatory functions in avian cells that complemented their antimicrobial and anti-endotoxic effects. A/HDP plus GABA mediated temporal induction of pro-inflammatory cytokines but no induction of any of the chemokines under investigation. This cocktail shows potential to protect against E. coli-related death, which is a major economic burden to the poultry industry.

Platelet-rich plasma (PRP) was prepared from human adult peripheral blood and from human umbilical cord (uc) blood and the properties were compared in a series of in vitro bioassays. Quantification of growth factors in PRP and platelet-poor plasma (PPP) fractions revealed increased levels of mitogenic growth factors PDGF-AB, PDGF-BB, and FGF-2, the angiogenic agent VEGF and the chemokine RANTES in ucPRP compared to adult PRP (aPRP) and PPP. To compare the ability of the various PRP products to stimulate proliferation of human bone marrow (BM), rat BM and compact bone (CB)-derived mesenchymal stem cells (MSC), cells were cultured in serum-free media for 4 and 7 days with varying concentrations of PRP, PPP, or combinations of recombinant mitogens. It was found that while all forms of PRP and PPP were more mitogenic than fetal bovine serum, ucPRP resulted in significantly higher proliferation by 7 days than adult PRP and PPP. We observed that addition of as little as 0.1% ucPRP caused greater proliferation of MSC effects than the most potent combination of recombinant growth factors tested, namely PDGF-AB + PDGF-BB + FGF-2, each at 10 ng/mL. Similarly, in chemotaxis assays, ucPRP showed greater potency than adult PRP, PPP from either source, or indeed than combinations of either recombinant growth factors (PDGF, FGF, and TGF-β1) or chemokines previously shown to stimulate chemotactic migration of MSC. Lastly, we successfully demonstrated that PRP and PPP represented a viable alternative to FBS containing media for the cryo-preservation of MSC from human and rat BM., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Unsafe abortion in India leads to significant morbidity and mortality. Abortion has been legal in India since 1971, and the availability of safe abortion services has increased. However, service availability has not led to a significant reduction in unsafe abortion. This study aimed to understand the gap between safe abortion availability and use of services in Bihar and Jharkhand, India by examining accessibility from the perspective of rural, Indian women., Methods: Two-stage stratified random sampling was used to identify and enroll 1411 married women of reproductive age in four rural districts in Bihar and Jharkhand, India. Data were collected on women's socio-demographic characteristics; exposure to mass media and other information sources; and abortion-related knowledge, perceptions and practices. Multiple linear regression models were used to explore the association between knowledge and perceptions about abortion., Results: Most women were poor, had never attended school, and had limited exposure to mass media. Instead, they relied on community health workers, family and friends for health information. Women who had knowledge about abortion, such as knowing an abortion method, were more likely to perceive that services are available (β = 0.079; p < 0.05) and have positive attitudes toward abortion (β = 0.070; p < 0.05). In addition, women who reported exposure to abortion messages were more likely to have favorable attitudes toward abortion (β = 0.182; p < 0.05)., Conclusions: Behavior change communication (BCC) interventions, which address negative perceptions by improving community knowledge about abortion and support local availability of safe abortion services, are needed to increase enabling resources for women and improve potential access to services. Implementing BCC interventions is challenging in settings such as Bihar and Jharkhand where women may be difficult to reach directly, but interventions can target individuals in the community to transfer information to the women who need this information most. Interpersonal approaches that engage community leaders and influencers may also counteract negative social norms regarding abortion and associated stigma. Collaborative actions of government, NGOs and private partners should capitalize on this potential power of communities to reduce the impact of unsafe abortion on rural women.

Background: In adult rats, initial exposure to antigens by a mucosal route triggers tolerance such that any subsequent re-exposure, even by a systemic route, results in suppression of immunity. The newborn's gut is semi-permeable for a finite period to allow maternal antibodies to enter the newborn's circulation. We propose that antigens introduced in extreme early life can readily traverse the gut wall and therefore circumvent induction of mucosal tolerance., Methodology/principle Findings: Rat pups were gavaged with low-doses of ovalbumin (OVA; oral exposure group) or saline (parenteral control group) every second day for several weeks followed by an intraperitoneal (i.p.) injection at 1 month of age. When gavage was initiated the day after birth, newborn oral exposure pups responded with significantly higher anti-OVA IgA, IgM, IgG2a, and IgG1 titres in their serum and anti-OVA IgA, IgG2a and IgG1 titres in their lungs compared to negative control pups. Oral exposure alone failed to induce immunity. Pups exposed to the same treatment regimen starting at 14 days of age showed induction of mucosal tolerance after i.p. immunization. Newborn oral exposure groups subjected to secondary i.p. immunization responded with significantly increased humoral immunity in lung and sera suggesting that once antigen-specific mucosal tolerance if circumvented, it persists. Lymphocytes derived from mesenteric lymph node cells re-simulated with OVA ex vivo, from newborn oral exposure pups exposed to secondary immunization produced significantly higher IFN-γ expression and lymphocyte proliferation relative to control pups indicating prevention of tolerance in the cell-mediated immune system., Conclusions/significance: This work demonstrates that newborns may be uniquely qualified to prevent induction of mucosal tolerance to oral antigens. These results should be further explored to establish whether prevention of tolerance by early life oral vaccination can be exploited to prime for mucosal as well as systemic immunity and thus protect this susceptible population against infectious diseases.

Neonatal Diarrheal Disease is responsible for significant economic losses to the livestock industries in Canada and around the world. Microbes responsible are diverse and include Escherichia coli , Salmonella, Rotavirus, Coronavirus and Cryptosporidia. While the use of antibiotics as a treatment for bacterial infections and as a prophylactic additive in feed has dramatically improved cattle production in recent decades, the increasing pressure to reduce or eliminate use of antibiotics in animals has caused the livestock industry to seek appropriate alternatives. Antimicrobial/Host Defense Peptides are natural compounds present on skin and in secretions in plants and animals that are microbicidal for bacteria, viruses, and parasites and they stimulate the immune system to combat infectious diseases. Our objective is to establish orally-obtained Host Defense Peptides (HDPs) as an alternative to antibiotics to protect against Neonatal Diarrheal Disease in calves. We devised a method to allow the cow udder to act as a factory to produce HDPs so that suckling calves will receive a continuous oral dose of HDPs over several weeks to protect them against neonatal diarrhea. We will use Adenovirus to deliver a gene coding for several HDPs in-frame into mammary epithelial cells. The epithelial cells will secrete the HDP protein into milk to be consumed by the suckling calves and trypsin in the calf gut will release the HDPs through cleavage. Thus, the novelty of this research lies not only in the proposed alternative to antibiotics to protect neonates against disease, but in the method by which we introduce the peptides to the suckling offspring., (Copyright © 2012 Published by Elsevier B.V.)

The crystal structure of the title compound, [Cu(2)(C(2)H(3)O(2))(4)(C(10)H(14)N(2)O)(2)], reveals a dinuclear Cu(II) complex located about a center of inversion. The coordination environment of each Cu(II) cation is distorted octa-hedral, composed of four bridging acetate ligands, an apical pyridine donor and is completed by a Cu-Cu bond. The amide H atom forms intra-molecular hydrogen bonds to two carboxyl O atoms. In the crystal, weak inter-molecular pyridine-amide C-H⋯O inter-actions are also present.

A novel bioactive sponge was created with a composite of type I collagen sponges or porous poly(e-caprolactone) (PCL) scaffolds, platelet-rich plasma (PRP), BMP2-loaded nanoporous silicon enclosure (NSE) microparticles, mineralizing peptide amphiphiles (PA), and mesenchymal stem cells (MSC). Primary MSC from cortical bone (CB)  tissue proved to form more and larger colony units, as well as produce more mineral matrix under osteogenic differentiation, than MSC from bone marrow (BM). Coating pre-treatments were optimized for maximum cell adhesion and mineralization, while a PRP-based gel carrier was created to efficiently deliver and retain MSC and  microparticles within a porous scaffold while simultaneously promoting cell recruitment, proliferation, and angiogenesis. Components and composite sponges were evaluated for osteogenic differentiation in vitro. Osteogenic sponges were loaded with MSC, PRP, PA, and NSE and implanted subcutaneously in rats to evaluate the formation of bone tissue and angiogenesis in vivo. It was found that the combination of a collagen sponge with CB MSC, PRP, PA, and the BMP2-releasing NSE formed the most bone and was most vascularized by four weeks compared to analogous composites featuring BM MSC or PCL or lacking PRP, PA, and NSE. This study indicates that CB MSC should be considered as an alternative to marrow as a source of stem cells, while the PRP-PA cell and microparticle delivery system may be utilized for diverse tissue engineering applications.

The title compound, C(17)H(18)O(3), prepared by microwave irradiation of benzophenone and dioxane, crystallizes in a racemic mixture that forms one-dimensional chains via strong hydrogen bonding of the hydroxy group to the adjacent symmetry-generated 1,4-dioxan-2-yl group; the O-H···O distance is 1.99 (3) Å and the O-H···O angle is 160 (2)°.

It is controversial whether naïve B cells are directly activated in response to TLR9 ligand, CpG ODN. Although bovine blood-derived CD21(+) B cells express TLR9 and proliferate in response to CpG in mixed-cell populations, purified bovine B cells do not proliferate significantly in response to CpG ODN, even when the B cell receptor is engaged. When co-cultured with CD14(+) myeloid cells and/or B-cell activating factor (BAFF), a cytokine produced by activated myeloid cells, there was a significant increase in CpG-specific B cell proliferation, and the number of large B cells in general or positive for CD25, all of which are markers for B cell activation. These data suggest that activated myeloid cells and BAFF prime B cells for significant CpG-specific activation. Understanding the signals required to mediate efficient CpG-induced, antigen-independent and T-cell independent activation of B cells has implications for polyclonal B cell activation and the development of autoimmune diseases., (Copyright © 2011 Elsevier Inc. All rights reserved.)