Elucidating the Mechanism of Efficient Eu(III) and Yb(III) Sensitisation from a Re(I) Tetrazolato Triangular Assembly.

The reaction of Re(CO)5Br with deprotonated 1H-(5-(2,2':6',2''-terpyridine)pyrid-2-yl)tetrazole yields a triangular assembly formed by tricarbonyl Re(I) vertices. Photophysical measurements reveal blue-green emission with a maximum at 520 nm, 32% quantum yield, and 2430 ns long-lived excited state decay lifetime in deaerated dichloromethane solution. Coordination of lanthanoid ions to the terpyridine units red-shifts the emission to 570 nm and also reveals efficient (90%) and fast sensitisation to both Eu(III) and Yb(III) at room temperature, with a similar rate constant kET of the order of 107 s-1. Efficient sensitisation of Eu(III) from Re(I) is unprecedented, especially when considering the close proximity in energy between the donor and acceptor excited states. On the other hand, comparative measurements at 77 K reveal that energy transfer to Yb(III) is two orders of magnitude slower than that to Eu(III). A two-step mechanism of sensitisation is therefore proposed, whereby the rate-determining step is a thermally activated energy transfer step between the Re(I) centre and the terpyridine functionality, followed by rapid energy transfer to the respective Ln(III) excited states. At 77 K, the direct Re(I) to Eu(III) energy transfer seems to proceed via a ligand-mediated superexchange Dexter-type mechanism.

Is shockwave therapy effective in the management of greater trochanteric pain syndrome? A systematic review and meta-analysis.

BACKGROUND: Evidence is lacking for the efficacy of shockwave therapy (SWT) in the treatment of greater trochanteric pain syndrome (GTPS). AIM: To investigate the efficacy of SWT on pain and function in the management of GTPS. METHODS: A systematic search of electronic databases and grey literature was conducted up to May 2023. Studies utilising SWT on adults for GTPS, providing measures of pain and/or function at baseline and at follow-up were considered for inclusion. Meta-analysis was undertaken using converted pain and functional outcomes. Studies were assessed for quality and risk of bias, and assigned a level of evidence as per the Grading of Recommendations, Assessment, Development and Evaluations criteria. RESULTS: Twelve articles (n = 1121 subjects) were included, including five randomised controlled trials (RCTs) and seven non-RCTs. No statistical differences were observed for pain over time f(1,5) = 1.349 (p = 0.298) or between SWT and control f(1,5) = 1.782 (p = 0.238). No significant differences in functional outcomes in short- (H = 2.591, p = 0.181) and medium-term follow-up (H = 0.189, p = 0.664) were identified between SWT and control. Moderate magnitude treatment effects for pain (Hedges-G [HG] 0.71) favouring SWT groups over control was identified, decreasing to low for function (HG 0.20). Further pain and functional treatment effects were identified at higher magnitudes across follow-up time-points in SWT groups compared to control. CONCLUSION: Moderate-quality evidence demonstrated no statistically significant improvements in pain and function post-SWT compared to control. Low-quality evidence established clinical improvements throughout all included studies favouring SWT over control. Consequently, owing to relatively low incidence of side effects, SWT should be considered a viable option for the management of GTPS. Issues with both clinical and statistical heterogeneity of studies and during meta-analysis require consideration, and more robust RCTs are recommended if the efficacy of SWT for the management of GTPS is to be comprehensively determined.

Trauma-informed Interventions in Early Childhood Education and Care Settings: A Scoping Review.

Trauma in early childhood is a significant public health concern. Early Childhood Education and Care (ECEC) services are uniquely positioned to buffer the negative impact of early childhood trauma on children. This scoping review synthesized studies evaluating trauma-informed interventions in ECEC settings through a systematic search of four relevant online databases (PsycINFO, Medline, ERIC, A+ Education). Fourteen studies met the inclusion criteria, with 12 ECEC center-based trauma-informed interventions evaluated. Types and components of trauma-informed interventions, outcomes, and measures are presented. Findings suggest that trauma-informed interventions in ECEC settings are nascent but growing. Increasingly, programs are adopting multi-tiered system of support to address early childhood trauma, with these models suggesting promising results. The predominant focus of ECEC center-based trauma-informed interventions was upskilling teachers through training and coaching, with studies focused on assessment of teacher-level outcomes. Child, organization, and caregiver-level outcomes are not explored to the same extent, with evaluation of organizational outcomes relying predominately on qualitative methods. Whilst the short-term outcomes of trauma-informed approaches in ECEC have been examined, longer-term impacts and the causal mechanistic pathways of such programs have yet to be explored.

Therapeutic potential of metal ions for COVID-19: insights from the papain-like protease of SARS-CoV-2.

Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two cysteine proteases responsible for the maturation and infectivity of SARS-CoV-2, processes and liberates functional proteins from the viral polyproteins and cleaves ubiquitin and ISG15 modifications to inhibit innate immune sensing. Consequently, PLpro is an attractive target for developing COVID-19 therapies. PLpro contains a zinc-finger domain important for substrate binding and structural stability. However, the impact of metal ions on the activity and biophysical properties of SARS-CoV-2 PLpro has not been comprehensively studied. Here, we assessed the impacts of metal ions on the catalytic activity of PLpro. Zinc had the largest inhibitory effect on PLpro, followed by manganese. Calcium, magnesium, and iron had smaller or no effects on PLpro activity. EDTA at a concentration of 0.5 mM was essential for PLpro activity, likely by chelating trace metals that inhibit PLpro. IC50 values for ZnCl2, ZnSO4, and MnCl2 of 0.42 ± 0.02 mM, 0.35 ± 0.01 mM, and 2.6 ± 0.3 mM were obtained in the presence of 0.5 mM EDTA; in the absence of EDTA, the estimated IC50 of ZnCl2 was 14 µM. Tryptophan intrinsic fluorescence analysis confirmed the binding of zinc and manganese to PLpro, and differential scanning calorimetry revealed that zinc but not manganese reduced ΔHcal of PLpro. The results of this study provide a reference for further work targeting PLpro to prevent and treat COVID-19.

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense.

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome-lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD-BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

Photoactive Metal Carbonyl Complexes Bearing N-Heterocyclic Carbene Ligands: Synthesis, Characterization, and Viability as Photoredox Catalysts.

This report details the synthesis and characterization of a small family of previously unreported, structurally related chromium, molybdenum, tungsten, manganese, and iron complexes bearing N-heterocyclic carbene and carbonyl supporting ligands. These complexes have the general form [ML(CO)3X] or [ML(CO)3], where X = CO or Br and L = 1-phenyl-3-(2-pyridyl)imidazolin-2-ylidene. Where possible, the solid-state, spectroscopic, electrochemical, and photophysical properties of these molecules were studied using a combination of experiment and theory. Photophysical studies reveal that decarbonylation occurs when these complexes are exposed to ultraviolet light, with the CO ligand being replaced with a labile acetonitrile solvent molecule. To obtain insights into the potential utility, scope, and applications of these complexes in visible-light-mediated photoredox catalysis, their capacity to facilitate a range of photoinduced reactions via the reductive or oxidative functionalization of organic molecules was investigated. These chromium, molybdenum, and manganese catalysts efficiently facilitated atom-transfer radical addition processes. In light of their photolability, these types of catalysts may potentially allow for the development of photoinduced reactions involving less conventional inner-sphere electron-transfer pathways.

Formation of an intersectoral network to support trans survivors of sexual assault: A survey of health and community organizations.

BACKGROUND: To address the growing international recognition of the inequities faced by transgender (trans) persons and the lack of services that attend to the specific concerns of trans sexual assault survivors, we undertook the development of an intersectoral network of hospital-based violence treatment centers and trans-positive community organizations to enhance available supports. AIMS: To examine anticipated involvement of organizations in the network and determine network activities, deliverables, and values. METHODS: We developed a survey with guidance from an advisory group of trans community members and their allies. Items on the survey related to network activities, deliverables, and values, which were also informed by key insights from earlier network planning meetings, were rated on a 5-point Likert scale for their importance (1 = not important at all, 5 = very important). RESULTS: Sixty-four out of 93 organizations invited responded to the survey, giving a response rate of 69%. The highest prioritized network activities were: improve access to support services for trans survivors, educate trans survivors on their rights/what to expect when seeking supports and information on organizations, provide ongoing education/training for service providers on trans-affirming care, and inform guidelines on appropriate and sensitive standards of care/better practices for trans survivors (means = 4.6). The highest prioritized deliverables were: provision of standardized sensitivity training on violence against trans persons for professionals and development of an online directory/resource list of trans-affirming service providers and organizations that is continuously updated (means = 4.5). Trauma- and violence-informed and trans-guided were the most highly rated values (means = 4.8). CONCLUSION: These findings have implications for healthcare and community leaders seeking to collaborate across sectors to address the inequities faced by trans persons experiencing sexual assault.

Measuring force generation within reconstituted microtubule bundle assemblies using optical tweezers.

Kinesins and microtubule associated proteins (MAPs) are critical to sustain life, facilitating cargo transport, cell division, and motility. To interrogate the mechanistic underpinnings of their function, these microtubule-based motors and proteins have been studied extensively at the single molecule level. However, a long-standing issue in the single molecule biophysics field has been how to investigate motors and associated proteins within a physiologically relevant environment in vitro. While the one motor/one filament orientation of a traditional optical trapping assay has revolutionized our knowledge of motor protein mechanics, this reductionist geometry does not reflect the structural hierarchy in which many motors work within the cellular environment. Here, we review approaches that combine the precision of optical tweezers with reconstituted ensemble systems of microtubules, MAPs, and kinesins to understand how each of these unique elements work together to perform large scale cellular tasks, such as but not limited to building the mitotic spindle. Not only did these studies develop novel techniques for investigating motor proteins in vitro, but they also illuminate ensemble filament and motor synergy that helps bridge the mechanistic knowledge gap between previous single molecule and cell level studies.

The promise of an intersectoral network in enhancing the response to transgender survivors of sexual assault.

OBJECTIVES: This study explores the promise of an intersectoral network in enhancing the response to transgender (trans) survivors of sexual assault. METHODS: One hundred and three representatives of healthcare and community organizations across Ontario, Canada were invited to participate in a survey. Respondents were asked to: 1) identify systemic challenges to supporting trans survivors, 2) determine barriers to collaborating across sectors, and 3) indicate how an intersectoral network might address these challenges and barriers. Descriptive statistics were used to summarize quantitative data and qualitative data were collated thematically. RESULTS: Sixty-seven representatives responded to the survey, for a response rate of 65%. Several themes capturing the challenges organizations face in supporting trans survivors were identified: Lack of knowledge and training among providers, Inadequate resources across organizations and institutions, and Limited access to and availability of appropriate services. Barriers to collaborating across sectors considered important by the overwhelming majority of respondents were: Lack of trans-positive service professionals (e.g., a paucity of sensitivity training), lack of resources (e.g., staff, staff time and workload, spaces to meet), and Institutional structures (e.g., oppressive policies, funding mandates). Four ways in which a network could address these challenges and barriers emerged from the data: Center the voices of trans communities in advocacy; Support competence of professionals to provide trans-affirming care; Provide the platform, strategies, and tools to aid in organizational change; and Create space for organizations to share ideas, goals, and resources. CONCLUSION: Our findings deepen our understanding of important impediments to enhancing the response to trans survivors of sexual assault and the role networks of healthcare and community organizations can play in comprehensively responding to complex health and social problems.

Therapeutic Efficacy of Antioxidants in Ameliorating Obesity Phenotype and Associated Comorbidities.

Obesity has been a worldwide epidemic for decades. Despite the abundant increase in knowledge regarding the etiology and pathogenesis of obesity, the prevalence continues to rise with estimates predicting considerably higher numbers by the year 2030. Obesity is characterized by an abnormal lipid accumulation, however, the physiological consequences of obesity are far more concerning. The development of the obesity phenotype constitutes dramatic alterations in adipocytes, along with several other cellular mechanisms which causes substantial increase in systemic oxidative stress mediated by reactive oxygen species (ROS). These alterations promote a chronic state of inflammation in the body caused by the redox imbalance. Together, the systemic oxidative stress and chronic inflammation plays a vital role in maintaining the obese state and exacerbating onset of cardiovascular complications, Type II diabetes mellitus, dyslipidemia, non-alcoholic steatohepatitis, and other conditions where obesity has been linked as a significant risk factor. Because of the apparent role of oxidative stress in the pathogenesis of obesity, there has been a growing interest in attenuating the pro-oxidant state in obesity. Hence, this review aims to highlight the therapeutic role of antioxidants, agents that negate pro-oxidant state of cells, in ameliorating obesity and associated comorbidities. More specifically, this review will explore how various antioxidants target unique and diverse pathways to exhibit an antioxidant defense mechanism.

Photophysical investigation of near infrared emitting lanthanoid complexes incorporating tris(2-naphthoyl)methane as a new antenna ligand.

A conjugated ß-triketone, tris(2-naphthoyl)methane (tnmH), has been synthesized and successfully utilized as an antenna moiety for sensitization of the trivalent lanthanoids Eu3+, Sm3+, Yb3+ and Nd3+, in an isomorphous series of mononuclear complexes formulated as [Ln(tnm)3(DMSO)2] (Ln3+ = Nd3+, Sm3+, Eu3+, Gd3+ and Yb3+). The photophysical properties of the materials were characterized as comprehensively as possible, with overall quantum yields, intrinsic quantum yields based on calculated radiative decays, and sensitization efficiencies reported. This investigation improves understanding of the sensitization processes occurring in the near-infrared (NIR) region, where quantitative data are currently scarce. In fact, the [Yb(tnm)3(DMSO)2] and its deuterated analogue, [Yb(tnm)3(d6-DMSO)2], present high values of overall quantum yield of 4% and 6%, respectively, which makes them useful and readily accessible references for future investigation of NIR-emitting systems.

Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) has been recognized as the most common liver disorder in developed countries. NAFLD progresses from fat accumulation in hepatocytes to steatohepatitis to further stages of fibrosis and cirrhosis. Simple steatosis, i.e. fat deposition in the liver, is considered benign and gives way to non-alcoholic steatohepatitis (NASH) with a higher probability of progressing to cirrhosis, and liver-related mortality. Evidence has been found that this progression has been associated with marked alterations in hepatocyte histology and a shift in marker expression of healthy hepatocytes including increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), adipocyte protein (aP2), CD36, interleukin-6 (IL-6), interleukin-18 (IL-18) and adiponectin. This progression shares much in common with the obesity phenotype, which involves a transformation of adipocytes from small, healthy cells to large, dysfunctional ones that contribute to redox imbalance and the progression of metabolic syndrome. Further, activation of Src/ERK signaling via the sodium potassium adenosine triphosphatase (Na/K-ATPase) α-1 subunit in impaired hepatocytes may contribute to redox imbalance, exacerbating the progression of NAFLD. This review hypothesizes that an adipogenic transformation of hepatocytes propagates redox imbalance and that the processes occurring in adipogenesis become activated in fat-laden hepatocytes in liver, thereby driving progression to NAFLD. Further, this review discusses therapeutic interventions to reverse NAFLD including the thiazolidinediones (TZDs) and a variety of antioxidant species. The peptide, pNaKtide, which is an antagonist of Na/K-ATPase signaling, is also proposed as a potential pharmacologic option for reducing reactive oxygen species (ROS) and reversing NAFLD by inhibiting the Na/K-ATPase-modulated ROS amplification loop.

A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma.

BACKGROUND: Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism. METHODS: The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network). RESULTS: A significant association of the coding polymorphism, 601A>G, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601A>G were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2. CONCLUSIONS: Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.