Systematic analysis of tup1 and cyc8 mutants reveals distinct roles for TUP1 and CYC8 and offers new insight into the regulation of gene transcription by the yeast Tup1-Cyc8 complex.

The Tup1-Cyc8 complex in Saccharomyces cerevisiae was one of the first global co-repressors of gene transcription discovered. However, despite years of study, a full understanding of the contribution of Tup1p and Cyc8p to complex function is lacking. We examined TUP1 and CYC8 single and double deletion mutants and show that CYC8 represses more genes than TUP1, and that there are genes subject to (i) unique repression by TUP1 or CYC8, (ii) redundant repression by TUP1 and CYC8, and (iii) there are genes at which de-repression in a cyc8 mutant is dependent upon TUP1, and vice-versa. We also reveal that Tup1p and Cyc8p can make distinct contributions to commonly repressed genes most likely via specific interactions with different histone deacetylases. Furthermore, we show that Tup1p and Cyc8p can be found independently of each other to negatively regulate gene transcription and can persist at active genes to negatively regulate on-going transcription. Together, these data suggest that Tup1p and Cyc8p can associate with active and inactive genes to mediate distinct negative and positive regulatory roles when functioning within, and possibly out with the complex.

Growing a provincial patient and family engagement network to optimize kidney care.

Patient and family engagement is crucial for a responsive health system and improves patient outcomes. However, few practical resources for purposeful engagement are available to health leaders. Over the past five years, BC Renal, the provincial kidney care network in British Columbia, developed, operationalized, and implemented a framework to enable meaningful patient and family engagement. An advisory committee, comprising patient partners and representatives from health authorities and the community, directs the outreach, resource development, and evaluation of patient and family engagement at BC Renal. Here, we describe how our network-wide patient engagement strategy was developed and expanded upon, and the progress so far. A 2022 survey reports that 95% were satisfied with the engagement opportunities, and narrative feedback suggests network members continue to adopt practical ways to collaborate more effectively. Health leaders, patient partners, and others continue to align operational and strategic activities to advance culture change in kidney care provincially.

Walk the Line: How Successful Are Efforts to Maintain Monogamy in Intimate Relationships?

Monogamy, typically defined as sexual and romantic exclusivity to one partner, is a near-universal expectation in committed intimate relationships in Western societies. Attractive alternative partners are a common threat to monogamous relationships. However, little is known about how individuals strive to protect their relationships from tempting alternatives, particularly those embedded in one's social network. The current exploratory study was guided by the Investment Model, which states that satisfaction, investments, and perceived alternatives to a relationship predict commitment, which in turn predicts relationship longevity. The study aimed to identify relationship and extradyadic attraction characteristics associated with monogamy maintenance efforts, specifically relationship commitment, as predicted by the Investment Model. The efficacy of monogamy maintenance efforts was assessed via sexual and emotional infidelity measures at a 2-month follow-up. U.S. adults in heterosexual intimate relationships (N = 287; 50.2% male; M age = 34.5 years; M relationship length = 87 months) were recruited online to complete the survey study. Through structural equation modelling, the Investment Model structure was replicated, and relationship commitment predicted use of relationship-enhancing efforts as well as self-monitoring/derogation efforts. Individuals who experienced reciprocated attraction used significantly more avoidance and self-monitoring/derogation efforts than did those who experienced unreciprocated attraction. Ultimately, monogamy maintenance efforts did not significantly predict success in maintaining monogamy at follow-up. These findings have important research, educational, and clinical implications relating to relationship longevity.

Youth Depression Screening with Parent and Self-Reports: Assessing Current and Prospective Depression Risk.

Few studies have examined the incremental validity of multi-informant depression screening approaches. In response, we examined how recommendations for using a multi-informant approach may vary for identifying concurrent or prospective depressive episodes. Participants included 663 youth (AgeM = 11.83; AgeSD = 2.40) and their caregiver who independently completed youth depression questionnaires, and clinical diagnostic interviews, every 6 months for 3 years. Receiver operating characteristic (ROC) analyses showed that youth-report best predicted concurrent episodes, and that both youth and parent-report were necessary to adequately forecast prospective episodes. More specifically, youth-reported negative mood symptoms and parent-reported anhedonic symptoms incrementally predicted future depressive episodes. Findings were invariant to youth's sex and age, and results from person and variable-centered analyses suggested that discrepancies between informants were not clinically meaningful. Implications for future research and evidence-based decision making for depression screening initiatives are discussed.

Characteristics of Child Psychiatric Outpatients at Highest Risk for Suicidal Thoughts and Behaviors.

On average, compared to non-referred youth, child psychiatric outpatients show elevated rates of suicidal thoughts and behaviors (STBs), which are predictors of completed suicide. Determining the psychopathology features that associate with highest risk for STBs among youth outpatients may yield opportunities for targeted prevention/intervention. Yet, outpatient studies are limited and have not systematically examined comorbidity and dimensional psychopathology. In 758 youth, aged 6-18, consecutively referred for neuropsychiatric evaluation, we examined the extent to which diagnostic groups, comorbid subgroups and dimensional symptoms associated with STBs. After controlling for comorbidity, mood, anxiety and conduct disorders associated with elevated STB risk. Regarding dimensions, symptoms of depression, aggression and psychosis all contributed to higher STB risk. Although ADHD (as a diagnosis or dimension) did not associate with elevated STB risk independently, ADHD that was comorbid with other conditions did. Suicide prevention/intervention efforts should be investigated in youth outpatients with the highest risk for STBs.

Effect of Varying Concentrations of Docosahexaenoic Acid on Amyloid Beta (1⁻42) Aggregation: An Atomic Force Microscopy Study.

Healthcare has advanced significantly, bringing with it longer life expectancies and a growing population of elders who suffer from dementia, specifically Alzheimer's disease (AD). The amyloid beta (Aß) peptide has been implicated in the cause of AD, where the peptides undergo a conformational change and form neurotoxic amyloid oligomers which cause neuronal cell death. While AD has no cure, preventative measures are being designed to either slow down or stop the progression of this neurodegenerative disease. One of these measures involves dietary supplements with polyunsaturated fatty acids such as docosahexaenoic acid (DHA). This omega-3 fatty acid is a key component of brain development and has been suggested to reduce the progression of cognitive decline. However, different studies have yielded different results as to whether DHA has positive, negative, or no effects on Aß fibril formation. We believe that these discrepancies can be explained with varying concentrations of DHA. Here, we test the inhibitory effect of different concentrations of DHA on amyloid fibril formation using atomic force microscopy. Our results show that DHA has a strong inhibitory effect on Aß1⁻42 fibril formation at lower concentrations (50% reduction in fibril length) than higher concentrations above its critical micelle concentration (70% increase in fibril length and three times the length of those at lower concentrations). We provide evidence that various concentrations of DHA can play a role in the inhibitory effects of amyloid fibril formation in vitro and help explain the discrepancies observed in previous studies.

Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery.

BACKGROUND AND AIMS: The aim is to evaluate the association between the use of intraoperative dexmedetomidine with an increase in recurrence-free survival (RFS) and overall survival (OS) after nonsmall cell lung cancer (NSCLC) surgery. MATERIAL AND METHODS: This was a propensity score-matched (PSM) retrospective study. Single academic center. The study comprised patients with Stage I through IIIa NSCLC. Patients were excluded if they were younger than 18 years. Primary outcomes of the study were RFS and OS. RFS and OS were evaluated using univariate and multivariate Cox proportional hazards models after PSM (n = 251/group) to assess the association between intraoperative dexmedetomidine use and the primary outcomes. The value of P < 0.05 was considered statistically significant. RESULTS: After PSM and adjusting for significant covariates, the multivariate analysis demonstrated no association between the use of dexmedetomidine and RFS (hazard ratio [HR] [95% confidence interval (CI)]: HR = 1.18, 95% CI: 0.91-1.53; P = 0.199). The multivariate analysis also demonstrated an association between the administration of dexmedetomidine and reduced OS (HR = 1.28, 95% CI: 1.03-1.59; P = 0.024). CONCLUSIONS: This study demonstrated that the intraoperative use of dexmedetomidine to NSCLC patients was not associated with a significant impact on RFS and but worsening OS. A randomized controlled study should be conducted to confirm the results of this study.

Platelet-to-Lymphocyte Ratio and Use of NSAIDs During the Perioperative Period as Prognostic Indicators in Patients With NSCLC Undergoing Surgery.

BACKGROUND: Hematological biomarkers of inflammation such as the neutrophil-to-lymphocytic rate have been reported as predictors of survival in a variety of cancers. The aim of the present study was to investigate the prognostic value of the perioperative platelet-to-lymphocyte ratio in patients with non-small-cell lung cancer (NSCLC) and to elucidate the effects of the perioperative use of nonsteroidal anti-inflammatory drugs (NSAIDs) on tumor recurrence and survival in patients undergoing surgical resection for NSCLC. METHODS: This retrospective study included data from 1,637 patients who underwent surgical resection for stage I, II, or III NSCLC. Perioperative data and tumor-related variables were included. Univariate and multivariable Cox proportional hazard ratio (HR) models were used to evaluate the association between perioperative platelet-to-lymphocyte ratio and NSAID use on recurrence-free survival (RFS) and overall survival (OS). RESULTS: Multivariate analysis showed that a preoperative platelet-to-lymphocyte ratio of at least 180 was associated with reduced rates of RFS (HR = 1.22; 95% confidence interval [CI], 1.03-1.45; P = .019) and OS (HR = 1.33; 95% CI, 1.10-1.62; P = .004). Perioperative use of NSAIDs showed no statistically significant changes in RFS and OS rates (P = .72 and P = .44, respectively). CONCLUSIONS: A higher preoperative inflammatory status is associated with decreased rates of RFS and OS in patients with NSCLC undergoing curative surgery. Perioperative use of NSAIDs was not found to be an independent predictor of survival.

Multi-Province Listeriosis Outbreak Linked to Contaminated Deli Meat Consumed Primarily in Institutional Settings, Canada, 2008.

A multi-province outbreak of listeriosis occurred in Canada from June to November 2008. Fifty-seven persons were infected with 1 of 3 similar outbreak strains defined by pulsed-field gel electrophoresis, and 24 (42%) individuals died. Forty-one (72%) of 57 individuals were residents of long-term care facilities or hospital inpatients during their exposure period. Descriptive epidemiology, product traceback, and detection of the outbreak strains of Listeria monocytogenes in food samples and the plant environment confirmed delicatessen meat manufactured by one establishment and purchased primarily by institutions was the source of the outbreak. The food safety investigation identified a plant environment conducive to the introduction and proliferation of L. monocytogenes and persistently contaminated with Listeria spp. This outbreak demonstrated the need for improved listeriosis surveillance, strict control of L. monocytogenes in establishments producing ready-to-eat foods, and advice to vulnerable populations and institutions serving these populations regarding which high-risk foods to avoid.

Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by dementia and memory loss for which no cure or effective prevention is currently available. Neurodegeneration in AD is linked to formation of amyloid plaques found in brain tissues of Alzheimer's patients during post-mortem examination. Amyloid plaques are composed of amyloid fibrils and small oligomers - insoluble protein aggregates. Although amyloid plaques are found on the neuronal cell surfaces, the mechanism of amyloid toxicity is still not well understood. Currently, it is believed that the cytotoxicity is a result of the nonspecific interaction of small soluble amyloid oligomers (rather than longer fibrils) with the plasma membrane. In recent years, nanotechnology has contributed significantly to understanding the structure and function of lipid membranes and to the study of the molecular mechanisms of membrane-associated diseases. We review the current state of research, including applications of the latest nanotechnology approaches, on the interaction of lipid membranes with the amyloid-ß (Aß) peptide in relation to amyloid toxicity. We discuss the interactions of Aß with model lipid membranes with a focus to demonstrate that composition, charge and phase of the lipid membrane, as well as lipid domains and rafts, affect the binding of Aß to the membrane and contribute to toxicity. Understanding the role of the lipid membrane in AD at the nanoscale and molecular level will contribute to the understanding of the molecular mechanism of amyloid toxicity and may aid into the development of novel preventive strategies to combat AD.

The influence of flocculation upon global gene transcription in a yeast CYC8 mutant.

The transcriptome from a Saccharomyces cerevisiae tup1 deletion mutant was one of the first comprehensive yeast transcriptomes published. Subsequent transcriptomes from tup1 and cyc8 mutants firmly established the Tup1-Cyc8 complex as predominantly acting as a repressor of gene transcription. However, transcriptomes from tup1/cyc8 gene deletion or conditional mutants would all have been influenced by the striking flocculation phenotypes that these mutants display. In this study, we have separated the impact of flocculation from the transcriptome in a cyc8 conditional mutant to reveal those genes (i) subject solely to Cyc8p-dependent regulation, (ii) regulated by flocculation only and (iii) regulated by Cyc8p and further influenced by flocculation. We reveal a more accurate list of Cyc8p-regulated genes that includes newly identified Cyc8p-regulated genes that were masked by the flocculation phenotype and excludes genes which were indirectly influenced by flocculation and not regulated by Cyc8p. Furthermore, we show evidence that flocculation exerts a complex and potentially dynamic influence upon global gene transcription. These data should be of interest to future studies into the mechanism of action of the Tup1-Cyc8 complex and to studies involved in understanding the development of flocculation and its impact upon cell function.

Patient and Clinician Experiences With the Combination of Virtual and In-Person Chronic Kidney Disease Care Since the COVID-19 Pandemic.

Background: Following onset of the COVID-19 pandemic, chronic kidney disease (CKD) clinics in BC shifted from established methods of mostly in-person care delivery to virtual care (VC) and thereafter a hybrid of the two. Objectives: To determine strengths, weaknesses, quality-of-care delivery, and key considerations associated with VC usage to inform optimal way(s) of integrating virtual and traditional methods of care delivery in multidisciplinary kidney clinics. Design: Qualitative evaluation. Setting: British Columbia, Canada. Participants: Patients and health care providers associated with multidisciplinary kidney care clinics. Methods: Development and delivery of semi-structured interviews of patients and health care providers. Results: 11 patients and/or caregivers and 12 health care providers participated in the interviews. Participants reported mixed experiences with VC usage. All participants foresaw a future where both VC and in-person care was offered. A reported benefit of VC was convenience for patients. Challenges identified with VC included difficulty establishing new therapeutic relationships, and variable of abilities of both patients and health care providers to engage and communicate in a virtual format. Participants noted a preference for in-person care for more complex situations. Four themes were identified as considerations when selecting between in-person and VC: person's nonmedical context, support available, clinical parameters and tasks to be completed, and clinic operations. Participants indicated that visit modality selection is an individualized and ongoing process involving the patient and their preferences which may change over time. Health care provider participants noted that new workflow challenges were created when using both VC and in-person care in the same clinic session. Limitations: Limited sample size in the setting of one-on-one interviews and use of convenience sampling which may result in missing perspectives, including those already facing challenges accessing care who could potentially be most disadvantaged by implementation of VC. Conclusions: A list of key considerations, aligned with quality care delivery was identified for health care providers and programs to consider as they continue to utilize VC and refine how best to use different visit modalities in different patient and clinical situations. Further work will be needed to validate these findings and evaluate clinical outcomes with the combination of virtual and traditional modes of care delivery. Trial registration: Not registered.

Contexte: Après le début de la pandémie de COVID-19, les cliniques d'insuffisance rénale chronique (IRC) de la Colombie-Britannique sont passées d'une prestation de soins traditionnelle fondée principalement sur les visites en personne à des soins en mode virtuel, puis à un modèle hybride combinant les deux méthodes. Objectifs: Déterminer les avantages et les faiblesses des soins en mode virtuel, ainsi que la qualité de la prestation des soins et les principaux facteurs à considérer relativement à l'utilization des soins en mode virtuel, afin d'informer sur les meilleurs moyens d'intégrer les méthodes virtuelles et traditionnelles de prestation des soins dans les cliniques multidisciplinaires de néphrologie. Conception: Évaluation qualitative. Cadre: Colombie-Britannique (Canada). Sujets: Patients et prestataires de soins associés à des cliniques multidisciplinaires de soins rénaux. Méthodologie: Élaboration et réalisation d'entrevues semi-structurées auprès de patients et de prestataires de soins de santé. Résultats: En tout, 11 patients et/ou soignants et 12 prestataires de soins de santé ont participé aux entrevues. Les participants ont fait état d'expériences mitigées avec les soins en mode virtuel. Tous les participants envisageaient un futur où les soins seront offerts tant en mode virtuel qu'en personne. Un des avantages mentionnés des soins en mode virtuel est la commodité pour les patients. Parmi les défis mentionnés figuraient la difficulté à établir de nouvelles relations thérapeutiques et les capacités variables des patients et des prestataires de soins de santé à établir une relation et à communiquer en mode virtuel. Les participants ont noté une préférence pour les soins en personne dans les situations plus complexes. Quatre thèmes ont été identifiés comme facteurs à prendre en compte dans le choix entre les soins virtuels ou en personne: le contexte non médical de la personne, l'aide disponible, les paramètres cliniques et les tâches à accomplir, et les opérations de la clinique. Les participants ont indiqué que le choix de la modalité pour les visites est un processus individualisé et continu impliquant le patient et ses préférences, lesquelles peuvent changer au fil du temps. Les prestataires de soins ont indiqué que le fait d'offrir à la fois des soins virtuels et en personne dans une même séance clinique créait de nouveaux défis en matière de flux de travail. Limites: La taille limitée de l'échantillon pour les entrevues individuelles et l'utilization d'un échantillonnage de commodité pourraient avoir manqué certains points de vue, notamment celui de personnes déjà confrontées à des difficultés d'accès aux soins et qui pourraient être les plus désavantagées par la mise en œuvre de soins en mode virtuel. Conclusion: Une liste de facteurs-clé à prendre en compte pour une prestation de soins de qualité a été établie à l'attention des prestataires de soins de santé et des programs qui continuent à utiliser les soins en mode virtuel, et décrit la meilleure façon d'utiliser les différentes modalités de visites dans différentes situations cliniques et pour différents patients. D'autres travaux seront nécessaires pour valider ces résultats et évaluer les résultats cliniques lorsqu'il y a combinaison des modes virtuel et traditionnel pour la prestation des soins.

The epidemiology of travel-related Salmonella Enteritidis in Ontario, Canada, 2010-2011.

BACKGROUND: Increases in the number of salmonellosis cases due to Salmonella Enteritidis (SE) in 2010 and 2011 prompted a public health investigation in Ontario, Canada. In this report, we describe the current epidemiology of travel-related (TR) SE, compare demographics, symptoms and phage types (PTs) of TR and domestically-acquired (DA) cases, and estimate the odds of acquiring SE by region of the world visited. METHODS: All incident cases of culture confirmed SE in Ontario obtained from isolates and specimens submitted to public health laboratories were included in this study. Demographic and illness characteristics of TR and DA cases were compared. A national travel survey was used to provide estimates for the number of travellers to various destinations to approximate rates of SE in travellers. Multivariate logistic regression was used to estimate the odds of acquiring SE when travelling to various world regions. RESULTS: Overall, 51.9% of SE cases were TR during the study period. This ranged from 35.7% TR cases in the summer travel period to 65.1% TR cases in the winter travel period. Compared to DA cases, TR cases were older and were less likely to seek hospital care. For Ontario travellers, the adjusted odds of acquiring SE was the highest for the Caribbean (OR 37.29, 95% CI 17.87-77.82) when compared to Europe. Certain PTs were more commonly associated with travel (e.g., 1, 4, 5b, 7a, Atypical) than with domestic infection. Of the TR cases, 88.9% were associated with travel to the Caribbean and Mexico region, of whom 90.1% reported staying on a resort. Within this region, there were distinct associations between PTs and countries. CONCLUSIONS: There is a large burden of TR illness from SE in Ontario. Accurate classification of cases by travel history is important to better understand the source of infections. The findings emphasize the need to make travellers, especially to the Caribbean, and health professionals who provide advice to travellers, aware of this risk. The findings may be generalized to other jurisdictions with travel behaviours in their residents similar to Ontario residents.

Hierarchical integration of agency and communion: a study of influential moral figures.

The purpose of this research is to (a) identify which of recent history's influential figures did and which did not personify moral excellence, and (b) to examine the motives that drove these individuals along such divergent paths. In Study 1, 102 social scientists evaluated the moral qualities of influential figures from Time Magazine's lists. In Study 2, we selected the 15 top ranking of these figures to comprise a moral exemplar group and the bottom 15 to comprise a comparison group of similarly influential people. We measured the motivational aspects of their personality (agency and communion) by content-analyzing extant speeches and interviews. Moral exemplars exhibited the hierarchical integration of agency and communion by treating agentic motives as a means to an end of communal motives. Comparison subjects, by contrast, personified unmitigated agency by treating motives of agency as both a means to an end and an end unto itself. These results imply that both the strength and structure of a person's motives account for moral behavior.

Immature ALS-associated mutant superoxide dismutases form variable aggregate structures through distinct oligomerization processes.

Protein misfolding and aggregation are hallmarks of many diseases, including amyotrophic lateral sclerosis (ALS). In familial ALS, aberrant self-association of mutant Cu,Zn-superoxide dismutase (SOD1) is implicated as a key contributor to disease. Mutations have the largest impacts on the stability of the most immature form of SOD1, the unmetallated, disulfide-reduced monomer (apoSH SOD1). Here we demonstrate that, despite the marginal stability of apoSH SOD1, aggregation is little correlated with the degree of protein unfolding, and multiple modes of aggregation occur, depending on the mutation and solution conditions. Light scattering and atomic force microscopy reveal two distinct mutant SOD1 behaviours: high aggregator mutants form abundant small assemblies, while low aggregator mutants form fewer, more fibre-like aggregates. Attenuated total reflectance-Fourier transform infrared spectroscopy and Thioflavin T binding show the aggregates maintain native-like anti-parallel beta structure. These results provide new evidence that ALS-associated mutations promote the aggregation of apoSH SOD1 through multiple pathways, with broad implications for understanding mechanisms of protein self-association in disease and biotechnology.

A Phase 1, Open-Label, Dose-Escalation Study of L-DOS47 in Combination With Pemetrexed Plus Carboplatin in Patients With Stage IV Recurrent or Metastatic Nonsquamous NSCLC.

Introduction: L-DOS47, a targeted urease-anti-CEACAM6 immunoconjugate, alters the acidity of the tumor microenvironment by increasing local ammonia production. In vitro, the cytotoxic effects of L-DOS47 were additive when combined with pemetrexed and carboplatin. Methods: This phase I, open-label, dose-escalation study evaluated the safety and tolerability of up to four cycles of L-DOS47 (administered on days 1, 8, and 15 of each cycle at doses ranging from 0.59 to 9.0 µg/kg) combined with pemetrexed and carboplatin in patients with stage IV nonsquamous NSCLC. Continued L-DOS47 treatment after the fourth cycle was allowed at the treating physicians' discretion. Results: A total of 14 patients received at least one dose of L-DOS47. Overall, L-DOS47 was well tolerated. Grade greater than or equal to 3 adverse events (AEs) were typically neutropenia related. Two grade greater than or equal to 3 AEs and no serious AEs were considered at least possibly related to L-DOS47. No dose-limiting toxicities were reported, so the maximum tolerated dose was not reached. The objective response rate was 41.7% with a median duration of response of 187 days. Clinical benefit was observed in 75.0% of the patients. After the first dose, L-DOS47 systemic exposure increased in a generally dose-proportional manner but decreased substantially with repeat dosing. Anti-L-DOS47 antibodies were detectable in 13 of 14 patients by cycle 2 with titers typically increasing with continued treatment. There was an apparent association between best overall response rate and highest anti-L-DOS47 antibody titer measured. Conclusions: L-DOS47 combined with standard pemetrexed and carboplatin chemotherapy is well tolerated in patients with recurrent or metastatic nonsquamous NSCLC at doses up to 9.0 µg/kg.

C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition.

The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into ß-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as Aß and α-synuclein.

Estimated epidemiologic parameters and morbidity associated with pandemic H1N1 influenza.

BACKGROUND: In the face of an influenza pandemic, accurate estimates of epidemiologic parameters are required to help guide decision-making. We sought to estimate epidemiologic parameters for pandemic H1N1 influenza using data from initial reports of laboratory-confirmed cases. METHODS: We obtained data on laboratory-confirmed cases of pandemic H1N1 influenza reported in the province of Ontario, Canada, with dates of symptom onset between Apr. 13 and June 20, 2009. Incubation periods and duration of symptoms were estimated and fit to parametric distributions. We used competing-risk models to estimate risk of hospital admission and case-fatality rates. We used a Markov Chain Monte Carlo model to simulate disease transmission. RESULTS: The median incubation period was 4 days and the duration of symptoms was 7 days. Recovery was faster among patients less than 18 years old than among older patients (hazard ratio 1.23, 95% confidence interval 1.06-1.44). The risk of hospital admission was 4.5% (95% CI 3.8%-5.2%) and the case-fatality rate was 0.3% (95% CI 0.1%-0.5%). The risk of hospital admission was highest among patients less than 1 year old and those 65 years or older. Adults more than 50 years old comprised 7% of cases but accounted for 7 of 10 initial deaths (odds ratio 28.6, 95% confidence interval 7.3-111.2). From the simulation models, we estimated the following values (and 95% credible intervals): a mean basic reproductive number (R0, the number of new cases created by a single primary case in a susceptible population) of 1.31 (1.25-1.38), a mean latent period of 2.62 (2.28-3.12) days and a mean duration of infectiousness of 3.38 (2.06-4.69) days. From these values we estimated a serial interval (the average time from onset of infectiousness in a case to the onset of infectiousness in a person infected by that case) of 4-5 days. INTERPRETATION: The low estimates for R0 indicate that effective mitigation strategies may reduce the final epidemic impact of pandemic H1N1 influenza.

Effects of angiotensin II on renal dopamine metabolism: synthesis, release, catabolism and turnover.

BACKGROUND/AIMS: Dopamine (DA) uptake inhibition in the renal cortex, elicited by angiotensin II (ANG II), is mediated by AT(1) receptors and signals through the phospholipase C pathway and activation of protein kinase C and CaM-kinase II. By this indirect way, ANG II stimulates renal Na(+),K(+)-ATPase activity through DA intracellular reduction. In the present work, we continued to study different aspects of renal DA metabolism in DA-ANG II interaction, such as DA synthesis, release, catabolism and turnover. METHODS: ANG II effects on DA synthesis, release, catabolism and turnover were measured in samples from the outer renal cortex of Sprague-Dawley rats. RESULTS: ANG II reduced renal aromatic acid decarboxylate activity without affecting basal secretion of DA or its KCl-induced release. Moreover, ANG II enhanced monoamine oxidase activity without altering catechol-o-methyl transferase activity and increased DA turnover. CONCLUSION: Current results as well as previous findings show that ANG II modifies DA metabolism in rat renal cortex by reducing DA uptake, decreasing DA synthesis enzyme activity and increasing monoamine oxidase activity, and DA turnover. Together, all these effects may reduce DA accumulation into renal cells and decrease its endogenous content and availability. This would prevent D1 receptor recruitment and stimulation, while diminishing DA inhibition of Na(+),K(+)-ATPase activity and stimulating sodium reabsorption.

The effects of melatonin, serotonin, tryptophan and NAS on the biophysical properties of DPPC monolayers.

Melatonin is a neurohormone that has been shown to be protective in Alzheimer's diseases against amyloid-ß (Aß) toxicity, which involves interaction of Aß with neuronal membrane. Non-specific interactions of melatonin with cell membrane may play a physiological role in this process by preserving membrane fluidity. In the brain, melatonin is derived from the amino acid tryptophan through a pathway that includes serotonin and N-acetylserotonin (NAS). How these molecules affect the membrane properties is not understood. In this work, we studied interactions of melatonin and its metabolic precursors tryptophan, serotonin and NAS with dipalmitoylphosphatidylcholine (DPPC) monolayers at the air-water interface using Langmuir monolayer technique. Analysis of compression isotherms, phase transitions and compressibility moduli indicate that all four molecules alter the DPPC monolayer properties in a structure and concentration dependent manner. This effect was most pronounced for melatonin followed by NAS. Melatonin and NAS both decreased the compressibility modulus and shifted the LE/LC phase transition suggesting an increase in the membrane fluidity. Tryptophan and serotonin caused less pronounced effects on the DPPC isotherm. These differences suggest different interaction mechanisms and may be attributed to the interplay between electrostatic and hydrophobic interactions of these molecules with the zwitterionic DPPC headgroups which correlate with water solubility and oil partition coefficients (LogS and LogP) of each the four molecules. The results here demonstrate how the physiochemical properties of indoles can affect lipid membranes which may shed light on the functional significance of these important neurochemicals and the neuroprotective mechanisms of melatonin.