Impacts of fire and prospects for recovery in a tropical peat forest ecosystem.

Uncontrolled fires place considerable burdens on forest ecosystems, compromising our ability to meet conservation and restoration goals. A poor understanding of the impacts of fire on ecosystems and their biodiversity exacerbates this challenge, particularly in tropical regions where few studies have applied consistent analytical techniques to examine a broad range of ecological impacts over multiyear time frames. We compiled 16 y of data on ecosystem properties (17 variables) and biodiversity (21 variables) from a tropical peatland in Indonesia to assess fire impacts and infer the potential for recovery. Burned forest experienced altered structural and microclimatic conditions, resulting in a proliferation of nonforest vegetation and erosion of forest ecosystem properties and biodiversity. Compared to unburned forest, habitat structure, tree density, and canopy cover deteriorated by 58 to 98%, while declines in species diversity and abundance were most pronounced for trees, damselflies, and butterflies, particularly for forest specialist species. Tracking ecosystem property and biodiversity datasets over time revealed most to be sensitive to recurrent high-intensity fires within the wider landscape. These megafires immediately compromised water quality and tree reproductive phenology, crashing commercially valuable fish populations within 3 mo and driving a gradual decline in threatened vertebrates over 9 mo. Burned forest remained structurally compromised long after a burn event, but vegetation showed some signs of recovery over a 12-y period. Our findings demonstrate that, if left uncontrolled, fire may be a pervasive threat to the ecological functioning of tropical forests, underscoring the importance of fire prevention and long-term restoration efforts, as exemplified in Indonesia.

Implementing supportive supervision in acute humanitarian emergencies: Lessons learned from Afghanistan and Ukraine.

Mental Health and Psychosocial Support (MHPSS) practitioners working in humanitarian contexts are at significant risk of mental health conditions, ultimately hindering the quality and sustainability of their work. Supportive supervision has shown to be effective in improving the wellbeing of MHPSS staff and volunteers and enhancing the effectiveness of MHPSS service delivery. Despite these proven benefits, there is a lack of standardised guidelines to inform supportive supervision within humanitarian contexts. To address this gap, the Trinity Centre for Global Health and the International Federation of the Red Cross Red Crescent Societies' Reference Centre for Psychocosial Support co-developed the 'Integrated Model for Supervision' (IMS) Handbook and supporting tools and led IMS trainings with four humanitarian organisations in Ukraine, Afghanistan, Jordan, and Nigeria from June-August 2021. The subsequent acute humanitarian emergencies that occurred in Afghanistan and Ukraine provided the opportunity to (i) examine the implementation of the IMS in the acute stages of two humanitarian crises and (ii) identify the challenges and lessons learned from this process. This study employed a case study design using semi-structured qualitative interviews with five MHPSS personnel (female: 4; male: 1) who had received training in the IMS and were directly involved in the implementation of supportive supervision using IMS guidelines in either Ukraine or Afghanistan. Results showed that participants identified the key steps needed for the implementation of supportive supervision and reported two significant barriers to implementation including the stress of a humanitarian crisis leading to competing responsibilities and priorities, staff shortages and time constraints as well as the challenge of creating a new supervision structure when none had existed previously. Overall, participants felt that the IMS resulted in improved knowledge, confidence, perceived support, team cohesion, staff wellbeing and was a helpful blueprint to guide the implementation of supportive supervision in humanitarian contexts.

Mapping the Postpartum Experience Through Obstetric Patient Navigation for Low-Income Individuals.

Background: Although the postpartum period is an opportunity to address long-term health, fragmented care systems, inadequate attention to social needs, and a lack of structured transition to primary care threaten patient wellbeing, particularly for low-income individuals. Postpartum patient navigation is an emerging innovation to address these disparities. Methods: This mixed-methods analysis uses data from the first year of an ongoing randomized controlled trial to understand the needs of low-income postpartum individuals through 1 year of patient navigation. We designed standardized logs for navigators to record their services, tracking mode, content, intensity, and target of interactions. Navigators also completed semistructured interviews every 3 months regarding relationships with patients and care teams, care system gaps, and navigation process. Log data were categorized, quantified, and mapped temporally through 1 year postpartum. Qualitative data were analyzed using the constant comparative method. Results: Log data from 50 participants who received navigation revealed the most frequent needs related to health care access (45.4%), health and wellness (18.2%), patient-navigator relationship building (14.8%), parenting (13.6%), and social determinants of health (8.0%). Navigation activities included supporting physical and mental recovery, accomplishing health goals, connecting patients to primary and specialty care, preparing for health system utilization beyond navigation, and referring individuals to community resources. Participant needs fluctuated, yielding a dynamic timeline of the first postpartum year. Conclusion: Postpartum needs evolved throughout the year, requiring support from various teams. Navigation beyond the typical postpartum care window may be useful in mitigating health system barriers, and tracking patient needs may be useful in optimizing postpartum care. Clinical Trial Registration: Registered April 19, 2019, enrollment beginning January 21, 2020, NCT03922334, https://clinicaltrials.gov/ct2/show/NCT03922334.

TET3 is a positive regulator of mitochondrial respiration in Neuro2A cells.

Ten-Eleven-Translocase (TET) enzymes contribute to the regulation of the methylome via successive oxidation of 5-methyl cytosine (5mC) to derivatives which can be actively removed by base-excision-repair (BER) mechanisms in the absence of cell division. This is particularly important in post-mitotic neurons where changes in DNA methylation are known to associate with changes in neural function. TET3, specifically, is a critical regulator of both neuronal differentiation in development and mediates dynamic changes in the methylome of adult neurons associated with cognitive function. While DNA methylation is understood to regulate transcription, little is known of the specific targets of TET3-dependent catalytic activity in neurons. We report the results of an unbiased transcriptome analysis of the neuroblastoma-derived cell line; Neuro2A, in which Tet3 was silenced. Oxidative phosphorylation (OxPhos) was identified as the most significantly down-regulated functional canonical pathway, and these findings were confirmed by measurements of oxygen consumption rate in the Seahorse bioenergetics analyser. The mRNA levels of both nuclear- and mitochondrial-encoded OxPhos genes were reduced by Tet3-silencing, but we found no evidence for differential (hydroxy)methylation deposition at these gene loci. However, the mRNA expression of genes known to be involved in mitochondrial quality control were also shown to be significantly downregulated in the absence of TET3. One of these genes; EndoG, was identified as a direct target of TET3-catalytic activity at non-CpG methylated sites within its gene body. Accordingly, we propose that aberrant mitochondrial homeostasis may contribute to the decrease in OxPhos, observed upon Tet3-downregulation in Neuro2A cells.

Genomic background of biotypes related to growth, carcass and meat quality traits in Duroc pigs based on principal component analysis.

As the swine industry continues to explore pork quality traits alongside growth, feed efficiency and carcass leanness traits, it becomes imperative to understand their underlying genetic relationships. Due to this increase in the number of desirable traits, animal breeders must also consider methods to efficiently perform direct genetic changes for each trait and evaluate alternative selection indexes with different sets of phenotypic measurements. Principal component analysis (PCA) and genome-wide association studies (GWAS) can be combined to understand the genetic architecture and biological mechanisms by defining biological types (biotypes) that relate these valuable traits. Therefore, the main objectives of this study were to: (1) estimate genomic-based genetic parameters; (2) define animal biotypes utilizing PCA; and (3) utilize GWAS to link the biotypes to candidate genes and quantitative trait loci (QTL). The phenotypic dataset included 2583 phenotypic records from female Duroc pigs from a terminal sire line. The pedigree file contained 193,764 animals and the genotype file included 21,309 animals with 35,651 single nucleotide polymorphisms (SNPs). Eight principal components (PCs), accounting for a total of 99.7% of the population variation, were defined for three growth, eight conventional carcass, 10 pork quality and 18 novel carcass traits. The eight biotypes defined from the PCs were found to be related to growth rate, maturity, meat quality and body structure, which were then related to candidate genes. Of the 175 candidate genes found, six of them [LDHA (SSC1), PIK3C3 (SSC6), PRKAG3 (SSC15), VRTN (SSC7), DLST (SSC7) and PAPPA (SSC1)] related to four PCs were found to be associated with previously defined QTL, linking the biotypes with biological processes involved with muscle growth, fat deposition, glycogen levels and skeletal development. Further functional analyses helped to make connections between biotypes, relating them through common KEGG pathways and gene ontology (GO) terms. These findings contribute to a better understanding of the genetic relationships between growth, carcass and meat quality traits in Duroc pigs, enabling breeders to better understand the biological mechanisms underlying the phenotypic expression of these traits.

Nutritional needs, resources, and barriers among unhoused adults cared for by a street medicine organization in Chicago, Illinois: a cross-sectional study.

BACKGROUND: Those experiencing houselessness rely on obtaining food from community organizers and donations. Simultaneously, the houseless face disproportionally high rates of medical conditions that may be affected by diet including diabetes, hypertension, and hyperlipidemia. There is limited literature on the resources and barriers of the houseless community regarding optimal nutrition from an actionable perspective. Further, less data is available on how street medicine organizations may best impact the nutrition of the unhoused they serve. Elucidating this information will inform how organizational efforts may best support the nutrition of the houseless community. METHODS: In partnership with the medical student-run organization, Chicago Street Medicine, at Northwestern University Feinberg School of Medicine, twenty adults experiencing houselessness in Chicago, Illinois participated in the cross-sectional study. A 10-item survey was verbally administered to characterize the participants' daily food intake, food sources, barriers, resources, and nutritional preferences and needs. All data was directly transcribed into REDCap. Descriptive statistics were generated. RESULTS: Individuals consumed a median of 2 snacks and meals per day (IQR: 1-3). No participant consumed adequate servings of every food group, with only one participant meeting the dietary intake requirements for one food group. Participants most often received their food from donations (n = 15), purchasing themselves (n = 11), food pantries (n = 4), and shelters (n = 3). Eleven of nineteen participants endorsed dental concerns as a major barrier to consuming certain foods. Twelve participants had access to a can opener and twelve could heat their meals on a stove or microwave. Seven had access to kitchen facilities where they may prepare a meal. Approximately half of participants had been counseled by a physician to maintain a particular diet, with most related to reducing sugar intake. CONCLUSION: Most houseless participants were unable to acquire a balanced diet and often relied on organizational efforts to eat. Organizations should consider the chronic health conditions, dentition needs, and physical resources and barriers to optimal nutrition when obtaining food to distribute to the unhoused.

Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation.

BACKGROUND: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. METHODS: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. RESULTS: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling. CONCLUSIONS: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.

Medicaid Coverage of Guidelines-Based Asthma Care Across 50 States, the District of Columbia, and Puerto Rico, 2021-2022.

INTRODUCTION: Asthma affects more than 25 million Americans, including 4.2 million children. The burden of asthma disproportionately affects people enrolled in Medicaid, among other disparate groups. Improved availability and accessibility of guidelines-based treatments and services may ensure positive health outcomes for people with asthma. In this article, we provide an update to the American Lung Association's Asthma Guidelines-Based Care Coverage Project (the Project) to determine the extent of asthma care coverage and associated barriers in Medicaid programs for all 50 states, the District of Columbia, and Puerto Rico, and examine improvements in coverage since 2017. METHODS: Findings from the Project, representing coverage from 2016-2017, were first published in Preventing Chronic Disease in 2018. The Project was updated in 2021 to reflect the National Asthma Education and Prevention Program guidelines 2020 Expert Panel Report-3 updates, which were finalized in December 2020. It now tracks coverage for 8 areas of guidelines-based care and 7 barriers to care in Medicaid programs by reviewing publicly available plan documents and engaging with Medicaid programs to review and confirm findings. RESULTS: Results from the Project, which reflect coverage in 2021-2022, show an increase in comprehensive coverage in Medicaid programs over the last 5 years. However, coverage remains inconsistent across programs, and barriers to accessing asthma care still exist. CONCLUSION: Although substantial improvement has been made to coverage, certain gaps and barriers to care must be addressed for patients to fully benefit from guidelines-based care to manage their asthma and improve health outcomes.

Characteristics of analytically confirmed gamma-hydroxybutyrate (GHB) positive patients in the emergency department: presentation, poly-drug use, disposition and impact on intensive care resource utilisation.

BACKGROUND: Gamma-hydroxybutyrate is a potent central nervous system depressant with a narrow recreational dose window and analytical detection time. We describe data relating to intoxicated patients presenting to emergency departments across metropolitan Adelaide who tested positive for gamma-hydroxybutyrate. This work was part of the Emergency Department Admission Blood Psychoactive Testing study. METHODS: Over a 15-month period, patients presenting to four metropolitan emergency departments with symptoms of drug intoxication were enrolled in the study. The methodology involved the collection of demographic and clinical data and a de-identified blood sample which underwent comprehensive toxicological analysis. Gamma-hydroxybutyrate was determined using an acid-catalysed cyclisation followed by liquid-liquid extraction and gas chromatography-mass spectrometry. Data relating to samples positive for gamma-hydroxybutyrate were examined. RESULTS AND DISCUSSION: A total of 1120 patients were enrolled between March 2019 and May 2020, 309 of whom were positive for gamma-hydroxybutyrate (27.6%). Of these, 256 (83%) were also positive for metamfetamine (methamphetamine). The most common clinical observation in gamma-hydroxybutyrate-positive patients was central nervous system depression (89%). There was a significant relationship between gamma-hydroxybutyrate status and sex; although males outnumbered females in absolute terms, a higher proportion of females (32%) tested positive for gamma-hydroxybutyrate than males (25%, P = 0.0155). Blood gamma-hydroxybutyrate concentrations ranged from 10 to 651 mg/L (0.096-6.2 mmol/L) and increasing gamma-hydroxybutyrate concentration correlated with severe toxicity. The presence of gamma-hydroxybutyrate had a significant impact on the patient discharge destination: the majority (69.2%) of gamma-hydroxybutyrate-positive patients were managed and discharged from the emergency department or their attached short stay wards. A significantly higher proportion of gamma-hydroxybutyrate-positive patients were admitted to the intensive care unit (28.2%) compared with gamma-hydroxybutyrate-negative patients (12.7%, chi-squared = 36.85, P <0 .001). Gamma-hydroxybutyrate positive cases accounted for 45.8% of all study-related intensive care unit admissions. CONCLUSIONS: Gamma-hydroxybutyrate is commonly detected in illicit drug-related emergency department presentations and is detected disproportionately in the patient cohort who require intensive care unit level care.

Implementation of postpartum navigation for low-income individuals at an urban academic medical center.

BACKGROUND: Patient navigation, a patient-centered intervention to promote comprehensive health care, is an emerging innovation in obstetrics to optimize postpartum care. We aimed to evaluate the implementation of a novel postpartum patient navigation program at an urban academic medical center. METHODS: This mixed-methods study analyzed the implementation of a postpartum patient navigation program within an ongoing randomized control trial. This study analyzed three navigators' logs of interactions with 50 patients, care team members, and community organizations throughout patients' first year postpartum. We categorized and quantified interactions by topic addressed, care team member interacted with, and communication mode used. We also conducted semi-structured interviews with each navigator every three months (5 interviews per navigator), emphasizing navigation experiences, relationships with patients and care teams, integration in the care team, and healthcare system gaps. Interview data were analyzed using the constant comparative method to identify themes using the constructs of the Consolidated Framework for Implementation Research (CFIR). RESULTS: Analysis of navigator logs revealed a high patient need level, especially in the first 3 months postpartum. CFIR-guided analysis of intervention characteristics revealed positive perceptions of navigation's utility due to its adaptability. Navigation's complexity, however, posed an early obstacle to implementation that diminished over time. Outer setting analysis indicated navigators addressed patient needs through interactions with multiple systems. Despite clinicians' initial unfamiliarity with navigation, inner setting analysis suggested ongoing communication and electronic medical record use facilitated integration into the care team. Regarding individual and process characteristics, findings emphasized how navigator self-efficacy and confidence increased with experience (individual) and was facilitated by comprehensive training and reflection (process). Overall, barriers to implementation included unfamiliarity, varied patient engagement, and innovation complexity. Facilitators included high patient need, communication with outside organizations, medical record usage, navigator characteristics (self-efficacy, communication skills, and personal growth), a comprehensive training period, consistent reflection, high relative advantage, and high adaptability to patient need. CONCLUSION: Patient navigation is a promising innovation to improve postpartum care coordination and support care team efforts. The successful implementation of navigation in this study indicates that, if shown to improve patient outcomes, obstetric navigation could be a component of patient-centered postpartum care.

Clinical management of immune-related adverse events following immunotherapy treatment in patients with non-small cell lung cancer.

The advent of checkpoint blockade-based immunotherapy is rapidly changing the management of lung cancer. Whereas past anticancer drugs' primary toxicity was hematologic, the newer agents have primarily autoimmune toxicity. Thus, it is no longer enough for oncology practitioners to be skilled only in hematology. They must also understand management of autoimmune conditions, leveraging the skills of the rheumatologist, endocrinologist and gastroenterologist in the process. Herein we describe the mechanism of action and toxicities associated with immune checkpoint blockade in patients with lung cancer and provide a framework for management of adverse events.

Bridging the postpartum gap: best practices for training of obstetrical patient navigators.

The postpartum period represents a critical window of opportunity to improve maternal short- and long-term health, including optimizing postpartum recovery, providing effective contraception, caring for mood disorders, managing weight, supporting lactation, initiating preventive care, and promoting cardiometabolic health. However, inadequate postpartum care, especially for individuals facing social and structural barriers, is common in the United States and contributes to suboptimal health outcomes with lasting consequences. Patient navigation is a patient-centered intervention that uses trained personnel to identify financial, cultural, logistical, and educational obstacles to effective healthcare and to mitigate these barriers to facilitate comprehensive and timely access to needed health services. Given the emerging evidence suggesting that patient navigation may be a promising method to improve health among postpartum individuals, our team developed a postpartum patient navigator training guide to be used in the Navigating New Motherhood 2 and other obstetrical navigation programs. Navigating New Motherhood 2 is a randomized trial exploring whether patient navigation by a trained, lay postpartum navigator for individuals with a low income can improve health and patient-reported outcomes during and after the postpartum period. Hiring and training patient navigators without health professional degrees are integral components of initiating a navigation program. However, patient navigator training is highly variable, and no guideline regarding key elements in such a training program exists for obstetrics specifically. Thus, this paper aimed to describe the core principles, content, and rationale for each element in a comprehensive postpartum patient navigator training program. Training should be centered around the following 6 core elements: (1) principles of patient navigation; (2) knowledge of pregnancy and postpartum care; (3) health education and health promotion principles; (4) cultural sensitivity and health equity; (5) care coordination and community resources; and (6) electronic medical record systems. These core elements can serve as a basis for the development of adaptable curricula for several institutions and contexts. In addition, we offer recommendations for the implementation of a navigator training program. A curriculum with built-in flexibility to meet community and institutional needs may promote the effective and sustainable use of patient navigation in the postpartum context.

Establishing the protocols for the South Australian Emergency Department Admission Blood Psychoactive Testing (EDABPT) programme for drug surveillance.

OBJECTIVE: ED presentations because of illicit use of psychotropic drugs and pharmaceuticals result in significant medical harm and resource consumption. Patient assessment is complicated by the regular emergence of new psychoactive substances, difficulties associated with their identification and a lack of information about their effects. Here we report the protocol for the Emergency Department Admission Blood Psychoactive Testing (EDABPT) programme, an observational study utilising clinical data capture and definitive drug identification to assess the medical impact and patterns of illicit drug use in the community, and their geographic and temporal fluctuations. The study provides data to an early warning system targeting an improved public health response to emerging drugs of concern. METHODS: Enrolment of adult patients presenting with suspected illicit drug use occurs at four major EDs in a single urban setting. Clinical and demographic data are collected by treating clinicians. Blood samples are collected at presentation and frozen on site prior to transport to a specialised forensic facility for comprehensive toxicological screening. RESULTS: Results are fed back to clinicians and disseminated more broadly via an existing local early warning system. Targeted warnings and public health releases are instigated where heightened risk or harm is identified. CONCLUSION: The study pairs city-wide patient enrolment with analytically confirmed toxicology results to allow broad sampling and identification of illicit drugs causing medical harm. It provides a mechanism for the identification of new agents as they emerge in the community, delivers a relevant and reliable source of information for public health agencies and clinicians and supplements existing local early warning mechanisms.

L-selectin regulates human neutrophil transendothelial migration.

The migration of circulating neutrophils towards damaged or infected tissue is absolutely critical to the inflammatory response. L-selectin is a cell adhesion molecule abundantly expressed on circulating neutrophils. For over two decades, neutrophil L-selectin has been assigned the exclusive role of supporting tethering and rolling - the initial stages of the multi-step adhesion cascade. Here, we provide direct evidence for L-selectin contributing to neutrophil transendothelial migration (TEM). We show that L-selectin co-clusters with PECAM-1 - a well-characterised cell adhesion molecule involved in regulating neutrophil TEM. This co-clustering behaviour occurs specifically during TEM, which serves to augment ectodomain shedding of L-selectin and expedite the time taken for TEM (TTT) to complete. Blocking PECAM-1 signalling (through mutation of its cytoplasmic tail), PECAM-1-dependent adhesion or L-selectin shedding, leads to a significant delay in the TTT. Finally, we show that co-clustering of L-selectin with PECAM-1 occurs specifically across TNF- but not IL-1ß-activated endothelial monolayers - implying unique adhesion interactomes forming in a cytokine-specific manner. To our knowledge, this is the first report to implicate a non-canonical role for L-selectin in regulating neutrophil TEM.

Dysregulation of 2-oxoglutarate-dependent dioxygenases by hyperglycaemia: does this link diabetes and vascular disease?

The clinical, social and economic burden of cardiovascular disease (CVD) associated with diabetes underscores an urgency for understanding the disease aetiology. Evidence suggests that the hyperglycaemia associated with diabetes is, of itself, causal in the development of endothelial dysfunction (ED) which is recognised to be the critical determinant in the development of CVD. It is further recognised that epigenetic modifications associated with changes in gene expression are causal in both the initiation of ED and the progression to CVD. Understanding whether and how hyperglycaemia induces epigenetic modifications therefore seems crucial in the development of preventative treatments. A mechanistic link between energy metabolism and epigenetic regulation is increasingly becoming explored as key energy metabolites typically serve as substrates or co-factors for epigenetic modifying enzymes. Intriguing examples are the ten-eleven translocation and Jumonji C proteins which facilitate the demethylation of DNA and histones respectively. These are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require the tricarboxylic acid metabolite, α-ketoglutarate and molecular oxygen (O2) as substrates and Fe (II) as a co-factor. An understanding of precisely how the biochemical effects of high glucose exposure impact upon cellular metabolism, O2 availability and cellular redox in endothelial cells (ECs) may therefore elucidate (in part) the mechanistic link between hyperglycaemia and epigenetic modifications causal in ED and CVD. It would also provide significant proof of concept that dysregulation of the epigenetic landscape may be causal rather than consequential in the development of pathology.

SMIFH2 inhibition of platelets demonstrates a critical role for formin proteins in platelet cytoskeletal dynamics.

BACKGROUND: Reorganization of the actin cytoskeleton is required for proper functioning of platelets following activation in response to vascular damage. Formins are a family of proteins that regulate actin polymerization and cytoskeletal organization via a number of domains including the FH2 domain. However, the role of formins in platelet spreading has not been studied in detail. OBJECTIVES: Several formin proteins are expressed in platelets so we used an inhibitor of FH2 domains (SMIFH2) to uncover the role of these proteins in platelet spreading and in maintenance of resting platelet shape. METHODS: Washed human and mouse platelets were treated with various concentrations of SMIFH2 and the effects on platelet spreading, platelet size, platelet cytoskeletal dynamics, and organization were analyzed using fluorescence and electron microscopy. RESULTS: Pretreatment with SMIFH2 completely blocks platelet spreading in both mouse and human platelets through effects on the organization and dynamics of actin and microtubules. However, platelet aggregation and secretion are unaffected. SMIFH2 also caused a decrease in resting platelet size and disrupted the balance of tubulin post-translational modification. CONCLUSIONS: These data therefore demonstrated an important role for formin-mediated actin polymerization in platelet spreading and highlighted the importance of formins in cross-talk between the actin and tubulin cytoskeletons.

L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling.

L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLex) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.

Integrin intracellular machinery in action.

Integrin-mediated adhesion to the extracellular matrix involves a surprisingly large number of intracellular proteins, the integrin-associated proteins (IAPs), which are a fraction of the total integrin adhesome. In this review we discuss how genetic approaches have improved our understanding of how each IAP contributes to integrin function, especially in the context of building a functional organism during development. We then begin the process of assembling IAP roles together into an integrated mechanism.