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Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like abdominal aortic aneurysms (AAA) is unknown. Here we demonstrate that Panx1 on endothelial cells, but not smooth muscle cells, orchestrate a cascade of signaling events to mediate vascular inflammation and remodeling. Mechanistically, Panx1 on endothelial cells acts as a conduit for ATP release that stimulates macrophage activation via P2X7 receptors and mitochondrial DNA release to increase IL-1β and HMGB1 secretion. Secondly, Panx1 signaling regulates smooth muscle cell-dependent intracellular Ca2+ release and vascular remodeling via P2Y2 receptors. Panx1 blockade using probenecid markedly inhibits leukocyte transmigration, aortic inflammation and remodeling to mitigate AAA formation. Panx1 expression is upregulated in human AAAs and retrospective clinical data demonstrated reduced mortality in aortic aneurysm patients treated with Panx1 inhibitors. Collectively, these data identify Panx1 signaling as a contributory mechanism of AAA formation. Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology. [ABSTRACT FROM AUTHOR]

Seafarers work in nomadic isolated work settings and are more likely to suffer from stress and fatigue in the workplace. Their work has thus been argued to have detrimental effects on their partner relationships. This paper forwards the idea that work conditions of seafarers may lead to social detachment from their close social relations (e.g. family) and that these specifically cause seafarers to exhibit a different behaviour in terms of one of the most important decisions they make when coming ashore — residential location choice. Our empirical analysis of former Danish seafarers and a sample of matched traditional workers suggests that individuals who until recently worked as seafarer to a lesser extent rely on family-based social relations than traditional workers when making residential location choices. They chose to locate close to their former peers, suggesting a shift in social attachments. The isolated lifestyles of seafarers influence social attachment. Geographic distances and social contexts are shown to interact and affect their choice of residential location. This has implications for our understanding of the well-being of seafarers and may offer new aspects on the recent development of the work conditions of seafarers. [ABSTRACT FROM AUTHOR]

Pannexin 1 (Panx1) is a ubiquitously expressed protein forming large conductance channels that are central to many distinct inflammation and injury responses. There is accumulating evidence showing ATP released from Panx1 channels, as well as metabolites, provide effective paracrine and autocrine signaling molecules that regulate different elements of the injury response. As channels with a broad range of permselectivity, Panx1 channels mediate the secretion and uptake of multiple solutes, ranging from calcium to bacterial derived molecules. In this review, we describe how Panx1 functions in response to different pro-inflammatory stimuli, focusing mainly on signaling coordinated by the vasculature. How Panx1 mediates ATP release by injured cells is also discussed. The ability of Panx1 to serve as a central component of many diverse physiologic responses has proven to be critically dependent on the context of expression, post-translational modification, interacting partners, and the mode of stimulation. [ABSTRACT FROM AUTHOR]

Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12−/− and PANX1−/− mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function. Microglia are involved in debris clearance and synaptic pruning, among other processes. However, their direct interaction with the brain vasculature is less clear. Here, the authors show that capillary-associated microglia (CAMs) regulate vascular tone via PANX1-P2RY12 signalling. [ABSTRACT FROM AUTHOR]

This article describes the process of integrating trauma-informed behavioral health practices into a pediatric primary care clinic serving low-income and minority families while facing barriers of financial, staffing, and time limitations common to many community healthcare clinics. By using an iterative approach to evaluate each step of the implementation process, the goal was to establish a feasible system in which primary care providers take the lead in addressing traumatic stress. This article describes (1) the process of implementing trauma-informed care into a pediatric primary care clinic, (2) the facilitators and challenges of implementation, and (3) the impact of this implementation process at patient, provider, and community levels. Given the importance of trauma-informed care, especially for families who lack access to quality care, the authors conceptualize this paper as a guide for others attempting to integrate best behavioral health practices into pediatric clinics while working with limited resources. [ABSTRACT FROM AUTHOR]

Background: Alar base reduction is a procedure of balance between multiple structures of the lower nasal vault. This study aimed to describe the alar cinch suture nasal sill excision combination technique and to present our consecutive patient series. Methods: The cinch suture nasal sill excision combination technique is described in a step-by-step fashion and illustrated by pre-, post-, and intra-operative photographs, as well as videos. A study of consecutive patients presenting for primary rhinoplasty who required bilateral alar base reduction from October 2016 to October 2019 was performed. Results: A total of 21 patients with a minimum of 12 months post-operative follow-up were included in the study. There were no major or minor complications. The technique involves dynamic manipulation of the nasal base structures and is highly applicable to every alar axis. Conclusions: The cinch suture nasal sill excision combination technique is a simple and durable technique for alar base reduction. It provides predictable outcomes while allowing for control of the lower nasal vault structures. Level of evidence: LeveI IV, therapeutic study. [ABSTRACT FROM AUTHOR]

Background: Although the effect of normal aging on the appearance of the ear lobule is well known and defined, this often a neglected aspect of facial rejuvenation. Rhytidectomy offers a great opportunity to surgically enhance the aging earlobe. The objective of this study was to provide a step-by-step description of the execution of the three-triangle rotation flap technique for aesthetic ear lobule reduction. Methods: The three-triangle rotation flap technique is described in a step-by-step fashion and illustrated by photographs and videos. All ear lobule reduction procedures that took place at our practice from December 2016 to February 2020 were retrospectively reviewed. Results: A total of 16 patients underwent bilateral ear lobule reduction during face lift, neck lift, or both, and 7 patients underwent bilateral lobule reduction in isolation. None of the patients experienced complications, and revisions were not performed or required. Conclusions: The three-triangle rotation flap technique relies on simple principles that can be adjusted to address all shapes and degrees of true ear lobule ptosis, as well as patient desire. It is employed in isolation or synchronous with rhytidectomy. When performed during rhytidectomy, it provides lobule stability and fixation. Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Background: In attempting to overcome the challenges associated with arm contouring, arm liposuction has been an area of focus in recent years. In appropriately selected patients, circumferential liposuction is the procedure of choice. The objective of this study is to describe our experience with the four-position four-entry site circumferential arm liposuction technique. Methods: All consecutive circumferential liposuction procedures that took place at our ambulatory surgical facility from January 2015 to November 2019 were retrospectively reviewed. The four-position four-entry site circumferential arm liposuction technique is described, and photographs as well as videos are presented. Results: A total of 35 patients underwent circumferential bilateral arm liposuction via the four-position four-entry site technique. All patients were female, and their average age was 43 years. The average BMI was 28.4 kg/m2, and the average follow-up was 481 days. The average volume of lipoaspirate was 1,514 ml per patient, and the average volume of aspirated fat was 1,052 ml per patient. There was no incident of infection, seroma, bleeding event or venous thromboembolism. Conclusions: For the right candidate, the four-entry site four-position circumferential arm liposuction is an efficient and reproducible technique, which produces predictable and pleasing results. Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI. [ABSTRACT FROM AUTHOR]

Development practitioners and policymakers often posit that promoting cash crop expansion to generate rural employment has the potential to alleviate poverty and improve food security. Focusing upon the recent expansion of oil palm production in the northern lowlands of Guatemala, we critically evaluate this claim. To do so, we draw upon survey data collected in two neighbouring villages – one where oil palm is the main land use, another where maize and secondary forest are prevalent – to investigate how the expanding cultivation of the cash crop shapes local food access and rural livelihoods. We find that oil palm has improved food access for some households with oil palm employment. However, number of beneficiaries is relatively small and the practice does not lift them from the ranks of the food insecure. For most households in the village where oil palm is prevalent, the ability to access food has decreased, as the expansion of oil palm has displaced staple grain production and eliminated relatively more inclusive forms of agricultural employment. In contrast, households from the village where staple maize production remains predominant are notably more food secure. We conclude that, in the absence of deep changes that address the underlying causes of widespread vulnerability in Guatemala's northern lowlands, the self-provisioning of maize and other staples will continue to serve as a cornerstone of food security, while the promotion of cash crops like oil palm will exacerbate inequalities in households' ability to access food. [ABSTRACT FROM AUTHOR]

Although refugees who are accepted for resettlement in a third country are guaranteed certain rights and experience safety from war and persecution, they face many mental health challenges. Using qualitative methods and constructivist grounded theory, we explored culturally specific perspectives on trauma and recovery among Burundian, Congolese, and Iraqi refugees resettled in the USA. Eighteen semi-structured interviews provided extensive data on the meaning of productivity and work, the ways in which they index normalcy and self-sufficiency, and how they create security that facilitates the healing process. Our inductive analyses revealed that participants emphasized the relationship between productivity and healing when they described recovery from trauma. Participants also discussed individual and structural facilitators and barriers to work. Finally, prominent themes emerged around gendered roles and expectations and the ways these function in refugee resettlement contexts that are shaped by policies that demand rapid economic self-sufficiency. Taken together, these findings suggest that policies that promote underemployment and foreclose opportunities for education and professional development may contribute negatively to refugee mental health, as well as keep refugees in poverty. [ABSTRACT FROM AUTHOR]

The contemporary process of financialization has been a major driver of the remarkable changes witnessed in global food and agricultural markets over the past decade, contributing to the rise and subsequent volatility of food and agricultural commodity prices since 2006. In the wake of these developments it has become clear that the turmoil has intensified the relationship between agriculture and finance in ways that have profound and enduring implications for the sector, and the people whose lives and livelihoods depend upon it. This symposium brings together four original research articles that contemplate the contemporary relationship between the agrifood and financial sectors. They examine a variety of overlapping themes, including the creation of financial assets from farmland and agricultural commodities, the activities of different types of investors in these assets in specific geographic contexts, and the challenges of governing this activity at the global scale. These articles show that the period of market volatility that began a decade ago re-invigorated investor interest in financial products linked to agriculture and farming, and inspired the packaging of new forms of financial assets in ways that have affected politics and practice on the ground, and are likely to leave a lasting legacy. [ABSTRACT FROM AUTHOR]

Posttranslational modification is a common cellular process that is used by cells to ensure a particular protein function. This can happen in a variety of ways, e.g., from the addition of phosphates or sugar residues to a particular amino acid, ensuring proper protein life cycle and function. In this review, we assess the evidence for ubiquitination, glycosylation, phosphorylation, S-nitrosylation as well as other modifications in connexins and pannexin proteins. Based on the literature, we find that posttranslational modifications are an important component of connexin and pannexin regulation. [ABSTRACT FROM AUTHOR]

Social and geographic displacement is a global phenomenon that precipitates novel stressors and disruptions that intersect with long-standing familial and social roles. Among the displaced are war-tom Iraqi refugee families, who must address these new obstacles in unconventional ways. This study explores how such disruptions have influenced associations between gender and apparent self-worth experienced by Iraqi refugee families upon relocation to the USA. Further, the psychosocial mechanisms requisite of any novel approach to a new social constmct are explored and reveal that production in the family is at the core of instability and shifting power dynamics during resettlement, preventing family members from "seeing the life" in the USA that they had envisioned prior to immigration. Over 200 semi-structured qualitative interviews with Iraqi participants and mental health providers were conducted over the course of the study, which demonstrate a plasticity among social roles in the family and community that transcends the notion of a simple role reversal, and illustrate the complex positionalities that families under stress must approximate during such physical and social displacement. [ABSTRACT FROM AUTHOR]

Endothelial nitric oxide synthase (eNOS, NOS3) is responsible for producing nitric oxide (NO)-a key molecule that can directly (or indirectly) act as a vasodilator and anti-inflammatory mediator. In this review, we examine the structural effects of regulation of the eNOS enzyme, including post-translational modifications and subcellular localization. After production, NO diffuses to surrounding cells with a variety of effects. We focus on the physiological role of NO and NO-derived molecules, including microvascular effects on vessel tone and immune response. Regulation of eNOS and NO action is complicated; we address endogenous and exogenous mechanisms of NO regulation with a discussion of pharmacological agents used in clinical and laboratory settings and a proposed role for eNOS in circulating red blood cells. [ABSTRACT FROM AUTHOR]

The article offers practical suggestions for adapting and implementing trauma-informed evidence-based practice (EBP) with refugee youth in real-world settings located in Western countries and proposes EBP's "three-legged stool" model to therapeutically address the impact of trauma in refugee youth.

Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation-sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis. [ABSTRACT FROM AUTHOR]

Using a mixed-method design with Bosnian students ( n = 63, ages 16-19) and their primary caregivers ( n = 50), we explored the impact of post-war adversities on adolescent adjustment, adolescent-caregiver relationships, and future outlook 8 years after the 1992-1995 Bosnian civil war. Adolescents and caregivers identified themes linking the war and its aftermath to ongoing emotional adjustment difficulties, relationships challenges, and negative future outlook. Adolescents' posttraumatic stress symptoms were positively correlated with self-report measures of interpersonal stressors, existential stressors, parental psychological control, and anxious/withdrawn symptoms. Parental psychological control partially mediated the association between interpersonal post-war adversities and posttraumatic stress symptoms. [ABSTRACT FROM AUTHOR]

Heparan sulfate proteoglycans act as co-receptors for many chemokines and growth factors. The sulfation pattern of the heparan sulfate chains is a critical regulatory step affecting the binding of chemokines and growth factors. N-deacetylase- N-sulfotransferase1 ( Ndst1) is one of the first enzymes to catalyze sulfation. Previously published work has shown that HSPGs alter tangent moduli and stiffness of tissues and cells. We hypothesized that loss of Ndst1 in smooth muscle would lead to significant changes in heparan sulfate modification and the elastic properties of arteries. In line with this hypothesis, the axial tangent modulus was significantly decreased in aorta from mice lacking Ndst1 in smooth muscle (SM22αcre +Ndst1 −/−, p < 0.05, n = 5). The decrease in axial tangent modulus was associated with a significant switch in myosin and actin types and isoforms expressed in aorta and isolated aortic vascular smooth muscle cells. In contrast, no changes were found in the compliance of smaller thoracodorsal arteries of SM22αcre +Ndst1 −/− mice. In summary, the major findings of this study were that targeted ablation of Ndst1 in smooth muscle cells results in altered biomechanical properties of aorta and differential expression of myosin and actin types and isoforms. [ABSTRACT FROM AUTHOR]

We tested whether state-level variations in early intervention program (EI) participation were consistent with rates of key risk factors for early developmental delay. Based on the results of prior studies, we focused on child poverty and low birth weight as risk factors, included state threshold for EI eligibility by category (classified as broad/moderate or narrow), and aggregated the states into regions. Bivariate analyses were done in SPSS 15.0. All data were for 2009. Results were tested against data for prior years to ascertain whether findings for 2009 were anomalous. Nationally, 2.67 % of the age-eligible population was served in EI (range among states, 1.24-6.51 %). Variation in EI participation was significant at the regional level. Early intervention participation was lowest in the south and highest in the northeast ( p < 0.01). Regional variations in low birth weight ( p < 0.01) and child poverty ( p < 0.01) were also significant. Both were highest in the south. While EI participation varied significantly by state eligibility standards, this factor did not entirely explain variance in utilization. Results for 2009 were representative of multi-year trend data. National EI utilization rates consistently lagged behind need as identified in epidemiologic studies from multiple sources. The results strongly suggest that there is a significant population of infants and toddlers who need but do not receive EI services, especially in the south. [ABSTRACT FROM AUTHOR]

A point source, non-stationary covariance structure model is proposed, having only one additional parameter over a standard, stationary covariance structure, spatial model. Additionally, the proposed model is demonstrated to fit better than the three extra parameter, point source, non-stationary spatial model proposed by Ecker and De Oliveira (Commun Stat Theory Methods 37:2066-2078, ). The proposed model is fit from a Bayesian perspective and illustrated using a house sales dataset from Cedar Falls, Iowa. [ABSTRACT FROM AUTHOR]

Autophagy, a highly conserved lysosomal degradation pathway, was initially characterized as a bulk degradation system induced in response to starvation. In recent years, autophagy has emerged also as a highly selective pathway, targeting various cargoes such as aggregated proteins and damaged organelles for degradation. The key factors involved in selective autophagy are autophagy receptors and adaptor proteins, which connect the cargo to the core autophagy machinery. In this review, we discuss the current knowledge about the only mammalian adaptor protein identified thus far, autophagy-linked FYVE protein (ALFY). ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. We also comment on the possible role of ALFY in the context of disease. [ABSTRACT FROM AUTHOR]

Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) ? (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to Hb ? and is abrogated by its genetic depletion. Mechanistically, endothelial Hb ? haem iron in the Fe3+ state permits NO signalling, and this signalling is shut off when Hb ? is reduced to the Fe2+ state by endothelial cytochrome b5 reductase 3 (CYB5R3, also known as diaphorase 1). Genetic and pharmacological inhibition of CYB5R3 increases NO bioactivity in small arteries. These data reveal a new mechanism by which the regulation of the intracellular Hb ? oxidation state controls NOS signalling in non-erythroid cells. This model may be relevant to haem-containing globins in a broad range of NOS-containing somatic cells. [ABSTRACT FROM AUTHOR]

Heparan sulfate proteoglycans are abundant matrix and membrane molecules. Smooth muscle specific deletion of one heparan sulfate biosynthetic enzyme, N-deacetylase- N-sulfotransferase1 leads to decreased vascular smooth muscle cell proliferation, and vascular wall thickness. We hypothesized that this may lead to changes in blood pressure in conscious mice. Blood pressure was measured via telemetry in SM22αCreNdst1( n = 4) and wild type ( n = 8) mice. Aorta and thoracodorsal artery luminal area is significantly smaller in SM22αCreNdst1 ( n = 4-8, P = 0.02, P = 0.0002) compared to wild type ( n = 7) mice. Diurnal differences were observed in both cohorts for systolic, diastolic, mean arterial blood pressure, and heart rate ( P < 0.001 from T test). No significant differences were found in the above parameters between the cohorts in either light or dark times using a linear mixed model. In conclusion, deletion of N-deacetylase- N-sulfotransferase1 in smooth muscle did not influence any of the blood pressure parameters measured despite significant decrease in aorta and thoracodorsal artery luminal area. [ABSTRACT FROM AUTHOR]

Arterial stiffness is a key marker in metabolic diseases and can be evaluated by arterial compliance. Most compliance measurements are performed in large conduit arteries in advanced stage of metabolic diseases, which may not provide information on mechanisms associated with the initiation of the pathology. For this reason, we compared arterial compliance of two different size arteries: carotid and a smaller artery (thoracodorsal artery, TDA). The arterial compliance was compared between control and high fat-fed mice for 6 weeks. We show that the compliance of the TDAs was dramatically reduced in high fat-fed mice whereas the compliance of the carotids remained unchanged. An abundance of collagen deposition in the media/adventitia of the carotids and TDAs was observed in high fat-fed mice. These results demonstrate that the structural and mechanical properties of small arteries are rapidly altered even after only 6 weeks of high fat feeding. [ABSTRACT FROM AUTHOR]

Apoptotic cells release 'find-me' signals at the earliest stages of death to recruit phagocytes. The nucleotides ATP and UTP represent one class of find-me signals, but their mechanism of release is not known. Here, we identify the plasma membrane channel pannexin 1 (PANX1) as a mediator of find-me signal/nucleotide release from apoptotic cells. Pharmacological inhibition and siRNA-mediated knockdown of PANX1 led to decreased nucleotide release and monocyte recruitment by apoptotic cells. Conversely, PANX1 overexpression enhanced nucleotide release from apoptotic cells and phagocyte recruitment. Patch-clamp recordings showed that PANX1 was basally inactive, and that induction of PANX1 currents occurred only during apoptosis. Mechanistically, PANX1 itself was a target of effector caspases (caspases 3 and 7), and a specific caspase-cleavage site within PANX1 was essential for PANX1 function during apoptosis. Expression of truncated PANX1 (at the putative caspase cleavage site) resulted in a constitutively open channel. PANX1 was also important for the 'selective' plasma membrane permeability of early apoptotic cells to specific dyes. Collectively, these data identify PANX1 as a plasma membrane channel mediating the regulated release of find-me signals and selective plasma membrane permeability during apoptosis, and a new mechanism of PANX1 activation by caspases. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium (Na) channels contribute to the regulation of cellular excitability due to their role in the generation and propagation of action potentials. They are composed of a pore-forming α subunit and are modulated by at least two of four distinct β subunits (β1–4). Recent studies have implicated a role for the intracellular domain of β subunits in modulating Na channel gating and trafficking. In β3, the intracellular domain contains a serine residue at position 161 that is replaced by an alanine in β1. In this study, we have probed the functional importance of β3S161 for modulating Na channel gating. Wild-type β3 and point mutations β3S161A or β3S161E were individually co-expressed in HEK 293 cells stably expressing human Nav1.2. WTβ3 expression increased Na current density, shifted steady-state inactivation in a depolarized direction, and accelerated the kinetics of recovery from inactivation of the Na current. Analogous effects were observed with β3S161E co-expression. In contrast, β3S161A abolished the shifts in steady-state inactivation and recovery from inactivation of the Na current, but did increase Na current density. Immunocytochemistry and Western blot experiments demonstrate membrane expression of WTβ3, β3S161E, and β3S161A, suggesting that the differences in Na channel gating were not due to disruptions in β subunit trafficking. These studies suggest that modification of β3S161 may be important in modulating Na-channel gating. [ABSTRACT FROM AUTHOR]

In order to better understand the effects of initial level of psychological disturbance on treatment outcome, a retrospective case control study of 95 couples who received couple therapy was conducted by sorting couples into one of four groups based on the degree of distress reported by individuals at intake: Neither distressed; both distressed; male distressed, female not distressed; female distressed, male not distressed. When partners started treatment with similar levels of disturbance both responded well in couple therapy. However, if the female reported clinical levels of disturbance at intake but her partner did not, outcome for the female was especially poor in contrast to outcomes for females receiving individual therapy. Clinically disturbed males showed significant gains in treatment even when their partners were not disturbed. These suggestive results argue for the possible value of conducting controlled studies of treatment assignment decisions that maximize positive outcomes. [ABSTRACT FROM AUTHOR]

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE2 over other prostaglandins, followed by more modest inductions of PGI2, and relatively smaller increases in PGF2α, PGD2, and TxB2. We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1–2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response. [ABSTRACT FROM AUTHOR]

The pulmonary alveolar epithelium consists of alveolar type I (AT1) and alveolar type II (AT2) cells. Interactions between these two cell types are necessary for alveolar homeostasis and remodeling. These interactions have been difficult to study in vitro because current cell culture models of the alveolar epithelium do not provide a heterocellular population of AT1 and AT2 cells for an extended period of time in culture. In this study, a new method for obtaining heterocellular cultures of AT1- and AT2-like alveolar epithelial cells maintained for 7 d on a rat tail collagen-fibronectin matrix supplemented with laminin-5 is described. These cultures contain cells that appear by their morphology to be either AT1 cells (larger flattened cells without lamellar bodies) or AT2 cells (smaller cuboidal cells with lamellar bodies). AT1-like cells stain for the type I cell marker aquaporin-5, whereas AT2-like cells stain for the type II cell markers surfactant protein C or prosurfactant protein C. AT1/AT2 cell ratios, cell morphology, and cell phenotype-specific staining patterns seen in 7-d-old heterocellular cultures are similar to those seen in alveoli in situ. This culture system, in which a mixed population of phenotypically distinct alveolar epithelial cells are maintained, may facilitate in vitro studies that are more representative of AT1-AT2 cell interactions that occur in vivo. [ABSTRACT FROM AUTHOR]

Assesses the adjustment of adolescents as they made the transition from junior high to high school. Changes in adolescents' sense of autonomy, perceived stressors, social support, sense of school membership, grade point average and attendance; Coping strategies of high school students; Mediating factors in student adjustment.

The precise role of TGF-β in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-β in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by >75% following TGF-β1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-β1. These `TGF-β-resistant' cells (RIE-Tr) were continuously exposed to TGF-β for >50 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-β-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIE-Tr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-β receptor (TβRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TβRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TβRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TβRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGF-β1 for the RIE-Tr cells. [ABSTRACT FROM AUTHOR]

Gout is an acute rheumatic disorder that occurs in connection with the deposition of monosodium urate (MSU) crystals in the joints. This disease is characterized by intermittent episodes of severe pain and inflammatory joint swelling which are seemingly driven by prostaglandins. In this study we investigated the effect of MSU crystals on arachidonic acid (AA) metabolism in the mouse. We have demonstrated that prostaglandins and other AA metabolites were transiently formed after MSU crystal injection with peak levels occurring after 10 min. In contrast, free AA levels remained high for 2–4 hours after MSU crystal injection. By contrast, when exogenous AA was administered instead of MSU crystals, both the eicosanoids and AA diminished at the same high rates. The metabolism of exogenously administered AA to eicosanoids was inhibited by pretreatment with MSU crystals. No inhibition of AA metabolism was observed when mice were pretreated with AA itself, Ca2+ ionophore (A23187), or zymosan. We conclude that the MSU crystal treatment of mice results in a transient eicosanoid production which is followed by attenuated AA metabolism. It could be that MSU crystals similarly inhibit AA metabolism in gout and thereby limit the duration of gout attacks. [ABSTRACT FROM AUTHOR]

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Copyright of Zeitschrift für Physik is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fertilization is essential for species survival. Although Izumo1 and Juno are critical for initial interaction between gametes, additional molecules necessary for sperm:egg fusion on both the sperm and the oocyte remain to be defined. Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts. Collectively, these data identify phosphatidylserine on viable sperm and PtdSer recognition receptors on oocytes as key players in sperm:egg fusion. Izumo and Juno are receptors on sperm and eggs respectively required for fusion, but other factors for sperm-egg fusion are poorly studied. Here, the authors report that phosphatidylserine, found mainly on cells marked for death, is also present on motile sperm, recognized by egg receptors, and is required for sperm-egg fusion. [ABSTRACT FROM AUTHOR]

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies. Isakson et al. report a genetically engineered minipig model of Neurofibromatosis Type 1 (NF1) that exhibits clinical hallmarks of the disease, including neurofibromas and optic pathway glioma. This model may expedite the development of imaging methods, biomarkers, and therapies for NF1 patients. [ABSTRACT FROM AUTHOR]

A new study calls for further investigation into the potential benefits and risks of COX-2 specific inhibitors (pages 698?701). [ABSTRACT FROM AUTHOR]

In the Eurasian Arctic, the most common lemming species are the Siberian lemming (Lemmus sibiricus) and the collared lemming (Dicrostonyx torquatus). Lemmings constitute the main food item for 5 common predators in the area: arctic fox; snowy owl; rough-legged buzzard; long-tailed skua; and pomarine skua. Hence, these predators form a foraging guild. We have studied factors influencing the structure of this guild. When comparing co-occurrence of the predators between 17 sites across Siberia, there were positive associations between the snowy owl and the two skuas, and a negative association between snowy owl and rough-legged buzzard. There was also a large variation in local population density among the predators, conceivably, due to the risk of intra-guild predation as well as the variation in food supply. There were significant relationships between lemming abundance and the abundance of each predator. An analysis of the predatory response by the arctic fox indicated a response pattern similar tothat of a delayed numerical response to lemming abundance. For this and other reasons, we propose that the arctic fox is a resident specialist predator on microtine rodents. Further, the birds appeared to be nomadic specialist predators with, perhaps, one exception, the rough-legged buzzard. [ABSTRACT FROM AUTHOR]