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Reports of toxic serum theophylline concentrations in adults following influenza vaccination prompted this study. Peak and trough serum theophylline concentrations were measured in eight severely asthmatic children before and after vaccination against influenza. All eight children had been treated with chronic theophylline therapy for at least one year prior to joining the study. No significant alteration of theophylline levels were seen up to 52 hours after vaccination. No clinical evidence of drug toxicity developed. [ABSTRACT FROM AUTHOR]

• Root traits are key indicators of ecosystem functions including nutrient acquisition. • We tested cover crop root functional trait variation across five agroecosystems. • Intercropping legume-grass cover crops stimulated acquisitive root functional traits. • Cover crop root traits were correlated with multiple soil metrics across sites. • We contribute the first cover crop study on drivers of root trait expression on farms. Cover crop trait diversity may enhance multiple ecosystem functions and environmental sustainability in agroecosystems, providing a mechanistic link between crop diversity and changes in ecosystem processes. In agroecosystems, root traits play a key role in functions related to soil nutrient cycling processes, but belowground traits of cover crops are poorly understood. In this study, we analyzed root functional traits of hairy vetch (V. villosa , a legume) and cereal rye (S. cereale , a grass) across five organically-managed agroecosystems in southeastern Michigan selected to span diverse soil fertility levels. Specifically, in this study we ask: (1) what is the extent of cover crop root functional trait variation and is this modified in mixture? (2) Does the expression of cover crop root traits co-vary in predictable patterns? And (3) Which soil properties best explain functional trait variability of cover crops? We found some support for root trait trade-offs; for instance, root C:N and root diameter were positively correlated for rye in mixture (p = 0.049), as were root %N and root length for rye in both mixture (p = 0.003) and monoculture (p < 0.0001). Acquisitive root traits (higher root length and specific root length) increased by 43–66% for vetch grown in mixture, and conservative traits (larger root diameter and higher C:N) were favored in monoculture. As expected, nitrogen in soil particulate organic matter pools, and plant-available phosphorus, were correlated with root trait expression across the farm gradient. These findings contribute to predictive understanding of root trait variation of cover crops across different environmental and management conditions, and inform the design of agroecosystems for delivery of belowground ecosystem services with cover crops. [ABSTRACT FROM AUTHOR]

A transgenic rat model expressing the human angiotensinogen gene [TGR(hAGT)L1623] manifests hypertension, cardiac hypertrophy, and systolic left ventricular dysfunction. A concomitant 4-fold increase in cardiac, but not plasma, angiotensin II (Ang II) implicates activation of the tissue-delimited cardiac renin-angiotensin system. To test the hypothesis that elevated Ang II in TGR(hAGT)L1623 rats impairs intracellular Ca2+ dynamics, cardiomyocytes were isolated from the left ventricles (LV) of 14-16-week-old TGR(hAGT)L1623 and Sprague Dawley (SD) control male rats. Voltage-clamp recordings upon stimulation to 0 mV from a -50 mV holding potential revealed that peak L-type Ca2+ channel current (I CaL) density at baseline was 29% higher in cardiomyocytes from TGR(hAGT)L1623 (-6.4 ± 0.4 pA/pF, n=28 cells from 7 rats) compared to SD (-4.9 ± 0.7 pA/pF, n=8 cells from 2 rats; p =0.03). Thus, elevated intracardiac Ang II accounts for the cardiac phenotype through increased intracellular Ca2+ load in cardiomyocytes. To counteract the Ang II-dependent elevation in cardiomyocyte I CaL, TGR(hAGT)L1623 rats with chronically implanted blood pressure telemetry probes were given the α2-adrenergic receptor agonist guanabenz for 4 weeks at a dose aimed at targeting sarcolemmal receptors without an effect on blood pressure or heart rate. Guanabenz treatment resulted in significantly reduced thickness of the LV posterior wall in diastole compared to vehicle (2.16 ± 0.02 vs. 2.39 ± 0.03 mm, respectively; n=3 in each group; p =0.02) as measured by transthoracic echocardiography. In conclusion, this study demonstrates for the first time a unique role for cardiomyocyte-expressed α2-adrenergic receptors in counteracting the adverse cardiac remodeling associated with increased cardiac Ang II content. [ABSTRACT FROM AUTHOR]

A correction to the article "Opposing roles for p16lnk4a and p19Arf in senescence and ageing caused by BubR1 insufficiency" that was published in a previous issue is presented.

The article presents a study related to the Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia. It analysis the mechanism of myosin-15 bound to F-actin and its impacts of deafness mutations on motor activity and actin nucleation. It also discusses how the rigor myosin-15 evokes structural changes in the filament actin (F-actin) while maintaining D-loop flexibility.

Allosteric regulation of heteromultimeric ATP-sensitive potassium (KATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for KATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948-962) of the SUR2A isoform, in the regulation of cardiac KATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of KATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the KATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore. [ABSTRACT FROM AUTHOR]

Background: A puzzle in evolution is the understanding of how the environment might drive subtle phenotypic variation, and whether this variation is adaptive. Under the neutral evolutionary theory, subtle phenotypes are almost neutral with little adaptive value. To test this idea, we studied the infraspecific variation in flower shape and color in Mammillaria haageana, a species with a wide geographical distribution and phenotypic variation, which populations are often recognized as infraspecific taxa. Results: We collected samples from wild populations, kept them in the greenhouse for at least one reproductive year, and collected newly formed flowers. Our first objective was to characterize tepal natural variation in M. haageana through geometric morphometric and multivariate pigmentation analyses. We used landmark-based morphometrics to quantify the trends of shape variation and tepal color-patterns in 20 M. haageana accessions, belonging to five subspecies, plus 8 M. albilanata accessions for comparison as the sister species. We obtained eight geometric morphometric traits for tepal shape and color-patterns. We found broad variation in these traits between accessions belonging to the same subspecies, without taxonomic congruence with those infraspecific units. Also the phenetic cluster analysis showed different grouping patterns among accessions. When we correlated these phenotypes to the environment, we also found that solar radiation might explain the variation in tepal shape and color, suggesting that subtle variation in flower phenotypes might be adaptive. Finally we present anatomical sections in M. haageana subsp. san-angelensis to propose some of the underlying tepal structural features that may give rise to tepal variation. Conclusions: Our geometric morphometric approach of flower shape and color allowed us to identify the main trends of variation in each accession and putative subspecies, but also allowed us to correlate these variation to the environment, and propose anatomical mechanisms underlying this diversity of flower phenotypes. [ABSTRACT FROM AUTHOR]

Boxplots show the Q1, Q2, and Q3 quantiles, and outliers. 4 Tepal shape and size variation according to the PCS axes. a, c, e, g depicts the PCS groups according to the previously proposed subspecies. b, d, f, h depicts the PCS groups according to their corresponding accession. Boxplots show the Q1, Q2, and Q3 quantiles, and outliers. [Extracted from the article]

α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-ARs, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca2+ and myocardial contractility. This previously unrecognized α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions in cardiac muscle. Specifically, in ventricular myocytes, nitric oxide (NO) and cGMP are the intracellular messengers of α2-AR signal transduction pathways that gauge the kinase-phosphatase balance and manage cellular Ca2+ handling preventing catecholamine-induced Ca2+ overload. Moreover, α2-AR signaling counterbalances phospholipase C – PKC-dependent mechanisms underscoring a broader cardioprotective potential under sympathoadrenergic and angiotensinergic challenge. Recruitment of such tissue-specific features of α2-AR under sustained sympathoadrenergic drive may, in principle, be harnessed to mitigate or prevent cardiac malfunction. However, cardiovascular disease may compromise peripheral α2-AR signaling limiting pharmacological targeting of these receptors. Prospective cardiac-specific gene or cell-based therapeutic approaches aimed at repairing or improving stress-protective α2-AR signaling may offer an alternative towards enhanced preservation of cardiac muscle structure and function. [ABSTRACT FROM AUTHOR]

Abstract Debilitating heart conditions, notably dilated and hypertrophic cardiomyopathies (CMs), are associated with point mutations in metavinculin, a larger isoform of the essential cytoskeletal protein vinculin. Metavinculin is co-expressed with vinculin at sub-stoichiometric ratios in cardiac tissues. CM mutations in the metavinculin tail domain (MVt) occur within the extra 68-residue insert that differentiates it from the vinculin tail domain (Vt). Vt binds actin filaments (F-actin) and promotes vinculin dimerization to bundle F-actin into thick fibers. While MVt binds to F-actin in a similar manner to Vt, MVt is incapable of F-actin bundling and inhibits Vt-mediated F-actin bundling. We performed F-actin co-sedimentation and negative-stain EM experiments to dissect the coordinated roles of metavinculin and vinculin in actin fiber assembly and the effects of three known metavinculin CM mutations. These CM mutants were found to weakly induce the formation of disordered F-actin assemblies. Notably, they fail to inhibit Vt-mediated F-actin bundling and instead promote formation of large assemblies embedded with linear bundles. Computational models of MVt bound to F-actin suggest that MVt undergoes a conformational change licensing the formation of a protruding sub-domain incorporating the insert, which sterically prevents dimerization and bundling of F-actin by Vt. Sub-domain formation is destabilized by CM mutations, disrupting this inhibitory mechanism. These findings provide new mechanistic insights into the ability of metavinculin to tune actin organization by vinculin and suggest that dysregulation of this process by CM mutants could underlie their malfunction in disease. Graphical Abstract Unlabelled Image Highlights • The cardiac tissue-specific splice isoform of vinculin, metavinculin, negatively regulates vinculin-mediated higher-order F-actin assembly. • Metavinculin cardiomyopathy mutants promote disordered F-actin assembly. • Computational modeling suggests that actin binding to metavinculin induces a conformational change within the metavinculin-specific insert region and its displaced N-terminus, to form a protruding sub-domain, that prevents dimerization and Vt-induced actin bundling. • Cardiomyopathy mutations are predicted to destabilize the protruding sub-domain thereby leading to the loss of metavinculin's regulatory role. [ABSTRACT FROM AUTHOR]

Mechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators. Here, we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding as a mechanosensing mechanism by which cytoskeletal tension can govern nuclear localization. • Tension recruits many tandem LIM domain proteins to the actin cytoskeleton • A conserved phenylalanine in each LIM domain is required for this localization • Mechanoresponsive LIM proteins directly bind F-actin only in the presence of force • This binding governs the ECM-rigidity-dependent nuclear localization of FHL2 Sun et al. show that mechanoresponsive tandem LIM domain proteins directly bind F-actin only in the presence of force through a conserved mechanism, governing their tension-dependent cytoskeletal localization in cells. Binding tensed cytoplasmic F-actin prevents the transcriptional co-activator FHL2 from entering the nucleus, facilitating mechanosensing through the cytoskeleton. [ABSTRACT FROM AUTHOR]

Initially observed on synthetic nanoparticles, the existence of biomolecular corona and its role in determining nanoparticle identity and function are now beginning to be acknowledged in biogenic nanoparticles, particularly in extracellular vesicles - membrane-enclosed nanoparticle shuttling proteins, nucleic acids, and metabolites which are released by cells for physiological and pathological communication - we developed a methodology based on fluorescence correlation spectroscopy to track biomolecular corona formation on extracellular vesicles derived from human red blood cells and amniotic membrane mesenchymal stromal cells when these vesicles are dispersed in human plasma. The methodology allows for tracking corona dynamics in situ under physiological conditions. Results evidence that the two extracellular vesicle populations feature distinct corona dynamics. These findings indicate that the dynamics of the biomolecular corona may ultimately be linked to the cellular origin of the extracellular vesicles, revealing an additional level of heterogeneity, and possibly of bionanoscale identity, that characterizes circulating extracellular vesicles.

A deeper knowledge on the formation and biological fate of polymer based gene vectors is needed for their translation into therapy. Here, polyplexes of polyethyleneimine (PEI) and silencing RNA (siRNA) are formed with theoretical N/P ratios of 2, 4 and 12. Fluorescence correlation spectroscopy (FCS) is used to study the formation of polyplexes from fluorescently labelled PEI and siRNA. FCS proves the presence of free PEI. From the analysis of the autocorrelation functions it was possible to determine the actual stoichiometry of polyplexes. FCS and fluorescence cross correlation spectroscopy (FCCS) are used to follow the fate of the polyplexes intracellularly. Polyplexes disassemble after 1 day inside cells. Positron emission tomography (PET) studies are conducted with radiolabelled polyplexes prepared with siRNA or PEI labelled with 2,3,5,6-tetrafluorophenyl 6-[ 18 F]-fluoronicotinate ([ 18 F]F-PyTFP). PET studies in healthy mice show that [ 18 F]siRNA/PEI and siRNA/[ 18 F]PEI polyplexes show similar biodistribution patterns with limited circulation in the bloodstream and accumulation in the liver. Higher activity for [ 18 F]PEI in the kidney and bladder suggests the presence of free PEI.

Background: Baseline disparities in non-discretionary risk factors, i.e., those not readily altered, like family size and work environment, appear to underlie the disproportionate COVID-19 infection rates seen among Hispanic persons and, at surge onsets, Black persons. No study has systematically compared such risk factors by race/ethnicity among infected individuals., Methods: Using a cross-sectional survey, we compared household, job, and socioeconomic characteristics among 260 Hispanic, non-Hispanic Black, and non-Hispanic White adults with confirmed or probable COVID-19 in New York from March to May 2020. We used logistic regression to identify independent relationships., Results: In bivariate analysis, we found significant differences by race/ethnicity in the following: (1) rates of household crowding (p < 0.001), which were highest for Hispanic patients (45.1%) and lowest for White patients (0.9%); (2) rates of non-healthcare frontline work (p < 0.001), which were highest for Hispanic patients (71.0% of those employed) and lowest for White patients (31.4%); (3) rates of working close to people (p < 0.001), which were highest for Black patients (69.4%) and lowest for Hispanic patients (32.3%); and (4) rates of frontline healthcare work (p = 0.004), which were higher for Black (44.9%) and White (44.3%) patients than Hispanic patients (19.4%). Adjusting for covariates eliminated most differences but not that for household crowding., Conclusions: Non-discretionary COVID-19 risk factors among patients in the initial surge differed substantially by race/ethnicity. Socioeconomic factors explained most differences, but household crowding was independently associated with Hispanic ethnicity. Our findings highlight the ongoing need for universal safeguards for US frontline workers, including mandated paid sick leave and expanded affordable housing options., (© 2022. W. Montague Cobb-NMA Health Institute.)

The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and mutations in myosin-15 cause hereditary deafness. In addition to transporting actin regulatory machinery to stereocilia tips, myosin-15 directly nucleates actin filament ("F-actin") assembly, which is disrupted by a progressive hearing loss mutation (p.D1647G, " jordan "). Here, we present cryo-electron microscopy structures of myosin-15 bound to F-actin, providing a framework for interpreting the impacts of deafness mutations on motor activity and actin nucleation. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin's D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. Adenosine diphosphate-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin's structural plasticity in a myosin nucleotide state-dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

Genetic mechanisms controlling root development are well-understood in plant model species, and emerging frontier research is currently dissecting how some of these mechanisms control root development in cacti. Here we show the patterns of root architecture development in a gradient of divergent lineages, from populations to species in Mammillaria . First, we show the patterns of variation in natural variants of the species Mammillaria haageana . Then we compare this variation to closely related species within the Series Supertexta in Mammillaria (diverging for the last 2.1 million years) in which M. haageana is inserted. Finally, we compared these patterns of variation to what is found in a set of Mammillaria species belonging to different Series (diverging for the last 8 million years). When plants were grown in controlled environments, we found that the variation in root architecture observed at the intra-specific level, partially recapitulates the variation observed at the inter-specific level. These phenotypic outcomes at different evolutionary time-scales can be interpreted as macroevolution being the cumulative outcome of microevolutionary phenotypic divergence, such as the one observed in Mammillaria accessions and species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 González-Sánchez, Santiago-Sandoval, Lara-González, Colchado-López, Cervantes, Vélez, Reyes-Santiago, Arias and Rosas.)

The Nuclear Factor-kappa B (NF-κB) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-κB signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF-κB, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro-inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF-κB into the nucleus. NF-κB translocation occurs after its inhibitory protein, IκB-α is phosphorylated which signals for its degradation releasing NF-κB so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule-depolymerizer, NT-07-16 reduces the phosphorylation of IκB-α and also decreases the association of NF-κB with tubulin which may affect the ability of NF-κB to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-κB signaling pathway leading to less NF-κB entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Hip fracture among older patients is a devastating injury in most cases. It profoundly affects the physical, mental, functional and social balance that patients used to have and, beyond the orthopedic injury, it reflects the aging process and its dire consequences. Some reports show that up to 50% of patients with hip fracture die within six months and many of those who survive do not recover their baseline independence and function. In recent decades the increase in life expectancy after 60 years of age has led to an exponential growth in hip fractures. This is why it is essential to determine the patient-related and environmental factors leading to the increased mortality rates seen in patients with hip fracture, to improve the survival and quality of life of older adults. The objective was to determine the association between hip fracture and mortality in patients over 65 years of age., Material and Methods: An observational, longitudinal, retrospective, descriptive, comparative case-control study was conducted. The clinical records of all patients over 65 years of age admitted to the Orthopedics Service, Hospital Regional <>, ISSSTE, with a diagnosis of hip fracture during the previous 12 months were analyzed, regardless of the type of fracture and treatment they received. A group of patients without hip fracture was used as control group. Total sample size was 50 patients with hip fracture and 50 patients without hip fracture. The following data were collected in data collection forms: age, sex, time elapsed since the fracture, survival at one year and, in the case of deceased patients, the cause of death (pneumonia, sepsis, arrhythmia, hydroelectrolytic imbalance, heart failure and others). The results obtained are shown as tables and charts to facilitate their visual understanding., Results: Patient demographics show that there were 40 (80%) female patients and 10 (20%) male patients with a diagnosis of hip fracture. The control group included 35 (70%) females and 15 (30) males. An association between hip fracture and increased mortality was found, with a significant p value of 0.001. The main cause of death among hip fracture patients in our study was sepsis in 7 (35%), while among the control group it was myocardial infarction in 3 (15%). Time wise, mortality was found to be higher within the first six months, with 10 deaths (50%), and within the first year, with six deaths (30%)., Discussion: Hip fracture is in fact a risk factor associated with mortality among patients over 65 years of age. Females are the group most prone to sustaining a hip fracture and, therefore, to increased mortality rates. The major cause of death among our patient population was sepsis, apparently caused by mismanagement of soft tissues, a poor aseptic technique during the surgical procedure, a long hospital stay or a poor family support network, and dementia, which is related to poor surgical wound care. The highest mortality rates were found in ages over 90 years, and they were associated with preexisting chronic-degenerative conditions. The age group at highest risk of hip fracture was 80-89 years. Patients with hip fracture should always be managed together with the internist and the geriatrician and they should be considered as orthopedic emergencies, as a long hospital stay and delayed surgical treatment are associated with major complications and increased mortality rates.

Uniquely gated by intracellular adenine nucleotides, sarcolemmal ATP-sensitive K(+) (K(ATP)) channels have been typically assigned to protective cellular responses under severe energy insults. More recently, K(ATP) channels have been instituted in the continuous control of muscle energy expenditure under non-stressed, physiological states. These advances raised the question of how K(ATP) channels can process trends in cellular energetics within a milieu where each metabolic system is set to buffer nucleotide pools. Unveiling the mechanistic basis of the K(ATP) channel-driven thermogenic response in muscles thus invites the concepts of intracellular compartmentalization of energy and proteins, along with nucleotide signaling over diffusion barriers. Furthermore, it requires gaining insight into the properties of reversibility of intrinsic ATPase activity associated with K(ATP) channel complexes. Notwithstanding the operational paradigm, the homeostatic role of sarcolemmal K(ATP) channels can be now broadened to a wider range of environmental cues affecting metabolic well-being. In this way, under conditions of energy deficit such as ischemic insult or adrenergic stress, the operation of K(ATP) channel complexes would result in protective energy saving, safeguarding muscle performance and integrity. Under energy surplus, downregulation of K(ATP) channel function may find potential implications in conditions of energy imbalance linked to obesity, cold intolerance and associated metabolic disorders.

Cocaine is the most frequently used illicit drug among individuals seeking emergency-room care, with fatal outcome most often attributable to the cardiovascular manifestations of drug abuse. While the symptomatic presentations of cocaine toxicity are increasingly understood, the molecular determinants that define outcome remain largely unknown. Here, we report that the susceptibility to cocaine-induced cardiotoxicity is genetically regulated. Targeted deletion of the KCNJ11-encoded Kir6.2 pore-forming subunit of sarcolemmal K(ATP) channels resulted in amplified vulnerability to the toxic effects of chronic cocaine abuse. Under the hyperadrenergic stress, imposed by daily 3-week-long intraperitoneal administration of 30 mg/kg cocaine in Kir6.2-knockout mice, failure to maintain cardiac homeostasis translated into decreased exercise tolerance revealed by poor treadmill stress performance, and dilated hypokinetic left hearts with aggravated cellular hypertrophy and pathognomonic characteristics of chronic cocaine-induced cardiac toxicity. This study therefore reveals a previously unrecognized role of Kir6.2-encoded K(ATP) channels in determining cardiovascular outcome in chronic cocaine abuse, identifying a novel molecular determinant of cocaine cardiotoxicity.

Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a K(ATP) channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.