Permissive Action Research Articles

Hematological parameters vary with life history stage in the pale‐breasted thrush Turdus leucomelas

The avian life cycle is composed by a progressive sequence of life history stages (LHS). Changes in energy expenditure and exposure to stressors at different LHS require corresponding changes in behavior, physiology, and morphology. Variation in hematological parameters, such hematocrit (Hct), hemoglobin (Hb), and heterophil to lymphocyte ratio (H/L ratio), can have permissive, stimulatory, and preparative actions to help maintain homeostasis through different LHS. Few studies have examined differences in these parameters among different LHS in free‐living birds, with most of them restricted to temperate zones. We collected blood samples and measured hematological parameters every week for over a year from a population of a common resident bird species in southeastern Brazil, the pale‐breasted thrush Turdus leucomelas. Hematocrit and hemoglobin concentration were highest during the onset of the reproduction and lowest during molt. Furthermore, H/L ratios were higher at the end of the reproduction, indicating that the breeding season could be the most stressful period of the year for this population of thrushes. There was no difference between sexes for any hematological parameter at any LHS. These results show that there is a permissive physiological effect for Hct and Hb to facilitate LHS transitions and that reproduction could be the most stressful event for this species. Lastly, these results mirror those from temperate species despite distinct environmental differences between these regions.

Assessment of cardiovascular autonomic dysfunction in untreated adult hypothyroid patients

Introduction and Aim: Hypothyroidism is an endocrine disorder with a high prevalence worldwide in the adult population. Due to the thyroid hormone’s widespread role in controlling metabolic processes to permissive action on the heart, patients with hypothyroidism suffer from a significant chance of acquiring cardiac autonomic dysfunction which further deteriorates the prognosis. Heart rate Variation analysis can be a possible way to detect this autonomic dysfunction early and may help in patient care. This study aims to assess Heart Rate Variability (HRV) parameters in untreated overt hypothyroid patients and compare the parameters of heart rate variability test with an age and sex-matched healthy control group. Materials and Methods: With the permission from the institutional ethics committee, 50 untreated hypothyroid patients are collected from the endocrine outpatient department and 50 healthy age, sex, and matched individuals are taken, maintaining proper inclusion and exclusion criteria. HRV analysis data is collected in both time and frequency domains in both groups and compared using statistical tools. Results: In our research, it is seen that compared to healthy control group, untreated hypothyroid patients have a significant alteration in the following parameters - SDNN (p<0.005) and RMSSD (p<0.009) in the time domain and LF (nu), LF (%), HF (%), LF/HF, HF (nu)[p<0.05] in the frequency domain. Conclusion: Due to several alterations in HRV parameters indicating sympathovagal disbalance in the hypothyroid patients, it can be concluded that untreated hypothyroid patients are prone to develop cardiovascular autonomic dysfunction and HRV analysis can be a possible way to detect it early.

Estrogen ameliorates sepsis-induced vascular hyporeactivity in thoracic aorta of female rats via permissive effect of GRα expression

ObjectiveEstrogen is correlated to the lower mortality and disease severity of female than that of male, which indicates the potential therapeutic role of estrogen supplement therapy in sepsis. The structure of Daidzein is similar to that of 17β estradiol (E2), an estrogen in human body, causing the exogenous Daidzein can interact with estrogen receptor as well as E2 in the body. We aim to explore the therapeutic role of estrogen in sepsis-induced vascular dysfunction. Also, we wonder if estrogen regulates blood pressure via glucocorticoid-mediated vascular reactivity. MethodsFemale SD rats received ovariectomy (OVX) to induce estrogen deficiency. After 12 weeks of administration, cecal ligation and puncture (CLP) was used to establish the in vivo model of sepsis. Lipopolysaccharide (LPS) was used to construct the in vitro model of sepsis in vascular smooth muscle cells (VSMCs). E2 and Daidzein were used for estrogen supplement therapy. ResultsE2 and Daidzein significantly inhibited inflammation infiltration and histopathological injury in thoracic aorta in the rat model with CLP. E2 and Daidzein improved carotid pressure and vascular hyporeactivity in sepsis rats with OVX. Importantly, E2 and Daidzein promoted glucocorticoid permissive action and increased glucocorticoid receptor α (GRα) expression in thoracic aorta smooth muscle cells. E2 and Daidzein upregulated GRα, and inhibits cytokine production, proliferative phenotype and cell migration in LPS-induced VSMCs. ConclusionEstrogen improved vascular hyporeactivity in thoracic aorta induced by sepsis via permissive effect of GRα expression.

The Roles of Atambua Customs and Challenges in Dealing with Garment Smuggling in Indonesia-Timor Leste Border Area

Border areas are often the center of crime and tend to be dominated by issues of transnational crimes, including garment smuggling, mainly used clothes. This study aims to examine the strategy of the Indonesian government in dealing with garment smuggling at the border area between East Nusa Tenggara (NTT) and Timor Leste. The Directorate General of Customs and Excise (DJBC) accordingly exercises its essential role in supervising goods in and out of the border area between Indonesia and other countries. This article discloses that although Atambua Customs and Excise agency has conducted preventive and repressive approaches mainly by carrying out operations, patrols, and surveillance activities at the border area, the used clothes smuggling remains problematic due to officials’ practices of bribery and residents’ permissive actions. The authors use the concepts of transnational crime, garment smuggling, and border security by utilizing a qualitative method with a case study model. Primary data is collected from interviews with the Atambua Customs and Excise agency, and secondary data is collected from documents, books, and websites.

Deletion of Androgen Receptor in LepRb Cells Improves Estrous Cycles in Prenatally Androgenized Mice.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis.

The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma.

Simple SummaryMost patients with pancreatic cancer initially respond to the first-choice drug gemcitabine, but the cancer cells rapidly acquire drug resistance, resulting in poor survival. In this study, we investigated whether the serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in gemcitabine resistance and the maintenance of pancreatic cancer stem cells (CSCs) in association with an Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator of transcription. Herein, we demonstrate that long-term exposure of PDAC cells to 5-HT leads to enhanced EZH2 expression which, in turn, allows upregulation of TPH1 and 5-HT7, resulting in EZH2-TPH1-5-HT7 axis operating in a feed-forward manner. The results suggest that the EZH2-TPH1-5-HT7 axis may be a highly efficient therapeutic target against drug-resistant pancreatic ductal adenocarcinoma (PDAC).In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT7, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT7. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT7. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT7 effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT7 axis leading to gemcitabine resistance and CSC population in PDAC.

Permissive action of H2O2 mediated ClUGT75 expression for auxin glycosylation and Al3+- tolerance in watermelon

Although Al3+-toxicity is one of the limiting factors for crop production in acidic soils, little is known about the Al3+-tolerance mechanism in watermelon, a fairly acid-tolerant crop. This work aimed to identify the interaction between the H2O2 scavenging pathway and auxin glycosylation relevant to watermelon Al3+-tolerance. By analyzing expressions of hormone-related ClUGTs and antioxidant enzyme genes in Al3+-tolerant (ZJ) and Al3+-sensitive (NBT) cultivars, we identified ClUGT75s (B1, B2, and D1) and ClSOD1-2-ClCAT as crucial components associated with Al3+-tolerance. Al3+-stress significantly increased H2O2 content by 92.7% in NBT and 42.3% in ZJ, accompanied by less Al3+-, auxin (IAA and IBA), and MDA contents in ZJ than NBT. These findings coincided with significant ClSOD1-2 expression and stable dismutation activity in NBT than ZJ. Hence, higher H2O2 content in the root apex of NBT than ZJ correlated with a significant increase in auxin content and ClSOD1-2 up-regulation. Moreover, Al3+-activated ClUGT75D1 and ClUGT75B2 in ZJ coincided with no considerable change in IBA content, suggesting that glycosylation-mediated changes in IBA content might be relevant to Al3+-tolerance in watermelon. Furthermore, exogenous H2O2 and IBA indicated ClUGT75D1 modulating IBA is likely dependent on H2O2 background. We hypothesize that a higher H2O2 level in NBT represses ClUGT75, resulting in increased auxin than those in ZJ roots. Thus, excess in both H2O2 and auxin aggravated the inhibition of root elongation under Al3+-stress. Our findings provide insights on the permissive action of H2O2 in the mediation of auxin glycosylation by ClUGT75 in root apex for Al3+-tolerance in watermelon.

Combined low-dose everolimus and low-dose tacrolimus after Alemtuzumab induction therapy: a randomized prospective trial in lung transplantation

BackgroundLong-term outcomes of lung transplantation are severely affected by comorbidities and development of chronic rejection. Among the comorbidities, kidney insufficiency is one of the most frequent and it is mainly caused by the cumulative effect of calcineurin inhibitors (CNIs). Currently, the most used immunosuppression protocols worldwide include induction therapy and a triple-drug maintenance immunosuppression, with one calcineurin inhibitor, one anti-proliferative drug, and steroids. Our center has pioneered the use of alemtuzumab as induction therapy, showing promising results in terms of short- and long-term outcomes. The use of alemtuzumab followed by a low-dose double drug maintenance immunosuppression, in fact, led to better kidney function along with excellent results in terms of acute rejection, chronic lung allograft dysfunction, and survival (Benazzo et al., PLoS One 14(1):e0210443, 2019). The hypothesis driving the proposed clinical trial is that de novo introduction of low-dose everolimus early after transplantation could further improve kidney function via a further reduction of tacrolimus. Based on evidences from kidney transplantation, moreover, alemtuzumab induction therapy followed by a low-dose everolimus and low-dose tacrolimus may have a permissive action on regulatory immune cells thus stimulating allograft acceptance.MethodsA randomized prospective clinical trial has been set up to answer the research hypothesis. One hundred ten patients will be randomized in two groups. Treatment group will receive the new maintenance immunosuppression protocol based on low-dose tacrolimus and low-dose everolimus and the control group will receive our standard immunosuppression protocol. Both groups will receive alemtuzumab induction therapy. The primary endpoint of the study is to analyze the effect of the new low-dose immunosuppression protocol on kidney function in terms of eGFR change. The study will have a duration of 24 months from the time of randomization. Immunomodulatory status of the patients will be assessed with flow cytometry and gene expression analysis.DiscussionFor the first time in the field of lung transplantation, this trial proposes the combined use of significantly reduced tacrolimus and everolimus after alemtuzumab induction. The new protocol may have a twofold advantage: (1) further reduction of nephrotoxic tacrolimus and (2) permissive influence on regulatory cells development with further reduction of rejection episodes.Trial registrationEUDRACT Nr 2018-001680-24. Registered on 15 May 2018

M1 receptors interacting with NMDAR enhance delay-related neuronal firing and improve working memory performance.

The recurrent excitatory circuits in dlPFC underlying working memory are known to require activation of glutamatergic NMDA receptors (NMDAR). The neurons in these circuits also rely on acetylcholine to maintain persistent activity, with evidence for actions at both nicotinic α7 receptors and muscarinic M1 receptors (M1R). It is known that nicotinic α7 receptors interact with NMDAR in these circuits, but the interactions between M1R and NMDAR on dlPFC neuronal activity are unknown. Here, we investigated whether M1Rs contribute to the permissive effects of ACh in dlPFC circuitry underlying working memory via interactions with NMDA receptors. We tested interactions between M1Rs and NMDARs in vivo on single neuron activity in rhesus macaques performing a working memory task, as well as on working memory behavior in rodents following infusion of M1R and NMDAR compounds into mPFC. We report that M1R antagonists block the enhancing effects of NMDA application, consistent with M1R permissive actions. Conversely, M1R positive allosteric modulators prevented the detrimental effects of NMDAR blockade in single neurons in dlPFC and on working memory performance in rodents. These data support an interaction between M1R and NMDARs in working memory circuitry in both primates and rats, and suggest M1Rs contribute to the permissive actions of ACh in primate dlPFC. These results are consistent with recent data suggesting that M1R agonists may be helpful in the treatment of schizophrenia, a cognitive disorder associated with NMDAR dysfunction.

SUN-012 Role of Leptin-Receptor Expressing Cells in the Pathogenesis of Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and is characterized by hyperandrogenism, oligo/anovulation, and/or polycystic ovaries. Many women with PCOS also suffer from adverse metabolic phenotypes, including central adiposity, insulin resistance, and glucose intolerance, which can exacerbate reproductive dysfunction. Androgens can act upon androgen receptors (AR), which are expressed in many reproductive and metabolic tissues, and contribute to the pathogenesis of PCOS. AR are highly expressed in the neuroendocrine hypothalamus in areas which regulate the hypothalamic-pituitary-gonadal axis and contribute to the central regulation of metabolism. Many phenotypes of PCOS can be modelled in rodents by administration of the non-aromatizable androgen dihydrotestosterone (DHT) during critical periods of development. Neuronal AR is key in the development of PCOS, as female mice with neuronal AR deletion who are exposed to androgen excess are protected against development of anovulation, polycystic ovaries, and metabolic abnormalities. Yet it is not known which populations of neurons confers this protection. We hypothesize that leptin-receptor (LepR) neurons participate in the pathogenesis of PCOS, as sub-populations of LepR neurons co-express AR in the hypothalamus, and LepR neurons are critical in the central regulation of energy homeostasis, and exert permissive actions on puberty and fertility. We have pre-natally androgenized (PNA) a mouse model of AR deletion specifically in LepR cells (LepRΔAR) and are conducting reproductive and metabolic phenotyping. As previously demonstrated, control PNA females show long periods of acyclicity, whereas LepRΔAR PNA female mice show a similar number of days in each stage of the estrous cycle, number of cycles, and cycle length as vehicle treated LepRΔAR females. Our findings indicate that a subpopulation of AR/LepR cells mediate the effects of prenatal androgen excess on female estrous cycles in a mouse model of PCOS-like phenotype.

The Arbitrariness Objection Against Permissivism

AbstractThe debate between Uniqueness and Permissivism concerns whether a body of evidence sometimes allows multiple doxastic attitudes towards a proposition. An important motivation for Uniqueness is the so-called ‘arbitrariness argument,’ which says that Permissivism leads to some unacceptable arbitrariness with regard to one's beliefs. An influential response to the argument says that the arbitrariness in beliefs can be avoided by invoking epistemic standards. In this paper, I argue that such a response to the arbitrariness argument is unsuccessful. Then I defend a new response: contrary to common conception, the arbitrariness resulted by Permissivism is acceptable. The basic idea is that the arbitrariness resulted by Permissivism is analogous to the arbitrariness in permissive actions and the latter arbitrariness is intuitively acceptable. I answer three possible objections against this analogy, which are all motivated by the thought that beliefs aim at the truth. In addressing the last objection, I draw inspiration from the recent debate on transformative experience.

Optimal Petri-Net Controller for Avoiding Collisions in a Class of Automated Guided Vehicle Systems

Automated guided vehicles (AGVs) are being extensively used for transportation and distribution of materials due to their high-efficiency. However, the vehicle-collision free problem is challenging since, when modeling these systems, there are indistinguishable and uncontrollable events due to the limited sensors and actuators. This paper proposes an approach to the design of a maximally permissive (optimal) controller to prevent vehicles from any collision based on Petri nets (PNs). For a typical class of AGV systems, a system modeling algorithm is presented using labeled PN, where indistinguishable events are represented by a set of transitions carrying the same label, and an uncontrollable event by an uncontrollable transition. By virtue of the PN model, the collision-free problem is formalized as a conjunction of linear constraints that are converted into admissible ones by an algorithm such that the computational overhead due to uncontrollable events is significantly reduced. In turn, a method is developed to compute the set of consistent markings for an observed sequence of labels that represent signals generated by sensors. Finally, given an observed sequence, a maximally permissive control action is computed to enforce a conjunction of admissible linear constraints based on the set of consistent markings. The approach well addresses the challenging issues caused by indistinguishable and uncontrollable events. A typical AGV system is utilized to illustrate and verify the theoretical results throughout the work.

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy.

Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoid receptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.

Critical role of angiotensin II type 2 receptors in the control of mitochondrial and cardiac function in angiotensin II-preconditioned rat hearts.

Angiotensin II preconditioning (APC) involves an angiotensin II type 1 receptor (AT1-R)-dependent translocation of PKCε and survival kinases to the mitochondria leading to cardioprotection after ischemia-reperfusion (IR). However, the role that mitochondrial AT1-Rs and angiotensin II type 2 receptors (AT2-Rs) play in APC is unknown. We investigated whether pretreatment of Langendorff-perfused rat hearts with losartan (L, AT1-R blocker), PD 123,319 (PD, AT2-R blocker), or their combination (L + PD) affects mitochondrial AT1-R, AT2-R, PKCε, PKCδ, Akt, PKG-1, MAPKs (ERK1/2, JNK, p38), mitochondrial respiration, cardiac function, and infarct size (IS). The results indicate that expression of mitochondrial AT1-Rs and AT2-Rs were enhanced by APC 1.91-fold and 2.32-fold, respectively. Expression of AT2-R was abolished by PD but not by L, whereas the AT1-R levels were abrogated by both blockers. The AT1-R response profile to L and PD was also shared by PKCε, Akt, MAPKs, and PKG-1, but not by PKCδ. A marked increase in state 3 (1.84-fold) and respiratory control index (1.86-fold) of mitochondria was observed with PD regardless of L treatment. PD also enhanced the post-ischemic recovery of rate pressure product (RPP) by 74% (p < 0.05) compared with APC alone. Losartan, however, inhibited the (RPP) by 44% (p < 0.05) before IR and reduced the APC-induced increase of post-ischemic cardiac recovery by 73% (p < 0.05). Finally, L enhanced the reduction of IS by APC through a PD-sensitive mechanism. These findings suggest that APC upregulates angiotensin II receptors in mitochondria and that AT2-Rs are cardioprotective through their permissive action on AT1-R signaling and the suppression of cardiac function.

Endogenous peripheral hydrogen sulfide is propyretic: its permissive role in brown adipose tissue thermogenesis in rats

What is the central question of this study? In fever, the most striking response in the acute phase reaction of systemic inflammation, plasma H2 S concentration increases. However, the role of endogenous peripheral H2 S in fever is unknown. What is the main finding and its importance? Endogenous peripheral H2 S is permissive for increased brown adipose tissue thermogenesis to maintain thermal homeostasis in cold environments as well as to mount fever. This finding expands the physiological role of the gaseous modulator as a key regulator of thermal control in health (thermal homeostasis) and disease (fever in systemic inflammation). In recent years, hydrogen sulfide (H2 S) has been reported as a gaseous modulator acting in several tissues in health and disease. In animal models of systemic inflammation, the plasma H2 S concentration increases in response to endotoxin (bacterial lipopolysaccharide, LPS). The most striking response in the acute phase reaction of systemic inflammation is fever, but we found no reports of the peripheral action of H2 S on this thermoregulatory response. We aimed at investigating whether endogenous systemic H2 S modulates LPS-induced fever. A temperature datalogger capsule was inserted in the abdominal cavity of male Wistar rats (220-270g) to record body core temperature. These animals received an i.p. injection of a systemic H2 S inhibitor (propargylglycine; 50 or 75mg kg-1 ), immediately followed by an i.p. injection of LPS (50 or 2500μg kg-1 ), and were exposed to different ambient temperatures (16, 22 or 27°C). At 22°C, but not at 27°C, propargylglycine at 75mg kg-1 significantly attenuated (P<0.0001) the fever induced by LPS (50μg kg-1 ), indicating a modulatory (permissive) action of endogenous peripheral H2 S on brown adipose tissue (BAT) thermogenesis. Evidence on the modulatory role of peripheral H2 S in BAT thermogenesis was strengthened when we discarded (i) the possible influence of the gas on febrigenic signalling (when measuring plasma cytokines), and (ii) its interaction with the nitric oxide pathway, and mainly when (iii) we carried out physiological and pharmacological activations of BAT. Endogenous peripheral H2 S modulates (permits) BAT activity not only in fever but also during maintenance of thermal homeostasis in cold environments.

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

The development of the nervous system involves the initial overproduction of synapses, which promotes connectivity. Hebbian competition between axons with different activities leads to the loss of roughly half of the overproduced elements and this refines connectivity. We used quantitative immunohistochemistry to investigate, in the postnatal day 7 (P7) to P9 neuromuscular junctions, the involvement of muscarinic receptors (muscarinic acetylcholine autoreceptors and the M₁, M₂, and M₄ subtypes) and adenosine receptors (A₁ and A_2A subtypes) in the control of axonal elimination after the mouse levator auris longus muscle had been exposed to selective antagonists in vivo. In a previous study we analyzed the role of each of the individual receptors. Here we investigate the additive or occlusive effects of their inhibitors and thus the existence of synergistic activity between the receptors. The main results show that the A_2A, M₁, M₄, and A₁ receptors (in this order of ability) delayed axonal elimination at P7. M₄ produces some occlusion of the M₁ pathway and some addition to the A₁ pathway, which suggests that they cooperate. M₂ receptors may modulate (by allowing a permissive action) the other receptors, mainly M₄ and A₁. The continued action of these receptors (now including M₂ but not M₄) finally promotes axonal loss at P9. All 4 receptors (M₂, M₁, A₁, and A_2A, in this order of ability) are necessary. The M₄ receptor (which in itself does not affect axon loss) seems to modulate the other receptors. We found a synergistic action between the M₁, A₁, and A_2A receptors, which show an additive effect, whereas the potent M₂ effect is largely independent of the other receptors (though can be modulated by M₄). At P9, there is a full mutual dependence between the A₁ and A_2A receptors in regulating axon loss. In summary, postnatal axonal elimination is a regulated multireceptor mechanism that involves the cooperation of several muscarinic and adenosine receptor subtypes.

Rapid permissive action of dexamethasone on the regulation of blood pressure in a rat model of septic shock.

Glucocorticoids (GCs) play a vital role in the regulation of blood pressure by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. GCs achieve this function by controlling vascular smooth muscle tone. Clinically, low to moderate doses of GCs are generally used in the treatment of septic shock in recent years. GCs are now known to have both genomic and non-genomic effects. While genomic effects of GCs were well studied, few non-genomic effects were reported, much less the non-genomic mechanisms. One of the most important characters of their non-genomic effects is short latency. The aim of this study was to determine whether GCs can rapidly regulate blood pressure by their permissive action on norepinephrine (NE). Adrenalectomized rats were subjected to cecal ligation and puncture to induce septic shock. The septic rats displayed a significant decrease in the blood pressure response to NE. Dexamethasone (DEX) rapidly restores this hyporeactivity to NE in adrenalectomized septic rats. Further studies showed that DEX potentiates the NE-induced shrinkage and actin cytoskeleton rearrangement of single cell from mesenteric arteries in a short time. These findings suggest that GCs probably exert their permissive actions on the pressure response to NE through rapid non-genomic mechanisms. In this article, we found that as an adjunctive therapy for septic shock, the use of GCs may involve a rapid permissive action, and non-genomic effects of GCs may be involved in these processes.

Species-Related Differences in the Properties of TRPC4 Channels in Intestinal Myocytes of Rodents

TRPC4 proteins form receptor-operated cation channels that are activated in synergy by M2 and M3 ACh receptors coupled to Gq/11 and Gi/o proteins, respectively. These channels are widely expressed in the brain and smooth muscles where they perform a number of important functions, including control of GABA release from the dendrites and cholinergic excitation of smooth muscles. The biophysical properties of TRPC4 currents directly activated by GTPγS in mouse cells remain mostly unknown. We, thus, aimed to investigate these channels in mouse ileal myocytes where a prominent TRPC4-mediated cation current termed mICAT is observed, and to compare the behavior of this current to that of the better studied mICAT in guinea-pig myocytes. Although cation current responses to carbachol at –50 mV (i.e., at the value close to the normal resting potential in these cells) were highly similar, mICAT in the mouse lacked the permissive action of intracellular Ca2+ on channel opening. The slope factor of the muscarinic cation conductance, which is a defining property of voltage-dependent behavior, was identical in both species. There were differences in the potential at which the current peaked at negative potentials, but not in the maximal current densities. Major differences were found in the kinetics of mICAT voltagedependent relaxations, which were much faster in the mouse. The above rodent species employ two different strategies for the open probability increase by activated G-proteins; the mean open time was shorter in the mouse compared to that in the guinea-pig (15.1 ± 5.2 msec, n = 8, vs. 80.0 ± 19.7 msec, n = 9; P < 0.01). Correspondingly, the instantaneous frequency of channel opening was much higher in the mouse (154.1 ± 18.8 sec–1 vs. 70.2 ± 7.3 sec–1 in the guinea-pig; P < 0.001). These functional differences are discussed based on structural differences found in the corresponding TRPC4 amino acid sequences of the two rodent species, which are mainly clustered in the cytosolic C-terminus of TRPC4 protein.

Rising Mercury, Rising Hostility

Recent social scientific research has examined connections between public opinion and weather conditions. This article contributes to this literature by analyzing the relationship between high temperature and survey response. Because hot temperatures are associated with aggression, irritation, and negativity, such conditions should lead to the expression of aggression, irritation, and negativity in survey response. This relationship is tested in a likely realm: feelings about policies relating to racial minorities. Data are drawn from the National Climatic Data Center and the 2010 Cooperative Congressional Election Study. Logistic regressions demonstrate that even after controlling for demographic and geographic factors, average daily temperatures above 74°F are associated with preferences for a stricter immigration policy as well as against permissive affirmative action policies. Acknowledging the role of this contextual variable reduces nonrandom error in estimates of public opinion on these issues.