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Introduction:The demipointedance position puts the ankle at high risk of overuse injury and posteromedial ankle pain due to increased ankle valgus forces. Previous work has shown that creating lower limb external rotation intrinsic to demipointewith hip external rotation reduces foot pronation that causes ankle valgus stress. Therefore, the purpose of this work was to examine long axis rotation kinematics of the hip, knee, and ankle as well as the ankle joint contact forces in demipointeto better understand the biomechanical impact(s) of the specific cue to increase hip external rotation in this position. Methods:Three-dimensional motion capture and force plate data were collected from 23 contemporary or ballet pre-professional dancers (age: 19.94 ± 1.34 years) who each performed 3 dancer-selected (DS) demipointepositions and 3 demipointeswith the cue to “externally rotate from the hips.” Results:The cue to increase hip external rotation resulted in significantly increased hip external rotation angle [DS: 37.5; 9.42° (median; interquartile range), Cued: 39.9; 10.8°, P< .0001)] and significantly reduced ankle eversion angle (DS: 8.13; 11.4°, Cued: 7.77; 10.3°, P= .023). However, total turnout angle was also significantly decreased (DS: 75.8; 7.91°, Cued: 75.4; 7.73°, P< .0001), which is undesirable for proper esthetic performance of demipointe. Total ankle joint force remained unchanged, but ankle eversion force was significantly reduced (DS: 15.3; 4.18 %bodyweight (BW), Cued: 14.7; 4.99 %BW, P< .0001) with use of the cue. Discussion/Conclusion:Utilization of a cue to increase hip external rotation was successful in increasing hip contribution to turnout angle and reducing injurious ankle eversion force. Further coaching using this cue may allow dancers to produce these advantageous mechanics while maintaining turnout angle.

A new method for measuring the magnetic properties of aqueous and organic solutions is presented. This approach is based on quantifying the force resulting from the sample’s interaction with a magnetic field. The experimental setup utilizes neodymium magnets attached to a stepper motor to adjust the distance between the magnets and the test sample, while an analytical balance serves as a strain gauge. Magnetic susceptibility measurements were performed on selected inorganic and organic solutions. A series of finite element simulations allowed us to convert experimental results to physical quantities describing magnetic susceptibilities of substances. The limit of detection (LoD) and limit of quantification (LoQ) values for the developed method of determining magnetic susceptibility were equal to 6.67·10–3M and 2.02·10–2M, respectively.

Let (X,d)be a compact metric space and lip(X,d)the closed subspace of the Lipschitz functions space Lip(X,d)whose elements fsatisfy the “vanishing” property limd(x,y)→0|f(x)-f(y)|d(x,y)=0.We consider characterizations of metric spaces (X,d)for which the completion of the space M(X)of Borel measures on (X,d)is isomorphic to lip(X,d)∗.

Stress is a major risk factor for psychiatric disorders. During and after exposure to stressors, the stress response may have pro- or maladaptive consequences, depending on several factors related to the individual response and nature of the stressor. However, the mechanisms mediating the long-term effects of exposure to stress, which may ultimately lead to the development of stress-related disorders, are still largely unknown. Epigenetic mechanisms have been shown to mediate the effects of the environment on brain gene expression and behavior. MicroRNAs, small non-coding RNAs estimated to control the expression of about 60% of all genes by post-transcriptional regulation, are a fundamental epigenetic mechanism. Many microRNAs are expressed in the brain, where they work as fine-tuners of gene expression, with a key role in the regulation of homeostatic balance, and a likely influence on pro- or maladaptive brain changes. Here we have selected a number of microRNAs, which have been strongly implicated as mediators of the effects of stress in the brain and in the development of stress-related psychiatric disorders. For all of them recent evidence is reported, obtained from rodent stress models, manipulation of microRNAs levels with related behavioral changes, and clinical studies of stress-related psychiatric disorders. Moreover, we have performed a bioinformatic analysis of the predicted brain-expressed target genes of the microRNAs discussed, and found a central role for mechanisms involved in the regulation of synaptic function. The complex regulatory role of microRNAs has suggested their use as biomarkers for diagnosis and treatment response, as well as possible therapeutic drugs. While, microRNA-based diagnostics have registered advancements, particularly in oncology and other fields, and many biotech companies have launched miRNA therapeutics in their development pipeline, the development of microRNA-based tests and drugs for brain disorders is comparatively slower.

By April 13, 2022, more than 4 months after the approval of BNT162b2 (Pfizer–BioNTech) for children, less than 40% of 5–11-year-olds in Italy had been vaccinated against COVID-19. Estimating how effective vaccination is in 5–11-year-olds in the current epidemiological context dominated by the omicron variant (B.1.1.529) is important to inform public health bodies in defining vaccination policies and strategies.

We study the higher integrability of weights satisfying a reverse Hölder inequality

Dancers represent a unique subset of athletes who face physical and psychological stressors throughout their careers. These challenges pose risks for injury, burnout, and diminished performance capacity. This article proposes a proactive intervention. The Active Resilience Training in Dance curriculum would provide dancers with useable instruction at key career inflection points (amateur to preprofessional, preprofessional to professional, and professional to retirement) to bolster the 4 pillars of their resilience (emotional, cognitive, spiritual, and physical).

Stress is a primary risk factor for several neuropsychiatric disorders. Evidence from preclinical models and clinical studies of depression have revealed an array of structural and functional maladaptive changes, whereby adverse environmental factors shape the brain. These changes, observed from the molecular and transcriptional levels through to large-scale brain networks, to the behaviours reveal a complex matrix of interrelated pathophysiological processes that differ between sexes, providing insight into the potential underpinnings of the sex bias of neuropsychiatric disorders. Although many preclinical studies use chronic stress protocols, long-term changes are also induced by acute exposure to traumatic stress, opening a path to identify determinants of resilient versus susceptible responses to both acute and chronic stress. Epigenetic regulation of gene expression has emerged as a key player underlying the persistent impact of stress on the brain. Indeed, histone modification, DNA methylation and microRNAs are closely involved in many aspects of the stress response and reveal the glutamate system as a key player. The success of ketamine has stimulated a whole line of research and development on drugs directly or indirectly targeting glutamate function. However, the challenge of translating the emerging understanding of stress pathophysiology into effective clinical treatments remains a major challenge.

Both the Thue–Morse and Rudin–Shapiro sequences are not suitable sequences for cryptography since their expansion complexity is small and their correlation measure of order 2 is large. These facts imply that these sequences are highly predictable despite the fact that they have a large maximum order complexity. Sun and Winterhof (2019) showed that the Thue–Morse sequence along squares keeps a large maximum order complexity. Since, by Christol’s theorem, the expansion complexity of this rarefied sequence is no longer bounded, this provides a potentially better candidate for cryptographic applications. Similar results are known for the Rudin–Shapiro sequence and more general pattern sequences. In this paper we generalize these results to any polynomial subsequence (instead of squares) and thereby answer an open problem of Sun and Winterhof. We conclude this paper by some open problems.

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature—the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.

IMPORTANCE: For patients with resected, nonmetastatic colorectal cancer (CRC), the optimal surveillance protocol remains unclear. OBJECTIVE: To evaluate whether serial circulating tumor DNA (ctDNA) levels detected disease recurrence earlier, compared with conventional postoperative surveillance, in patients with resected CRC. DESIGN, SETTING, AND PARTICIPANTS: This study included patients (n = 58) with stage I, II, or III CRC who underwent radical surgical resection at 4 Swedish hospitals from February 2, 2007, to May 8, 2013. Eighteen patients received adjuvant chemotherapy at the discretion of their clinicians, who were blinded to the ctDNA results. Blood samples were collected at 1 month after the surgical procedure and every 3 to 6 months thereafter for ctDNA analysis. Patients were followed up until metachronous metastases were detected, or for a median of 49 months. Data analysis was performed from March 1, 2009, to June 23, 2018. MAIN OUTCOMES AND MEASURES: Sensitivity and timing of ctDNA positivity were compared with those of conventional surveillance modalities (computed tomographic scans and serum carcinoembryonic antigen tests) for the detection of disease recurrence. RESULTS: This study included 319 blood samples from 58 patients, with a median (range) age of 69 (47-83) years and 34 males (59%). The recurrence rate among patients with positive ctDNA levels was 77% (10 of 13 patients). Positive ctDNA preceded radiologic and clinical evidence of recurrence by a median of 3 months. Of the 45 patients with negative ctDNA throughout follow-up, none (0%; 95% CI, 0%-7.9%) experienced a relapse, with a median follow-up of 49 months. However, 3 (6%; 95% CI, 1.3%-17%) of the 48 patients without relapse had a positive ctDNA result, which subsequently fell to undetectable levels during follow-up. CONCLUSION AND RELEVANCE: Although these findings need to be validated in a larger, prospective trial, they suggest that ctDNA analysis could complement conventional surveillance strategies as a triage test to stratify patients with resected CRC on the basis of risk of disease recurrence.

It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.

Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Valbut not in BDNFMet/Metmice. Hippocampal neurogenesis was reduced in BDNFMet/Metmice compared with BDNFVal/Valmice. BDNFMet/Metmice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Metmice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Metmuscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise.

This article presents some new conceptual and interpretative paradigms concerning offshoring Information Technology services, in the light of the most recent market trends. In the current competitive scenario, IT structures are increasingly asked to “participate” in the development and innovation of business, rather than being merely a “support” for the value chain activities, managed merely on the basis of technical and economic efficiency. We start by confuting two traditional concepts: first, that only activities which are quite distinct from the core-business can be candidates for outsourcing, and secondly that the advantage to be derived from offshore outsourcing is above all a matter of costs. What is meant by “success” in this new perspective? We analyse the main critical factors in an offshoring contract enhancing value creation and business strategy. Particular attention is paid to the analysis of the main drivers of solution design and ongoing management in IT offshoring strategies.

We prove that any weight $$v\in L^1_{loc}({{\mathbb {R}}})$$ v∈Lloc1(R) $$v:{{\mathbb {R}}}\rightarrow [0,+\infty )$$ v:R→[0,+∞) of the Muckenhoupt class $$A_\infty $$ A∞ has the form $$v=h^\prime $$ v=h′ where $$h:{{\mathbb {R}}}\rightarrow {{\mathbb {R}}}$$ h:R→R is a bi-Sobolev map. As an application we improve the known results on exact continuation and reciprocal imbeddings for Gehring $$G_q$$ Gq and Muckenhoupt $$A_p$$ Ap classes, providing exact bounds in all cases. The method relies on a duality formula due to Johnson and Neugebauer [Rev Mat Iberoam 3(2)249–273, (1987)] $$\begin{aligned} A_p((h^{-1} )^\prime ) =G_q(h^\prime ), \end{aligned}$$ Ap((h-1)′)=Gq(h′), $$\frac{1}{p}+\frac{1}{q}=1$$ 1p+1q=1 .

In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a ‘gene modifier’ in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.

Irish dance is growing in popularity and competitiveness; however, very little research has focused specifically on this genre of dance. The purpose of this study was to analyze the types of dance injuries incurred by Irish dancers. A chart review was performed to identify all injuries associated with Irish dance seen in the sports medicine or orthopaedic clinics at the investigators’ hospital over an 11-year period. “Injury” was defined as any dance-related pain or disorder that led to evaluation in the clinics. Survey data were also collected from study participants. Ultimately, 255 patients from over 30 different schools of dance were seen with injuries directly related (726 clinic visits) or partially related (199 visits) to Irish dance. Participants ranged in age from 4 to 47, with 95% (243/255) under the age of 19. These 255 patients received 437 diagnoses. Almost 80% of the injuries (348/437) were attributable to overuse, and 20.4% were acute and traumatic injuries (89/437). Ninety-five percent (95.9%) of injuries involved the hip or lower extremity. The most common sites were the foot (33.2%), ankle (22.7%), knee (19.7%), and hip (14.4%). Typical diagnoses were tendon injury (13.3%), apophysitis (11.4%), patellofemoral pain and instability (10.8%), stress injury (10.1%), and muscle injury (7.8%). The majority of traumatic injuries were seen in clinic within 3 weeks, but less than a quarter of overuse injuries were seen that quickly. The most common treatment, prescribed to 84.3% of patients, was physical therapy and home exercises, and the majority of dancers (64.3%) were able to return to full dance activity after injury.

Introduction:Mood and anxiety disorders are among the major causes of disability worldwide. Despite clear need for better therapies, efforts to develop novel drugs have been relatively unsuccessful. One major reason is lack of translation into neuropsychopharmacology of the impressive recent array of knowledge accrued by clinical and preclinical researches on the brain. Here focus is on epigenetics mechanisms, including microRNAs, which seem particularly promising for the identification of new targets for alternative pharmacological approaches.Areas covered:First, the current knowledge about epigenetic mechanisms, including DNA methylation, posttranslational modification of histone proteins, focusing on histone methylation and acetylation, and posttranscriptional modulation of gene expression by microRNAs is described. Then evidence showing involvement of epigenetics and microRNAs in the pathophysiology of mood and anxiety disorders as well as evidence showing that some of the currently employed antidepressants and mood stabilizers also affect epigenetic and microRNA mechanisms are reviewed. Finally current evidence and novel approaches in favor of drugs regulating epigenetic and microRNA mechanisms as potential therapeutics for these disorders are discussed.Expert opinion:Although still in its infancy, research investigating the effects of pharmacological modulation of epigenetic and microRNA mechanisms in neuropsychiatric disorders continues to provide encouraging findings, suggesting new avenues for treatment of mood and anxiety disorders.

Antidepressant drugs represent one of the main forms of effective treatment for the amelioration of depressive symptoms. Most available antidepressants increase extracellular levels of monoamines. However, it is now recognized that monoamine levels and availability are only part of the story, and that antidepressants whose mechanism of action is mainly based on the modulation of monoaminergic systems may not be able to satisfy the unmet needs of depression. Therefore, a number of compounds, developed for their potential antidepressant activity, are endowed with putative mechanisms of action not affecting traditional monoamine targets. This article briefly reviews, within a mechanistic perspective, the pharmacological profiles of representative antidepressants from each class, including monoamine oxidase inhibitors, tricyclics, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors, antidepressants interacting with dopaminergic, melatonergic, glutamatergic, or neuropeptide systems. The undesirable side effects of currently used antidepressants, which can often be a reason for lack of compliance, are also considered.

ObjectivesTo estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination.DesignRetrospective cohort study.SettingItaly, 27 December 2020 to 7 November 2021.Participants33 250 344 people aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection.Main outcome measuresSARS-CoV-2 infection and severe covid-19 (admission to hospital or death). Data were divided by weekly time intervals after vaccination. Incidence rate ratios at different time intervals were estimated by multilevel negative binomial models with robust variance estimator. Sex, age group, brand of vaccine, priority risk category, and regional weekly incidence in the general population were included as covariates. Geographic region was included as a random effect. Adjusted vaccine effectiveness was calculated as (1−IRR)×100, where IRR=incidence rate ratio, with the time interval 0-14 days after the first dose of vaccine as the reference.ResultsDuring the epidemic phase when the delta variant was the predominant strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased (P<0.001) from 82% (95% confidence interval 80% to 84%) at 3-4 weeks after the second dose of vaccine to 33% (27% to 39%) at 27-30 weeks after the second dose. In the same time intervals, vaccine effectiveness against severe covid-19 also decreased (P<0.001), although to a lesser extent, from 96% (95% to 97%) to 80% (76% to 83%). High risk people (vaccine effectiveness −6%, −28% to 12%), those aged ≥80 years (11%, −15% to 31%), and those aged 60-79 years (2%, −11% to 14%) did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine.ConclusionsThe results support the vaccination campaigns targeting high risk people, those aged ≥60 years, and healthcare workers to receive a booster dose of vaccine six months after the primary vaccination cycle. The results also suggest that timing the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to the wider eligible population might be warranted.

The hypotheses on the pathophysiology of depression /mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the “hypothesis of neuroplasticity. ” In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A2A receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A2A receptors might play a pathogenetic role in HD. In agreement, changes in A2A receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A2A receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A2A receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A2A receptors may represent a suitable target to develop drugs against HD.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A2A receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A2A receptors might play a pathogenetic role in HD. In agreement, changes in A2A receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A2A receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A2A receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A2A receptors may represent a suitable target to develop drugs against HD.

Adenosine A2A-dopamine D2 receptor interactions play a very important role in striatal function. A2A-D2 receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. Thus, there is evidence for the coexistence of two reciprocal antagonistic interactions between A2A and D2 receptors in the same neurons, the GABAergic enkephalinergic neurons. An antagonistic A2A-D2 intramembrane receptor interaction, which depends on A2A-D2 receptor heteromerization and Gq/11-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A2A-D2 receptor interaction at the adenylyl-cyclase level, which depends on Gs/olf- and Gi/o- type V adenylyl-cyclase signaling, modulates protein phosphorylation and gene expression. Finally, under conditions of upregulation of an activator of G protein signaling (AGS3), such as during chronic treatment with addictive drugs, a synergistic A2A-D2 receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between Gs/olf - and Gi/o-coupled receptors on the activation of types II/IV adenylyl cyclase, leading to a paradoxical increase in protein phosphorylation and gene expression upon co-activation of A2A and D2 receptors. The analysis of A2-D2 receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction.

Sleep disturbances are often associated with depression and mood disorders, and certain manipulations of the sleep–wake cycle are effective as therapeutic interventions in the treatment of depression. Dysregulated circadian rhythms are thereby considered as causal. Circadian rhythms in mammals are mainly regulated by a core biological clock, located in the hypothalamic suprachiasmatic nucleus; its pacemaker activity is regulated by light and nonphotic modulatory pathways, and the driving mechanisms are serotonergic input from the raphe and the hormone melatonin originating from the pineal gland. In line, the concentration of brain serotonin and the levels of 5-HT2Creceptors are high and highly expressed there. Agomelatine, a novel antidepressant drug with proven clinical efficacy in major depressive disorder, has a unique mechanism of action; it acts as an agonist at melatonergic MT1and MT2receptors and as an antagonist at 5-HT2Creceptors. In animals, agomelatine was shown to increase noradrenaline and dopamine (but not serotonin) in the frontal cortex, to resynchronize the sleep–wake cycle in models with disrupted circadian rhythms, and to exhibit a clear antidepressant effect in various animal models of depression. On the basis of the functional relationship between melatonergic and serotonergic signaling in the suprachiasmatic nucleus, and given agomelatine's affinity at melatonergic and 5-HT2Creceptors, the therapeutic efficacy of the drug may be due to the potential synergy of its action at these different receptors.

Adenosine is one of the principal neuromodulators in the brain and acts on four specific receptor subtypes: the A1, A2A, A2B and A3 receptors. Adenosine concentrations normally reached in the extracellular space are in the nanomolar range and may stimulate the high affinity A1 and A2A receptors. Inhibitory effects on neurotransmission are mediated mainly by A1 receptors while excitatory effects are mediated by A2A receptors. Adenosine has an overall net inhibitory effect on neurotransmission. Under normoxic conditions, A3 receptors do not exert a significant effect on neurotransmission and no data are available concerning the effect of A2B receptors. Given its ability to modulate neurotransmission, adenosine plays several physiological roles in the brain. It controls motility, acts as an endogenous anticonvulsant, and affects pain control, sleep, cognition and memory. It is also likely to be involved in the tonic modulation of affective states and consequently in social interaction and aggressive behaviour. Under pathological conditions, adenosine plays an important role in neuroprotective mechanisms interacting with A1 and A2A receptors and more recently there is evidence that A3 receptors are also involved. It has been demonstrated that A2A antagonists may be useful for control of symptoms and potentially for neuroprotection in Parkinson's disease. One possible approach in cerebral ischaemia is that of agents increasing locally the extracellular concentration of adenosine and of using A2A antagonists. Recent data support the putative utility of A2A receptor ligands in Huntington's disease.

Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.

CaM kinase II, a regulator of synaptic plasticity, is implicated in pathophysiology and pharmacology of psychiatric disorders. Chronic treatment with antidepressants desipramine and reboxetine up-regulated CaM kinase II in neuronal cell bodies of hippocampus. mRNAprotein expression for CaM kinase II was unchanged, whereas Thr286phosphorylation was increased in pyramidalgranular cell bodies, suggesting that increased phosphorylation is responsible for kinase activation. Short-term treatment of neuronal cultures with reboxetine reduced kinase activation in a concentration-dependent manner. The short-term inhibitory effect of reboxetine suggests that kinase up-regulation during antidepressant drug treatment is an adaptive response compensating for initial functional down-regulation.

Adenosine is an endogenous modulator that regulates many Central Nervous System functions, and whose effects are mediated by four G-protein coupled receptors (A1 , A2A , A2B , A3 ). Adenosine A2A receptors have been recently regarded as promising targets for the development of neuroprotective strategies. In particular, since an abnormal glutamate outflow is thought to play a crucial role in triggering the cellular events leading to excitotoxic neuronal death, and since A2A receptors positively modulate glutamate outflow, it has been supposed that their blockade could represent a suitable approach to the treatment of neurodegenerative diseases. In agreement with this hypothesis, both the genetic inactivation and the pharmacological blockade of A2A receptors proved effective in several models of brain injury. In some studies, the neuroprotective effects of A 2A receptor antagonists correlated well with their ability to prevent injury- or toxin- stimulated glutamate outflow. The “beneficial” effects of A2A receptor antagonists at the pre-synaptic sites (namely their ability to attenuate glutamate release), however, seem to occur only at very low doses and at certain time points after the insult is given. Moreover, A2A receptor antagonists seem unable to prevent the toxic effects elicited by direct stimulation of post-synaptic NMDA receptors. It is concluded that, although A2A antagonists show clear neuroprotective effects in models of brain injury, their actual therapeutic potential needs to be confirmed in a wider range of doses, at different stages of brain injury as well as in models of neurodegenerative diseases, in which pre- and post-synaptic effects play different relative roles.

We introduce the class Epqof functions satisfying a new integral reverse inequality and we study the relationships with the classical Gehring and Muckenhaupt classes. In our main result, we prove higher integrability properties that generalize and improve the results obtained in [7] and [1].

There is growing evidence for the existence of not only homomeric, but also functional heteromeric receptor complexes, particularly involving G protein coupled receptors (GPCRs). These include adenosine A2A-dopamine D2 and adenosine A2A-glutamate mGlu5 receptor complexes. The role of these receptor complexes in receptor function seems to be multiple, involving hetero-modulation of ligand recognition, signalling and trafficking. The preferential localization of A2A-D2 and A2A-mGlu5 receptor complexes is in the dendritic spines of striatopallidal GABAergic neurons. Results obtained from behavioral and in vivo microdialysis experiments have shown an important role of mGlu5-A2A-D2 receptor interactions in the modulation of the function of the striatopallidal GABAergic neurons. The striatopallidal GABAergic neurons play a key role in the pathophysiology of basal ganglia disorders, like Parkinson's disease, and it is a common pathway for the rewarding effects of opiates and psychostimulants and for the antipsychotic effects of neuroleptics. The formation of receptor complexes modifies the single receptor transducing characteristics and leads to the appearance of “emergent properties”. Thus, the study of mGlu5-A2A-D2 receptor interactions in the striatum reveals new properties of these GPCRs and gives indications for a new rational approach for drug therapy in neuro-psychiatric disorders and drug addiction.

In 6-hydroxydopamine-lesioned rats, the selective mGlu5receptor agonist (RS)-2-Cholro-5-Hydroxyphenylglycine (CHPG, 1-6 μg/10 μl intracerebroventricularly) significantly inhibited contralateral turning induced by quinpirole and, to a lesser extent, that induced by SKF 38393. The inhibitory effects of CHPG on quinpirole-induced turning were significantly potentiated by an adenosine A2Areceptor agonist (CGS 21680, 0.2 mg/kg IP) and attenuated by an A2Areceptor antagonist (SCH 58261, 1 mg/kg IP). In rat striatal membranes, CHPG (100–1,000 nM) significantly reduced the affinity of the high-affinity state of D2receptors for the agonist, an effect potentiated by CGS 21680 (30 nM). These results show the occurrence of functional interactions among mGlu5, adenosine A2A, and dopamine D2receptors in the regulation of striatal functioning, and suggest that mGlu5receptors may be regarded as alternative/integrative targets for the development of therapeutic strategies in the treatment of Parkinson’s disease.

The present study investigated the effect of long-term (15 mg/kg for 15 days) and acute (15 mg/kg, single administration) treatment with desmethylimipramine, a tricyclic antidepressant drug, on calcium/calmodulin-dependent protein kinase II (CaMKII), a kinase implicated in the mechanism of antidepressant drug action. Similar to selective and non-selective serotonin reuptake inhibitors, long-term, but not acute, treatment with desmethylimipramine markedly increased the activity of CaMKII in the hippocampal synaptic vesicle fraction (+51.9%). The kinase activity was also increased in the same fraction of frontal cortex (+24.2%) and in the striatum (+45.9%), although in this last area the mechanism appeared to be different because the protein level of the kinase was also markedly increased (+43.7%). However, the effect of treatment was not restricted to the presynaptic kinase, because CaMKII activity was also increased in the total cellular cytosol in cortical areas. The autonomous (calcium-independent) activity of CaMKII was assayed for the first time after antidepressant treatment, and found to be increased in synaptic vesicles of all three areas. These results confirmed the involvement of CaMKII in antidepressant drug action and suggested that modulation of transmitter release is a primary component in the action of psychotropic drugs.Neuropsychopharmacology (2001) 24 21–30.10.1016/S0893-133X(00)00176-7

The intrastriatal perfusion of the selective metabotropic glutamate (mGlu)5receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 1000 μM) significantly increased (∼100, p< 0.05) glutamate extracellular levels with respect to basal values. The potentiating effect of CHPG was prevented by the selective mGlu5 receptor antagonist 2-methyl-6(phenyl-ethynyl)-pyridine (MPEP, 250 μM)) and by the adenosine A2Areceptor antagonist SCH 58261 (2 mg/kg, i.p.). The results show that mGlu5receptors are involved in the regulation of striatal glutamate release and suggest an involvement of adenosine A2Areceptors in mGlu5 receptor-mediated effects.

In order to verify whether striatal group I metabotropic glutamate (mGlu) receptors undergo functional alteration in ageing, the effects induced by the selective agonist 3,5-dihydroxyphenylglycine (DHPG) in the striatum of young (3 months) and aged (24–25 months old) rats were compared. The ability of DHPG to stimulate phosphoinositide (PI) hydrolysis (striatal slices), to influence striatal dopamine release (in vivomicrodialysis) and to potentiate the effects of NMDA on extracellular field potential amplitude (extracellular recordings on striatal slices) was reduced in the striatum of old vsyoung rats. These results show an age-dependent reduction in the functional response of striatal group I mGlu receptors, which may be one of the factors underlying the reduced ability of aged striatum to integrate information.

In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats, a rodent model of Parkinson's disease (PD), the adenosine A2Areceptor antagonist SCH 58261 significantly increased (+180%, p< .01) the number of rotations induced by a low dose of quinpirole (a dopamine D2receptor agonist), while it did not significantly modify the effects of a comparably low dose of SKF 38393 (a dopamine D1receptor agonist). The dose-dependent potentiating effects of SCH 58261 on quinpirole-induced turning were similar in caffeine-treated rats (1 g/l in drinking water over 14 days) and control animals (tap water). The selective potentiating effects of SCH 58261 on D2-dependent turning confirm the existence of a potent and specific A2A/D2receptor-receptor interaction. The persistence of the potentiating effects of SCH 58261 after chronic caffeine intake suggests that no tolerance should develop towards the antiparkinsonian effects of adenosine A2Areceptor antagonists with chronic treatment.