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Background and Purpose: Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)‐interacting protein 2 (CYFIP2), as a component of the Wiskott–Aldrich syndrome protein family verprolin‐homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine‐968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. Experimental Approach: We performed cocaine reward‐related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock‐in mice to investigate the role of CYFIP2 in regulating cocaine reward. Key Results: CYFIP2 S968F mutation attenuated cocaine‐induced behavioural sensitization and conditioned place preference. Cocaine‐induced c‐Fos was not observed in the NAc of CYFIP2 S968F knock‐in mice. However, c‐Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine‐associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity‐mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC‐NAc pathway and observed that optogenetic activation of the NAc or mPFC‐NAc pathway induced reward‐related behaviours. This effect was not observed in the S968F mutation in CYFIP2. Conclusion and Implications: These results suggest that CYFIP2 plays a role in controlling cocaine‐mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward. [ABSTRACT FROM AUTHOR]

Non‐associative learning plays an important role in the biological and cognitive systems and is one of the important pathways for unsupervised learning in biology. The proposed non‐associative learning memristive circuit is composed of a synapse module, a memristive neuron module, and a response boosting module. The circuit can simulate the characteristics of habituation and sensitization, which attenuates the output response when receiving repeated input stimuli and augments the output response when receiving strong input stimuli, and the circuit also has a certain anti‐interference ability. Additionally, the designed circuit is suitable for adaptive replication experiments in visual systems and automatic exposure compensation systems, demonstrating the practicality of the circuit. [ABSTRACT FROM AUTHOR]

Recently, we showed that while atogepant—a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist—does not fully prevent activation of meningeal nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C fibres and late response probability in Aδ fibres. The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons. In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 versus 1/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 versus 5/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant's inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant' ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated Aδ fibres. Atogepant's inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation. [ABSTRACT FROM AUTHOR]

Repeated cocaine use produces adaptations in brain function that contribute to long‐lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity‐regulated cytoskeleton‐associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)—a brain region linked to CUD‐related behavior. We show here that repeated, non‐contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience‐dependent sensitization of conditioned place preference (CPP). In contrast to the global Arc KO mice, viral‐mediated reduction of Arc in the adult male, but not female, NAc (shArcNAc) reduced both CPP and cocaine‐induced locomotor activity, but without altering basal miniature or evoked glutamatergic synaptic transmission. Interestingly, cell type‐specific knockdown of Arc in D1 dopamine receptor‐expressing NAc neurons reduced cocaine‐induced locomotor sensitization, but not cocaine CPP; whereas, Arc knockdown in D2 dopamine receptor‐expressing NAc neurons reduced cocaine CPP, but not cocaine‐induced locomotion. Taken together, our findings reveal that global, developmental loss of Arc produces hypersensitized cocaine responses; however, these effects cannot be explained by Arc's function in the adult mouse NAc since Arc is required in a cell type‐ and sex‐specific manner to support cocaine‐context associations and locomotor responses. [ABSTRACT FROM AUTHOR]

Ventilatory responses to hypoxia and hypercapnia play a vital role in maintaining gas exchange homeostasis and in adaptation to high-altitude environments. This study investigates the mechanisms underlying sensitization of hypoxic and hypercapnic ventilatory response (HVR and HCVR, respectively) in individuals acclimatized to moderate high altitude (3,800 m). Thirty-one participants underwent chemoreflex testing using the Duffin-modified rebreathing technique. Measures were taken at sea level and after 2 days of acclimatization to high altitude. Ventilatory recruitment threshold (VRT), HCVR-Hyperoxia, HCVR-Hypoxia, and HVR were quantified. Acclimatization to high altitude resulted in increased HVR (P < 0.001) and HCVR-Hyperoxia (P < 0.001), as expected. We also observed that the decrease in VRT under hypoxic test conditions significantly contributed to the elevated HVR at high altitude since the change in VRT across hyperoxic and hypoxic test conditions was greater at high altitudes compared to baseline sea-level tests (P = 0.043). Pre-VRT, or basal, ventilation also increased at high altitudes (P < 0.001), but the change did not differ between oxygen conditions. Taken together, these data suggest that the increase in HVR at high altitude is at least partially driven by a larger decrease in the VRT in hypoxia versus hyperoxia at high altitude compared to sea level. This study highlights the intricacies of respiratory adaptations during acclimatization to moderate high altitude, shedding light on the roles of the VRT, baseline respiratory drive, and two-slope HCVR in this process. These findings contribute to our understanding of how human respiratory control responds to hypoxic and hypercapnic challenges at high altitude. NEW & NOTEWORTHY: We report the first measurements of the hypoxic ventilatory response (HVR) after 2 days at high altitude using a CO2 rebreathing technique. We evaluated mechanisms by which the HVR becomes elevated with acclimatization (increased hypercapnic ventilatory response sensitivity in hypoxia, increased baseline respiratory drive in hypoxia, or lower ventilatory recruitment thresholds in hypoxia). For the first time, we report that decreases in the ventilatory recruitment threshold in hypoxia contribute to elevated HVR at high altitude. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1), classified as a class I carcinogen, is a widespread mycotoxin that poses a serious threat to public health and economic development, and the food safety problems caused by AFB1 have aroused worldwide concern. The development of accurate and sensitive methods for the detection of AFB1 is significant for food safety monitoring. In this work, a sandwich-type photoelectrochemical (PEC) biosensor for AFB1 detection was constructed on the basis of an aptamer–antibody structure. A good photocurrent response was obtained due to the sensitization of In2S3 by Ru(bpy)32+. In addition, this sandwich-type sensor constructed by modification with the antibody, target detector, and aptamer layer by layer attenuated the migration hindering effect of photogenerated carriers caused by the double antibody structure. The aptamer and antibody synergistically recognized and captured the target analyte, resulting in more reliable PEC response signals. CdSe@CdS QDs-Apt were modified as a signal-off probe onto the sensor platform to quantitatively detect AFB1 with a "signal-off" response, which enhanced the sensitivity of the sensor. The PEC biosensor showed a linear response range from 10−12 to 10−6 g mL−1 with a detection limit of 0.023 pg mL−1, providing a feasible approach for the quantitative detection of AFB1 in food samples. [ABSTRACT FROM AUTHOR]

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4‐mediated itch sensation remains unclear. Here, we showed that LPS‐mediated TRPV4 sensitization exacerbated GSK101‐induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4‐knockout mice, suggesting LPS acted through a TLR4‐dependent mechanism. Mechanistically, LPS enhanced GSK101‐evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4‐PI3K‐AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4‐TRPV4 interaction in itch signal amplification. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 S1 potentiated the neuroinflammatory response to LPS 7d and 9d later. • SARS-CoV-2 S1 potentiated the physiological response to LPS 7d later. • SARS-CoV-2 S1 potentiated the behavioral response to LPS 7d later. • SARS-CoV-2 S1 reduced basal corticosterone (CORT) levels in brain. • SARS-CoV-2 S1 might disinhibit/prime brain immune processes via reduced CORT. Long COVID is a major public health consequence of COVID-19 and is characterized by multiple neurological and neuropsychatric symptoms. SARS-CoV-2 antigens (e.g., spike S1 subunit) are found in the circulation of Long COVID patients, have been detected in post-mortem brain of COVID patients, and exhibit neuroinflammatory properties. Considering recent observations of chronic neuroinflammation in Long COVID patients, the present study explores the idea that antigens derived from SARS-CoV-2 might produce a long-term priming or sensitization of neuroinflammatory processes, thereby potentiating the magnitude and/or duration of the neuroinflammatory response to future inflammatory insults. Rats were administered S1 or vehicle intra-cisterna magna and 7d later challenged with vehicle or LPS. The neuroinflammatory, physiological, and behavioral responses to LPS were measured at various time points post-LPS. We found that prior S1 treatment potentiated many of these responses to LPS suggesting that S1 produces a protracted priming of these processes. Further, S1 produced a protracted reduction in basal brain corticosteroids. Considering the anti-inflammatory properties of corticosteroids, these findings suggest that S1 might disinhibit innate immune processes in brain by reducing anti-inflammatory drive, thereby priming neuroinflammatory processes. Given that hypocortisolism is observed in Long COVID, we propose that similar S1-induced innate immune priming processes might play role in the pathophysiology of Long COVID. [ABSTRACT FROM AUTHOR]

Anthropogenic noise can affect a number of behavioral, physiological, and ecological aspects of animals from major taxonomic groups, raising serious conservation concerns. For example, noise pollution impacts communicative behavior and perception of signals, movements and distribution, as well as predator–prey interactions, such as hunting success or predator detection and predation risk assessment. We have carried out an experimental playback study, in which we investigated whether exposure to anthropogenic noise (sound of a tractor) distracts free-ranging barn swallows Hirundo rustica from paying attention to an approaching human "predator" (the "cognitive distraction" hypothesis), or whether noise leads to increased responsiveness to this "predator" (the "increased threat" hypothesis). The subjects were male barn swallows attending their breeding territories during the time when the females were incubating. We found that barn swallow males initiated flight at significantly greater distances to the approaching human "predator" in the noise treatment than during the quiet control trials. These results suggest that anthropogenic noise causes increased vigilance and reactivity rather than a distraction, enabling birds to avoid the "predator" more quickly. We further discuss the mechanism behind the increased alertness in response to noise and contrast the "increased threat" mechanism, usually tested in previous studies, with an alternative "cognitive sensitization" mechanism. [ABSTRACT FROM AUTHOR]

Cognitive reappraisal is widely recognized as an effective emotion regulation strategy. In laboratory research, negative ratings from image-based reappraisal tasks are typically aggregated within trial condition, and the average difference in reported negative affect between conditions serves as a measure of reappraisal success. We aggregated and re-analyzed trial-level data from 27 picture-based reappraisal experiments to which we had access in order to examine the robustness of the reappraisal effect and estimate the power to detect this effect within different sample sizes. Then, we leveraged the database to conduct novel tests of potential trial-level factors (time and previous trial type) that may impact reappraisal success. These allowed us to test among competing hypotheses about how negative affect may change based on these factors: habituation, sensitization, practice, and fatigue. We observed a small but significant linear decrease in negative emotion over time in look and regulation conditions (habituation). We also observed a small but significant interaction between previous trial and current trial, such that seeing a negative image on a previous trial resulted in slightly higher ratings of negative emotion, but this effect was relatively diminished if the previous trial also involved reappraisal. The database is an open, novel resource for those designing and conducting picture-based reappraisal tasks. [ABSTRACT FROM AUTHOR]

Rationale: In previous animal model studies, it was shown that drug sensitization is dependent upon physical environmental conditions. However, the effects of social housing conditions on drug sensitization is much less known. Objective: The aim of the present study was to investigate the effects of social conditions, through the size of housing groups, on ethanol stimulant effects and ethanol-induced behavioral sensitization in mice. Materials and methods: Male and female Swiss mice were housed in groups of different sizes (isolated mice, two mice per cage, four mice per cage and eight mice per cage) during a six-week period. A standard paradigm of ethanol-induced locomotor sensitization was then started with one daily injection of 2.5 g/kg ethanol for 8 consecutive days. Results: The results show that social housing conditions affect the acute stimulant effects of ethanol. The highest stimulant effects were observed in socially isolated mice and then gradually decreased as the size of the group increased. Although the rate of ethanol sensitization did not differ between groups, the ultimate sensitized levels of ethanol-induced stimulant effects were significantly reduced in mice housed in groups of eight. Conclusions: These results are consistent with the idea that higher levels of acute and sensitized ethanol stimulant effects are observed in mice housed in stressful housing conditions, such as social isolation. [ABSTRACT FROM AUTHOR]

Aims: This study aims to investigate the pharmacological effects and the underlying mechanism of cannabidiol (CBD) on methamphetamine (METH)‐induced relapse and behavioral sensitization in male mice. Methods: The conditioned place preference (CPP) test with a biased paradigm and open‐field test were used to assess the effects of CBD on METH‐induced relapse and behavioral sensitization in male mice. RNA sequencing and bioinformatics analysis was employed to identify differential expressed (DE) circRNAs, miRNAs, and mRNAs in the nucleus accumbens (NAc) of mice, and the interaction among them was predicted using competing endogenous RNAs (ceRNAs) network analysis. Results: Chronic administration of CBD (40 mg/kg) during the METH withdrawal phase alleviated METH (2 mg/kg)‐induced CPP reinstatement and behavioral sensitization in mice, as well as mood and cognitive impairments following behavioral sensitization. Furthermore, 42 DEcircRNAs, 11 DEmiRNAs, and 40 DEmRNAs were identified in the NAc of mice. The circMeis2‐miR‐183‐5p‐Kcnj5 network in the NAc of mice is involved in the effects of CBD on METH‐induced CPP reinstatement and behavioral sensitization. Conclusions: This study constructed the ceRNAs network for the first time, revealing the potential mechanism of CBD in treating METH‐induced CPP reinstatement and behavioral sensitization, thus advancing the application of CBD in METH use disorders. [ABSTRACT FROM AUTHOR]

In this issue of Neuron , Chen et al. 1 found that lateral septum Esr1-expressing cells respond to both non-drug and drug rewards. Mice will lever press for optogenetic stimulation of these neurons, which are also critical to methamphetamine locomotor sensitization, conditioned place preference, self-administration, and reinstatement. In this issue of Neuron , Chen et al. found that lateral septum Esr1-expressing cells respond to both non-drug and drug rewards. Mice will lever press for optogenetic stimulation of these neurons, which are also critical to methamphetamine locomotor sensitization, conditioned place preference, self-administration, and reinstatement. [ABSTRACT FROM AUTHOR]

Aggressive behavior is a range of acts that result in physical and psychological harm to the perpetrator, and other students, thus hindering learning activities. This study investigated the relationship between exposure to violent videos and aggressive behavior among public secondary students in Kwara State, Nigeria. The survey method with a correlational design was adopted. A total sample of 381 participants was involved using the stratified random sampling technique. A research-designed questionnaire titled Exposure to Violent Videos and Aggressive Behaviour Questionnaire (EVABQ) was used to collect the data. Pearson's product-moment correlation and t-test statistics were used to analyze the hypotheses. Results revealed a positive relationship between exposure to violent videos and aggressive behavior. The results showed statistically significant differences in exposure to violent videos and aggressive behavior among public secondary students based on gender and age. Male respondents were more exposed to violent videos and had more aggressive behavior than females. In contrast, students below 15 years old were more exposed to violent videos and exhibited aggressive behavior than 15 years and above. Therefore, school counselors should sensitize public secondary students to the influence of exposure to violent videos on aggressive behavior, especially among males and students below 15 years old. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory disease based on genetic and immune alterations and is part of the atopic symptom complex, including allergic rhinitis, allergic conjunctivitis, and bronchial asthma. A disturbed barrier function facilitates antigen penetration through the skin, with the subsequent development of allergic contact dermatitis (ACD). The gold standard for diagnosing ACD is epicutaneous (patch) testing, also applied to objectify contact sensitization in AD. This study aimed to determine the frequency of contact allergy (CA) among individuals with atopic history and the allergens that caused ACD in those cases. We studied 453 individuals tested in the period 2009-2022. Of these, a subpopulation of 189 individuals with atopic diathesis was identified. A retrospective analysis was used. Using clinical and allergological methods, we divided the tested patients according to sex, age, professional occupation, and areas of the body affected by dermatitis and identified the most common contact allergens that cause positive reactions and ACD. In conclusion, our results highlight the possibility of developing ACD in people with atopic diathesis. As far as we know, our study is the first one in Bulgaria to examine the frequency of contact sensitization in AD patients. [ABSTRACT FROM AUTHOR]

Wild fruits are potentially natural foods, healthy and economically important in our communities. Lack of data on the nutritive and medicinal values of the wild fruits leave them neglected in our communities. Investigation on medicinal use and antioxidant potential of wild fruits in the drylands area of Shinyanga region was conducted in 2022 at Iselamagazi ward (33° 8'14.52"E to 33° 8'26.97"E and 3°32'28.44"S to 3°32'40.38"S) in Shinyanga rural District. Wild fruits were collected using standard methods from the purposely selected areas while ethnomedicinal information was collected using a questionnaire method. Extraction of plant material was done by solvent extraction method using ethanol 99.8% v/v as a solvent. Extract of the wild fruits were evaluated calorimetrically using the spectrophotometer UV-Visible model 6305 Jenway, UK. Ethnomedicinal information from the questionnaire were also collated. Antioxidant properties were obtained using 2, 2-diphenyl-1picrylhydrazyl DPPH) method. Results indicate that the wild fruits are potential natural antioxidants with total phenolic content (gallic acid equivalence) ranging from 19.513-175.983 mg GAE/g and total flavonoid content (Ruta graveolens) ranging from 9.171-176.99 mg RUE/g. Adansonia digitata showed the highest antioxidant capacity (175.983mg GAE/g) and Trema orientalis showed the lowest antioxidant capacity (17.898mg GAE/g). Scavenging ability values of the fruits ranged from 0.368-44.77 taurine (TAU) in total phenolic and 0.233-5.68 TAU in total flavonoid content. More than 20 diseases were reported to be treated by the investigated fruits based on ethnomedicinal information of the investigated community. Propagation and fruits utilization sensitization of the wild fruits in our communities will improve health and livelihood but also conserve our environments. [ABSTRACT FROM AUTHOR]

Purpose: In recent years, research has yielded new information regarding the impact of intense, long-term alcohol consumption on the development of permanent changes in the central nervous system. The present study examines the mechanisms related to the existence of addiction memory, sensitization and allostasis. A dual-process model was also created, which analyses the role of conscious and automatic mechanisms in the functioning of addicts. The aim of the article is to present these mechanisms and to consider the implications of their existence for the course of therapy. Views: The mechanisms analysed shed new light on some of the negative phenomena occurring during and after therapy, such as frequent abstinence after treatment, switching addictions, and returning to drinking after a long period of abstinence. The existence of these mechanisms should also change the character of addiction therapy, which has so far focused mainly on conscious aspects and ignored the existence of automatic ones. Attempts are already being made to implement the dual-process model in addiction therapy. Conclusions: A better understanding of the mechanisms resulting from the dual-process model can significantly influence perspectives regarding functioning in addiction and the course of therapy. These processes merit further research, as do possible therapeutic interventions based on them. [ABSTRACT FROM AUTHOR]

The article presents the discussion on prevalence of allergies in Germany is striking affecting nearly a third of its population. Topics include prevalent being detectable sensitizations, where individuals exhibit IgE antibodies against specific allergens without corresponding symptoms; and considering factors such as individual susceptibility, allergen dose, and environmental triggers.

Background: Cow’s Milk protein allergy (CMA) is a common finding in infants and young children (2-3%). Its diagnosis is a multifaceted aspect including medical history, clinical examination, diagnostic elimination diets, oral challenge tests (OCT), skin prick tests (SPTs) and specific immunoglobulin E (sIgE) measurements. We aimed to assess the value of SPT and sIgE for diagnosis of infants with CMA in routine clinical practice. Methods: This cross-sectional study included 102 infants with suspected CMA. They were subjected to OCT, SPT with pasteurized cow's milk and measurement of serum sIgE for cow’s milk by immunoblot technique. Results: Seventy-two infants (70.59%) showed positive allergic reactions with OCT. Comparing SPT to OCT, sensitivity was 75%, specificity was 68.7%, predictive value for negative (PVN) was 59% and predictive value for positive (PVP) was 93.1%. Comparing sIgE to OCT, sensitivity was 68.1%, specificity was 96.7%, PVN was 69% and PVP was 98%. Comparing both SPT and sIgE together to OCT, sensitivity was 62.5%, specificity was 96.6%, PVN was 51.8% and PVP was 97.8%. Conclusions: For clinical practice, our findings suggest that correlation between SPT and sIgE is significant regarding CMA diagnosis. Therefore, these tests can be used together for diagnosis of CMA. However, still some cases can be only diagnosed with positive OCT with non-detectable sensitization. Therefore, a detailed history is a major factor in assessing CMA. In addition, definition of new optimal cut-offs for sIgE and SPT to cow’s milk can improve the accuracy of these tests, hoping to avoid unnecessary and potentially dangerous OTC. [ABSTRACT FROM AUTHOR]

The main goal of the publication is to understand and bring closer the issue of extreme poverty among the social challenges through the help of gamification and to find the necessary tools to overcome it. In my work, I examine the role gamification can play in social awareness. My key question was how a gamification program can contribute to enabling people to imagine themselves in the lives of their disadvantaged peers and thus become sensitive to their problems. I also wanted to find out if such a game can motivate participants to take real action and initiate actual assistance. In my research, I examine the experiences of a two-round sensitization program involving participants. The method of investigation includes observation and structured questionnaire surveys. Throughout the process, I summarize the findings in professional roundtable discussions with the stakeholders. [ABSTRACT FROM AUTHOR]

Introduction: The diagnostics of plant-derived food allergy may be challenging. However, the recognition of sensitization patterns in defined populations, especially in children, is clinically relevant as it enables the use of secondary prophylaxis to prevent life-threatening complications. Aim: To investigate the rates and sensitization patterns to nut allergens in children from central Poland. Material and methods: The retrospective assessment concerned data of 598 children diagnosed in a single centre due to suspected food allergy. The analysis included the results of component-based multiparametric assay Allergy Explorer2 (ALEX2). Results: The sensitization to particular nut allergens varied among patients, depending on their age and nut type. The sensitization to any nut was found in 67% of children, whereas sensitization to hazelnut and peanut was the most common (56% and 55% of all children, respectively). Hazelnut sensitization was predominant in every age, and its prevalence increased with age, while peanut sensitization was detected in more than half of individuals from all groups, except for teenagers (44% of cases). Among hazelnut molecules sensitization to Cor a 1.04 was the most prevalent (74% of sensitized children), and for peanut allergens - Ara h 1 (65% of sensitized patients). The simultaneous sensitization to hazelnut, peanut and walnut (two or all of them) was found in almost half of the entire group. Conclusions: Component-based diagnostics enables differentiation between primary and cross-reactive sensitization to nut allergens and detects co-sensitization. The clinical relevance of the latter observation is remarkable as co-sensitization increases the risk of life-threatening reactions even in trace nut contamination. [ABSTRACT FROM AUTHOR]

This artistic investigation is based on personally experienced symptoms caused by nervous disorders and is to be seen as a graphic phenomenology. Drawing physical sensations raises fundamental questions as to the very possibility of visual repre sentation and of conveying to others what cannot be seen. Efforts to come to grips with bodily perception that has been altered as a result of a chronic illness lead, by dint of introspection and externalization, to a new understanding of one's own body. In addition, the graphic catalogue of physical sensations can provide a stimulus for a response on the part of other persons affected by the disease while, at the same time, contributing in a general way to conveying what is simply difficult to formulate in words. [ABSTRACT FROM AUTHOR]

Rationale: Exposure to rewards can alter behavioral reactivity to them. For example, stimulants sensitize locomotor activation, whereas sexual experience sensitizes copulatory behaviors. Moreover, rewards can cross-sensitize one another. Although stimulants are known to cross-sensitize locomotor effects, the evidence for cross-sensitization between stimulants and sex is less clear. Objectives: This study determined the effects of single and repeated pre-exposure to methylphenidate (MPH) or sex on one another in adult male rats. Methods: Cross-sensitization between MPH (5 mg/kg) and sex (30 min with sexually experienced female) was examined. Adult male rats were pre-exposed to 0, 1, or 10 trials of either sex or MPH before being exposed to the other reward. Locomotor chambers were used in MPH trials. Bilevel chambers were used in sexual trials, and sexual behaviors were video scored. Results: The amount of prior sexual experience differentially influenced the ceiling of MPH-dependent sensitization; in the last drug trial, locomotion was highest in males given 1 previous sexual trial compared with 0 or 10. Compared with MPH-naive males, pre-exposure to MPH (1 and 10 trials) reduced the number of ejaculations without impacting sexual performance (intromission/mount latency and frequency). Conclusions: These findings indicate that the degree of pre-exposure to a reward can differentially affect reactivity to novel rewards. The results showed that previous findings of cross-sensitization between amphetamine and sex do not extend to MPH. However, exposure to MPH prior to sexual experience can increase the amount of sexual stimulation needed to achieve ejaculation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify aeroallergens susceptibility patterns of atopic children living in the city of Antalya, southwest of Turkey. Methods: One thousand seven hundred five patients (2-18 years) who applied to the pediatric allergy immunology outpatient clinic between April 2018-March 2020 were included in the study. The demographic and clinical characteristics of patients with at least one allergic sensitization in the skin prick test were evaluated. Results: A total of 761 patients were evaluated, comprising 57.69% males and 42.31% females, with a median age of 9.25 years (range, 6.25-12.9 years). Of the total patients 54.01% had asthma (AS), 89.22% had allergic rhinitis (AR), (45.33%) had both AS and AR and 11.83% had atopic dermatitis. Sensitivity to house dust mites (HDMs) was the most common sensitivity (66.23%), followed by animal dander (39.68%) and cockroach (34.56%). Other allergens were grass pollen (32.33%), mold (31.54%), weed mixture pollen (29.04%), olive tree (27.86%), and tree mixture (14.98%), respectively. More than one allergen sensitization was detected in 537 (70.6%) patients. AR was more common in boys (p=0028). Pollen sensitivity was higher in children with AR than in children without AR (p<0.001). Conclusion: In our study in which allergen sensitivity was determined in atopic children in our region, the most common allergens were HDMs, cockroachs and animal dander, which are indoor allergens. [ABSTRACT FROM AUTHOR]

Rationale: Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA. Objective: We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later. Results: The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice. Conclusions: These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs. [ABSTRACT FROM AUTHOR]

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization. [Display omitted] • snRNA-seq identifies the transcriptional cell types in the septal region • Optogenetic activation of LSEsr1 neurons promotes positive reinforcement • METH exposures enhance LSEsr1 neuronal excitability via upregulation of HCN1 • LSEsr1 neurons are critical for METH reward and behavior sensitization Chen et al. elucidate the intricate molecular, circuit, and functional architecture of the septal area and identify Esr1-expressing neurons in the LS as a key driver of reward seeking and methamphetamine addiction. These findings open new avenues for exploring how the septal region regulates reward and addiction. [ABSTRACT FROM AUTHOR]

Rationale: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.Objectives: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.Methods: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.Results: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.Conclusions: Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear.The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice.Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition.The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock.Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination. [ABSTRACT FROM AUTHOR]

Sensory adaptation is the process whereby brain circuits adjust neuronal activity in response to redundant sensory stimuli. Although sensory adaptation has been extensively studied for individual neurons on timescales of tens of milliseconds to a few seconds, little is known about it over longer timescales or at the population level. We investigated population-level adaptation in the barrel field of the mouse somatosensory cortex (S1BF) using in vivo two-photon calcium imaging and Neuropixels recordings in awake mice. Among stimulus-responsive neurons, we found both adapting and facilitating neurons, which decreased or increased their firing, respectively, with repetitive whisker stimulation. The former outnumbered the latter by 2:1 in layers 2/3 and 4; hence, the overall population response of mouse S1BF was slightly adapting. We also discovered that population adaptation to one stimulus frequency (5 Hz) does not necessarily generalize to a different frequency (12.5 Hz). Moreover, responses of individual neurons to repeated rounds of stimulation over tens of minutes were strikingly heterogeneous and stochastic, such that their adapting or facilitating response profiles were not stable across time. Such representational drift was particularly striking when recording longitudinally across 8–9 days, as adaptation profiles of most whisker-responsive neurons changed drastically from one day to the next. Remarkably, repeated exposure to a familiar stimulus paradoxically shifted the population away from strong adaptation and toward facilitation. Thus, the adapting vs. facilitating response profile of S1BF neurons is not a fixed property of neurons but rather a highly dynamic feature that is shaped by sensory experience across days. [Display omitted] • S1 barrel cortex neurons range from strongly facilitating to strongly adapting • They show dramatic drift and stochasticity in their adaptation response • Repeated experience across days shapes the S1 population toward facilitation • Adaptation comes from the thalamus, but facilitation may require top-down modulation Dobler, Suresh et al. use in vivo two-photon calcium imaging across cortical layers in the somatosensory barrel cortex to show that sensory adaptation to repetitive whisker stimulation is stochastic at the level of individual neurons but also manifests population drift and is shaped by sensory experience at the population level. [ABSTRACT FROM AUTHOR]

Pavlovian conditioning is typically distinguished from sensitization but a Pavlovian conditional stimulus (CS) also results in sensitization. A Pavlovian CS can sensitize responding to a probe stimulus that is related to the unconditional stimulus (US) or to the US itself. Pavlovian sensitization has been studied in the defensive, sexual, and feeding systems. In Pavlovian sensitization, the focus is not on a conditional response (CR) directly elicited by the CS but on the response mode that is activated by the CS. Activation of a response mode increases the probability of particular responses and also increases reactivity to various stimuli. Pavlovian sensitization reflects this increased stimulus reactivity. Pavlovian sensitization helps uncover successful learning in situations where a conventional CR does not occur. Pavlovian sensitization also encourages broadening our conceptions of Pavlovian conditioning to include changes in afferent processes. Implications for biological fitness and for basic and translational research are discussed. • Pavlovian sensitization is especially important when learning is not evident in a conditional response. • Pavlovian sensitization is of biological significance because it improves reactivity to unconditional stimuli. • Pavlovian sensitization encourages reconsidering common assumptions about the nature of sensitization. • Pavlovian sensitization highlights the importance of afferent processes in the neurobiology of learning and extinction. [ABSTRACT FROM AUTHOR]

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice, using locomotor activity as a proxy for differences in opioid sensitivity that may be related to the pathophysiology and treatment of autism spectrum disorders. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants. [ABSTRACT FROM AUTHOR]

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D -mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D -mutant cancers, for whom effective treatments are currently lacking. [Display omitted] • HRS-4642, a KRAS G12D inhibitor, demonstrated preclinical anti-tumor effects • HRS-4642 treatment led to objective responses in patients with KRAS G12D mutation • Proteasome serves as a sensitization target for HRS-4642 to enhance anti-tumor efficacy • HRS-4642 alone or combined with carfilzomib effectively shaped the tumor microenvironment Zhou et al. report the potent preclinical and clinical anti-tumor efficacy of a KRAS G12D-specific inhibitor, HRS-4642, and its sensitizing combinational strategy with carfilzomib. This work provides novel therapeutics for solid tumor patients harboring KRAS G12D mutation, for whom effective targeted therapies are lacking. [ABSTRACT FROM AUTHOR]

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Objective: This study aimed to provide a novel evaluation of adolescent sensitization to interparental conflict (IPC), which is thought to be a critical factor in understanding multifinality in risk outcomes. Background: Adolescentsʼ threat and self‐blame appraisals of IPC are mechanisms of risk for subsequent maladjustment. Youth who are exposed to high levels of frequent, intense, and unresolved interparental conflict are thought to become more reactive to future conflicts, a process labeled sensitization. We hypothesized that adolescents with more extensive histories of IPC would exhibit sensitization operationalized as greater intraindividual responsiveness to daily IPC. Sensitization may explain why some youth are more adversely affected by IPC than others. Method: A 21‐day daily diary study was conducted with 150 adolescents (61.3% girls) in 9th and 10th grade (Mage = 14.61) who resided in two‐caregiver families. Adolescents provided global and daily reports of IPC and threat and self‐blame appraisals. Results: Results from multilevel models support a sensitization hypothesis for threat appraisals: Adolescents with greater histories of IPC exhibited stronger tendencies to appraise daily IPC as threatening. No support for sensitization was found for self‐blaming attributions. Conclusion: Findings suggest a specific underlying process to sensitization in which accumulated exposure to IPC may lead adolescents to perceive subsequent conflicts as more threatening to them or the well‐being of the family. Implications: Sensitization to IPC may involve the interaction of multiple timescales, including daily instances of conflict. Understanding historical exposure to IPC may guide interventionistsʼ efforts when working with adolescents coping with IPC. [ABSTRACT FROM AUTHOR]

[Display omitted] The behavioral sensitization, characterized by escalated behavioral responses triggered by recurrent exposure to psychostimulants, involves neurobiological mechanisms that are brain-region and cell-type specific. Enduring neuroadaptive changes have been observed in response to methamphetamine (METH) within the orbitofrontal cortex (OFC), the cell-type specific transcriptional alterations in response to METH sensitization remain understudied. In this study, we utilized Single-nucleus RNA-sequencing (snRNA-seq) to profile the gene expression changes in the OFC of a rat METH sensitization model. The analyses of differentially expressed genes (DEGs) unveiled cell-type specific transcriptional reactions associated with METH sensitization, with the most significant alterations documented in microglial cells. Bioinformatic investigations revealed that distinct functional and signaling pathways enriched in microglia-specific DEGs majorly involved in macroautophagy processes and the activation of N-methyl-D-aspartate ionotropic glutamate receptors (NMDAR). To validate the translational relevance of our findings, we analyzed our snRNA-seq data in conjunction with a transcriptomic study of individuals with opioid use disorder (OUD) and a large-scale Genome-Wide Association Studies (GWAS) from multiple externalizing phenotypes related to drug addiction. The validation analysis confirmed the consistent expression changes of key microglial DEGs in human METH addiction. Moreover, the integration with GWAS data revealed associations between addiction risk genes and the DEGs observed in specific cell types, particularly microglia and excitatory neurons. Our study highlights the importance of cell-type specific transcriptional alterations in the OFC in the context of METH sensitization and their potential translational relevance to human drug addiction. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in stress-induced sensitization (SIS) of behavioral responses, in which a particular stressor triggers a state of hyper-responsiveness to other stressors after an incubation period, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents SIS; blocking NOS-2 90 min after stress also prevents stress-induced sensitization, as does blocking calcium-activated potassium channels in this latter time window. Stress-induced sensitization is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce stress-induced sensitization. • Behavioral sensitization after alarm substance exposure • Activation of forebrain glutamate • Activation of forebrain nitric oxide • Blocking NOS-cGMP pathway prevents sensitization. [ABSTRACT FROM AUTHOR]

• Clavulanic acid inhibits methamphetamine (METH) behavioral sensitization in mice. • METH-sensitized mice display changes in glutaminase (GLS, GLS2) mRNA levels. • GLS mRNA levels in nucleus accumbens of METH-sensitized mice are decreased. • GLS2 mRNA levels in nucleus accumbens of METH-sensitized mice are increased. • Clavulanic acid normalized METH-induced decrease in GLS mRNA levels. Clavulanic acid (CLAV) is a component of Augmentin® that preserves antibiotic efficacy by inhibiting β-lactamase activity. It also enhances cellular glutamate uptake and is a potential CNS therapeutic. Because increased glutamate transmission in brain reward circuits facilitates methamphetamine (METH) locomotor activation and sensitization, we tested the hypothesis that CLAV inhibits acute and sensitized locomotor responses to METH in mice and investigated effects of CLAV on METH-induced changes in glutaminase, the major glutamate-producing enzyme in the brain. Acute METH (3 mg/kg) produced hyperlocomotion that was reduced by CLAV (20 mg/kg but not 10 mg/kg). Mice injected with METH (3 mg/kg) every other day for 9 d and then challenged with METH 27 d later displayed locomotor sensitization. CLAV (10 mg/kg), when injected 15 min before each METH injection during the 9-d exposure interval, blocked locomotor sensitization induced by METH challenge. In METH-sensitized mice, mRNA levels of both isoforms of glutaminase (GLS and GLS2) were altered in the nucleus accumbens compared to mice exposed to a single injection of METH (i.e. , GLS decreased and GLS2 increased). CLAV normalized the METH-induced GLS deficit but not the increase in GLS2. In summary, CLAV reduced acute and sensitized locomotor responses to METH and normalized the METH-induced reduction of GLS gene expression in the NAC. Given that glutaminases belong to the β-lactamase superfamily and CLAV is a β-lactamase inhibitor, our data point toward studying glutaminase as a therapeutic target of CLAV. [ABSTRACT FROM AUTHOR]

Eating a food reduces the desire to eat more of that food. General-process theories of motivation posit that eating a food also increases the motivation to eat other foods—an effect known as cross-stimulus sensitization. The authors propose that eating a food selectively sensitizes consumers to its complements rather than to all foods. Eating a food activates a goal to consume foods that consumers perceive to be well paired with the consumed food. In five experiments, imagined and actual consumption of a food sensitized participants to complementary foods but not to unrelated or semantically associated foods. These findings suggest that cross-stimulus sensitization is more specific and predictable than previously assumed. The authors identify goal activation as the process through which cross-stimulus sensitization occurs and can be instilled. [ABSTRACT FROM AUTHOR]

Disordered eating behaviors are a current public health concern since their progression can lead to the development of a full criteria eating disorder. Sensitization to repeated intake of high energy density (HED) foods is associated with excess weight gain over time, but less is known about relationships with assessments of disordered eating. Thus, this study aims to understand how disordered eating behaviors refunlate to the influence of the food environment and sensitization. 163 adolescents – 50 % female and 13.2 mean age – were followed for 24 months. Sensitization was assessed by comparing the relative reinforcing value (RRV) of HED food at baseline and after two weeks of daily intake; sensitization was defined as RRV of food after repeated intake. Study participants also completed the EDE-Q, and Power of Food Scale (PFS). We conducted multivariate general linear models to examine these associations. Sensitization status and PFS scores at baseline were positively associated with EDE-Q subscale scores cross-sectionally, but not longitudinally, at baseline and 24 months. We found that sensitization to HED food and higher susceptibility to food cues relates to increased disordered eating behaviors and both at baseline and at 24-months. These findings suggest that sensitization to repeated HED food intake and the food environment might be a risk factor for later engagement in disordered eating behaviors. Future studies should address the temporal relationships among these factors and the role that social norms around body weight and weight stigma may play in the development of these behaviors. • Disordered eating behaviors associate with the food environment and sensitization. • Sensitization to reinforcing value of food can lead to higher eating disorder risk. • The home food environment increases disordered eating behaviors onset over time. [ABSTRACT FROM AUTHOR]

Previous research has shown that exposure to nicotine and other drugs of abuse stimulate dopaminergic neurons in the mesolimbic circuit. Sustained activation of this circuit by prolonged exposure to drugs promotes locomotor sensitization. However, there are inconsistent reports about nicotine-induced locomotor sensitization when assessed among different developmental stages. We evaluated exploratory behavior on specific areas of the open field as an indicator of behavioral disinhibition and general locomotor activity as an indicator of nicotine-induced locomotor sensitization, to further explore the mechanisms underlying behavioral adaptations to nicotine exposure in animals from different developmental stages. We found that while adolescent and adult rats are equally responsive to nicotine-induced locomotor sensitization, nicotine disrupts inhibition of risk-related behavior only in adolescent rats. Together, our results suggest that chronic daily exposure to nicotine promotes potentiation of its stimulant effects on locomotor activity. In adolescents, this effect is accompanied by a decreased capacity to inhibit risk-related behaviors under the acute effect of the drug. [ABSTRACT FROM AUTHOR]

Objective: To examine the cross‐sectional association of ascending pain mechanisms, implicated in pain sensitization, and descending pain modulation with pain patterns and unpredictability of pain. Methods: The Multicenter Osteoarthritis Study is a longitudinal cohort of older adults with or at risk of knee osteoarthritis. Peripheral and central ascending pain mechanisms were assessed using quantitative sensory tests, pressure pain thresholds using a handheld pressure algometer (knee/peripheral and wrist/central), and temporal summation using weighted probes (wrist/central). Descending modulation was assessed by conditioned pain modulation using pressure pain thresholds and a forearm ischemia test. Pain patterns were characterized based on responses to the Intermittent and Constant Osteoarthritis Pain questionnaire: 1) no intermittent or constant pain, 2) intermittent pain only, 3) constant pain only, and 4) combined constant and intermittent pain. A question regarding frequency assessed unpredictable pain. We assessed the association of quantitative sensory test measures to pain patterns using regression models with generalized estimating equations. Results: There were 2,794 participants (mean age 63.9 years, body mass index 29.5 kg/m2, and 57% female). Lower pain sensitization by wrist pressure pain threshold (odds ratio [OR] 0.80 [95% confidence interval (95% CI) 0.68, 0.93]) and adequate conditioned pain modulation (OR 1.45 [95% CI 1.10, 1.92]) were associated with having constant ± intermittent pain compared with intermittent pain only. Higher pain sensitization (by pressure pain thresholds and temporal summation) was associated with a higher likelihood of unpredictable pain. Conclusion: Knee pain patterns appear to be related to peripheral ± central facilitated ascending pain mechanisms and descending modulatory mechanisms. These findings highlight the need for a broader approach to understanding pain mechanisms by symptomatic disease progression. [ABSTRACT FROM AUTHOR]

Area reduction of a circuit is a promising solution for decreasing the power consumption and the chip cost. Timing constraints should be preserved after a delay increase of resized circuit gates to guarantee proper circuit operation. Sensitization of paths should also be considered in timing analysis of circuit to prevent pessimistic resizing of circuit gates. In this work, a greedy area reduction algorithm is proposed which is pathbased and benefits well from viability analysis as the sensitization method. A proper metric based on viability conditions is presented to guide the algorithm towards selecting useful circuit nodes to be resized with acceptable performance and area reduction results. Instead of using gate slacks in resizing the candidate gates, all circuit gates are down-sized first and then the sizes of circuit gates that violate the circuit timing constraint are increased. This approach leads to considerable improvement in the complexity and performance of the proposed method. Results show that area improvement of about 88% is achievable. Comparison to a pessimistic method also reveals that on average 14.2% growth in area improvement is obtained by the presented method. [ABSTRACT FROM AUTHOR]

Prevalence of allergy to fungi is around 3-10%. The most prevalent species involved in sensitizations are Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, and Penicillium notatum. Our main objective was to estimate the prevalence of fungal sensitization and its variation across Spain. Following the ICH-GCP, we recruited 1156 patients from 15 allergy departments in Spain. Hospitals were selected by bioclimatic areas. Patients underwent a skin prick test (SPT) with fungi, pollens, house dust mites, and animal dander. Specific IgE to Alternaria alternata and Alt a 1 was assessed in patients with positive SPT to fungi. Of the 233 patients (20.2%) sensitized to at least one of the five fungi tested, 162 (69.5%) were sensitized to Alternaria alternata and Alt a 1, of whom 113 (69.8%) were children; 181 (77.7%) were also polysensitized to other allergens. Alternaria alternata and Alt a 1 sensitization was present in 25.4% of patients in the Continental area, 12.0% in the Mediterranean area, 7.0% in the Semidesertic area, and 2.3% in the Oceanic area. Prevalence of sensitization to the other tested sources was 63.8% to pollens, 60.5% to house dust mite, and 38.1% to animal dander. We concluded that the prevalence of fungal allergy is increasing. Fungi are still the fourth source of allergen sensitization. Alternaria alternata sensitization is the most prevalent in allergic patients to fungi. Alt a 1 is present in almost 90% of the patients sensitized to Alternaria alternata. [ABSTRACT FROM AUTHOR]

Objective: Allergic sensitization is one of the key components for the development of allergies. Polysensitization seems to be related to the persistence and severity of allergic diseases. Furthermore, allergic sensitization has a predictive role in the development of allergies. The aim of this study was to characterize the pattern of sensitization of atopic patients treated at different pediatric allergy referral centers in Brazil. Methods: A nation-wide transversal multicenter study collected data on patients attended in Brazil. Peripheral blood samples were collected to determine the serum levels of allergenspecific IgE. If allergen-specific IgE was higher than 0.1 kUA/L, the following specific components were quantified. Results: A total of 470 individuals were enrolled in the study. Mite sensitization was the most frequent kind in all participants. A high frequency of sensitization to furry animals and grasses featured in the respiratory allergies. Regarding components, there was a predominance of sensitization to Der p 1 and Der p 2. It has been verified that having a food allergy, atopic dermatitis, or multimorbidity are risk factors for the development of more severe allergic disease. Conclusion: Studies on the pattern of allergic sensitization to a specific population offer tools for the more effectual prevention, diagnosis, and treatment of allergic diseases. Sensitization to dust mites house was the most prevalent in the evaluated sample. High rates of sensitization to furry animals also stand out. Patients with food allergy, atopic dermatitis, or multimorbidity appear to be at greater risk for developing more severe allergic diseases. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we aimed to evaluate the level of central sensitization (CS) and its relationship with health profile, including neuropathic pain and sleep quality in Behcet's disease (BD). Method: Eighty-eight patients with BD and 60 healthy controls (HCs) were included in the study between May 2018 and February 2019. Nottingham health profile (NHP), pain DETECT, Pittsburgh sleep quality index (PSQI) questionnaires and the central sensitization inventory (CSI) were administered to all participants. To evaluate the correlations of the NHP, PSQI, and PDQ scores with the CSI score, the CSI was modified for each questionnaire. The activity of BD was determined by the Behcet's disease current activity form (BDCAF). Results: CSI scores were significantly higher in patients with BD than HCs (BD: 41.2 ±21.1 vs HCs: 20.4 ±16.9, p < .001). Clinical CS was detected in 69.3% of patients with BD and 28.3% of HCs (p < .001). Severe or extreme CS (CSI score ≥ 50) was present in 37.5% of patients with BD and 5.0% of HCs (p < .001). There were high correlations between the modified CSI scores and the NHP, PDQ and PSQI scores in patients with BD (R = 0.804; p < .001, Rho = 0.698; p < .001, and Rho = 0.734; p < .001, respectively). There was significant correlation between CSI and BDCAF scores (Rho= 0.470, p < .001). Conclusion: CS is more frequent and more severe in patients with BD than in HCs. There is a strong correlation between the severity of CS and poor health profile in patients with BD. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase reactant that mediates innate immune responses triggered by LPS. Recent studies indicated a positive correlation of circulating LBP level with chronic low-grade inflammation, a condition present in many non-communicable diseases. We determined the association of serum LBP concentration with allergic sensitization in a general pediatric population. Serum LBP was measured in a sample of children (n = 356; mean age = 9.6 ± 0.2 years) in this population-based cross-sectional study. Skin prick tests (SPTs) were performed to assess allergic sensitization to 22 common inhalant and food allergens. One hundred and seven children (30.1%) were nonsensitized, 160 (44.9%) were monosensitized, and 89 (25.0%) were polysensitized. Children who were mono- or polysensitized had a significantly higher median serum LBP level (25.5 ng/mL, inter-quartile range [IQR] 20.3–30.7) than those who were nonsensitized (20.3 ng/mL, IQR = 14.81–25.8, P < 0.0001). Multivariate logistic regression analysis with adjustment for confounders indicated that serum LBP level was positively associated with allergic sensitization overall (adjusted odds ratio [aOR] 1.041; 95% CI 1.007–1.076, P = 0.016), with sensitization to food allergens in particular (aOR 1.080, 95% CI 1.029–1.133, P = 0.002), but not with sensitization to aeroallergens (aOR 1.010, 95% CI 0.982–1.040, P = 0.467). LBP level was not associated with allergic diseases after adjustment. We suggest the possibility of sensitization to food allergens may be related to gut-derived low-grade inflammation, and large sized longitudinal investigations are needed to elucidate the relationship. [ABSTRACT FROM AUTHOR]

Introduction: Sublingual immunotherapy (SLIT) has been shown to be efficacious in patients with airway allergic diseases. However, less data have been demonstrated to show the efficacy of SLIT in patients with atopic dermatitis (AD). Aim: This study is to evaluate, in a randomized controlled study, the effect of SLIT with house dust mite (HDM) in patients with mild--moderate AD. Material and methods: AD patients aged 4 to 60 years with a Scoring Atopic Dermatitis (SCORAD) score of 7--40 and sensitization to HDM were enrolled in the study. SLIT or control treatment was given for 24 months. SCORAD, visual analog scale (VAS) score were recorded at 6, 12, 24 month, and rescue medications were required to be recorded in the diary card. A serum level of specific IgE was tested at 24-month treatment. Results: Ninety-six patients were enrolled, and forty-eight were allocated to SLIT. Thirty-nine patients in the SLIT group and thirty-eight patients in the control group completed the study. The patients in the SLIT group had significantly decreased ΔSCORAD, VAS and rescue medication score from 12 months' treatment compared with the control group (p < 0.05). At 24 months of treatment, no significant change of specific IgE (p < 0.05) was observed in both groups. No severe adverse events were reported during the treatment. Conclusions: Two years' SLIT to HDM significantly improved the clinical symptoms and reduced drug use in patients with mild--moderate AD. SLIT may represent an additional therapeutic tool for the treatment of AD in properly selected patients. [ABSTRACT FROM AUTHOR]