Premeiotic pairing of homologous chromosomes during Drosophila male meiosis.

In the early stages of meiosis, maternal and paternal chromosomes pair with their homologous partner and recombine to ensure exchange of genetic information and proper segregation. These events can vary drastically between species and between males and females of the same species. In Drosophila, in contrast to females, males do not form synaptonemal complexes (SCs), do not recombine, and have no crossing over; yet, males are able to segregate their chromosomes properly. Here, we investigated the early steps of homolog pairing in Drosophila males. We found that homolog centromeres are not paired in germline stem cells (GSCs) and become paired in the mitotic region before meiotic entry, similarly to females. Surprisingly, male germline cells express SC proteins, which localize to centromeres and promote pairing. We further found that the SUN/KASH (LINC) complex and microtubules are required for homolog pairing as in females. Chromosome movements in males, however, are much slower than in females and we demonstrate that this slow dynamic is compensated in males by having longer cell cycles. In agreement, slowing down cell cycles was sufficient to rescue pairing-defective mutants in female meiosis. Our results demonstrate that although meiosis differs significantly between males and females, sex-specific cell cycle kinetics integrate similar molecular mechanisms to achieve proper centromere pairing.

Nonylphenol releases arachidonic acid in rat Sertoli cells via activation of PKA and PLA2.

In brief: The endocrine disruptor, nonylphenol (NP) increases 20:4n-6 release in Sertoli cells via PKA/cPLA2 activation. Our data show that lipid metabolism could be a target of NP-induced abnormal reproductive outcomes. Abstract: Nonylphenol (NP), an endocrine-disrupting chemical, is an environmental contaminant, and many notorious effects on male fertility have been reported in animal models and wild-type species. Here, we evaluated the effects of NP in follicle-stimulating hormone (FSH) signal transduction pathways and lipid metabolism using an in vitro model of rat Sertoli cell (SC) primary culture. Results show that an acute (1 h) SC exposure to NP (10 µM) increased the intra- and extra-cellular concentrations of free fatty acids (FFAs), mainly arachidonic acid (20:4n-6). Phosphatidylinositol seemed to be the major phospholipid source of this 20:4n-6 release by activation of the protein kinase A (PKA)/cytoplasmic phospholipase A2 (cPLA2) pathway. NP also increased diacylglycerols (DAG) levels and the expression (mRNA) of cyclooxygenase 2 (Cox2) and prostaglandin E2 (PGE2) levels. It is noteworthy that accumulation of lipid droplets took place after 24 h NP exposition, which was prevented by both a PKA inhibitor and a PLA2 inhibitor. Like FSH, NP triggers the release of 20:4n-6, which is a substrate for PGE2 synthesis via PKA/PLA2 activation. In addition, NP induces the formation of DAG, which could be required as a cofactor of the PKC-mediated activation of the COX2 inflammatory pathway. Our findings suggest that NP alters lipid homeostasis in SCs by inducing the activation of pro-inflammatory pathways that may trigger adverse effects in testis physiology over time. Concomitantly, the SC enhances the acylation of surplus FFAs (including 20:4n-6) in neutral lipids as a protective mechanism to shield itself from lipotoxicity and pro-inflammatory signals.

When symptoms are more than reflux.

45 year-old male patient with history of heartburn and regurgitation of non-acid food in the immediate postprandial period, with no symptomatic improvement after anti-acid treatment. The patient underwent an upper endoscopy that was unremarkable. A high-resolution impedance manometry (HRIM) was performed according to Chicago Protocol 4.0, as well as an additional solid test meal, with findings of rumination syndrome (RS) (figure 1). The study was completed with a 24-hour impedance pH monitoring that showed, in the immediate postprandial period, episodes of reflux that reached the proximal sensor followed by a normal swallow (figure 2). Abdominophrenic biofeedback was started with clinical improvement and anti-acid treatment was maintained at once a day. Discussion: RS is diagnosed by a complete clinical history, using the Rome IV or DSM-5 criteria (figure 3). Due to lack of knowledge of the disease and the fact that regurgitation can be present in other conditions including gastroesophageal reflux disease and achalasia, most patients undergo multiple tests and visit several physicians before reaching the diagnosis1. The gold standard investigation for RS, in cases where there are diagnostic doubts, is HRIM with solid meal administration, that shows a sudden increase in intragastric pressure > 30 mmHg concurrent with a drop in impedance and both simultaneous lower and upper esophageal sphincter relaxation, that may or may not be followed by re-swallowing food2. Rumination episodes can appear spontaneously (type 1) or may be preceded by a reflux episode (type 2) or a supragastric belch (type 3)3. 24-hour impedance pH monitoring cannot confirm de diagnosis, but during rumination, in the majority of episodes, the refluxed material reaches the proximal esophagus2.

A Visual-Vestibular Model to Predict Motion Sickness for Linear and Angular Motion.

OBJECTIVE: This study proposed a model to predict passenger motion sickness under the presence of a visual-vestibular conflict and assessed its performance with respect to previously recorded experimental data. BACKGROUND: While several models have been shown useful to predict motion sickness under repetitive motion, improvements are still desired in terms of predicting motion sickness in realistic driving conditions. There remains a need for a model that considers angular and linear visual-vestibular motion inputs in three dimensions to improve prediction of passenger motion sickness. METHOD: The model combined the subjective vertical conflict theory and human motion perception models. The proposed model integrates visual and vestibular sensed 6 DoF motion signals in a novel architecture. RESULTS: Model prediction results were compared to motion sickness data obtained from studies conducted in motion simulators as well as on-road vehicle testing, yielding trends that are congruent with observed results in both cases. CONCLUSION: The model demonstrated the ability to predict trends in motion sickness response for conditions in which a passenger performs a task on a handheld device versus facing forward looking ahead under realistic driving conditions. However, further analysis across a larger population is necessary to better assess the model's performance. APPLICATION: The proposed model can be used as a tool to predict motion sickness under different levels of visual-vestibular conflict. This can be leveraged to design interventions capable of mitigating passenger motion sickness. Further, this model can provide insights that aid in the development of passenger experiences inside autonomous vehicles.

Practical approach to irritable bowel syndrome-diarrhea beyond low-FODMAP diet.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered defecation, usually accompanied by abdominal bloating or distension. The integrated model of bidirectional interaction between the central, autonomic, enteric nervous system, the microbiome, and the gut barrier allows a better understanding of the pathophysiology of IBS, as well as consideration of potential therapeutic strategies. IBS with predominant diarrhea (IBS-D) represents a therapeutic challenge. Dietary changes or restrictions are most commonly used by patients in an attempt at symptom control. Therefore, a number of diets, especially low-FODMAP diet, have increasingly gained interest as a therapy for IBS-D or mixed IBS. However, this kind of diet, while effective, is not exempt of problems. It is therefore necessary that other therapeutic options be considered while bearing pathophysiological mechanisms and general symptom management in mind.

Risk of COVID-19 transmission in esophageal, anorectal manometry and 24-hour impedance-pH monitoring.

BACKGROUND: the impact of the COVID-19 pandemic has led to the interruption of most manometry or impedance-pH monitoring studies. The risk of restarting activities is unknown. OBJECTIVE: assess the risk of SARS-CoV-2 virus infection, both to patients and healthcare workers, in relation to esophageal and anorectal functional tests during the pandemic without protective measures. METHOD: a questionnaire was designed to determine whether patients and healthcare workers had COVID-19, confirmed by either a test or compatible symptoms, after functional studies were performed from January until March 2020. RESULTS: the survey was answered by 263 (92.9 %) patients. Four (1.52 %) patients had confirmed COVID-19 in the two weeks after the functional test (adjusted rate 8.34 cases per 1,000 [95 % CI -0.06-16.74], OR 0.84 [95 % CI: 0.83-0.85], p < 0.001) and no patient after anorectal manometry. Another five had only compatible symptoms, for a total of nine patients (3.42 %) (adjusted rate 27.50 cases/1,000 [95 % CI: 7.27-47.74], OR 2.84 [95 % CI: 2.81-2.87]). In the total study period, 18.25 % had confirmed COVID-19 or compatible symptoms. The average number of days between the procedure and the first day of symptoms was progressively shortened (January: 56 days, February: 33 days, March: 10.5 days). Two of ten healthcare workers (20 %) had confirmed COVID-19. CONCLUSIONS: the risk of COVID-19 infection when performing functional tests is low and more related to the evolution of the pandemic rather than to the procedure itself. The small number of healthcare workers included in the study does not allow a definitive conclusion to be drawn on their risk of infection.

Obstructed defecation syndrome: a diagnostic and therapeutic challenge.

Obstructed defecation syndrome produces constipation with anal blockage and a feeling of incomplete evacuation, due to either anatomic and functional causes. This is a complex and multifactorial entity due to diverse etiological factors that may coexist in many patients. Therefore, a diagnostic approach requires structural and functional assessment. The concordance between findings of diagnostic tests is suboptimal, thus an individualized analysis is mandatory in each patient. Therapeutic strategies require the best understanding of anatomic and functional aspects. Consequently, this entity is a diagnostic and therapeutic challenge.

tRNA processing defects induce replication stress and Chk2-dependent disruption of piRNA transcription.

RNase P is a conserved endonuclease that processes the 5' trailer of tRNA precursors. We have isolated mutations in Rpp30, a subunit of RNase P, and find that these induce complete sterility in Drosophila females. Here, we show that sterility is not due to a shortage of mature tRNAs, but that atrophied ovaries result from the activation of several DNA damage checkpoint proteins, including p53, Claspin, and Chk2. Indeed, we find that tRNA processing defects lead to increased replication stress and de-repression of transposable elements in mutant ovaries. We also report that transcription of major piRNA sources collapse in mutant germ cells and that this correlates with a decrease in heterochromatic H3K9me3 marks on the corresponding piRNA-producing loci. Our data thus link tRNA processing, DNA replication, and genome defense by small RNAs. This unexpected connection reveals constraints that could shape genome organization during evolution.

Independent factors associated with the impact of gastroesophageal reflux disease on health-related quality of life.

BACKGROUND: although a number of factors have been associated with a deterioration in quality of life in gastroesophageal reflux disease, it is not known which has an independent influence. OBJECTIVE: to evaluate factors independently associated with the impact of gastroesophageal reflux disease on health-related quality of life. METHODS: a post-hoc analysis of a prospective cohort of patients diagnosed with gastroesophageal reflux disease was performed. The patients completed validated questionnaires to evaluate health-related quality of life (SF 36), gastroesophageal reflux disease (GERQ) and psychological factors (STAI and SCL 90R). RESULTS: the study included 98 patients. The univariate analysis showed that a deterioration in the physical component of the SF36 was significantly associated with female gender, educational level, age, weight loss, severity of typical symptoms, supraesophageal symptoms and monthly income. The mental component was significantly associated with alcohol consumption, epigastric pain and lower scores on the STAI and SCL90 questionnaires. The multivariate analysis showed an independent association between the physical component of the SF36 and educational level (ß = 0.29; p < 0.01), severity of symptoms (ß = -0.38; p < 0.001), body mass index (ß = -0.30; p < 0.005), state anxiety (ß = 0.28; p < 0.01), female gender (ß = -0.23; p < 0.05) and dyspepsia (ß = -0.21; p < 0.05). Associated variables within the mental component included state anxiety (ß = -0.39; p < 0.01) and depression (ß = -0.32; p < 0.05). CONCLUSIONS: the principal factors independently associated with a deterioration in health-related quality of life in patients with gastroesophageal reflux disease included the severity of typical symptoms and the presence of dyspepsia. There is also an additional impact of body mass index and the psychological component.

The lipid habitats of neurotransmitter receptors in brain.

Neurotransmitter receptors, the macromolecules specialized in decoding the chemical signals encrypted in the chemical signaling mechanism in the nervous system, occur either at the somatic cell surface of chemically excitable cells or at specialized subcellular structures, the synapses. Synapses have lipid compositions distinct from the rest of the cell membrane, suggesting that neurotransmitter receptors and their scaffolding and adaptor protein partners require specific lipid habitats for optimal operation. In this review we discuss some paradigmatic cases of neurotransmitter receptor-lipid interactions, highlighting the chemical nature of the intervening lipid species and providing examples of the receptor mechanisms affected by interaction with lipids. The focus is on the effects of cholesterol, glycerophospholipids and covalent fatty acid acylation on neurotransmitter receptors. We also briefly discuss the role of lipid phase states involving lateral heterogeneities of the host membrane known to modulate membrane transport, protein sorting and signaling. Modulation of neurotransmitter receptors by lipids occurs at multiple levels, affecting a wide span of activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, and recycling, among other important functional properties at the synapse.

Pregestational fructose-induced metabolic syndrome in Wistar rats causes sexually dimorphic behavioral changes in their offspring.

Metabolic syndrome (MetS), marked by enduring metabolic inflammation, has detrimental effects on cognitive performance and brain structure, influencing behavior. This study aimed to investigate whether maternal MetS could negatively impact the neurodevelopment and metabolism of offspring. To test this hypothesis, 2 months old female Wistar rats were subjected to a 10-week regimen of tap water alone or supplemented with 20% fructose to induce MetS. Dams were mated with healthy males to generate litters: OC (offspring from control dams) and OMetS (offspring from dams with MetS). To isolate prenatal effects, all pups were breastfed by control nurse dams, maintaining a standard diet and water ad libitum until weaning. Behavioral assessments were conducted between postnatal days (PN) 22 and 95, and metabolic parameters were analyzed post-sacrifice on PN100. Results from the elevated plus maze, the open field, and the marble burying tests revealed a heightened anxiety-like phenotype in OMetS females. The novel object recognition test showed that exclusively OMetS males had long-term memory impairment. In the reciprocal social interaction test, OMetS displayed a lower number of social interactions, with a notable increase in "socially inactive" behavior observed exclusively in females. Additionally, in the three-chamber test, social preference and social novelty indexes were found to be lower solely among OMetS females. An increase in visceral fat concomitantly with hypertriglyceridemia was the relevant postmortem metabolic finding in OMetS females. In summary, maternal MetS leads to enduring damage and adverse effects on offspring neurobehavior and metabolism, with notable sexual dimorphism.

The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

Chaperoning α7 neuronal nicotinic acetylcholine receptors.

The α7 subtype of nicotinic acetylcholine receptors (AChRs) is one of the most abundant members of the Cys-loop family of receptors present in the central nervous system. It participates in various physiological processes and has received much attention as a potential therapeutic target for a variety of pathologies. The importance of understanding the mechanisms controlling AChR assembly and cell-surface delivery lies in the fact that these two processes are key to determining the functional pool of receptors actively engaged in synaptic transmission. Here we review recent studies showing that RIC-3, a protein originally identified in the worm Caenorhabditis elegans, modulates the expression of α7 AChRs in a subtype-specific manner. Potentiation of AChR expression by post-transcriptional events is also critically assessed.

The position of the double bond in monounsaturated free fatty acids is essential for the inhibition of the nicotinic acetylcholine receptor.

Free fatty acids (FFAs) are non-competitive antagonists of the nicotinic acetylcholine receptor (AChR). Their site of action is supposedly located at the lipid-AChR interface. To elucidate the mechanism involved in this antagonism, we studied the effect that FFAs with a single double-bond at different positions (ω6, ω9, ω11 and ω13 cis-18:1) have on different AChR properties. Electrophysiological studies showed that only two FFAs (ω6 and ω9) reduced the duration of the channel open-state. The briefest component of the closed-time distribution remained unaltered, suggesting that ω6 and ω9 behave as allosteric blockers. Fluorescence resonance energy transfer studies indicated that all FFAs locate at the lipid-AChR interface, ω6 being restricted to annular sites and all others occupying non-annular sites. The perturbation of the native membrane order by FFAs was evaluated by DPH (1,6-diphenyl-1,3,5-hexatriene) and Laurdan fluorescence polarization studies, with the greatest decrease observed for ω9 and ω11. AChR conformational changes produced by FFAs present at the lipid bilayer were evaluated by fluorescence quenching studies of pyrene-labeled AChR and also using the AChR conformational-sensitive probe crystal violet. All cis-FFAs produced AChR conformational changes at the transmembrane level, but only ω9, ω11 and ω13 perturbed the resting state. Thus, the position and isomerism of the torsion angle of unsaturated FFAs are probably a key factor in terms of AChR blockage, suggesting that FFAs with a unique cis double bond at a superficial position inside the membrane directly inhibit AChR function by perturbing a potential conserved core structure for AChR gating at that level.

Nicotinic Acetylcholine Receptor Dysfunction in Addiction and in Some Neurodegenerative and Neuropsychiatric Diseases.

The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through genetic mutations or abnormal receptor function, can lead to aberrant neural circuitry that triggers disease. The review focuses on the nicotinic acetylcholine receptor (nAChR) and its role in addiction and in neurodegenerative and neuropsychiatric diseases and epilepsy. Cholinergic dysfunction is associated with inflammatory processes mainly through the involvement of α7 nAChRs expressed in brain and in peripheral immune cells. Evidence suggests that these neuroinflammatory processes trigger and aggravate pathological states. We discuss the preclinical evidence demonstrating the therapeutic potential of nAChR ligands in Alzheimer disease, Parkinson disease, schizophrenia spectrum disorders, and in autosomal dominant sleep-related hypermotor epilepsy. PubMed and Google Scholar bibliographic databases were searched with the keywords indicated below.

Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats.

Fructose is a common sweetener found in the daily diet supplemented to many processed and ultra-processed foods and beverages. Consumption of fructose-sweetened beverages has drastically increased in the last decades and is widely associated with metabolic disease, systemic pro-inflammatory status, and adverse transgenerational effects. To date, the impact of maternal fructose intake in brain function of the offspring is less explored. Therefore, the aim of this study was first, to investigate adverse effects in developmental milestones of the progeny of mothers with metabolic syndrome (MetS), induced by ad libitum consumption of a 20% fructose solution, and second to identify possible molecular changes in the nervous system of the newborns associated with maternal fructose intake. Wistar rats were randomly separated into two groups with access to water or fructose (20% w/v in water) for 10 weeks. After MetS was confirmed, dams were mated with control males and continued drinking water or fructose solution during gestation. At postnatal day (PN) 1, a subgroup of offspring of each sex was sacrificed and brains were dissected for oxidative stress and inflammatory status analysis. Changes in the developmental milestones due to maternal fructose consumption were studied (PN3-PN21) in another subgroup of offspring. Sexually dimorphic effects were found on the progeny's acquisition of neurodevelopmental milestones, in brain lipid peroxidation, neuroinflammation, and antioxidative defensive response. Our results suggest that dams' MetS, induced by fructose intake, disrupts brain redox homeostasis in female offspring and affects sensorimotor brain circuitry which may have a translational value for studying neurodevelopmental diseases.

Results of haploidentical transplant in patients with donor-specific antibodies: a survey on behalf of the Spanish Group of Hematopoietic Transplant and Cell Therapy.

Background: Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT. Methods: We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes. Results: Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI >10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI >20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF. Conclusions: Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF.

[Pleomorphic xanthoastrocytoma with intraventricular extension and anaplastic transformation in an adult patient: Case report]. / Xantoastrocitoma pleomórfico con extensión intraventricular y transformación anaplásica en paciente adulto: caso clínico.

Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade astrocytic tumour that usually occurs in the superficial cerebral hemispheres of children and young adults. Although it has a relatively favourable prognosis, malignant progression of these tumours has been described. Therefore, we present an unusual case of a 54-year-old male with a right, multicystic, parietooccipital tumour extending through the ipsilateral ventricle. After surgical resection, histological examination revealed a lesion with pleomorphic cells, cytoplasmic lipidisation, intensely eosinophilic granular bodies, well-delimitated unique nuclei and focal, positive immunoreactivity for synaptophysin, glial fibrillary acidic protein (GFAP), S-100 protein, vimentin and CD56. Once other tumours, such as giant cell metastatic carcinoma or primary lesion like subependymal giant cell astrocytoma, were ruled out, a final diagnosis of XAP was established. After a follow-up period of 9 months, the patient suffered an extensive and local tumour relapse considered inoperable, with progressive neurological deterioration and radiological findings of malignant progression. The brain biopsy procedure revealed anaplastic changes, including necrosis foci, higher mitotic activity (5×10 high-power fields) and a 10% proliferation index measured by Ki67 labelling. The present case showed intraventricular extension and a more aggressive behaviour, both uncommon in these tumours (similar to anaplastic astrocytoma or glioblastoma multiforme), thus demanding an initial, optimal surgical treatment with close clinical and radiological follow-up, due to the high potential for malignant transformation of XAPs.

Dendritic spine membrane proteome and its alterations in autistic spectrum disorder.

Dendritic spines are small protrusions stemming from the dendritic shaft that constitute the primary specialization for receiving and processing excitatory neurotransmission in brain synapses. The disruption of dendritic spine function in several neurological and neuropsychiatric diseases leads to severe information-processing deficits with impairments in neuronal connectivity and plasticity. Spine dysregulation is usually accompanied by morphological alterations to spine shape, size and/or number that may occur at early pathophysiological stages and not necessarily be reflected in clinical manifestations. Autism spectrum disorder (ASD) is one such group of diseases involving changes in neuronal connectivity and abnormal morphology of dendritic spines on postsynaptic neurons. These alterations at the subcellular level correlate with molecular changes in the spine proteome, with alterations in the copy number, topography, or in severe cases in the phenotype of the molecular components, predominantly of those proteins involved in spine recognition and adhesion, reflected in abnormally short lifetimes of the synapse and compensatory increases in synaptic connections. Since cholinergic neurotransmission participates in the regulation of cognitive function (attention, memory, learning processes, cognitive flexibility, social interactions) brain acetylcholine receptors are likely to play an important role in the dysfunctional synapses in ASD, either directly or indirectly via the modulatory functions exerted on other neurotransmitter receptor proteins and spine-resident proteins.

Interactions between the Nicotinic and Endocannabinoid Receptors at the Plasma Membrane.

Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this "effort-sharing" mechanism has evolved to optimize crosstalk, separation, or coupling, where/when appropriate. We focus on a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as a paradigmatic example.