Ordering dynamics of nonlinear voter models.

We study the ordering dynamics of nonlinear voter models with multiple states, also providing a discussion of the two-state model. The rate with which an individual adopts an opinion scales as the qth power of the number of the individual's neighbors in that state. For q>1 the dynamics favor the opinion held by the most agents. The ordering to consensus is driven by deterministic drift, and noise plays only a minor role. For q<1 the dynamics favors minority opinions, and for multistate models the ordering proceeds through a noise-driven succession of metastable states. Unlike linear multistate systems, the nonlinear model cannot be reduced to an effective two-state model. We find that the average density of active interfaces in the model with multiple opinion states does not show a single exponential decay in time for q<1, again at variance with the linear model. This highlights the special character of the conventional (linear) voter model, in which deterministic drift is absent. As part of our analysis, we develop a pair approximation for the multistate model on graphs, valid for any positive real value of q, improving on previous approximations for nonlinear two-state voter models.

Restorative effects of (+)-epicatechin in a rodent model of aging induced muscle atrophy: underlying mechanisms.

Sarcopenia is a progressive and generalized age-related skeletal muscle (SkM) disorder characterized by the accelerated loss of muscle mass (atrophy) and function. SkM atrophy is associated with increased incidence of falls, functional decline, frailty and mortality. In its early stage, SkM atrophy is associated with increased pro-inflammatory cytokine levels and proteasome-mediated protein degradation. These processes also link to the activation of atrophy associated factors and signaling pathways for which, there is a lack of approved pharmacotherapies. The objective of this study, was to characterize the capacity of the flavanol (+)-epicatechin (+Epi) to favorably modulate SkM mass and function in a rat model of aging induced sarcopenia and profile candidate mechanisms. Using 23 month old male Sprague-Dawley rats, an 8 weeks oral administration of the +Epi (1 mg per kg per day in water by gavage) was implemented while control rats only received water. SkM strength (grip), treadmill endurance, muscle mass, myofiber area, creatine kinase, lactate dehydrogenase, troponin, α-actin, tumor necrosis factor (TNF)-α and atrophy related endpoints (follistatin, myostatin, NFκB, MuRF 1, atrogin 1) were quantified in plasma and/or gastrocnemius. We also evaluated effects on insulin growth factor (IGF)-1 levels and downstream signaling (AKT/mTORC1). Treatment of aged rats with +Epi, led to significant increases in front paw grip strength, treadmill time and SkM mass vs. controls as well as beneficial changes in makers of myofiber integrity. Treatment significantly reversed adverse changes in plasma and/or SkM TNF-α, IGF-1, atrophy and protein synthesis related endpoints vs. controls. In conclusion, +Epi has the capacity to reverse sarcopenia associated detrimental changes in regulatory pathways leading to improved SkM mass and function. Given these results and its recognized safety and tolerance profile, +Epi warrants consideration for clinical trials.

[Survey to know the perception of sexual education in adolescents]. / Encuesta para conocer la percepción sobre la educación sexual en adolescentes.

OBJECTIVE: Sex education is essential for an accurate approach of sexuality in adolescents, being more effective when it is carried out at early ages. This study aimed to estimate the sexual health knowledge and the information in this regard perceived by adolescents, as well as where it came from. METHODS: A cross-sectional observational study was performed in students from two public high schools in Castilla-La Mancha who were surveyed about sexual knowledge. Comparisons were made by using the Student's t test or Mann Whitney U test, the Chi-square test (or Fisher's exact test) depending on the variables. RESULTS: 248 students were included (68.1% from Madridejos and 31.9% from Herencia) with a mean age of 14.67±1.1 years. The 47.2% were women. Only 4.8% of the participants affirm to talk about sexuality with their parents. The 56% declared had consumed pornographic content, with a mean first access age of 12.8±1 years. Significant statistically differences were found between the information received in schools and in the familiar surroundings, being alcohol and drug intake, sexually transmitted infections (STI), and contraceptive methods more frequently treated at the educational centers. A 25% of the surveyed students who reported having performed sexual relations stated not having used condom. Approximately, half of the participants did not perceive a high risk of getting STIs (HIV, herpes and chlamydia) in the case of having sex without condom. CONCLUSIONS: There is a lack of sexual knowledge in adolescents, perceiving a noteworthy heterogeneity in the offered information depending on it is received in high school or in familiar surroundings.

OBJECTIVE: La educación sexual es un pilar fundamental para un correcto enfoque de la sexualidad en los adolescentes, siendo más efectiva si se realiza en edades tempranas. El objetivo de este trabajo se fundamentó en estimar los conocimientos de salud sexual y la información percibida por los adolescentes, así como de dónde provenía. METHODS: Se realizó un estudio observacional transversal en estudiantes de dos centros educativos públicos de Castilla-La Mancha a los que se les realizó una encuesta sobre conocimientos de sexualidad. Se hicieron comparaciones mediante t de student o U de Mann Whitney, o test de Chi-cuadrado (o test exacto de Fisher), según variables. RESULTS: Se incluyeron 248 encuestados/as (68,1% de Madridejos y 31,9% de Herencia) con una edad media de 14,67±1,1 años. El 47,2% fueron mujeres. Solo un 4,8% de los/as encuestados/as afirmaron hablar sobre sexualidad con sus progenitores. Un 56% afirmaron haber consumido contenido pornográfico, siendo la edad media de la primera visualización de 12,8±1 años. Se encontraron diferencias estadísticamente significativas entre la información recibida en los centros educativos y el ámbito familiar, tratándose más frecuentemente el consumo de alcohol y drogas, las infecciones de transmisión sexual (ITS) y los métodos anticonceptivos en los centros. Un cuarto de los/as encuestados/as que afirmaron haber tenido relaciones sexuales no habían utilizado preservativo. Aproximadamente, la mitad de los/as participantes no percibieron un riesgo alto de contraer ITS (VIH, herpes y clamidia) en el caso de mantener relaciones sexuales sin preservativo. CONCLUSIONS: Existe una falta de educación sexual en los/as adolescentes, percibiendo gran heterogeneidad en los conocimientos ofrecidos en los centros educativos y el ámbito familiar.

Encuesta para conocer la percepción sobre la educación sexual en adolescentes / Survey to know the perception of sexual education in adolescents

Fundamentos: la educación sexual es un pilar fundamental para un correcto enfoque de la sexualidad en los adolescentes, siendo más efectiva si se realiza en edades tempranas. El objetivo de este trabajo se fundamentó en estimar los conocimientos de salud sexual y la información percibida por los adolescentes, así como de dónde provenía. Métodos: se realizó un estudio observacional transversal en estudiantes de dos centros educativos públicos de castilla-la mancha a los que se les realizó una encuesta sobre conocimientos de sexualidad. Se hicieron comparaciones mediante t de student o u de mann whitney, o test de chi-cuadrado (o test exacto de fisher), según variables. Resultados: se incluyeron 248 encuestados/as (68,1% de madridejos y 31,9% de herencia) con una edad media de 14,67±1,1 años. El 47,2% fueron mujeres. Solo un 4,8% de los/as encuestados/as afirmaron hablar sobre sexualidad con sus progenitores. Un 56% afirmaron haber consumido contenido pornográfico, siendo la edad media de la primera visualización de 12,8±1 años. Se encontraron diferencias estadísticamente significativas entre la información recibida en los centros educativos y el ámbito familiar, tratándose más frecuentemente el consumo de alcohol y drogas, las infecciones de transmisión sexual (its) y los métodos anticonceptivos en los centros. Un cuarto de los/as encuestados/as que afirmaron haber tenido relaciones sexuales no habían utilizado preservativo. Aproximadamente, la mitad de los/as participantes no percibieron un riesgo alto de contraer its (vih, herpes y clamidia) en el caso de mantener relaciones sexuales sin preservativo. Conclusiones: existe una falta de educación sexual en los/as adolescentes, percibiendo gran heterogeneidad en los conocimientos ofrecidos en los centros educativos y el ámbito familiar.(AU)

Background: sex education is essential for an accurate approach of sexuality in adolescents, being more effective when it is carried out at early ages. This study aimed to estimate the sexual health knowledge and the information in this regard perceived by adolescents, as well as where it came from.methods: a cross-sectional observational study was performed in students from two public high schools in castilla-la mancha who were surveyed about sexual knowledge. Comparisons were made by using the student’s t test or mann whitney u test, the chi-square test (or fisher’s exact test) depending on the variables.results: 248 students were included (68.1% from madridejos and 31.9% from herencia) with a mean age of 14.67±1.1 years. The 47.2% were women. Only 4.8% of the participants affirm to talk about sexuality with their parents. The 56% declared had consumed pornographic content, with a mean first access age of 12.8±1 years. Significant statistically differences were found between the information received in schools and in the familiar surroundings, being alcohol and drug intake, sexually transmitted infections (sti), and contraceptive methods more frequently treated at the educational centers. A 25% of the surveyed students who reported having performed sexual relations stated not having used condom. Approximately, half of the participants did not perceive a high risk of getting stis (hiv, herpes and chlamydia) in the case of having sex without condom.conclusions: there is a lack of sexual knowledge in adolescents, perceiving a noteworthy heterogeneity in the offered informa-tion depending on it is received in high school or in familiar surroundings.(AU)

Pleurotus ostreatus as a model mushroom in genetics, cell biology, and material sciences.

Pleurotus ostreatus, also known as the oyster mushroom, is a popular edible mushroom cultivated worldwide. This review aims to survey recent progress in the molecular genetics of this fungus and demonstrate its potential as a model mushroom for future research. The development of modern molecular genetic techniques and genome sequencing technologies has resulted in breakthroughs in mushroom science. With efficient transformation protocols and multiple selection markers, a powerful toolbox, including techniques such as gene knockout and genome editing, has been developed, and numerous new findings are accumulating in P. ostreatus. These include molecular mechanisms of wood component degradation, sexual development, protein secretion systems, and cell wall structure. Furthermore, these techniques enable the identification of new horizons in enzymology, biochemistry, cell biology, and material science through protein engineering, fluorescence microscopy, and molecular breeding. KEY POINTS: • Various genetic techniques are available in Pleurotus ostreatus. • P. ostreatus can be used as an alternative model mushroom in genetic analyses. • New frontiers in mushroom science are being developed using the fungus.

Metatranscriptomics sheds light on the links between the functional traits of fungal guilds and ecological processes in forest soil ecosystems.

Soil fungi belonging to different functional guilds, such as saprotrophs, pathogens, and mycorrhizal symbionts, play key roles in forest ecosystems. To date, no study has compared the actual gene expression of these guilds in different forest soils. We used metatranscriptomics to study the competition for organic resources by these fungal groups in boreal, temperate, and Mediterranean forest soils. Using a dedicated mRNA annotation pipeline combined with the JGI MycoCosm database, we compared the transcripts of these three fungal guilds, targeting enzymes involved in C- and N mobilization from plant and microbial cell walls. Genes encoding enzymes involved in the degradation of plant cell walls were expressed at a higher level in saprotrophic fungi than in ectomycorrhizal and pathogenic fungi. However, ectomycorrhizal and saprotrophic fungi showed similarly high expression levels of genes encoding enzymes involved in fungal cell wall degradation. Transcripts for N-related transporters were more highly expressed in ectomycorrhizal fungi than in other groups. We showed that ectomycorrhizal and saprotrophic fungi compete for N in soil organic matter, suggesting that their interactions could decelerate C cycling. Metatranscriptomics provides a unique tool to test controversial ecological hypotheses and to better understand the underlying ecological processes involved in soil functioning and carbon stabilization.

Systematic Review and Meta-Analysis: Prevalence of Non-Alcoholic Fatty Liver Disease and Liver Fibrosis in Patients with Inflammatory Bowel Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common concomitant condition in patients with inflammatory bowel disease (IBD). We aim to assess the magnitude of this association. METHODS: We searched MEDLINE, EMBASE and Scopus libraries for the period up to February 2023 to identify studies reporting cohorts of IBD patients in which NALFLD was evaluated. RESULTS: Eighty-nine studies were analyzed. The overall prevalence of NAFLD was 24.4% (95%CI, 19.3-29.8) in IBD, 20.2% (18.3-22.3) in Crohn's disease and 18.5% (16.4-20.8) for ulcerative colitis. Higher prevalence was found in male compared to female patients, in full papers compared to abstracts, and in cross-sectional studies compared to prospective and retrospective ones. The prevalence of NAFLD in IBD has increased in studies published from 2015 onwards: 23.2% (21.5-24.9) vs. 17.8% (13.2-22.9). Diagnostic methods for NAFLD determined prevalence figures, being highest in patients assessed by controlled attenuation parameter (38.8%; 33.1-44.7) compared to ultrasonography (28.5%; 23.1-34.2) or other methods. The overall prevalence of fibrosis was 16.7% (12.2-21.7) but varied greatly according to the measurement method. CONCLUSION: One-quarter of patients with IBD might present with NAFLD worldwide. This proportion was higher in recent studies and in those that used current diagnostic methods.

Factors influencing xerostomia and oral health-related quality of life in polymedicated patients.

OBJECTIVES: To evaluate whether the severity of xerostomia in older polymedicated patients impacts oral health-related quality of life (OHRQoL). BACKGROUND: Medication-associated xerostomia is common in older people. Xerostomia may impair OHRQoL. MATERIALS AND METHODS: This cross-sectional study included older hypertensive patients from two health centres. We assessed the severity of xerostomia and OHRQoL using the Xerostomia Inventory (XI) tool, and the Oral Health Impact Profile-14 (OHIP-14) instrument, respectively. We measured unstimulated (UWS) and stimulated (SWS) salivary flows. Univariate and multiple linear regression analyses evaluated the associations of XI and OHIP-14 and different explanatory variables. RESULTS: Of the 218 patients enrolled, 51.8% had xerostomia, and 38.1% and 27.5% suffered from UWS and SWS hyposalivation, respectively. Patients with xerostomia, UWS, and SWS hyposalivation scored significantly higher on the XI. However, only those with xerostomia or UWS hyposalivation had significantly higher OHIP-14 scores. A moderate correlation was observed between XI and OHIP-14 scores. The multiple regression model showed that factors with the greatest impact on XI were the patient's complaint of xerostomia, UWS flow rate, age and sex. However, only the XI score was significantly associated with the OHIP-14 score. CONCLUSION: Xerostomia has a negative impact on OHRQoL in older polymedicated patients, but this impact is less than in other types of xerostomia. Longitudinal studies are needed to determine whether changes in the detected explanatory variables influence XI and OHIP scores in these patients.

Transcriptome Metabolic Characterization of Tuber borchii SP1-A New Spanish Strain for In Vitro Studies of the Bianchetto Truffle.

Truffles are ascomycete hypogeous fungi belonging to the Tuberaceae family of the Pezizales order that grow in ectomycorrhizal symbiosis with tree roots, and they are known for their peculiar aromas and flavors. The axenic culture of truffle mycelium is problematic because it is not possible in many cases, and the growth rate is meager when it is possible. This limitation has prompted searching and characterizing new strains that can be handled in laboratory conditions for basic and applied studies. In this work, a new strain of Tuber borchii (strain SP1) was isolated and cultured, and its transcriptome was analyzed under different in vitro culture conditions. The results showed that the highest growth of T. borchii SP1 was obtained using maltose-enriched cultures made with soft-agar and in static submerged cultures made at 22 °C. We analyzed the transcriptome of this strain cultured in different media to establish a framework for future comparative studies, paying particular attention to the central metabolic pathways, principal secondary metabolite gene clusters, and the genes involved in producing volatile aromatic compounds (VOCs). The results showed a transcription signal for around 80% of the annotated genes. In contrast, most of the transcription effort was concentrated on a limited number of genes (20% of genes account for 80% of the transcription), and the transcription profile of the central metabolism genes was similar in the different conditions analyzed. The gene expression profile suggests that T. borchii uses fermentative rather than respiratory metabolism in these cultures, even in aerobic conditions. Finally, there was a reduced expression of genes belonging to secondary metabolite clusters, whereas there was a significative transcription of those involved in producing volatile aromatic compounds.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Peto's Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

Chemical Composition, Antioxidant Properties, and Antibacterial Activity of Essential Oils of Satureja macrostema (Moc. and Sessé ex Benth.) Briq.

Satureja macrostema is a plant that is located in various regions of Mexico and is used in a traditional way against illness. Essential oils (EOs) were obtained from leaves Satureja macrostema and the chemical composition was evaluated by gas chromatography-mass spectrometry (GC-MS). The antioxidant effect of the oil was assayed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and by Trolox Equivalent Antioxidant Capacity (TEAC). In vitro antibacterial activity against Escherichia coli and Staphylococcus aureus was determined using a broth microdilution assay and thin layer chromatography-direct bioautography (TLC-DB) to identify active antibacterial compounds. The EOs analysis showed 21 compounds, 99% terpenes, and 96% oxygenated monoterpenes, with trans-piperitone epoxide (46%), cis-piperitone epoxide (22%), and piperitenone oxide (11%) as more abundant compounds. Likewise, S. macrostema EOs showed an antioxidant activity of DPPH = 82%, with 50% free radical scavenging (IC50) = 7 mg/mL and TEAC = 0.005, an antibacterial effect against E. coli of 73% inhibition, and 81% over S. aureus at dose of 100 µL of undiluted crude oil. The TLC-DB assay showed that the most active compounds were derived from piperitone. The comparison with other studies on S. macrostema shows variability in the compounds and their abundances, which can be attributed to climatic factors and the maturity of plants with similar antioxidant and antibacterial activities.

Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species. Are there any patterns that can explain differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight and decreases with gestation time, contrary to Peto’s Paradox. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism.

Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine ß-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal ß-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.

Risk factors associated with xerostomia and reduced salivary flow in hypertensive patients.

OBJECTIVE: The aim of this study was to evaluate the risk factors associated with xerostomia and hyposalivation in a group of hypertensive patients. SUBJECTS AND METHODS: A cross-sectional study was conducted. Hypertensive patients belonged to two healthcare centers were included. Xerostomia was assessed by asking a question and using the Xerostomia Inventory. Unstimulated salivary flow was collected. Different epidemiological variables were analyzed such as age, sex, habits, diseases, drugs, and blood pressure. RESULTS: 221 individuals were included. Xerostomia was reported in 51.13% of patients. Patients with xerostomia suffered more from osteoarthritis and diaphragmatic hernia. These patients took more anticoagulants (acenocoumarol), antiarrhythmics (amiodarone), analgesics (paracetamol) and epilepsy drugs (pregabalin) and less platelet aggregation inhibitors and angiotensin II receptor blockers (losartan). Unstimulated flow was reduced in 37.56% of patients. Patients suffering hyposalivation presented more diseases such as anxiety, infectious or parasitic diseases, hepatitis C, diaphragmatic hernia, and osteoarthritis. These patients took more repaglinide, thiazides, anti-inflammatories, anti-rheumatics, glucosamine, diazepam, and selective beta-2-adrenoreceptor agonists and less combinations of candesartan and diuretics. CONCLUSIONS: Xerostomia and hyposalivation are frequent in hypertensive patients. It is advisable to take into consideration the comorbidities and the drugs they receive, since they can increase the risk of these salivary disorders.

Recurrent repeat expansions in human cancer genomes.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3-8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

Local and global ordering dynamics in multistate voter models.

We investigate the time evolution of the density of active links and of the entropy of the distribution of agents among opinions in multistate voter models with all-to-all interaction and on uncorrelated networks. Individual realizations undergo a sequence of eliminations of opinions until consensus is reached. After each elimination the population remains in a metastable state. The density of active links and the entropy in these states varies from realization to realization. Making some simple assumptions we are able to analytically calculate the average density of active links and the average entropy in each of these states. We also show that, averaged over realizations, the density of active links decays exponentially, with a timescale set by the size and geometry of the graph, but independent of the initial number of opinion states. The decay of the average entropy is exponential only at long times when there are at most two opinions left in the population. Finally, we show how metastable states comprising only a subset of opinions can be artificially engineered by introducing precisely one zealot in each of the prevailing opinions.

Sex differences in early and term placenta are conserved in adult tissues.

BACKGROUND: Pregnancy complications vary based on the fetus's genetic sex, which may, in part, be modulated by the placenta. Furthermore, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different timepoints throughout pregnancy and comparisons to adult tissues remains poorly characterized. METHODS: Here, we collect and characterize sex differences in gene expression in term placentas (≥ 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx. RESULTS: We identify 268 and 53 sex-differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex-differentially expressed genes observed in the term placentas, 31 are also sex-differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex-differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males. CONCLUSIONS: We find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full-term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes.

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system ­ which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins ­ has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells.

Usefulness of implementing the OHIP-14 questionnaire to assess the impact of xerostomia and hyposalivation on quality of life in patients with primary Sjögren's syndrome.

BACKGROUND: The aim of this study is to analyze if the results of the Oral Health Impact Profile-14 questionnaire (OHIP-14) in patients with primary Sjögren's syndrome (pSS) are correlated with salivary flow and level of xerostomia. METHODS: This observational cross-sectional study was conducted in 61 patients (60 women, one man, mean age 57.64 [13.52]) diagnosed of pSS according to the American-European Criteria (2002). After recording demographic, medical and dental data (decayed-missing-filled teeth index [DMFT]), unstimulated (UWS) and stimulated (SWS) salivary flows were collected. Subsequently, UWS flow was categorized into two groups (<0.1 ml/min and ≥0.1 ml/min) and SWS into three groups (<0.1 ml/min, 0.1-0.7 ml/min and >0.7 ml/min). Patients also filled out a visual analog scale (VAS) for xerostomia and OHIP-14 for self-reported quality of life (QoL). RESULTS: Data showed positive and significant correlation between OHIP-14 and xerostomia, based on VAS results (r = 0.52; p = 0.001). Furthermore, there was a negative correlation between UWS and OHIP-14 scores (r = -0.34; p = 0.006) and VAS for xerostomia (r = -0.22; p = 0.09). No significant correlation was found between SWS and OHIP-14 or VAS neither between DMFT and OHIP-14. When assessing the level of QoL by the UWS and SWS flow categories a significant association was found for UWS (p = 0.001) but not for SWS (p = 0.11). The OHIP-14 values were higher in the groups with lower salivary flow. The multiple linear regression to predict OHIP-14 only selected VAS for xerostomia as a statistically significant predictor. CONCLUSIONS: Increased level of xerostomia and reduced UWS flow decrease oral health-related QoL in patients with pSS.