Modulation of contextual fear acquisition and extinction by acute and chronic relaxin-3 receptor (RXFP3) activation in the rat retrosplenial cortex.

The retrosplenial cortex (RSC) plays a central role in processing contextual fear conditioning. In addition to corticocortical and thalamocortical projections, the RSC receives subcortical inputs, including a substantial projection from the nucleus incertus in the pontine tegmentum. This GABAergic projection contains the neuropeptide, relaxin-3 (RLN3), which inhibits target neurons via its Gi/o-protein-coupled receptor, RXFP3. To assess this peptidergic system role in contextual fear conditioning, we bilaterally injected the RSC of adult rats with an adeno-associated-virus (AAV), expressing the chimeric RXFP3 agonist R3/I5 or a control AAV, and subjected them to contextual fear conditioning. The R3/I5 injected rats did not display any major differences to control-injected and naïve rats but displayed a significantly delayed extinction. Subsequently, we employed acute bilateral injections of the specific RXFP3 agonist peptide, RXFP3-Analogue 2 (A2), into RSC. While the administration of A2 before each extinction trial had no impact on the extinction process, treatment with A2 before each acquisition trial resulted in delayed extinction. In related anatomical studies, we detected an enrichment of RLN3-immunoreactive nerve fibers in deep layers of the RSC, and a higher level of co-localization of RXFP3 mRNA with vesicular GABA transporter (vGAT) mRNA than with vesicular glutamate transporter-1 (vGLUT1) mRNA across the RSC, consistent with an effect of RLN3/RXFP3 signalling on the intrinsic, inhibitory circuits within the RSC. These findings suggest that contextual conditioning processes in the RSC involve, in part, RLN3 afferent modulation of local inhibitory neurons that provides a stronger memory acquisition which, in turn, retards the extinction process.

RASopathies influences on neuroanatomical variation in children.

BACKGROUND: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD). METHODS: This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. We compared structural T1-weighted images, using vertex-based analysis for cortical measures and Desikan ROI parcellation for subcortical volumes on children with RASopathies (n=91, mean age = 8.81, SD = 2.12) to sex- and age-matched TD (n=74, mean age=9.07, SD = 1.77). RESULTS: Compared to TD, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibit divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall children with NS display decreased volumes in striatal and thalamic structures and children with NF1 display increased volumes in the hippocampus, amygdala, and thalamus. CONCLUSIONS: Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

Some key parameters in contextual fear conditioning and extinction in adult rats.

Contextual fear conditioning is a behavioral paradigm used to assess hippocampal-dependent memory in experimental animals. Perception of the context depends on activation of a distinct population of neurons in the hippocampus and in hippocampal-related areas that process discrete aspects of context perception. In the absence of any putatively associated cue, the context becomes the salient element that may warn of an upcoming aversive event; and in particular conditions, animals generalize this warning to any new or similar context. In this study we evaluated the effects of the number of sessions, the number of unconditioned stimuli per acquisition session and the distribution of extinction sessions to assess fear acquisition and extinction and determine under which conditions generalization occurred in adult, male rats. We observed that the organization and spacing of sessions were relevant factors in the acquisition and extinction of contextual fear memories. Extinction occurred with significantly greater robustness when sessions were spread over two days. Furthermore, results indicated that exposure to a single 0.3 mA, 0.5 s footshock in two different sessions could produce context-specific fear, while more acquisition sessions or more footshocks within a single session produced a generalization of the fear response to a new context. Notably, when generalization occurred, successive re-exposure to the generalized context produced extinction in a similar way to the paired exposure. Together, the present findings identify clear procedural and behavioral parameters amenable to neural systems analysis of three clinically relevant outcomes of contextual fear conditioning, i.e., memory acquisition, storage and extinction.

Making Visible the Myths About Cyber-Sexual Violence Against Women: An Analysis of Social Reactions Toward Victims on Twitter.

Cyber-sexual violence is a prevalent and harmful form of aggression committed against women, yet little attention has been paid to the attitudes about cyber-sexual violence. This research therefore aimed to explore the negative attitudes or myths that serve to justify, minimize, and deny the experiences of cyber-sexual violence disclosed by women on Twitter. Using a thematic analysis, we analyzed 4,048 replies to 18 experiences reported on Twitter around the time of the International Day for the Elimination of Violence against Women. After the data were cleaned and coded, the results revealed 18 myths about cyber-sexual violence, grouped into four main themes: (1) minimization/conceptualization, (2) victim blaming, (3) factors related to the diffusion context, and (4) exonerating the perpetrator's responsibility. This study constitutes the first attempt to analyze the myths surrounding cyber-sexual violence on Twitter, including content areas not yet addressed in the literature, such as contextual factors. Strikingly, most of the analyzed reactions appeared to deny and downplay the importance of sexually aggressive behaviors perpetrated against women online, suggesting that these beliefs could influence the underreporting of cyber-sexual violence. Based on these data, it was concluded that while Twitter can serve as a useful "loudspeaker" for victims, it is also a mechanism by which myths about cyber-sexual violence can be supported and disseminated. Finally, it highlights the importance to consider the influence of online cultural frame on the social perception of cyber-sexual violence and point out the specific beliefs that educators, researches and psychologist could work though psychoeducational programs.

Identification of a HIV-1 circulating BF1 recombinant form (CRF75_BF1) of Brazilian origin that also circulates in Southwestern Europe.

Introduction: The high recombinogenic potential of HIV-1 has resulted in the generation of countless unique recombinant forms (URFs) and around 120 reported circulating recombinant forms (CRFs). Here we identify through analyses of near full-length genomes (NFLG) a new HIV-1 CRF derived from subtypes B and F1. Methods: HIV-1 protease-reverse transcriptase (Pr-RT) sequences were obtained by RT-PCR amplification from plasma RNA. Near full-length genome sequences were obtained after amplification by RT-PCR in 5 overlapping fragments. Phylogenetic sequence analyses were performed via maximum likelihood. Mosaic structures were analyzed by bootscanning and phylogenetic analyses of genome segments. Temporal and geographical estimations of clade emergence were performed with a Bayesian coalescent method. Results: Through phylogenetic analyses of HIV-1 Pr-RT sequences obtained by us from samples collected in Spain and downloaded from databases, we identified a BF1 recombinant cluster segregating from previously reported CRFs comprising 52 viruses, most from Brazil (n = 26), Spain (n = 11), and Italy (n = 9). The analyses of NFLG genomes of 4 viruses of the cluster, 2 from Spain and 2 from Italy, allowed to identify a new CRF, designated CRF75_BF1, which exhibits a complex mosaic structure with 20 breakpoints. All 4 patients harboring CRF75_BF1 viruses studied by us had CD4+ T-cell lymphocyte counts below 220/mm3 less than one year after diagnosis, a proportion significantly higher (p = 0.0074) than the 29% found in other patients studied in Spain by us during the same period. The origin of the clade comprising CRF75_BF1 and related viruses was estimated around 1984 in Brazil, with subsequent introduction of CRF75_BF1 in Italy around 1992, and migration from Italy to Spain around 1999. Conclusion: A new HIV-1 CRF, designated CRF75_BF1, has been identified. CRF75_BF1 is the 6th CRF of South American origin initially identified in Western Europe, reflecting the increasing relationship of South American and European HIV-1 epidemics. The finding of low CD4+ T-cell lymphocyte counts early after diagnosis in patients harboring CRF75_BF1 viruses warrants further investigation on the virulence of this variant.

Efficacy of Insulin Titration Driven by SMS in Improving Glycemic Control in People with Type 2 Diabetes.

AIM: To evaluate the efficacy of the self-management of insulin titration based on information received by the Short Message Service (SMS). METHODS: A case-control study including 59 subjects in each arm with 16 weeks of follow-up was performed. The inclusion criteria were: (1) Subjects with type 2 diabetes (T2D) under basal insulin treatment; (2) Suboptimal glycemic control: HbA1c ≥ 7.5% and fasting capillary blood glucose (FCBG) > 140 mg/dL (>3 times per week). Subjects were invited to use an insulin titration service based on SMS feedback aimed at optimizing glycemic control depending on fasting blood glucose levels. Psychological aspects were evaluated in the interventional group by means of validated questionnaires (DDS, HADS and SF-12). RESULTS: The intervention group achieved a lower mean FCBG (126 mg/dL ± 34 vs. 149 mg/dL ± 46, p = 0.001) and lower HbA1c (7.5% ± 1.3 vs. 7.9% ± 0.9, p = 0.021) than the control group. In addition, the intervention group showed a significant improvement in psychological aspects related to Emotional Burden (p = 0.031), Regimen Distress (p < 0.001), Depression (p = 0.049) and Mental Health (p < 0.01). CONCLUSIONS: The SMS-guided titration was effective in terms of improving glucometric parameters in comparison with the standard of care and improved significant psychological aspects-mainly, the stress associated with insulin treatment.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics.

Peptides and peptidomimetics are attractive drug candidates because of their high target specificity and low-toxicity profiles. Developing peptidomimetics using hydrocarbon (HC)-stapling or other stapling strategies has gained momentum because of their high stability and resistance to proteases; however, they have limitations. Here, we take advantage of the α-methyl group and an aromatic phenyl ring in a unique unnatural amino acid, α-methyl-l-phenylalanine (αF), and propose a novel, noncovalent stapling strategy to stabilize peptides. We utilized this strategy to create an α-helical B-chain mimetic of a complex insulin-like peptide, human relaxin-3 (H3 relaxin). Our comprehensive data set (in vitro, ex vivo, and in vivo) confirmed that the new high-yielding B-chain mimetic, H3B10-27(13/17αF), is remarkably stable in serum and fully mimics the biological function of H3 relaxin. H3B10-27(13/17αF) is an excellent scaffold for further development as a drug lead and an important tool to decipher the physiological functions of the neuropeptide G protein-coupled receptor, RXFP3.

Postnatal development of the relaxin-3 innervation of the rat medial septum.

Introduction: The septal area provides a rich innervation to the hippocampus regulating hippocampal excitability to different behavioral states and modulating theta rhythmogenesis. However, little is known about the neurodevelopmental consequences of its alterations during postnatal development. The activity of the septohippocampal system is driven and/or modulated by ascending inputs, including those arising from the nucleus incertus (NI), many of which contain the neuropeptide, relaxin-3 (RLN3). Methods: We examined at the molecular and cellular level the ontogeny of RLN3 innervation of the septal area in postnatal rat brains. Results: Up until P13-15 there were only scattered fibers in the septal area, but a dense plexus had appeared by P17 that was extended and consolidated throughout the septal complex by P20. There was a decrease in the level of colocalization of RLN3 and synaptophysin between P15 and P20 that was reversed between P20 and adulthood. Biotinylated 3-kD dextran amine injections into the septum, revealed retrograde labeling present in the brainstem at P10-P13, but a decrease in anterograde fibers in the NI between P10-20. Simultaneously, a differentiation process began during P10-17, resulting in fewer NI neurons double-labeled for serotonin and RLN3. Discussion: The onset of the RLN3 innervation of the septum complex between P17-20 is correlated with the onset of hippocampal theta rhythm and several learning processes associated with hippocampal function. Together, these data highlight the relevance and need for further analysis of this stage for normal and pathological septohippocampal development.

Nucleus incertus projections to rat medial septum and entorhinal cortex: rare collateralization and septal-gating of temporal lobe theta rhythm activity.

Nucleus incertus (NI) neurons in the pontine tegmentum give rise to ascending forebrain projections and express the neuropeptide relaxin-3 (RLN3) which acts via the relaxin-family peptide 3 receptor (RXFP3). Activity in the hippocampus and entorhinal cortex can be driven from the medial septum (MS), and the NI projects to all these centers, where a prominent pattern of activity is theta rhythm, which is related to spatial memory processing. Therefore, we examined the degree of collateralization of NI projections to the MS and the medial temporal lobe (MTL), comprising medial and lateral entorhinal cortex (MEnt, LEnt) and dentate gyrus (DG), and the ability of the MS to drive entorhinal theta in the adult rat. We injected fluorogold and cholera toxin-B into the MS septum and either MEnt, LEnt or DG, to determine the percentage of retrogradely labeled neurons in the NI projecting to both or single targets, and the relative proportion of these neurons that were RLN3-positive ( +). The projection to the MS was threefold stronger than that to the MTL. Moreover, a majority of NI neurons projected independently to either MS or the MTL. However, RLN3 + neurons collateralize significantly more than RLN3-negative (-) neurons. In in vivo studies, electrical stimulation of the NI induced theta activity in the MS and the entorhinal cortex, which was impaired by intraseptal infusion of an RXFP3 antagonist, R3(BΔ23-27)R/I5, particularly at ~ 20 min post-injection. These findings suggest that the MS plays an important relay function in the NI-induced generation of theta within the entorhinal cortex.

Switching from treatment with sensor augmented pump to hybrid closed loop system in type 1 diabetes: Impact on glycemic control and neuropsychological tests in the real world.

AIMS: The aim of this study is to assess in the real world the impact of initiating hybrid closed loop (HCL) on glycemic control and quality of life in patients using sensor-augmented pump (SAP). METHODS: In this prospective study, patients using SAP changed to an HCL system in a specialized hospital. HCL devices used were Medtronic 780G®, Tandem Control-IQ® and Diabeloop® system. Glucometric data and hypoglycemia and neuropsychological tests were assessed at baseline and 3 months after initiating HCL. RESULTS: A total of 66 consecutive patients were included (74% women, mean age 44 ± 11 years, diabetes duration 27.2 ± 11 years). Significant improvements were observed in coefficient of variation (from 35.6% to 33.1%), time in range (from 62.2 % to 73.8%), time above 180 mg/dl (from 26.9% to 18%), time below 70 mg/dl (from 3.3% to 2.1%) and time below 55 mg/dl (from 0.7% to 0.3%). In addition, significant improvements were observed in fear of hypoglycemia and grade of distress associated to treatment and to interpersonal sphere. CONCLUSIONS: Switching from SAP to HCL system improves time in range and reduces time in hypoglycemia and glycemic variability at 3 months. These changes are accompanied by significant reduction of neuropsychological burden related to diabetes.

Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS): Study design and harmonization.

INTRODUCTION: Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS) is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in Latin America (LA). Our aim is to present the study design and discuss the strategies used for multicultural harmonization. METHODS: This 1-year RCT (working on a 1-year extension) investigates the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention, primarily on cognitive function. An external harmonization process was carried out to follow the FINGER model, and an internal harmonization was performed to ensure this study was feasible and comparable across the 12 participating LA countries. RESULTS: Currently, 1549 participants have been screened, and 815 randomized. Participants are ethnically diverse (56% are Nestizo) and have high cardiovascular risk (39% have metabolic syndrome). DISCUSSION: LatAm-FINGERS overcame a significant challenge to combine the region's diversity into a multi-domain risk reduction intervention feasible across LA while preserving the original FINGER design.

Bio-Based Adsorption as Ecofriendly Method for Wastewater Decontamination: A Review.

Intense human activities have for years contributed to the pollution of the environment by many dangerous pollutants such as heavy metals, pesticides, or polycyclic aromatic hydrocarbons. There are many conventional methods used to control pollution, with practical and/or financial drawbacks. Therefore, in recent years, an innovative, easy-to-implement and inexpensive adsorption method has been developed to recover waste and clean up water from micropollutants. Firstly, this article aims to summarize the issues related to water remediation and to understand the advantages and disadvantages of the methods classically used to purify water. In particular, this review aims to provide a recent update of the bio-based adsorbents and their use. Differently from the majority of the reviews related to wastewater treatment, in this article several classes of pollutants are considered. Then, a discussion about the adsorption process and interactions involved is provided. Finally, perspectives are suggested about the future work to be done in this field.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: 1. How Ras-MAPK activating variants of PTPN11 / SOS1 protein-coding genes affect brain anatomy. 2. The relationship between PTPN11 gene expression levels and brain anatomy, and 3. The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 ( n = 30) or SOS1 ( n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA) and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area ( d 's<-0.8), and extensive effects on SA ( d 's>|0.8|) and CT ( d 's>|0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Sex differences in markers of oxidation and inflammation. Implications for ageing.

Sexual dimorphism is a key factor to consider in the ageing process given the impact that it has on life expectancy. The oxidative-inflammatory theory of ageing states that the ageing process is the result of the establishment of oxidative stress which, due to the interplay of the immune system, translates into inflammatory stress, and that both processes are responsible for the damage and loss of function of an organism. We show that there are relevant gender differences in a number of oxidative and inflammatory markers and propose that they may account for the differential lifespan between sexes, given that males display, in general, higher oxidation and basal inflammation. In addition, we explain the significant role of circulating cell-free DNA as a marker of oxidative damage and an inductor of inflammation, connecting both processes and having the potential to become a useful ageing marker. Finally, we discuss how oxidative and inflammatory changes take place differentially with ageing in each sex, which could also have an impact on the sex-differential lifespan. Further research including sex as an essential variable is needed to understand the grounds of sex differences in ageing and to better comprehend ageing itself.

Sex differences in neuroimmunoendocrine communication. Involvement on longevity.

Endocrine, nervous, and immune systems work coordinately to maintain the global homeostasis of the organism. They show sex differences in their functions that, in turn, contribute to sex differences beyond reproductive function. Females display a better control of the energetic metabolism and improved neuroprotection and have more antioxidant defenses and a better inflammatory status than males, which is associated with a more robust immune response than that of males. These differences are present from the early stages of life, being more relevant in adulthood and influencing the aging trajectory in each sex and may contribute to the different life lifespan between sexes.

Preferential looking to eyes versus mouth in early infancy: heritability and link to concurrent and later development.

BACKGROUND: From birth, infants orient preferentially to faces, and when looking at the face, they attend primarily to eyes and mouth. These areas convey different types of information, and earlier research suggests that genetic factors influence the preference for one or the other in young children. METHODS: In a sample of 535 5-month-old infant twins, we assessed eye (relative to mouth) preference in early infancy, i.e., before neural systems for social communication and language are fully developed. We investigated the contribution of genetic and environmental factors to the preference for looking at eyes, and the association with concurrent traits and follow-up measures. RESULTS: Eye preference was independent from all other concurrent traits measured, and had a moderate-to-high contribution from genetic influences (A = 0.57; 95% CI: 0.45, 0.66). Preference for eyes at 5 months was associated with higher parent ratings of receptive vocabulary at 14 months. No statistically significant association with later autistic traits was found. Preference for eyes was strikingly stable across different stimulus types (e.g., dynamic vs. still), suggesting that infants' preference at this age does not reflect sensitivity to low-level visual cues. CONCLUSIONS: These results suggest that individual differences in infants' preferential looking to eyes versus mouth to a substantial degree reflect genetic variation. The findings provide new leads on both the perceptual basis and the developmental consequences of these attentional biases.

Brain structure in autoimmune Addison's disease.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison's disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19-43 years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.