GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet.

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

Assessing the Match Physical Responses of International Referees for Footballers with Cerebral Palsy: A Tournaments and Halves Comparative Analysis.

Similar to conventional football, the modality dedicated to footballers with cerebral palsy (CP) requires referees who cope with the physical demands imposed during competitive matches to apply the rules of the game. While a significant body of research has explored the physical demands on referees in mainstream football, there is a noticeable lack of data regarding CP football. This study aimed to examine the physical response of international referees participating in different levels of world competitions for footballers with CP. Thirteen international referees, who officiated 49 matches in the men's 2022 World Cup (1st to 15th ranked teams) and 2022 World Championships (16th to 30th ranked teams), participated in this study. A cross-sectional design was used to determine the physical responses and compare the 1st and 2nd halves and the performance in the different tournaments, recording physical variables throughout the matches. Significant higher physical responses were observed in the World Cup in comparison to the World Championship. Overall, high-level tournaments have been shown to elicit more intense physical responses from referees officiating CP football matches compared to lower-level tournaments. For the World Cup, a significantly higher number of accelerations and decelerations were registered in the 1st half compared to the 2nd half. This information may be useful for the strength and conditioning coaches of referees to plan weekly training sessions more specifically and adjust the periodical training load and post-match recovery protocols.

Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation.

The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus-independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic-pituitary-adrenal neuroendocrine axis.

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet.

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions, therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here we investigated the effects of a long-term (12 month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild type (WT) Wistar male and female rats. Our main findings were that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increased thermogenesis and brain glucose uptake in male rats and modified the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. RNA-sequencing was also used to show that GHSR-KO rats had upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuated ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating was reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

Chlorpromazine, an Inverse Agonist of D1R-Like, Differentially Targets Voltage-Gated Calcium Channel (CaV) Subtypes in mPFC Neurons.

The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal CaV conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV2.1, CaV2.3, or CaV3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.

Variation of the acoustic parameters: f0, jitter, shimmer and alpha ratio in relation with different background noise levels.

BACKGROUND AND OBJECTIVES: Research involving acoustic analysis does not always consider the level of background noise in the room where the recording process is going to be carried out, or if they do, the maximum value of background noise used varies from author to author. The objective of this research is to establish if the parameters: f0, Jitter, Shimmer and Alpha ratio vary in relation to different levels of background noise in the room where the recording process is carried out and to establish a maximum value of this. MATERIALS AND METHODS: The Praat program was used to get the average value of the parameters: f0, Jitter, Shimmer and Alpha ratio from a voice sample of 33 subjects inside an Audiometric booth whose background noise level was 28,1 dB(A). A statistical comparison was made between the average value of each parameter as the background noise increased in relation to the average values ​​obtained with the baseline background noise of the cabin for each parameter. RESULTS: The f0 and Alpha ratio parameters show reliable values ​​up to a background noise level of 47,7 dB(A), while the Jitter and Shimmer parameters do so up to a background noise level of 43,8 dB(A). CONCLUSIONS: Considering that the acoustic parameters are all obtained from the same recording, we can point out that the recommended maximum background noise level in the room where the recordings are made should not exceed 43,8 dB(A).

Percepción de la calidad de vida en para-deportistas y no deportistas chilenos con lesión cerebral / Perception of quality of life in chilean para-athletes and non-athletes with brain injury

Cornejo, M. I., Henríquez, M., Herrera, F., Muñoz, F., Bernardes, N., Auricchio, J. R., y Castelli-Correia de Campos, L. F. (2022). Percepción de la calidad de vida en para- deportistas y no deportistas chilenos con lesión cerebral. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 20 (2), 1-18. La calidad de vida (CV) y la actividad física son aspectos relevantes en la salud de la población, y esta última con un impacto positivo en las personas con discapacidad. Debido a esto, los objetivos de este estudio fueron comparar las características e identificar la asociación entre los dominios de la percepción de la CV entre un grupo de personas con lesión cerebral que practican fútbol, para-deportistas (PD) y personas con lesión cerebral no para-deportistas (NPD), además determinar si existen diferencias en la percepción de la CV según las diferentes clases deportivas (FT1, FT2 y FT3). El estudio se desarrolló en Chile, donde se aplicó el cuestionario WHOQOL-BREF para determinar la CV de los participantes. Los resultados identificaron una relación positiva y significativa entre los distintos dominios de la CV (p < .001, r = .44 - .67). Además, se observó una mejor percepción de la CV en los PD (p < .001, TE = 1.18, grande) en comparación con lo reportado por el grupo NPD. Por otro lado, no se obtuvieron diferencias significativas entre los dominios para las diferentes clases deportivas en el grupo PD. Estos datos refuerzan la idea de que la práctica deportiva influye en la participación social y en la percepción de la CV en PD con lesión cerebral. El desarrollo conjunto de los factores asociados entre la salud y el bienestar socioemocional podrían colaborar con la consolidación de la práctica deportiva y de actividad física, los cuales, a su vez son beneficiosos para las personas con discapacidad tal como lo plantean los objetivos del desarrollo sostenible en su agenda de trabajo provista al año 2030.

Cornejo, M. I., Henríquez, M., Herrera, F., Muñoz, F., Bernardes, N., Auricchio, J. R., y Castelli-Correia de Campos, L. F. (2022). Perception of quality of life in chilean para-athletes and non-athletes with brain injury. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 20 (2), 1-16. Quality of life (QOL) and physical activity are relevant aspects in the health of the population, and the latter has a positive impact on people with disabilities. For this reason, the objectives of this study were to compare the characteristics and identify the association between the domains of QOL perception between a group of people with brain injury who practice soccer, para-athletes (PD) and non-para-athletes with brain injury (NPD), as well as to determine if there are differences in the perception of QOL according to the different sports classes (FT1, FT2 and FT3). The study was carried out in Chile, where the WHOQOL-BREF questionnaire was applied to determine the QOL of participants. The results identified a positive and significant relationship between the different domains of QOL (p < .001, r = .44 - .67). In addition, a better perception of QoL was observed in the PDs (p < .001, TE = 1.18, large) compared to that reported by the NPD group. On the other hand, no significant differences between domains were obtained for the different sport classes in the PD group. These data reinforce the idea that sport practice influences social participation and perception of QoL in PD with brain injury. The joint development of the factors associated between health and socioemotional well-being could collaborate in the consolidation of sports practice and physical activity, which, in turn, are beneficial for people with disabilities, as proposed by the Sustainable Development Goals in their work agenda foreseen for the year 2030.

Cornejo, M. I., Henríquez, M., Herrera, F., Muñoz, F., Bernardes, N., Auricchio, J. R., y Castelli-Correia de Campos, L. F. (2022). Percepção da qualidade de vida em paratletas e não-atletas chilenos com lesões cerebrais. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 20 (2), 1-16. Qualidade de vida (QV) e atividade física são aspectos relevantes da saúde da população, tendo esta última um impacto positivo sobre as pessoas com deficiências. Portanto, os objetivos deste estudo foram comparar as características e identificar a associação entre os domínios da percepção de QV entre um grupo de pessoas com lesões cerebrais que praticam futebol, paratletas (P) e pessoas com lesões cerebrais não paratletas (NP), e determinar se existem diferenças na percepção de QV de acordo com as diferentes classes esportivas (FT1, FT2 e FT3). O estudo foi realizado no Chile, onde o questionário WHOQOL-BREF foi utilizado para determinar o QV dos participantes. Os resultados identificaram uma relação positiva e significativa entre os diferentes domínios da QV (p < 0,001, r = 0,44 - 0,67). Além disso, uma melhor percepção de QV foi observada nos Ps (p < 0,001, TE = 1,18, grande) em comparação com a relatada pelo grupo NP. Por outro lado, não foram obtidas diferenças significativas entre os domínios para as diferentes classes esportivas do grupo P. Estes dados reforçam a ideia de que a prática esportiva influencia a participação social e a percepção da QV nos P com lesão cerebral. O desenvolvimento conjunto de fatores associados à saúde e ao bem-estar socioemocional poderia contribuir para a consolidação da prática do esporte e da atividade física, que, por sua vez, são benéficos para as pessoas com deficiência, conforme estabelecido nas Metas de Desenvolvimento Sustentável em sua agenda para 2030.

Sialolithiasis: mineralogical composition, crystalline structure, calculus site, and epidemiological features.

The purpose of this paper was to describe the characteristics of salivary calculi and their relationship to epidemiological factors, through a cross-sectional study. We analysed 100 calculi obtained in 2017-2021. Patient data including age, time since onset of symptoms, gland involved, and site of location in the salivary system were studied. The calculi were studied to determine their morphological features using scanning electron microscopy and energy dispersive plain radiographic analysis. Most of the calculi had formed in the submandibular gland (SG) (82%). The mean age of patients at onset was 45.83 years; patients presenting parotid gland (PG) stones were somewhat older (p = 0.031). The mean time since the onset of symptoms was longer in PG calculi (p = 0.038). The most common lithiasis site was the main duct (74%), followed by the hilum (22%). Hilar stones were the largest (p < 0.05) and heaviest (p = 0.028). Octacalcium phosphate (OCP) was the most common crystalline phase (Cp) founded, followed by hydroxyapatite (HA) and whitlockite (WH). Specifically, OCP had a higher presence in PG calculi (p = 0.029) and WH was the most common phase in SG calculi (p = 0.017). The most prevalent site of lithiasis was the main duct, and the largest and heaviest calculi were found in the SG. PG stones were associated with a longer history of symptoms and older age. OCP was the most frequent Cp of the calculi studied, and the main Cp in PG stones. WH was the predominant Cp in SG stones. The Cp of the calculi was not influenced by location, patient age, or time of symptoms.

Design and characterization of a triazole-based growth hormone secretagogue receptor modulator inhibiting the glucoregulatory and feeding actions of ghrelin.

The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that regulates essential physiological functions. In particular, activation of GHSR in response to its endogenous agonist ghrelin promotes food intake and blood glucose increase. Therefore, compounds aimed at blocking GHSR signaling constitute potential options against obesity-related metabolic disorders. We have previously developed potent ligands of GHSR based on a triazole scaffold. Here, we report a new 3,4,5-trisubstituted 1,2,4-triazole compound, named JMV 6616, that potently blocks GHSR activity in vitro and in vivo. Specifically, in HEK293T cells JMV 6616 behaves as an inverse agonist since it binds to GHSR and inhibits its ghrelin-independent signaling. Accordingly, using purified labeled GHSR assembled into lipid nanodiscs we found that JMV 6616 decreases GHSR-catalyzed G protein activation and stabilizes an inactive receptor conformation. Importantly, JMV 6616 also acts on native GHSR since it blocks the insulinostatic effect of ghrelin in pancreatic islets. In mice, JMV 6616 inhibits blood glucose-raising effects of ghrelin treatment and the orexigenic actions of acute ghrelin administration. Together, our data suggest that this triazole-derived modulator of GHSR holds promise to mitigate several pathological features associated with eating and metabolic disorders.

The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond.

Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.

Neuromuscular Fatigue in Cerebral Palsy Football Players after a Competitive Match According to Sport Classification and Playing Position.

This study aimed to determine the rated perceived exertion (RPE) and match load (RPE-ML) to compare pre-post-match vertical jump (VJ) capacity according to cerebral palsy (CP) players' sport classes (i.e., FT1−FT3) and playing positions and to explore whether the neuromuscular performance variation is associated with the internal load of para-footballers with CP. Fifty-six male para-footballers performed two VJ tests before and immediately after a competitive CP football match, followed by measurements of the players' RPE and RPE-ML. There were no significant differences (p > 0.05) in the pairwise comparisons for RPE and RPE-ML according to sport classes and playing position. A significant reduction in the VJ performance was found for each player sport class and playing position in squat jump (SJ) (p < 0.01; 0.24 < dg < 0.58) and countermovement jump (CMJ) (p < 0.05; 0.22 < dg < 0.45). Regarding the pairwise comparisons, players with the minimal impairment criteria (FT3) obtained higher deficit scores during SJ than those belonging to the FT1 and FT2 (p = 0.003; 1.00 < dg < 1.56). Defenders experienced the lowest performance compared to midfielders and attackers in SJ performance (p = 0.027; 0.94 < dg < 1.28). Significant correlations were obtained between ΔSJ or ΔCMJ and RPE or RPE-ML (r = −0.58 to −0.75; p < 0.001). These findings provide novel information supporting the notion that fatigue induced after a competitive match causes notable impairments in VJ performance differentiated according to sport class and playing position in para-footballers with CP.

Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice.

Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.

Comparison of the Acoustic Parameters Obtained With Different Smartphones and a Professional Microphone.

Smartphones allow good quality recordings; however, it cannot be claimed that the acoustic parameters obtained from them are comparable to those obtained with a professional microphone. The objective of this study is to establish whether there are significant differences when comparing the values ​​of six acoustic parameters obtained from recordings using four smartphones and a professional microphone. The Praat programme was used to obtain the acoustic parameters: f0, Jitter, Shimmer, HNR, Alpha Ratio and L1 - L0 of the recording of a sustained vowel /a/ using iPhone SE, iPhone 6, Samsung S8, Huawei Y7 and the Behringer ECM 8000 microphone. The sample was made up of 26 men and 26 women, from 18 to 26 years old without declared voice pathology. The repeated sample ANOVA test was used to compare the values. All the equipment show reproducibility between consecutive repeated measurements. The parameters f0 and Jitter were the only ones that did not show significant differences between the smartphones and the professional microphone. None of the smartphones studied can replace the professional microphone in voice recording for the evaluation of the six parameters analysed, except for f0 and Jitter.

ACE2 internalization induced by a SARS-CoV-2 recombinant protein is modulated by angiotensin II type 1 and bradykinin 2 receptors.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system (RAS) recently identified as the membrane receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we aim to study whether two receptors from RAS, the angiotensin receptor type 1 (AT1R) and the bradykinin 2 receptor (B2R) modulate ACE2 internalization induced by a recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein. Also, we investigated the impact of ACE2 coexpression on AT1R and B2R functionality. MATERIALS AND METHODS: To study ACE2 internalization, we assessed the distribution of green fluorescent protein (GFP) signal in HEK293T cells coexpressing GFP-tagged ACE2 and AT1R, or B2R, or AT1R plus B2R in presence of RBD alone or in combination with AT1R or B2R ligands. To estimate ACE2 internalization, we classified GFP signal distribution as plasma membrane uniform GFP (PMU-GFP), plasma membrane clustered GFP (PMC-GFP) or internalized GFP and calculated its relative frequency. Additionally, we investigated the effect of ACE2 coexpression on AT1R and B2R inhibitory action on voltage-gated calcium channels (CaV2.2) currents by patch-clamp technique. KEY FINDINGS: RBD induced ACE2-GFP internalization in a time-dependent manner. RBD-induced ACE2-GFP internalization was increased by angiotensin II and reduced by telmisartan in cells coexpressing AT1R. RBD-induced ACE2-GFP internalization was strongly inhibited by B2R co-expression. This effect was mildly modified by bradykinin and rescued by angiotensin II in presence of AT1R. ACE2 coexpression impacted on B2R- and AT1R-mediated inhibition of CaV2.2 currents. SIGNIFICANCE: Our work contributes to understand the role of RAS modulators in the susceptibility to SARS-CoV-2 infection and severity of COVID-19.

What Is the Relationship between Trunk Control Function and Arm Coordination in Adults with Severe-to-Moderate Quadriplegic Cerebral Palsy?

Adults with tetraparesis cerebral palsy (i.e., wheelchair users) tend to experience more accelerated ageing, resulting in physical deterioration that increases the impact of the disability, leading to a loss of mobility that interferes with people's daily activities and participation in the community. The aim of this work is to study the relationship between trunk control and the function of the less-affected arm in this population. For this purpose, 41 para-athletes were invited to participate in this study, performing five tests to assess upper limb coordination, two tests to assess manual dexterity [i.e., Box and Block Test (BBT) and Box and Ball Test (BBLT)] and three tests to assess intra-limb coordination in different planes. Trunk control was assessed in both static and dynamic sitting conditions. The results show moderate correlations between static postural control and manual dexterity tests in the BBT (r = -0.553; p = 0.002) and BBLT (r = -0.537; p = 0.004). Large correlations were also found between static postural control and intra-limb tasks in horizontal (r = 0.769; p = 0.001) and vertical movements (r = 0.739; p = 0.009). Better static trunk control is related to a better upper limb function in the sagittal plane. Considerations and implications are explained in the manuscript.

Manejo de las lesiones anexiales en el embarazo y actualización del abordaje laparoscópico / Management of adnexal masses in pregnancy and an update of the laparoscopic approach

Resumen El manejo del tumor anexial en embarazadas sigue siendo un desafío. El objetivo del siguiente trabajo es realizar una revisión bibliográfica, en la que se abordarán las diferentes alternativas en cuanto a diagnóstico y manejo del tumor anexial en embarazadas, así como también indicaciones de abordaje quirúrgico y recomendaciones para una cirugía segura. Los tumores anexiales en embarazadas son poco frecuentes, y la mayoría son benignos y tipo funcionales. La ecografía ha sido fundamental para lograr diferenciar su carácter benigno o maligno. El manejo puede ser expectante o quirúrgico. El manejo quirúrgico se reserva para ciertas características de las lesiones anexiales. En cuanto a la vía operatoria, la literatura apoya la laparoscopia mostrando que existen múltiples beneficios al compararla con la laparotomía. Para el abordaje quirúrgico existen opciones en cuanto a la técnica, siendo estas anexectomía o quistectomía. Resulta fundamental tener consideraciones especiales en la técnica debido a los cambios fisiológicos de las embarazadas, como por ejemplo la altura uterina y el tamaño del tumor anexial. A modo de conclusión, el manejo de los tumores anexiales en el embarazo sigue siendo controversial y se extrapola principalmente basándose en la literatura de pacientes no gestantes u otros procedimientos quirúrgicos en embarazadas.

Abstract Nowadays the management of the adnexal tumors in pregnant women is still a challenge. The purpose of this article is to perform a bibliographic review and present the differential diagnosis, management, and surgical approaches for the women in this condition. Adnexal tumors in pregnant women are rare, most of them are benign corresponding to functional cysts. In order to differentiate benign from malignant tumors, Ultrasonography has been one of the most important imaging advances. The management can be either expectant or surgical. Surgical management is referred for tumors with certain specific characteristics. In relation to surgical management, the literature supports laparoscopy, showing greater benefits in comparison to laparotomy. There are different options for this kind of approach. Its mandatory to have special considerations in the technique due to the physiological changes in pregnant women, some examples are the uterine and the tumor size. The management of the adnexal tumors in pregnancy is still controversial, its based on studies of non-pregnant patients or other kinds of surgeries in pregnant women.

Ghrelin treatment induces rapid and delayed increments of food intake: a heuristic model to explain ghrelin's orexigenic effects.

Ghrelin is a stomach-derived peptide hormone with salient roles in the regulation of energy balance and metabolism. Notably, ghrelin is recognized as the most powerful known circulating orexigenic hormone. Here, we systematically investigated the effects of ghrelin on energy homeostasis and found that ghrelin primarily induces a biphasic effect on food intake that has indirect consequences on energy expenditure and nutrient partitioning. We also found that ghrelin-induced biphasic effect on food intake requires the integrity of Agouti-related peptide/neuropeptide Y-producing neurons of the hypothalamic arcuate nucleus, which seem to display a long-lasting activation after a single systemic injection of ghrelin. Finally, we found that different autonomic, hormonal and metabolic satiation signals transiently counteract ghrelin-induced food intake. Based on our observations, we propose a heuristic model to describe how the orexigenic effect of ghrelin and the anorectic food intake-induced rebound sculpt a timely constrain feeding response to ghrelin.

Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke.

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.