GABAergic synapses between auditory efferent neurons and type II spiral ganglion afferent neurons in the mouse cochlea.

Cochlear outer hair cells (OHCs) are electromotile and are implicated in mechanisms of amplification of responses to sound that enhance sound sensitivity and frequency tuning. They send information to the brain through glutamatergic synapses onto a small subpopulation of neurons of the ascending auditory nerve, the type II spiral ganglion neurons (SGNs). The OHC synapses onto type II SGNs are sparse and weak, suggesting that type II SGNs respond primarily to loud and possibly damaging levels of sound. OHCs also receive innervation from the brain through the medial olivocochlear (MOC) efferent neurons. MOC neurons are cholinergic yet exert an inhibitory effect on auditory function as they are coupled to alpha9/alpha10 nicotinic acetylcholine receptors (nAChRs) on OHCs, which leads to calcium influx that gates SK potassium channels. The net hyperpolarization exerted by this efferent synapse reduces OHC activity-evoked electromotility and is implicated in cochlear gain control, protection against acoustic trauma, and attention. MOC neurons also label for markers of gamma-aminobutyric acid (GABA) and GABA synthesis. GABAB autoreceptor (GABABR) activation by GABA released from MOC terminals has been demonstrated to reduce ACh release, confirming important negative feedback roles for GABA. However, the full complement of GABAergic activity in the cochlea is not currently understood, including the mechanisms that regulate GABA release from MOC axon terminals, whether GABA diffuses from MOC axon terminals to other postsynaptic cells, and the location and function of GABAA receptors (GABAARs). Previous electron microscopy studies suggest that MOC neurons form contacts onto several other cell types in the cochlea, but whether these contacts form functional synapses, and what neurotransmitters are employed, are unknown. Here we use immunohistochemistry, optical neurotransmitter imaging and patch-clamp electrophysiology from hair cells, afferent dendrites, and efferent axons to demonstrate that in addition to presynaptic GABABR autoreceptor activation, MOC efferent axon terminals release GABA onto type II SGN afferent dendrites with postsynaptic activity mediated by GABAARs. This synapse may have multiple roles including developmental regulation of cochlear innervation, fine tuning of OHC activity, or providing feedback to the brain about MOC and OHC activity.

Factors associated with non-treatment of hypertension and gender differences at baseline in the ELSA-Brasil cohort.

The treatment of arterial hypertension (AH) contributes to the reduction of morbidity and mortality. Gender differences are likely to play a role, as non-treatment is associated with clinical and sociodemographic aspects. The aim of this study was to investigate the factors associated with non-treatment of AH and gender differences in hypertensive individuals from the ELSA-Brasil cohort. The study was conducted with 5,743 baseline hypertensive cohort participants. AH was considered if there was a previous diagnosis or if systolic blood pressure (SBP) was ≥140 and/or diastolic BP (DBP) was ≥90 mmHg. Sociodemographic and anthropometric data, lifestyle, comorbidities, and use of antihypertensive medications were evaluated through interviews and in-person measurements. Treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) or other antihypertensive medications and non-treatment were evaluated with multivariate logistic regression. Non-treatment was observed in 32.8% of hypertensive individuals. Of the 67.7% treated individuals, 41.1% received RAASi. Non-treatment was associated with alcohol consumption in women (OR=1.41; 95%CI: 1.15-1.73; P=0.001), lowest schooling level in men (OR=1.70; 95%CI: 1.32-2.19; P<0.001), and younger age groups in men and women (strongest association in males aged 35-44 years: OR=4.58, 95%CI: 3.17-6.6, P<0.001). Among those using RAASi, a higher proportion of white, older individuals, and with more comorbidities was observed. The high percentage of non-treatment, even in this civil servant population, indicated the need to improve the treatment cascade for AH. Public health policies should consider giving special attention to gender roles in groups at higher risk of non-treatment to reduce inequities related to AH in Brazil.

Factors associated with non-treatment of hypertension and gender differences at baseline in the ELSA-Brasil cohort

The treatment of arterial hypertension (AH) contributes to the reduction of morbidity and mortality. Gender differences are likely to play a role, as non-treatment is associated with clinical and sociodemographic aspects. The aim of this study was to investigate the factors associated with non-treatment of AH and gender differences in hypertensive individuals from the ELSA-Brasil cohort. The study was conducted with 5,743 baseline hypertensive cohort participants. AH was considered if there was a previous diagnosis or if systolic blood pressure (SBP) was ≥140 and/or diastolic BP (DBP) was ≥90 mmHg. Sociodemographic and anthropometric data, lifestyle, comorbidities, and use of antihypertensive medications were evaluated through interviews and in-person measurements. Treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) or other antihypertensive medications and non-treatment were evaluated with multivariate logistic regression. Non-treatment was observed in 32.8% of hypertensive individuals. Of the 67.7% treated individuals, 41.1% received RAASi. Non-treatment was associated with alcohol consumption in women (OR=1.41; 95%CI: 1.15-1.73; P=0.001), lowest schooling level in men (OR=1.70; 95%CI: 1.32-2.19; P<0.001), and younger age groups in men and women (strongest association in males aged 35-44 years: OR=4.58, 95%CI: 3.17-6.6, P<0.001). Among those using RAASi, a higher proportion of white, older individuals, and with more comorbidities was observed. The high percentage of non-treatment, even in this civil servant population, indicated the need to improve the treatment cascade for AH. Public health policies should consider giving special attention to gender roles in groups at higher risk of non-treatment to reduce inequities related to AH in Brazil.

Adherencia a la campaña de vacunación de la gripe 2020/21 en el contexto de la pandemia de SARS-CoV-2. Análisis de los cambios en la gestión: un estudio piloto / Adherence to influenza vaccination campaign 2020/21 in the pandemic SARS-CoV-2. Context analysis in management changes: A pilot study

Introducción Las campañas de vacunación contra la gripe alcanzan coberturas por debajo de lo deseado y recomendado. Lo que en el contexto actual de pandemia por SARS-CoV-2 cobra mayor relevancia. Nuestro objetivo consiste en evaluar el impacto en la cobertura vacunal alcanzada de una serie de estrategias de implementación vacunal llevadas a cabo. Material y métodos Se introdujo una serie de estrategias de implementación de la vacunación en nuestra zona básica de salud como la captación activa y la ampliación horaria entre otras, se evaluó y comparó la cobertura vacunal alcanzada en la campaña actual con las previas, tanto a las 8 semanas como al final de la campaña. Además, se llevó a cabo un estudio transversal mediante una encuesta para valorar el impacto que habían tenido las medidas. Resultados En la semana 8 de la campaña detectamos diferencias significativas en cuanto al incremento de la cobertura vacunal alcanzada respecto a años previos, resultado que se confirmó al finalizar la campaña alcanzándose diferencias significativas (p<0,05) de cobertura vacunal en todos los centros estudiados, datos que fueron a favor de la efectividad de las estrategias empleadas. Conclusiones Las estrategias de implementación vacunal empleadas se han mostrado efectivas, logrando un incremento de hasta un 74% en las dosis totales administradas respecto a campañas previas y de hasta un 15% en la cobertura vacunal alcanzada en mayores de 64 años; pese al contexto de pandemia y al aumento de los movimientos antivacunas (AU)

Introduction Vaccination campaigns against influenza virus achieve coverages under recommended and desired values. In current context of SARS-CoV-2 pandemic it becomes more relevant. Our objective is to evaluate the impact on vaccination coverage of a set of implementation strategies carried out. Material and method Vaccine implementation strategies were introduced in our basic health zone as active caption of patients and schedule extension. Then the vaccination coverage achieved in the current campaign was evaluated and compared with previous in the 8th week and at the end of the campaign. Besides, a transversal study through a survey was carried out to measure the impact of the applied strategies. Result In the 8th week of the campaign significant differences were detected in the increase of vaccination coverage compared with previous years. These results were confirmed at the end of the campaign, getting a significant difference (<.05) of vaccination coverage in all the studied centers, these data support the effectivity of the applied strategies. Conclusions The vaccine implementation strategies applied have shown effectivity, achieving an increase of until 74% in the total administered doses compared to previous campaigns and even a 15% of vaccination coverage increased in the group of patients older than 64 years; even in a pandemic context and the increasing of anti-vaccine movements (AU)

[Adherence to influenza vaccination campaign 2020/21 in the pandemic SARS-CoV-2. Context analysis in management changes: A pilot study]. / Adherencia a la campaña de vacunación de la gripe 2020/21 en el contexto de la pandemia de SARS-CoV-2. Análisis de los cambios en la gestión: un estudio piloto.

INTRODUCTION: Vaccination campaigns against influenza virus achieve coverages under recommended and desired values. In current context of SARS-CoV-2 pandemic it becomes more relevant. Our objective is to evaluate the impact on vaccination coverage of a set of implementation strategies carried out. MATERIAL AND METHODS: Vaccine implementation strategies were introduced in our basic health zone as active caption of patients and schedule extension. Then the vaccination coverage achieved in the current campaign was evaluated and compared with previous in the 8th week and at the end of the campaign. Besides, a transversal study through a survey was carried out to measure the impact of the applied strategies. RESULTS: In the 8th week of the campaign significant differences were detected in the increase of vaccination coverage compared with previous years. These results were confirmed at the end of the campaign, getting a significant difference (<.05) of vaccination coverage in all the studied centers, these data support the effectivity of the applied strategies. CONCLUSIONS: The vaccine implementation strategies applied have shown effectivity, achieving an increase of until 74% in the total administered doses compared to previous campaigns and even a 15% of vaccination coverage increased in the group of patients older than 64 years; even in a pandemic context and the increasing of anti-vaccine movements.

Proteomic profile of vitrified in vitro-produced bovine embryos (Bos taurus indicus).

BACKGROUND: The proteomic profile of cryopreserved in vitro produced bovine embryos is little known but can provide insights on the successful application of cryo procedures in support of animal breeding. OBJECTIVE: To identify embryonic proteins and biomarkers related to improved cryotolerance of vitrified in vitro produced bovine embryos. MATERIALS AND METHODS: Proteins were isolated from embryo pools (n = 25 embryos per replicate) and analyzed using the nanoLC - MS/MS system. Further, the UniProtKB database (Uniprot -http://www.uniprot.org/) was used for protein identification. Proteins were classified based on their molecular mass, isoelectric point, and enzymatic activity. Post-translational modification predictions and functional gene ontology analysis were performed as well. Finally, a protein-protein interaction network was created to shed light on the embryo interactome. RESULTS: Based on the MS/MS approach, 66 proteins were identified from vitrified Bos taurus embryos. The retrieved proteins were presumably annotated, which allowed a description of the qualitative and functional aspects of the embryo proteome after the vitrification process. CONCLUSION: These findings allowed us to conclude that in vitro-produced vitrified embryos expressed proteins that underlie biological processes related to reproduction, stress and lipid metabolic process, which are essential to maintain embryo viability. doi.org/10.54680/fr22410110512.

α,ß-Amyrin prevents steatosis and insulin resistance in a high-fat diet-induced mouse model of NAFLD via the AMPK-mTORC1-SREBP1 signaling mechanism.

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of α,ß-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.

SEOM clinical guidelines for the treatment of head and neck cancer (2020)

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease (AU)

SEOM clinical guidelines for the treatment of head and neck cancer (2020).

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease.

The efficacy of 8-hydroxyquinoline derivatives in controlling the fungus Ilyonectria liriodendri, the causative agent of black foot disease in grapevines.

AIM: The purpose of this study was to evaluate the in vitro and in vivo efficiency of derivatives of 8-Hydroxyquinoline (8HQ) in controlling the fungus Ilyonectria liriodendri. METHODS AND RESULTS: The in vitro tests consisted of assessing its susceptibility to the minimal inhibitory concentration (MIC) and the inhibition of mycelial growth. While the in vivo tests consisted of applying and assessing the most effective products for the protection of wounds, in both preventive + curative and curative forms. The MIC values for PH 151 (6·25 µg ml-1 ) showed better results when compared to the fungicides tebuconazole (>50 µg ml-1 ) and mancozeb (12·5 µg ml-1 for strain 176 and 25 µg ml-1 for strain 1117). PH 151 significantly inhibited mycelial growth, while mancozeb did not differ from the control. In in vivo tests, PH 151 again demonstrated excellent results in vitro, especially when applied preventively. CONCLUSIONS: The derivative of 8HQ PH 151 was effective in controlling the fungus I. liriodendri in vitro and proved to be a promising option for protecting wounds. SIGNIFICANCE AND IMPACT OF THE STUDY: This study points to the prospect of an effective and safe preventive antifungal product, which would enable the use of pesticides in vine culture to be reduced.

Validity of computed tomography in diagnosing midfacial fractures.

The aim of this study was to evaluate the sensitivity, accuracy, and reliability of two-dimensional computed tomography (2D-CT) scans (axial, coronal, sagittal planes) and three-dimensional computed tomography (3D-CT) reconstructions in diagnosing midfacial fractures in relation to actual fractures identified clinically and during surgery (gold standard). The imaging diagnosis was performed by a radiologist and an oral and maxillofacial surgeon. Sixty-two patients with a total of 429 midfacial fractures were included. Frontal sinus and nose fractures were easily diagnosed. For the three CT planes, there was a statistically significant difference between the CT examination and the gold standard for five to seven of the nine bones evaluated, while for 3D-CT, a difference was observed only for fractures of the orbital floor. The inter-observer agreement between the oral and maxillofacial surgeon and the radiologist was 75.5%. In conclusion, in this study 3D-CT reconstructions showed significantly the best sensitivity, accuracy, and reliability for the diagnosis of midfacial fractures. The sagittal reconstructions were the least diagnostic of the 2D-CT images. For areas where the parameters studied showed less agreement and hence a more difficult diagnosis, we recommend a combination of 3D and 2D-CT images to improve diagnostic accuracy.

α, ß-Amyrin prevents steatosis and insulin resistance in a high-fat diet-induced mouse model of NAFLD via the AMPK-mTORC1-SREBP1 signaling mechanism

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of α,β-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.

Topology-induced dynamics in a network of synthetic oscillators with piecewise affine approximation.

In synthetic biology approaches, minimal systems are used to reproduce complex molecular mechanisms that appear in the core functioning of multi-cellular organisms. In this paper, we study a piecewise affine model of a synthetic two-gene oscillator and prove existence and stability of a periodic solution for all parameters in a given region. Motivated by the synchronization of circadian clocks in a cluster of cells, we next consider a network of N identical oscillators under diffusive coupling to investigate the effect of the topology of interactions in the network's dynamics. Our results show that both all-to-all and one-to-all coupling topologies may introduce new stable steady states in addition to the expected periodic orbit. Both topologies admit an upper bound on the coupling parameter that prevents the generation of new steady states. However, this upper bound is independent of the number of oscillators in the network and less conservative for the one-to-all topology.

Cell cycle period control through modulation of clock inputs.

In this work, we study period control of the mammalian cell cycle via coupling with the cellular clock. For this, we make use of the oscillators' synchronization dynamics and investigate methods of slowing down the cell cycle with the use of clock inputs. Clock control of the cell cycle is well established via identified molecular mechanisms, such as the CLOCK:BMAL1-mediated induction of the wee1 gene, resulting in the WEE1 kinase that represses the active form of mitosis promoting factor (MPF), the essential cell cycle component. To investigate the coupling dynamics of these systems, we use previously developed models of the clock and cell cycle oscillators and center our studies on unidirectional clock [Formula: see text] cell cycle coupling. Moreover, we propose an hypothesis of a Growth Factor (GF)-responsive clock, involving a pathway of the non-essential cell cycle complex cyclin D/CDK4. We observe a variety of rational ratios of clock to cell cycle period, such as: 1:1, 3:2, 4:3, and 5:4. Finally, our protocols of period control are successful in effectively slowing down the cell cycle by the use of clock modulating inputs, some of which correspond to existing drugs.

Characterizing network topology using first-passage analysis.

Understanding the topological characteristics of complex networks and how they affect navigability is one of the most important goals in science today, as it plays a central role in various economic, biological, ecological, and social systems. Here we apply first-passage analysis tools to investigate the properties and characteristics of random walkers in networks with different topology. Starting with the simplest two-dimensional square lattice, we modify its topology incrementally by randomly reconnecting links between sites. We characterize these networks by first-passage time from a significant number of random walkers without interaction, varying the departure and arrival locations. We also apply the concept of first-passage simultaneity, which measures the likelihood of two walkers reaching their destination together. These measures, together with the site occupancy statistics during the processes, allowed us to differentiate the studied networks, especially the random networks from the scale-free networks, by their navigability. We also show that small-world features can also be highlighted with the proposed technique.

Control of synchronization ratios in clock/cell cycle coupling by growth factors and glucocorticoids.

The cell cycle and the circadian clock are essential cyclic cellular processes often synchronous in healthy cells. In this work, we use previously developed mathematical models of the mammalian cell cycle and circadian cellular clock in order to investigate their dynamical interactions. Firstly, we study unidirectional cell cycle → clock coupling by proposing a mechanism of mitosis promoting factor (MPF)-controlled REV-ERBα degradation. Secondly, we analyse a bidirectional coupling configuration, where we add the CLOCK : BMAL1-mediated MPF repression via the WEE1 kinase to the first system. Our simulations reproduce ratios of clock to cell cycle period in agreement with experimental observations and give predictions of the system's synchronization state response to a variety of control parameters. Specifically, growth factors accelerate the coupled oscillators and dexamethasone (Dex) drives the system from a 1 : 1 to a 3 : 2 synchronization state. Furthermore, simulations of a Dex pulse reveal that certain time regions of pulse application drive the system from 1 : 1 to 3 : 2 synchronization while others have no effect, revealing the existence of a responsive and an irresponsive system's phase, a result we contextualize with observations on the segregation of Dex-treated cells into two populations.