Enhancement of the medial olivocochlear system prevents hidden hearing loss

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; Chrna9 KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI; Chrna9L9′T KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In Chrna9 KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the Chrna9L9′T KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium.Fil: Boero, Luis Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Castagna, Valeria Carolina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Di Guilmi, Mariano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Goutman, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Elgoyhen, Ana Belen. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Gomez Casati, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Strengthening of the Efferent Olivocochlear System Leads to Synaptic Dysfunction and Tonotopy Disruption of a Central Auditory Nucleus

The auditory system in many mammals is immature at birth but precisely organized in adults. Spontaneous activity in the inner ear plays a critical role in guiding this maturation process. This is shaped by an efferent pathway that descends from the brainstem and makes transient direct synaptic contacts with inner hair cells. In this work, we used an α9 cholinergic nicotinic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9'T, L9'T) to further understand the role of the olivocochlear system in the correct establishment of auditory circuits. Wave III of auditory brainstem responses (which represents synchronized activity of synapses within the superior olivary complex) was smaller in L9'T mice, suggesting a central dysfunction. The mechanism underlying this functional alteration was analyzed in brain slices containing the medial nucleus of the trapezoid body (MNTB), where neurons are topographically organized along a mediolateral (ML) axis. The topographic organization of MNTB physiological properties observed in wildtype (WT) was abolished in L9'T mice. Additionally, electrophysiological recordings in slices indicated MNTB synaptic alterations. In vivo multielectrode recordings showed that the overall level of MNTB activity was reduced in the L9'T The present results indicate that the transient cochlear efferent innervation to inner hair cells during the critical period before the onset of hearing is involved in the refinement of topographic maps as well as in setting the properties of synaptic transmission at a central auditory nucleus.SIGNIFICANCE STATEMENT Cochlear inner hair cells of altricial mammals display spontaneous electrical activity before hearing onset. The pattern and firing rate of these cells are crucial for the correct maturation of the central auditory pathway. A descending efferent innervation from the CNS contacts the hair cells during this developmental window. The present work shows that genetic enhancement of efferent function disrupts the orderly topographic distribution of biophysical and synaptic properties in the auditory brainstem and causes severe synaptic dysfunction. This work adds to the notion that the transient efferent innervation to the cochlea is necessary for the correct establishment of the central auditory circuitry.Fil: Di Guilmi, Mariano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Boero, Luis Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; ArgentinaFil: Castagna, Valeria C.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; ArgentinaFil: Rodríguez Contreras, Adrián. City University Of New York. The City College Of New York.; Estados UnidosFil: Wedemeyer, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Gomez Casati, Maria Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentin

Inner Ear Genes Underwent Positive Selection and Adaptation in the Mammalian Lineage

The mammalian inner ear possesses functional and morphological innovations that contribute to its unique hearing capacities. The genetic bases underlying the evolution of this mammalian landmark are poorly understood. We propose that the emergence of morphological and functional innovations in the mammalian inner ear could have been driven by adaptive molecular evolution. In this work, we performed a meta-analysis of available inner ear gene expression data sets in order to identify genes that show signatures of adaptive evolution in the mammalian lineage. We analyzed ∼1,300 inner ear expressed genes and found that 13% show signatures of positive selection in the mammalian lineage. Several of these genes are known to play an important function in the inner ear. In addition, we identified that a significant proportion of genes showing signatures of adaptive evolution in mammals have not been previously reported to participate in inner ear development and/or physiology. We focused our analysis in two of these genes: STRIP2 and ABLIM2 by generating null mutant mice and analyzed their auditory function. We found that mice lacking Strip2 displayed a decrease in neural response amplitudes. In addition, we observed a reduction in the number of afferent synapses, suggesting a potential cochlear neuropathy. Thus, this study shows the usefulness of pursuing a high-throughput evolutionary approach followed by functional studies to track down genes that are important for inner ear function. Moreover, this approach sheds light on the genetic bases underlying the evolution of the mammalian inner ear.Fil: Pisciottano, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Cinalli, Alejandro Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Stopiello, Juan Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Castagna, Valeria Carolina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Gomez Casati, Maria Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Franchini, Lucia Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Effectiveness of vaccination against SARS-CoV-2 Omicron variant infection, symptomatic disease, and hospitalization: a systematic review and meta-analysis

Background This meta-analysis aims to assess the effectiveness of the current Sars-Cov2 vaccine regimens against Omicron infection. A secondary endpoint aims to investigate the waning effectiveness of primary vaccination against symptomatic infection and related hospitalization. Research design and methods The systematic review started on 1 December 2021 and was concluded on 1 March 2022. Random-effects frequentist meta-analyses and multiple meta-regressions were performed. Results In total, 15 studies are included in the quantitative synthesis. According to the meta-analysis results, the overall risk of Sars-Cov2 infection in vaccinated individuals is on average 31 center dot 5% lower than the infection risk in unvaccinated while vaccinated with one booster dose have a 70 center dot 4% risk reduction of Omicron infection compared to unvaccinated. In particular, one booster dose significantly decreases by 69% the risk of symptomatic Omicron infection with respect to unvaccinated. Six months after the primary vaccination, the average risk reduction declines to 22% against symptomatic infection and to 55% against hospitalization. Conclusions Primary vaccination does not provide sufficient protection against symptomatic Omicron infection. Although the effectiveness of the primary vaccination against hospitalization due to Omicron remains significantly above 50% after 3 months, it dramatically fades after 6 months

"Integrating China in the International Consortium for Personalized Medicine": The Coordination and Support Action to Foster Collaboration in Personalized Medicine Development between Europe and China

"Integrating China in the International Consortium for Personalized Medicine" (IC2PerMed) is a coordination and support action funded within the Horizon 2020 work program. Following the guidance of the International Consortium for Personalized Medicine (ICPerMed), the project's overarching aim is to align the European Union and China's research agendas in the field of personalized medicine (PM) to enable a swift development of PM approaches in the EU with strong leverage upon EU-Chinese collaboration. Living in the CO­VID-19 era, we are witnessing how the challenges imposed by the pandemic all around the globe have been acting as a catalyst for collaborations and knowledge sharing among national health systems worldwide. Given the strong interest on behalf of both Europe and China in the advancement of PM approaches, now more than ever, a cross-border collaboration between the 2 powers can accelerate the effective translation of such innovation to healthcare systems, advance research, and ensure that such change follows the directions toward the path of sustainability. IC2PerMed developments will be led by European and Chinese experts equally assembled into 3 Working Groups: (1) people and organization, (2) innovation and market, and (3) research and clinical studies in PM. This complex and dynamic network of actions thrives on dialog, cooperation, and alignment of research at national and global levels; work in the direction taken by IC2PerMed shall pave the way toward the realization of PM's full potential, prevent it from becoming a burden for healthcare systems, and, rather, prove that it provides an essential and irreplaceable contribution to their effectiveness, efficiency, and sustainability

Molecular typing and differences in biofilm formation and antibiotic susceptibilities among Prototheca strains isolated in Italy and Brazil.

Bovine mastitis caused by Prototheca is a serious and complex problem that accounts for high economic losses in the dairy industry. The main objective of this study was to identify and characterize at genetic level different Prototheca strains and provide the most complete data about protothecal antibiotic resistance. The study involves 46 isolates from Italian (13 strains) and Brazilian (33 strains) mastitic milk. These strains were identified by multiplex PCR and single strand conformation polymorphism analysis and characterized by randomly amplified polymorphic DNA (RAPD)-PCR. Moreover, biofilm production and antibiotic susceptibility were evaluated. Forty-two strains resulted as Prototheca zopfii genotype 2, whereas 4 isolates could belong to a potential new Prototheca species. The RAPD-PCR, performed with 3 primers (M13, OPA-4, and OPA-18), showed a notable heterogeneity among isolates and grouped the strains according to the species and geographical origin. Biofilm production was species-dependent and P. zopfii genotype 2 strains were classified as strong biofilm producers. In vitro antibiotic susceptibility tests indicated that Prototheca strains were susceptible to antibacterial drugs belonging to aminoglycosides group; the highest activity against Prototheca strains was observed in the case of colistin sulfate, gentamicin, and netilmicin (100% of susceptible strains). It is interesting to note that all the Italian P. zopfii genotype 2 strains showed lower minimum inhibitory concentration values than the Brazilian ones. Nisin showed more efficacy than lysozyme and potassium sorbate, inhibiting 31% of the strains. Results obtained in this study confirmed that RAPD-PCR is a rapid, inexpensive, and highly discriminating tool for Prototheca strains characterization and could give a good scientific contribution for better understanding the protothecal mastitis in dairy herd

Preventing presbycusis in mice with enhanced medial olivocochlear feedback

"Growing old" is the most common cause of hearing loss. Agerelated hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation ("synaptopathy") is an early contributor to agerelated auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10 cholinergic nicotinic receptors gating kinetics ("gain of function" nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calciumgated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.Fil: Boero, Luis Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacología; ArgentinaFil: Castagna, Valeria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacología; ArgentinaFil: Terreros, Gonzalo. Universidad de Chile; ChileFil: Moglie, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Silva, Sebastián. Universidad de Chile; ChileFil: Maass, Juan C.. Universidad de Chile; ChileFil: Fuchs, Paul A.. University Johns Hopkins; Estados UnidosFil: Delano, Paul H.. Universidad de Chile; ChileFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacología; ArgentinaFil: Gomez Casati, Maria Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Curso de Formação Agroecológica e Cidadã para a inclusão produtiva de jovens camponeses

O Curso de Formação Agroecológica e Cidadã fez parte de um projeto executado entre 2013 e 2014 pelo Centro Transdisciplinar em Educação do Campo e Desenvolvimento Rural da Faculdade UnB Planaltina, em parceria com a Secretaria Nacional da Juventude. Com o objetivo de iniciar uma proposta de politica pública para formação da juventude rural, foi proposto um piloto para formar 300 jovens rurais da região Centro Oeste. Era previsto que ao longo do curso, fossem elaborados, com estes jovens e a partir de suas demandas, projetos produtivos coletivos com potencial de geração de renda, considerando as potencialidades dos territórios rurais onde vivem. As atividades de formação ocorreram com base na Pedagogia da Alternância, incluindo as etapas de Tempo Escola e Tempo Comunidade. Seis eixos temáticos foram trabalhados, os quais buscaram atender à proposta multidisciplinar do projeto, sendo: Território e agricultura; Organização social, Cooperativismo e econômica solidária; Agroecologia e processos produtivos; Novas tecnologias e desenvolvimento rural; Atividades Pedagógicas de Cultura e Organicidade; Intervenções psicológicasOs projetos produtivos foram elaborados pela equipe baseados nas demandas dos jovens e deverão ser implementados futuramente pelas comunidades.Eje: B1 Sistemas de producción de base agroecológica (Relatos de experiencias).Facultad de Ciencias Agrarias y Forestale

Curso de Formação Agroecológica e Cidadã para a inclusão produtiva de jovens camponeses

O Curso de Formação Agroecológica e Cidadã fez parte de um projeto executado entre 2013 e 2014 pelo Centro Transdisciplinar em Educação do Campo e Desenvolvimento Rural da Faculdade UnB Planaltina, em parceria com a Secretaria Nacional da Juventude. Com o objetivo de iniciar uma proposta de politica pública para formação da juventude rural, foi proposto um piloto para formar 300 jovens rurais da região Centro Oeste. Era previsto que ao longo do curso, fossem elaborados, com estes jovens e a partir de suas demandas, projetos produtivos coletivos com potencial de geração de renda, considerando as potencialidades dos territórios rurais onde vivem. As atividades de formação ocorreram com base na Pedagogia da Alternância, incluindo as etapas de Tempo Escola e Tempo Comunidade. Seis eixos temáticos foram trabalhados, os quais buscaram atender à proposta multidisciplinar do projeto, sendo: Território e agricultura; Organização social, Cooperativismo e econômica solidária; Agroecologia e processos produtivos; Novas tecnologias e desenvolvimento rural; Atividades Pedagógicas de Cultura e Organicidade; Intervenções psicológicasOs projetos produtivos foram elaborados pela equipe baseados nas demandas dos jovens e deverão ser implementados futuramente pelas comunidades.Eje: B1 Sistemas de producción de base agroecológica (Relatos de experiencias).Facultad de Ciencias Agrarias y Forestale

Curso de Formação Agroecológica e Cidadã para a inclusão produtiva de jovens camponeses

O Curso de Formação Agroecológica e Cidadã fez parte de um projeto executado entre 2013 e 2014 pelo Centro Transdisciplinar em Educação do Campo e Desenvolvimento Rural da Faculdade UnB Planaltina, em parceria com a Secretaria Nacional da Juventude. Com o objetivo de iniciar uma proposta de politica pública para formação da juventude rural, foi proposto um piloto para formar 300 jovens rurais da região Centro Oeste. Era previsto que ao longo do curso, fossem elaborados, com estes jovens e a partir de suas demandas, projetos produtivos coletivos com potencial de geração de renda, considerando as potencialidades dos territórios rurais onde vivem. As atividades de formação ocorreram com base na Pedagogia da Alternância, incluindo as etapas de Tempo Escola e Tempo Comunidade. Seis eixos temáticos foram trabalhados, os quais buscaram atender à proposta multidisciplinar do projeto, sendo: Território e agricultura; Organização social, Cooperativismo e econômica solidária; Agroecologia e processos produtivos; Novas tecnologias e desenvolvimento rural; Atividades Pedagógicas de Cultura e Organicidade; Intervenções psicológicasOs projetos produtivos foram elaborados pela equipe baseados nas demandas dos jovens e deverão ser implementados futuramente pelas comunidades.Eje: B1 Sistemas de producción de base agroecológica (Relatos de experiencias).Facultad de Ciencias Agrarias y Forestale