Clinical and forensic aspects of potassium iodide: Suddenly in high demand across Europe due to fears of radiation poisoning from a nuclear attack in Ukraine.

Potassium iodide has demonstrated several therapeutic applications over time, being the choice for shielding the thyroid during radiation emergencies involving radioiodine release. Amidst the ongoing military conflict between Ukraine and Russia and the growing concern regarding the potential deployment of nuclear weapons, there has been a surge in the demand for potassium iodide across Europe. This work aimed to comprehensively review the current knowledge regarding the pharmacology, physiology, adverse effects, the protective role in reducing the risk of thyroid cancer and recommendations for potassium iodide use during radiation emergencies. Evidence on adverse effects is scarce, as potassium iodide is generally well-tolerated. Guidelines for thyroid blocking with potassium iodide during radiation emergencies suggest that, among populations vulnerable to radioiodine exposure, the benefits of potassium iodide outweigh the risks of adverse effects. Controversial topics surrounding the utilization of potassium iodide in radiation emergencies include the prophylaxis in iodine-deficient regions and following the detonation of dirty bombs, whether granule formulations versus tablets should be used and mental health concerns. Although the rise in demand seems to be a justified security measure, it is essential to recognize that potassium iodide protects the thyroid from radioiodine and does not impact the body's absorption of other radioactive materials or defend against external radiation exposure.

A fermented milk drink with Umbu (Spondias tuberosa) pulp and whey is effective for weight gain and re-nutrition in malnourished: An in vivo study in mice and children.

Malnutrition is considered one of the major public health problems worldwide and negatively affects the growth, development and learning of schoolchildren. This study developed and evaluated a fermented milk drink with added Umbu (Spondias tuberosa) pulp in the weight gain and renutrition of mice submitted to malnutrition by calorie restriction, and in malnourished children. The supplementation with this fermented milk drink contributed to an increase of 7.2 % in body weight, and 64.3 % in albumin, and a reduction of 35 % in cholesterol in malnourished mice. In humans, a group of nine malnourished children consumed a daily 200 mL serving of the milk drink (for 60 days). For humans, the fermented milk drink allowed an increase of 16.5 % in body weight, and 20.9 % in body mass index in malnourished children. In conclusion, fermented milk drink has a positive effect on the re-nutrition of malnourished mice and helps to improve the nutritional status of malnourished children.

Human primordial germ cell-like cells specified from resetting precursors develop in human hindgut organoids.

Human primordial germ cells (hPGCs), the precursors of eggs and sperm, start their complex development shortly after specification and during their migration to the primitive gonads. Here, we describe protocols for specifying hPGC-like cells (hPGCLCs) from resetting precursors and progressing them with the support of human hindgut organoids. Resetting hPGCLCs (rhPGCLCs) are specified from human embryonic stem cells (hESCs) transitioning from the primed into the naive state of pluripotency. Hindgut organoids are also derived from hESCs after a sequential differentiation into a posterior endoderm/hindgut fate. Both rhPGCLCs and hindgut organoids are combined and co-cultured for 25 d. The entire procedure takes ~1.5 months and can be successfully implemented by a doctoral or graduate student with basic skills and experience in hESC cultures. The co-culture system supports the progression of rhPGCLCs at a developmental timing analogous to that observed in vivo. Compared with previously developed hPGCLC progression protocols, which depend on co-cultures with mouse embryonic gonadal tissue, our co-culture system represents a developmentally relevant model closer to the environment that hPGCs first encounter after specification. Together with the potential for investigations of events during hPGC specification and early development, these protocols provide a practical approach to designing efficient models for in vitro gametogenesis. Notably, the rhPGCLC-hindgut co-culture system can also be adapted to study failings in hPGC migration, which are associated with the etiology of some forms of infertility and germ cell tumors.

Resenha do livro "Educação Física Menor" / Review of the book "Minor Physical Education" / Reseña del libro "Educación Física Menor"

O livro "Educação Física Menor" problematiza e propõe alternativas diante do chamado currículo cultural ou pós-crítico de Educação Física. Faz isso, a partir de dois gestos: problematizando algumas acepções culturalistas e almejando a singularização ou a minoração das perspectivas "maiores" do componente, a partir de uma conceitualização das filosofias de pensadores como Foucault, Deleuze e Guattari.

The book "Minor Physical Education" problematizes and proposes alternatives to the so-called cultural or post-critical curriculum of Physical Education. It does this from two gestures: problematizing some culturalist acceptations and aiming at the singularization or the minimization of the "major" perspectives of the component, from a conceptualization of the philosophies of thinkers such as Foucault, Deleuze and Guattari.

El libro "Educación Física Menor" problematiza y propone alternativas al llamado currículo cultural o postcrítico de la Educación Física. Lo hace a través de dos gestos: problematizando algunos conceptos culturalistas y apuntando a singularizar o disminuir las perspectivas "mayores" del componente, a partir de una conceptualización de las filosofías de pensadores como Foucault, Deleuze y Guattari.

Within- and between-day reliability and repeatability of neuromuscular function assessment in females and males.

The study evaluated the reliability and repeatability of the force and surface electromyography activity (EMG) outcomes obtained through voluntary and electrically evoked contractions of knee extensors in females (n = 18) and males (n = 20) and compared these data between sexes. Maximal isometric voluntary contractions (iMVCs) of knee extensors associated with electrical stimulation of the femoral nerve were performed over 4 days (48-h interval), with the first day involving familiarization procedures, the second involving three trials (1-h interval), and the third and fourth involving just one trial. The intraclass correlation coefficient (ICC), coefficient of variation (CV), and repeatability of outcomes from within- and between-day trials were determined for each sex. Females presented lower maximal voluntary force during iMVC (iMVCForce) and associated vastus lateralis EMG activity (root mean square, RMSVL), force evoked by potentiated doublet high-frequency (Db100Force) and single stimuli (Qtw), and M-wave amplitude than males (P ≤ 0.01, partial eta squared ≥0.94). Voluntary activation (VA) and RMSVL/M-wave amplitude did not differ between sexes. iMVCForce, VA, Db100Force, Qtw, and M-wave amplitude were the most reliable outcomes in within-day trials, with similar results between sexes (ICC > 0.62; CV < 6.4%; repeatability: 12.2%-22.6%). When investigating between-day trials, the iMVCForce, VA, Db100Force, and Qtw were the most reliable (ICC > 0.66; CV < 7.5%; repeatability: 13.2%-33.45%) with similar results between sexes. In conclusion, females presented lower iMVCForce and evoked response than males. Although reliability and repeatability statistics vary between trials, data (e.g., from EMG or force signal), and sexes, most of the outcomes obtained through this technique are reliable in females and males.NEW & NOTEWORTHY Although reliability and repeatability of knee extensors vary according to the type of neuromuscular function outcome (e.g., from force or EMG responses), the trial intervals (i.e., hours or days), and the sex of the participant, most force and EMG outcomes obtained through these neuromuscular assessment protocols present ICC > 0.75, very good CV (<10%), and repeatability <25% in within- and between-day trials in both sexes.

Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aß1-42 to Model Early Alzheimer's Disease.

The intracerebroventricular (icv) injection of amyloid peptides (Aß) models Alzheimer's disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A2A receptors (A2AR). Since A2AR overfunction is sufficient to trigger memory deficits, we tested if A2AR were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A2AR overfunction could be a trigger of AD. Six to eight days after Aß-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A2AR in hippocampal synapses. A2AR blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7-8 days after Aß-icv injection. Fifteen days after Aß-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A2AR, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A2AR precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A2AR could be a trigger of memory deterioration in AD.

Adenosine A2A Receptors Shut Down Adenosine A1 Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A1 and A2A receptors (A1R, A2AR), respectively. Supramaximal activation of A1R can block hippocampal synaptic transmission, and the tonic engagement of A1R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A2AR activation decreases A1R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A1R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A2AR with CGS21680 (30 nM) decreased the potency of the A1R agonist CPA (6-60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A2AR play a key role in dampening A1R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A1R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.

Caffeic acid recovers ischemia-induced synaptic dysfunction without direct effects on excitatory synaptic transmission and plasticity in mouse hippocampal slices.

Caffeic acid is a polyphenolic compound present in a vast array of dietary components. We previously showed that caffeic acid reduces the burden of brain ischemia joining evidence by others that it can attenuate different brain diseases. However, it is unknown if caffeic acid affects information processing in neuronal networks. Thus, we now used electrophysiological recordings in mouse hippocampal slices to test if caffeic acid directly affected synaptic transmission, plasticity and dysfunction caused by oxygen-glucose deprivation (OGD), an in vitro ischemia model. Caffeic acid (1-10 µM) was devoid of effect on synaptic transmission and paired-pulse facilitation in Schaffer collaterals-CA1 pyramidal synapses. Also, the magnitude of either hippocampal long-term potentiation (LTP) or the subsequent depotentiation were not significantly modified by 10 µM caffeic acid. However, caffeic acid (10 µM) increased the recovery of synaptic transmission upon re-oxygenation following 7 min of OGD. Furthermore, caffeic acid (10 µM) also recovered plasticity after OGD, as heralded by the increased magnitude of LTP after exposure. These findings show that caffeic acid does not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of caffeic acid may allow the design of hitherto unrecognized novel neuroprotective strategies.

Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer's Disease.

Alzheimer's disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization. Long-term potentiation (LTP) was decreased in the prefrontal cortex (PFC), but not in the CA1 hippocampus or amygdala. This was associated with a decreased density of sirtuin-1 in cerebrocortical synaptosomes and a decreased density of sirtuin-1 and sestrin-2 in total cerebrocortical extracts, without alterations of sirtuin-3 levels or of synaptic markers (syntaxin, synaptophysin, SNAP25, PSD95). However, activation of sirtuin-1 did not affect or recover PFC-LTP deficit in APP/PS1 female mice; instead, inhibition of sirtuin-1 increased PFC-LTP magnitude. It is concluded that mood and memory dysfunction in 9-month-old female APP/PS1 mice is associated with a parallel decrease in synaptic plasticity and in synaptic sirtuin-1 levels in the prefrontal cortex, although sirtiun1 activation failed to restore abnormal cortical plasticity.

Texto descrente: em defesa das multiplicidades na Educação Física / Unbelievable text: in defense of multilicities in Physical Education / Texto increíble: en defensa de las multilicidades en la Educación Física

O presente artigo, de tipo ensaístico, lança mão daquilo que chama de descrença associada à Educação e, mais especificamente, à Educação Física, para defender as multiplicidades, inspirados pelos escritos de Deleuze e Guattari (2011a, 2011b, 2012a, 2012b). A descrença torna-se uma espécie de primeira fase para a aposta na multiplicidade, visto que ao desacreditar a representação, aquilo que está além dos(as) docentes, dos (as) alunos (as) e da escola, passa-se a crer naquilo que se vive aqui e agora, no território em que se habita. Visando lançar o olhar para os problemas educacionais a fim de rechaçar a representação que assola o pensamento escolar e que faz reverberar os velhos cacoetes necessários ao mercado de trabalho ­ habilidades, competências ­, este texto objetiva instigar uma docência que assuma uma postura cartográfica, mais exploratória e menos decalcadora.

This essay, of an essay type, makes use of what it calls disbelief associated with Education and, more specifically, with Physical Education, to defend multiplicities, inspired by the writings of Deleuze and Guattari (2011a, 2011b, 2012a, 2012b). Disbelief becomes a kind of first phase for the bet on multiplicity, since by discrediting representation, what is beyond the teachers, the students and the school, one starts to believe in what is lives here and now, in the territory in which one inhabits. Aiming to cast a look at educational problems in order to reject the representation that plagues school thinking and that makes the old taunts necessary for the job market ­ skills, competences ­ reverberate, the text aims to instigate a teaching that assumes a cartographic posture, more exploratory and less tracing.

Este ensayo, de tipo ensayístico, se sirve de lo que denomina descreimiento asociado a la Educación y, más concretamente, a la Educación Física, para defender las multiplicidades, inspirándose en los escritos de Deleuze y Guattari (2011a, 2011b, 2012a, 2012b). El descreimiento se convierte en una especie de primera fase para la apuesta por la multiplicidad, ya que al desprestigiar la representación, lo que está más allá de los docentes, los alumnos y la escuela, se pasa a creer en lo que se vive aquí y ahora, en el territorio que se habita. Con el objetivo de lanzar una mirada a los problemas educativos para rechazar la representación que plaga el pensamiento escolar y que hace resonar las viejas burlas necesarias para el mercado de trabajo ­ habilidades, competencias ­, el texto pretende instigar una enseñanza que asume una postura cartográfica, más exploratorio y menos rastreador.

Effects of Chronic Caffeine Consumption on Synaptic Function, Metabolism and Adenosine Modulation in Different Brain Areas.

Adenosine receptors mainly control synaptic function, and excessive activation of adenosine receptors may worsen the onset of many neurological disorders. Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity and multi-omics analyses indicate that caffeine intake modifies synaptic and metabolic processes, it is unclear how caffeine intake affects behavior, synaptic plasticity and its modulation by adenosine. We now report that male mice drinking caffeinated water (0.3 g/L) for 2 weeks were behaviorally indistinguishable (locomotion, mood, memory) from control mice (drinking water) and displayed superimposable synaptic plasticity (long-term potentiation) in different brain areas (hippocampus, prefrontal cortex, amygdala). Moreover, there was a general preservation of the efficiency of adenosine A1 and A2A receptors to control synaptic transmission and plasticity, although there was a tendency for lower levels of endogenous adenosine ensuring A1 receptor-mediated inhibition. In spite of similar behavioral and neurophysiological function, caffeine intake increased the energy charge and redox state of cortical synaptosomes. This increased metabolic competence likely involved a putative increase in the glycolytic rate in synapses and a prospective greater astrocyte-synapse lactate shuttling. It was concluded that caffeine intake does not trigger evident alterations of behavior or of synaptic plasticity but increases the metabolic competence of synapses, which might be related with the previously described better ability of animals consuming caffeine to cope with deleterious stimuli triggering brain dysfunction.

Specification of human germ cell fate with enhanced progression capability supported by hindgut organoids.

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2-3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12-13 and in an E16-17 gastrulating embryo. In vitro, hPGC-like cells (hPGCLCs) can be specified from the intermediary pluripotent stage or peri-gastrulation precursors. Here, we explore the broad spectrum of hPGCLC precursors and how different precursors impact hPGCLC development. We show that resetting precursors can give rise to hPGCLCs (rhPGCLCs) in response to BMP. Strikingly, rhPGCLCs co-cultured with human hindgut organoids progress at a pace reminiscent of in vivo hPGC development, unlike those derived from peri-gastrulation precursors. Moreover, rhPGCLC specification depends on both EOMES and TBXT, not just on EOMES as for peri-gastrulation hPGCLCs. Importantly, our study provides the foundation for developing efficient in vitro models of human gametogenesis.

The impact of inosine on hippocampal synaptic transmission and plasticity involves the release of adenosine through equilibrative nucleoside transporters rather than the direct activation of adenosine receptors.

Inosine has robust neuroprotective effects, but it is unclear if inosine acts as direct ligand of adenosine receptors or if it triggers metabolic effects indirectly modifying the activity of adenosine receptors. We now combined radioligand binding studies with electrophysiological recordings in hippocampal slices to test how inosine controls synaptic transmission and plasticity. Inosine was without effect at 30 µM and decreased field excitatory post-synaptic potentials by 14% and 33% at 100 and 300 µM, respectively. These effects were prevented by the adenosine A1 receptor antagonist DPCPX. Inosine at 300 (but not 100) µM also decreased the magnitude of long-term potentiation (LTP), an effect prevented by DPCPX and by the adenosine A2A receptor antagonist SCH58261. Inosine showed low affinity towards human and rat adenosine receptor subtypes with Ki values of > 300 µM; only at the human and rat A1 receptor slightly higher affinities with Ki values of around 100 µM were observed. Affinity of inosine at the rat A3 receptor was higher (Ki of 1.37 µM), while it showed no interaction with the human orthologue. Notably, the effects of inosine on synaptic transmission and plasticity were abrogated by adenosine deaminase and by inhibiting equilibrative nucleoside transporters (ENT) with dipyridamole and NBTI. This shows that the impact of inosine on hippocampal synaptic transmission and plasticity is not due to a direct activation of adenosine receptors but is instead due to an indirect modification of the tonic activation of these adenosine receptors through an ENT-mediated modification of the extracellular levels of adenosine.

Repercussões sindêmicas no desenvolvimento do PIBID/educação física em uma universidade sul-mineira: entre desafios e experiências exitosas / Syndemic repercussions on the development of PIBID/Physical Education at a south-minier university: between challenges and successful experiences / Repercusiones sindémicas en el desarrollo del PIBID/Educación Física en una universidad del sur minier: entre desafíos y experiencias exitosas

Objetivo: o artigo em tela visa demonstrar como a pandemia repercutiu no desenvolvimento do Programa Institucional de Bolsas de Iniciação da Docência (PIBID) de Educação Física em uma Universidade localizada no Sul de Minas Gerais. Para tanto, problematiza os principais pontos recorrentes encontrados nos relatórios de experiências elaborados por pibidianos/as integrantes do subprojeto mencionado. Entre as tendências retratadas, constatou-se enunciados relativos à atuação na escola, com ênfase nos principais desafios encontrados durante o percurso diante do modelo de Ensino Remoto Emergencial (ERE). Metodologia: Trata-se de uma pesquisa de análise documental, com quadro teórico desenvolvido a partir de referenciais os quais discutem a pandemia (aqui sendo tratada como sindemia), o ensino remoto e o PIBID. Resultados e discussão: Conforme mencionado, os materiais empíricos foram produzidos a partir dos relatórios de experiências que os discentes entregaram para seus coordenadores ao fim do programa lançado pelo edital N°03/2020. Realizamos a interpretação dos dados utilizando como inspiração o método investigativo do gesto arquivístico em consonância com a atitude crítica. Os resultados indicaram que os pibidianos/as da Educação Física afirmaram se apropriar dos conhecimentos trabalhados no interior do subprojeto, mesmo com a mudança repentina do ensino presencial para o ERE. Conclusão: Os documentos analisados evidenciaram, além disso, enunciados que apontam a eficácia das novas tecnologias da informação e comunicação, quando empregadas de modo responsável e enquanto recurso pedagógico

Objective: The article in question aims to demonstrate how the pandemic had an impact on the development of the Institutional Teaching Initiation Scholarship Program (PIBID) for Physical Education at a University located in the South of Minas Gerais. To this end, it problematizes the main recurring points found in the experience reports prepared by Pibidians members of the mentioned subproject. Among the trends portrayed, statements related to work at school were found, with an emphasis on the main challenges encountered during the journey in the face of the Emergency Remote Education (ERE) model. Methodology: This is documentary analysis research, with a theoretical framework developed from references which discuss the pandemic (here being treated as a syndemic), remote teaching and PIBID. Results and discussion: As mentioned, the empirical materials were produced based on experience reports that Pibidianos delivered to their coordinators at the end of the program launched by notice N°03/2020. We interpret the data using as inspiration the investigative method of the archival gesture in line with the critical attitude. The results revealed that the Physical Education students managed to appropriate the knowledge worked within the subproject, even with the sudden change from face-to-face teaching to ERE. Conclusion: The documents analyzed also showed the effectiveness of new information and communication technologies, when used responsibly and as a pedagogical resource

Objetivo: El artículo en cuestión tiene como objetivo demostrar cómo la pandemia tuvo impacto en el desarrollo del Programa Institucional de Becas de Iniciación a la Docencia (PIBID) en Educación Física en una Universidad ubicada en el Sur de Minas Gerais. Para ello, problematiza los principales puntos recurrentes encontrados en los relatos de experiencia elaborados por los pibidianos miembros del mencionado subproyecto. Entre las tendencias retratadas, se encontraron declaraciones relacionadas con el trabajo en la escuela, con énfasis en los principales desafíos encontrados durante el camino frente al modelo de Educación a Distancia de Emergencia (ERE). Metodología: Se trata de una investigación de análisis documental, con un marco teórico desarrollado a partir de referentes que discuten la pandemia (tratada aquí como sindemia), la enseñanza a distancia y el PIBID. Resultados y discusión: Como se mencionó, los materiales empíricos fueron elaborados a partir de relatos de experiencia que los Pibidianos entregaron a sus coordinadores al finalizar el programa lanzado mediante la convocatoria N°03/2020. Interpretamos los datos inspirándonos en el método investigativo del gesto archivístico en consonancia con la actitud crítica. Los resultados revelaron que los estudiantes de Educación Física lograron apropiarse de los conocimientos trabajados dentro del subproyecto, incluso con el cambio brusco de la docencia presencial al ERE. Conclusión: Los documentos analizados también mostraron la efectividad de las nuevas tecnologías de la información y la comunicación, cuando se utilizan de manera responsable y como recurso pedagógico

CD73-Mediated Formation of Extracellular Adenosine Is Responsible for Adenosine A2A Receptor-Mediated Control of Fear Memory and Amygdala Plasticity.

Adenosine A2A receptors (A2AR) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A2AR activation is ensured by ATP-derived extracellular adenosine formed by ecto-5'-nucleotidase or CD73. We now tested whether CD73 is also responsible to provide for the activation of A2AR in controlling fear memory and amygdala long-term potentiation (LTP). The bilateral intracerebroventricular injection of the CD73 inhibitor αß-methylene ADP (AOPCP, 1 nmol/ventricle/day) phenocopied the effect of the A2AR blockade by decreasing the expression of fear memory, an effect disappearing in CD73-knockout (KO) mice and in forebrain neuronal A2AR-KO mice. In the presence of PPADS (20 µM) to eliminate any modification of ATP/ADP-mediated P2 receptor effects, both AOPCP (100 µM) and the A2AR antagonist, SCH58261 (50 nM), decreased LTP magnitude in synapses of projection from the external capsula into the lateral amygdala, an effect eliminated in slices from both forebrain neuronal A2AR-KO mice and CD73-KO mice. These data indicate a key role of CD73 in the process of A2AR-mediated control of fear memory and underlying synaptic plasticity processes in the amygdala, paving the way to envisage CD73 as a new therapeutic target to interfere with abnormal fear-like emotional processing.

Thebromine Targets Adenosine Receptors to Control Hippocampal Neuronal Function and Damage.

Theobromine is a caffeine metabolite most abundant in dark chocolate, of which consumption is linked with a lower risk of cognitive decline. However, the mechanisms through which theobromine affects neuronal function remain ill-defined. Using electrophysiological recordings in mouse hippocampal synapses, we now characterized the impact of a realistic concentration of theobromine on synaptic transmission and plasticity. Theobromine (30 µM) facilitated synaptic transmission while decreasing the magnitude of long-term potentiation (LTP), with both effects being blunted by adenosine deaminase (2 U/mL). The pharmacological blockade of A1R with DPCPX (100 nM) eliminated the theobromine-dependent facilitation of synaptic transmission, whereas the A2AR antagonist SCH58261 (50 nM), as well as the genetic deletion of A2AR, abrogated the theobromine-induced impairment of LTP. Furthermore, theobromine prevented LTP deficits and neuronal loss, respectively, in mouse hippocampal slices and neuronal cultures exposed to Aß1-42 peptides, considered a culprit of Alzheimer's disease. Overall, these results indicate that theobromine affects information flow via the antagonism of adenosine receptors, normalizing synaptic plasticity and affording neuroprotection in dementia-related conditions in a manner similar to caffeine.

Single-cell roadmap of human gonadal development.

Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries1. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal-mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15+ and TREM2+ fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.

Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.

BACKGROUND: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA. OBJECTIVE: We investigated the role of B cells in XLN pathogenesis. METHODS: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response. RESULTS: XLN patients had normal naive B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells. CONCLUSIONS: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching.

Self-organising human gonads generated by a Matrigel-based gradient system.

BACKGROUND: Advances in three-dimensional culture technologies have led to progression in systems used to model the gonadal microenvironment in vitro. Despite demonstrating basic functionality, tissue organisation is often limited. We have previously detailed a three-dimensional culture model termed the three-layer gradient system to generate rat testicular organoids in vitro. Here we extend the model to human first-trimester embryonic gonadal tissue. RESULTS: Testicular cell suspensions reorganised into testis-like organoids with distinct seminiferous-like cords situated within an interstitial environment after 7 days. In contrast, tissue reorganisation failed to occur when mesonephros, which promotes testicular development in vivo, was included in the tissue digest. Organoids generated from dissociated female gonad cell suspensions formed loosely organised cords after 7 days. In addition to displaying testis-specific architecture, testis-like organoids demonstrated evidence of somatic cell differentiation. Within the 3-LGS, we observed the onset of AMH expression in the cytoplasm of SOX9-positive Sertoli cells within reorganised testicular cords. Leydig cell differentiation and onset of steroidogenic capacity was also revealed in the 3-LGS through the expression of key steroidogenic enzymes StAR and CYP17A1 within the interstitial compartment. While the 3-LGS generates a somatic cell environment capable of supporting germ cell survival in ovarian organoids germ cell loss was observed in testicular organoids. CONCLUSION: The 3-LGS can be used to generate organised whole gonadal organoids within 7 days. The 3-LGS brings a new opportunity to explore gonadal organogenesis and contributes to the development of more complex in vitro models in the field of developmental and regenerative medicine.