Somatostatin interneurons control the timing of developmental desynchronization in cortical networks.

Synchronous neuronal activity is a hallmark of the developing brain. In the mouse cerebral cortex, activity decorrelates during the second week of postnatal development, progressively acquiring the characteristic sparse pattern underlying the integration of sensory information. The maturation of inhibition seems critical for this process, but the interneurons involved in this crucial transition of network activity in the developing cortex remain unknown. Using in vivo longitudinal two-photon calcium imaging during the period that precedes the change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) interneurons as critical modulators of this switch in mice. Modulation of the activity of SST+ cells accelerates or delays the decorrelation of cortical network activity, a process that involves regulating the maturation of parvalbumin-expressing (PV+) interneurons. SST+ cells critically link sensory inputs with local circuits, controlling the neural dynamics in the developing cortex while modulating the integration of other interneurons into nascent cortical circuits.

Parvalbumin interneuron deficits in schizophrenia.

Parvalbumin-expressing (PV+) interneurons represent one of the most abundant subclasses of cortical interneurons. Owing to their specific electrophysiological and synaptic properties, PV+ interneurons are essential for gating and pacing the activity of excitatory neurons. In particular, PV+ interneurons are critically involved in generating and maintaining cortical rhythms in the gamma frequency, which are essential for complex cognitive functions. Deficits in PV+ interneurons have been frequently reported in postmortem studies of schizophrenia patients, and alterations in gamma oscillations are a prominent electrophysiological feature of the disease. Here, I summarise the main features of PV+ interneurons and review clinical and preclinical studies linking the developmental dysfunction of cortical PV+ interneurons with the pathophysiology of schizophrenia.

Cortical somatostatin long-range projection neurons and interneurons exhibit divergent developmental trajectories.

The mammalian cerebral cortex contains an extraordinary diversity of cell types that emerge by implementing different developmental programs. Delineating when and how cellular diversification occurs is particularly challenging for cortical inhibitory neurons because they represent a small proportion of all cortical cells and have a protracted development. Here, we combine single-cell RNA sequencing and spatial transcriptomics to characterize the emergence of neuronal diversity among somatostatin-expressing (SST+) cells in mice. We found that SST+ inhibitory neurons segregate during embryonic stages into long-range projection (LRP) neurons and two types of interneurons, Martinotti cells and non-Martinotti cells, following distinct developmental trajectories. Two main subtypes of LRP neurons and several subtypes of interneurons are readily distinguishable in the embryo, although interneuron diversity is likely refined during early postnatal life. Our results suggest that the timing for cellular diversification is unique for different subtypes of SST+ neurons and particularly divergent for LRP neurons and interneurons.

Thioarylation of 6-Amino-2,3,6-trideoxy-d-manno-oct-2-ulosonic Acid (IminoKdo): Access to 3,6-Disubstituted Picolinates and Mechanistic Insights.

In this work, we present a metal-free coupling protocol for the regio- and stereoselective C3-thioarylation of 6-amino-2,3,6-trideoxy-d-manno-oct-2-ulosonic acid (iminoKdo). The developed procedure enables the coupling of electron-rich, electron-deficient, and hindered arylthiols, providing a series of C3-modified iminoKdo derivatives in moderate to good yields. Elucidation of active species through controlled experimental studies and time-lapse 31 P NMR analysis provides insights into the reaction mechanism. We demonstrate that, following a tandem Staudinger/aza-Wittig reaction of an azido-containing keto ester, an inseparable equimolar mixture of imine/enamine is formed. The enamine then undergoes a Stork-like nucleophilic attack with the in situ-formed disulfide reagent, resulting in the formation of the coupling products. Additionally, we describe a rarely reported acid-promoted aromatization of the C3-thioarylated iminoKdo skeleton into 3,6-disubstituted picolinates, which are reminiscent of dichotomines.

The single-cell and spatial transcriptional landscape of human gastrulation and early brain development.

The emergence of the three germ layers and the lineage-specific precursor cells orchestrating organogenesis represent fundamental milestones during early embryonic development. We analyzed the transcriptional profiles of over 400,000 cells from 14 human samples collected from post-conceptional weeks (PCW) 3 to 12 to delineate the dynamic molecular and cellular landscape of early gastrulation and nervous system development. We described the diversification of cell types, the spatial patterning of neural tube cells, and the signaling pathways likely involved in transforming epiblast cells into neuroepithelial cells and then into radial glia. We resolved 24 clusters of radial glial cells along the neural tube and outlined differentiation trajectories for the main classes of neurons. Lastly, we identified conserved and distinctive features across species by comparing early embryonic single-cell transcriptomic profiles between humans and mice. This comprehensive atlas sheds light on the molecular mechanisms underlying gastrulation and early human brain development.

Synthesis of immunostimulatory saponins: A sweet challenge for carbohydrate chemists.

Saponins are a large family of natural glycosides showing a wide range of biological activities. Current research efforts on saponins as vaccine adjuvants have been mainly focused on the development of synthetic analogs. By mimicking the immunomodulatory saponins from Quillaja saponaria (QS), less complex and readily accessible analogs have been synthesized to improve the industrial applicability and efficacy of saponins as vaccine adjuvants. Through the exploration of several structural modifications on the skeleton of QS saponins, including changes in the sugar and aglycone compositions as well as in the nature and configuration of the glycosidic bonds, structure-activity relationship (SAR) studies developed by Pr. Gin in the early 2010s were taken as a starting point for the development of a new generation of immunomodulatory candidates. In this review, the recent synthetic strategies and SAR studies of mono- and bidesmosidic QS saponins are discussed. Original concepts of vaccination including self-adjuvanticity and the development of saponin-based glycoconjugates are described. The synthesis and semi-synthesis of saponin alternatives to QS, such as Momordica saponin and onjisaponin derivatives, are also discussed in this review.

Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.

BACKGROUND: While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition. METHODS: Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population. RESULTS: Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability. CONCLUSIONS: We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders.

Cortical wiring by synapse type-specific control of local protein synthesis.

Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. We identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of messenger RNA {mRNA} translation in a cell type-specific and synapse type-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV+ interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system.

Evaluation of Azido 3-Deoxy-d-manno-oct-2-ulosonic Acid (Kdo) Analogues for Click Chemistry-Mediated Metabolic Labeling of Myxococcus xanthus DZ2 Lipopolysaccharide.

Metabolic labeling paired with click chemistry is a powerful approach for selectively imaging the surfaces of diverse bacteria. Herein, we explored the feasibility of labeling the lipopolysaccharide (LPS) of Myxococcus xanthus-a Gram-negative predatory social bacterium known to display complex outer membrane (OM) dynamics-via growth in the presence of distinct azido (-N3) analogues of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo). Determination of the LPS carbohydrate structure from strain DZ2 revealed the presence of one Kdo sugar in the core oligosaccharide, modified with phosphoethanolamine. The production of 8-azido-8-deoxy-Kdo (8-N3-Kdo) was then greatly improved over previous reports via optimization of the synthesis of its 5-azido-5-deoxy-d-arabinose precursor to yield gram amounts. The novel analogue 7-azido-7-deoxy-Kdo (7-N3-Kdo) was also synthesized, with both analogues capable of undergoing in vitro strain-promoted azide-alkyne cycloaddition (SPAAC) "click" chemistry reactions. Slower and faster growth of M. xanthus was displayed in the presence of 8-N3-Kdo and 7-N3-Kdo (respectively) compared to untreated cells, with differences also seen for single-cell gliding motility and type IV pilus-dependent swarm community expansion. While the surfaces of 8-N3-Kdo-grown cells were fluorescently labeled following treatment with dibenzocyclooctyne-linked fluorophores, the surfaces of 7-N3-Kdo-grown cells could not undergo fluorescent tagging. Activity analysis of the KdsB enzyme required to activate Kdo prior to its integration into nascent LPS molecules revealed that while 8-N3-Kdo is indeed a substrate of the enzyme, 7-N3-Kdo is not. Though a lack of M. xanthus cell aggregation was shown to expedite growth in liquid culture, 7-N3-Kdo-grown cells did not manifest differences in intrinsic clumping relative to untreated cells, suggesting that 7-N3-Kdo may instead be catabolized by the cells. Ultimately, these data provide important insights into the synthesis and cellular processing of valuable metabolic labels and establish a basis for the elucidation of fundamental principles of OM dynamism in live bacterial cells.

Molecular and cellular evolution of the primate dorsolateral prefrontal cortex.

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates.

Serotonergic regulation of bipolar cell survival in the developing cerebral cortex.

One key factor underlying the functional balance of cortical networks is the ratio of excitatory and inhibitory neurons. The mechanisms controlling the ultimate number of interneurons are beginning to be elucidated, but to what extent similar principles govern the survival of the large diversity of cortical inhibitory cells remains to be investigated. Here, we investigate the mechanisms regulating developmental cell death in neurogliaform cells, bipolar cells, and basket cells, the three main populations of interneurons originating from the caudal ganglionic eminence and the preoptic region. We found that all three subclasses of interneurons undergo activity-dependent programmed cell death. However, while neurogliaform cells and basket cells require glutamatergic transmission to survive, the final number of bipolar cells is instead modulated by serotonergic signaling. Together, our results demonstrate that input-specific modulation of neuronal activity controls the survival of cortical interneurons during the critical period of programmed cell death.

Neuroinflammation and galectins: a key relationship in neurodegenerative diseases.

Neurodegeneration is a pathological condition that is associated with the loss of neuronal function and structure. In neurodegenerative diseases, mounting evidence indicates that neuroinflammation is a common factor that contributes to neuronal damage and neurodegeneration. Neuroinflammation is characterized by the activation of microglia, the neuroimmune cells of the central nervous system (CNS), which have been implicated as active contributors to neuronal damage. Glycan structure modification is defining the outcome of neuroinflammation and neuronal regeneration; moreover, the expression of galectins, a group of lectins that specifically recognize ß-galactosides, has been proposed as a key factor in neuronal regeneration and modulation of the inflammatory response. Of the different galectins identified, galectin-1 stimulates the secretion of neurotrophic factors in astrocytes and promotes neuronal regeneration, whereas galectin-3 induces the proliferation of microglial cells and modulates cell apoptosis. Galectin-8 emerged as a neuroprotective factor, which, in addition to its immunosuppressive function, could generate a neuroprotective environment in the brain. This review describes the role of galectins in the activation and modulation of astrocytes and microglia and their anti- and proinflammatory functions within the context of neuroinflammation. Furthermore, it discusses the potential use of galectins as a therapeutic target for the inflammatory response and remodeling in damaged tissues in the central nervous system.

Input-specific control of interneuron numbers in nascent striatal networks.

The assembly of functional neuronal circuits requires appropriate numbers of distinct classes of neurons, but the mechanisms through which their relative proportions are established remain poorly defined. Investigating the mouse striatum, we found that the two most prominent subtypes of striatal interneurons, parvalbumin-expressing (PV+) GABAergic and cholinergic (ChAT+) interneurons, undergo extensive programmed cell death between the first and second postnatal weeks. Remarkably, the survival of PV+ and ChAT+ interneurons is regulated by distinct mechanisms mediated by their specific afferent connectivity. While long-range cortical inputs control PV+ interneuron survival, ChAT+ interneuron survival is regulated by local input from the medium spiny neurons. Our results identify input-specific circuit mechanisms that operate during the period of programmed cell death to establish the final number of interneurons in nascent striatal networks.

Mouse and human share conserved transcriptional programs for interneuron development.

Genetic variation confers susceptibility to neurodevelopmental disorders by affecting the development of specific cell types. Changes in cortical and striatal γ-aminobutyric acid­expressing (GABAergic) neurons are common in autism and schizophrenia. In this study, we used single-cell RNA sequencing to characterize the emergence of cell diversity in the human ganglionic eminences, the transitory structures of the human fetal brain where striatal and cortical GABAergic neurons are generated. We identified regional and temporal diversity among progenitor cells underlying the generation of a variety of projection neurons and interneurons. We found that these cells are specified within the human ganglionic eminences by transcriptional programs similar to those previously identified in rodents. Our findings reveal an evolutionarily conserved regulatory logic controlling the specification, migration, and differentiation of GABAergic neurons in the human telencephalon.

Understanding the causes and consequences of variability in infant ERP editing practices.

The current study examined the effects of variability on infant event-related potential (ERP) data editing methods. A widespread approach for analyzing infant ERPs is through a trial-by-trial editing process. Researchers identify electroencephalogram (EEG) channels containing artifacts and reject trials that are judged to contain excessive noise. This process can be performed manually by experienced researchers, partially automated by specialized software, or completely automated using an artifact-detection algorithm. Here, we compared the editing process from four different editors-three human experts and an automated algorithm-on the final ERP from an existing infant EEG dataset. Findings reveal that agreement between editors was low, for both the numbers of included trials and of interpolated channels. Critically, variability resulted in differences in the final ERP morphology and in the statistical results of the target ERP that each editor obtained. We also analyzed sources of disagreement by estimating the EEG characteristics that each human editor considered for accepting an ERP trial. In sum, our study reveals significant variability in ERP data editing pipelines, which has important consequences for the final ERP results. These findings represent an important step toward developing best practices for ERP editing methods in infancy research.

Mutations associated with pyrethroid resistance in Varroa mite, a parasite of honey bees, are widespread across the United States.

BACKGROUND: Managed honey bees are key pollinators of many crops and play an essential role in the United States food production. For more than ten years, beekeepers in the United States have been reporting high rates of colony losses. One of the drivers of these losses is the parasitic mite Varroa destructor. Maintaining healthy honey bee colonies in the United States is dependent on a successful control of this mite. The pyrethroid tau-fluvalinate (Apistan®) was among the first synthetic varroacides registered in the United States. With over 20 years of use, mites resistant to Apistan® have emerged, and so it is unsurprising that treatment failures have been reported. Resistance to tau-fluvalinate in US mite populations is associated with point mutations at position 925 of the voltage-gated sodium channel. RESULTS: Here, we have generated a distribution map of pyrethroid resistance alleles in Varroa samples collected from US apiaries in 2016 and 2017, using a high throughput allelic discrimination assay based on TaqMan®. Our results evidence that knockdown resistance (kdr)-type mutations are widely distributed in Varroa populations across the country showing high variability among apiaries. We used these data to predict the phenotype of the mites in the case of treatments with pyrethroids. CONCLUSION: We highlight the relevance of monitoring the resistance in mite populations to achieve an efficient control of this pest. We also put forward the benefits of implementing this methodology to provide data for designing pest management programs aiming to control Varroa. © 2021 Society of Chemical Industry.

Cáncer cervicouterino en Jujuy: Descripción de casos y evaluación de cumplimiento de tratamiento oncológico / Cervical Cancer in Jujuy province: description of cases and evaluation of compliance with oncological treatment

INTRODUCCIÓN: El cáncer cervicouterino (CC) es la cuarta causa de muerte por cáncer en mujeres. Las demoras en el tratamiento se asocian a un peor control de la enfermedad. Los objetivos de este estudio fueron describir las características de mujeres con diagnóstico de CC en la red pública de Jujuy y evaluar el grado de cumplimiento del tratamiento oncológico. MÉTODOS: Se realizó un estudio observacional de cohorte retrospectiva de mujeres con diagnóstico de CC en 2015 y 2016 en el Hospital Pablo Soria (centro de derivación provincial). Se registraron las fechas de las principales modalidades terapéuticas: cirugía, quimioterapia, radioterapia y braquiterapia. Se definió la duración recomendada de tratamiento según la literatura, considerando las diferentes combinaciones de terapéuticas (60, 90 o 120 días). RESULTADOS: Se incluyó a 78 mujeres con diagnóstico de CC. Entre quienes presentaban indicación de tratamiento oncológico, el 64% (n=48) no cumplió con el tratamiento indicado, por no haberlo iniciado (n=17) o por concluirlo en un intervalo mayor al recomendado (n=31). Entre las mujeres que iniciaron tratamiento, 48% (n=28) lo finalizó a tiempo. Tener más de 5 hijos se asoció a incumplimiento de tratamiento con quimio-radioterapia. La modalidad de inicio más tardío fue la braquiterapia, que debía realizarse en otra provincia por falta de disponibilidad local. DISCUSIÓN: El cumplimiento subóptimo del tratamiento de CC continúa siendo un problema de salud pública

Cervical Cáncer in Jujuy province: description of cases and evaluation of compliance with oncological treatment / Cáncer cervicouterino en jujuy: descripción de casos y evaluación de cumplimiento de tratamiento oncológico

RESUMEN INTRODUCCIÓN : El cáncer cervicouterino (CC) es la cuarta causa de muerte por cáncer en mujeres. Las demoras en el tratamiento se asocian a un peor control de la enfermedad. Los objetivos de este estudio fueron describir las características de mujeres con diagnóstico de CC en la red pública de Jujuy y evaluar el grado de cumplimiento del tratamiento oncológico. MÉTODOS : Se realizó un estudio observacional de cohorte retrospectiva de mujeres con diagnóstico de CC en 2015 y 2016 en el Hospital Pablo Soria (centro de derivación provincial). Se registraron las fechas de las principales modalidades terapéuticas: cirugía, quimioterapia, radioterapia y braquiterapia. Se definió la duración recomendada de tratamiento según la literatura, considerando las diferentes combinaciones de terapéuticas (60, 90 o 120 días). RESULTADOS : Se incluyó a 78 mujeres con diagnóstico de CC. Entre quienes presentaban indicación de tratamiento oncológico, el 64% (n=48) no cumplió con el tratamiento indicado, por no haberlo iniciado (n=17) o por concluirlo en un intervalo mayor al recomendado (n=31). Entre las mujeres que iniciaron tratamiento, 48% (n=28) lo finalizó a tiempo. Tener más de 5 hijos se asoció a incumplimiento de tratamiento con quimio-radioterapia. La modalidad de inicio más tardío fue la braquiterapia, que debía realizarse en otra provincia por falta de disponibilidad local. DISCUSIÓN : El cumplimiento subóptimo del tratamiento de CC continúa siendo un problema de salud pública.

ABSTRACT INTRODUCTION : Cervical cáncer (CC) is the fourth cause of cancer-related death among women worldwide. Delays in treatment are associated with worse disease control. The objectives of this study were to describe the characteristics of women with newly-diagnosed CC in the Argentine province of Jujuy, and to evaluate the degree of treatment compliance. METHODS : An observational retrospective cohort study was conducted on women with CC diagnosed at Hospital Pablo Soria (state-wide referral center in Jujuy) in 2015-2016. Dates of the main treatment modalities were registered (surgery, chemotherapy, radiotherapy and brachytherapy). Recommended treatment duration was extracted from the literature, considering the different treatment combinations (60, 90 or 120 days). RESULTS : A total of 78 women with CC were included. Of all women who were prescribed oncological treatment, 64% (n=48) showed inappropriate compliance, either due to not having started treatment (n=17) or due to delays in completion of treatment (n=31). Among women who initiated treatment, 48% (n=28) completed it on time. For women receiving chemotherapy and radiotherapy, having more than 5 children was associated with treatment delays. Brachytherapy showed longer delays than other treatment modalities, due to lack of local availability and the need to travel to a different province for treatment. DISCUSSION : Suboptimal compliance with CC treatment remains a public health issue.