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Leguminous plants are known to require phosphorus fertilizers and inoculation with nitrogen fixing rhizobia for optimum yield but other nutrients may also be lacking. In this study, the most limiting nutrients for legume growth were determined in soils where the crops had not responded to P and rhizobial inoculation in field trials, using the double pot technique. Soils were collected from 17 farmers' fields in West Kenya, Northern Nigeria, Eastern and Southern Rwanda, South-west and North-west Sierra Leone. Plant growth and mean biomass were measured on soils to which a full nutrient solution, containing phosphorus (P), potassium (K), magnesium (Mg), sulfur (S) and micronutrients (MN) were added, and which were compared to a control (no nutrient added), and individual omissions of each nutrient. The relationship between soil properties and nutrient deficiencies was explored. Nutrient limitations were found to differ between soils, both within and across countries. Generally, each soil was potentially deficient in at least one nutrient, with K, P, Mg, MN and S emerging as most limiting in 88, 65, 59, 18, and 12% of tested soils, respectively. While K was the most limiting nutrient in soils from Kenya and Rwanda, P was most limiting in soils from Nigeria. P and K were equally limiting in soils from Sierra Leone. Mg was found limiting in two soils from Kenya and three soils from Rwanda and one soil each in Nigeria and Sierra Leone. Micronutrients were found to be limiting in one soil from Nigeria and one soil from Rwanda. Estimates of nutrient deficiency using growth and mean biomass were found to be correlated with each other although the latter proved to be a more sensitive measure of deficiency. With few exceptions, the relation between soil parameters and nutrient deficiencies was weak and there were no significant relations between deficiency of specific nutrients and the soil content of these elements. Although our results cannot be translated directly to the field, they confirm that individual and multiple nutrient deficiencies were common in these “non-responsive” soils and may have contributed to reported low yields. This highlights the need for balanced nutrition in legume production in SSA.

O presente artigo expõe considerações teóricas que buscam refletir, criticamente, como a educação e os processos de estratificação são tratados no contexto contemporâneo mediante os paradigmas neoliberais. Desse modo, esboça breves considerações acerca da trajetória das políticas de financiamento da educação brasileira e do seu respectivo sistema de avaliação por meio do Índice de Desenvolvimento da Educação Básica - IDEB. Ressalta a correlação entre o IDEB das escolas da rede municipal e a renda familiar da cidade de Montes Claros localizada no Norte de Minas Gerais. Ressalta a necessidade uma abordagem multidimensional capaz de interpretar as fragmentações e os deslocamentos contidos em um contexto social que ultrapassem as variáveis oriundas da política de incentivo financeiro aos municípios e às escolas que atingem as metas previstas pelo IDEB.

Tissue engineering strategies aim at characterizing and at optimizing the cellular component that is combined with biomaterials, for improved tissue regeneration. Here, we present the immunoMap of apical papilla, the native tissue from which SCAPs are derived. We characterized stem cell niches that correspond to a minority population of cells expressing Mesenchymal stromal/Stem Cell (CD90, CD105, CD146) and stemness (SSEA4 and CD49f) markers as well as endothelial cell markers (VWF, CD31). Based on the colocalization of TKS5 and cortactin markers, we detected migration-associated organelles, podosomes-like structures, in specific regions and, for the first time, in association with stem cell niches in normal tissue. From six healthy teenager volunteers, each with two teeth, we derived twelve cell banks, isolated and amplified under 21 or 3% O 2 . We confirmed a proliferative advantage of all banks when cultured under 3% versus 21% O 2 . Interestingly, telomerase activity was similar to that of the highly proliferative hiPSC cell line, but unrelated to O 2 concentration. Finally, SCAPs embedded in a thixotropic hydrogel and implanted subcutaneously in immunodeficient mice were protected from cell death with a slightly greater advantage for cells preconditioned at 3% O 2 .

Huntington disease (HD) is a neurodegenerative disorder caused by polyglutamine-encoding CAG repeat expansion in the huntingtin (HTT) gene. HTT is involved in the axonal transport of vesicles containing brain-derived neurotrophic factor (BDNF). In HD, diminished BDNF transport leads to reduced BDNF delivery to the striatum, contributing to striatal and cortical neuronal death. Pridopidine is a selective and potent sigma-1 receptor (S1R) agonist currently in clinical development for HD. The S1R is located at the endoplasmic reticulum (ER)-mitochondria interface, where it regulates key cellular pathways commonly impaired in neurodegenerative diseases. We used a microfluidic device that reconstitutes the corticostriatal network, allowing the investigation of presynaptic dynamics, synaptic morphology and transmission, and postsynaptic signaling. Culturing primary neurons from the HD mouse model Hdh CAG140/+ provides a "disease-on-a-chip" platform ideal for investigating pathogenic mechanisms and drug activity. Pridopidine rescued the trafficking of BDNF and TrkB resulting in an increased neurotrophin signaling at the synapse. This increased the capacity of HD neurons to release glutamate and restored homeostasis at the corticostriatal synapse. These data suggest that pridopidine enhances the availability of corticostriatal BDNF via S1R activation, leading to neuroprotective effects., Competing Interests: Declaration of Competing Interest Michael R. Hayden is CEO of Prilenia Therapeutics. Michal Geva and Noga-Gershoni Emek are employees of Prilenia Therapeutics. Frédéric Saudou received a research grant from Teva Pharmaceutical and then from Prilenia during the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All additional authors have declared that no conflict of interest exists., (Copyright © 2022. Published by Elsevier Inc.)

Background: Perineuronal nets (PNNs) are specialized extracellular matrix structures mainly found around fast-spiking parvalbumin (FS-PV) interneurons. In the adult, their degradation alters FS-PV-driven functions, such as brain plasticity and memory, and altered PNN structures have been found in neurodevelopmental and central nervous system disorders such as Alzheimer's disease, leading to interest in identifying targets able to modify or participate in PNN metabolism. The serine protease tissue-type plasminogen activator (tPA) plays multifaceted roles in brain pathophysiology. However, its cellular expression profile in the brain remains unclear and a possible role in matrix plasticity through PNN remodeling has never been investigated., Result: By combining a GFP reporter approach, immunohistology, electrophysiology, and single-cell RT-PCR, we discovered that cortical FS-PV interneurons are a source of tPA in vivo. We found that mice specifically lacking tPA in FS-PV interneurons display denser PNNs in the somatosensory cortex, suggesting a role for tPA from FS-PV interneurons in PNN remodeling. In vitro analyses in primary cultures of mouse interneurons also showed that tPA converts plasminogen into active plasmin, which in turn, directly degrades aggrecan, a major structural chondroitin sulfate proteoglycan (CSPG) in PNNs., Conclusions: We demonstrate that tPA released from FS-PV interneurons in the central nervous system reduces PNN density through CSPG degradation. The discovery of this tPA-dependent PNN remodeling opens interesting insights into the control of brain plasticity., (© 2022. The Author(s).)

Huntington's disease (HD) is a late-onset neurological disorder for which therapeutics are not available. Its key pathological mechanism involves the proteolysis of polyglutamine-expanded (polyQ-expanded) mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes an HTT (HTTΔ12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon 12. We show that HTTΔ12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTTΔ12 retained overall biochemical and structural properties similar to those of wt-HTT. We generated mice in which HTT exon 12 was truncated and found that the canonical exon 12 was dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking. Finally, we pharmacologically induced HTTΔ12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon 12 splice switching from HTT may provide an alternative therapeutic strategy for HD.

Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell-derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

BDNF levels are reduced in the chronically stressed brain, in the area of hippocampus. Part of the hippocampal BDNF is provided by neuronal projection of the entorhinal cortex. Studying the cortico-hippocampal transport of BDNF in vivo is technically difficult. Here, we describe a protocol that reproduces mouse cortico-hippocampal circuit in vitro by plating neurons on the microfluidic devices and infecting the neurons with virus-encoding BDNF-mCherry, which allows investigation of the effects of elevated corticosterone levels on BDNF axonal transport. For complete details on the use and execution of this protocol, please refer to Agasse et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.

The neuronal serine protease tissue-type Plasminogen Activator (tPA) is an important player of the neuronal survival and of the synaptic plasticity. Thus, a better understanding the mechanisms regulating the neuronal trafficking of tPA is required to further understand how tPA can influence brain functions. Using confocal imaging including living cells and high-resolution cell imaging combined with an innovating labeling of tPA, we demonstrate that the neuronal tPA is contained in endosomal vesicles positives for Rabs and in exosomal vesicles positives for synaptobrevin-2 (VAMP2) in dendrites and axons. tPA-containing vesicles differ in their dynamics with the dendritic tPA containing-vesicles less mobile than the axonal tPA-containing vesicles, these laters displaying mainly a retrograde trafficking. Interestingly spontaneous exocytosis of tPA containing-vesicles occurs largely in dendrites.

The anti-apoptotic proteins Bcl-x L and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-x L activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-x L strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-x L strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling., Competing Interests: DV, CA, K-UP and RM are co-inventors on the following patent 'Treatment of neurological or neurodegenerative disorders' (WO2011023250A1). The original patent W02011023250A1 was completed and now published under the number W02014187879A2 (additional references: EP2805972A1, WO2014187879A3). The present invention relates to the field of antibodies. In particular, it provides an anti-NMDA antibody or fragment or derivative thereof which is effective in inhibiting the deleterious effects of tissue-type plasminogen activator (tPA) mediated by N-methyl-d-aspartate (NMDA) receptors being toxic to neurons and inflicting damage to the neurovascular unit/blood–brain barrier (BBB) or regulating it in a way that leads to pathological consequences.

Few interventions have targeted perceived stress as a co-occurring construct central to substance use and subsequent HIV/AIDS risk reduction among African American urban young adults. The Color It Real Program was a seven session, weekly administered age-specific and culturally-tailored intervention designed to provide substance abuse and HIV education and reduce perceived stress among African Americans ages 18 to 24 in Atlanta, GA. Effectiveness was assessed through a quasi-experimental study design that consisted of intervention (n = 122) and comparison (n = 70) groups completing a pre- and post-intervention survey. A series of Analysis of Variance (ANOVA) tests were used to assess pre- to post-intervention changes between study groups. For intervention participants, perceived stress levels were significantly reduced by the end of the intervention (t(70) = 2.38, p = 0.020), condom use at last sexual encounter significantly increased (F = 4.43, p = 0.0360), intervention participants were significantly less likely to drink five or more alcoholic drinks in one sitting (F = 5.10, p = 0.0245), and to use clean needles when injecting the drug (F = 36.99, p = 0.0001). This study is among the first of its kind to incorporate stress management as an integral approach to HIV/SA prevention. The program has implications for the design of other community-based, holistic approaches to addressing substance use and risky behaviors for young adults.

Tissue-type plasminogen activator (tPA) a serine protease is constituted of five functional domains through which it interacts with different substrates, binding proteins, and receptors. In the last years, great interest has been given to the clinical relevance of targeting tPA in different diseases of the central nervous system, in particular stroke. Among its reported functions in the central nervous system, tPA displays both neurotrophic and neurotoxic effects. How can the protease mediate such opposite functions remain unclear but several hypotheses have been proposed. These include an influence of the degree of maturity and/or the type of neurons, of the level of tPA, of its origin (endogenous or exogenous) or of its form (single chain tPA versus two chain tPA). In this review, we will provide a synthetic snapshot of our current knowledge regarding the natural history of tPA and discuss how it sustains its pleiotropic functions with focus on excitotoxic/ischemic neuronal death and neuronal survival.

Congenital bronchial atresia is a congenital obliteration of a segmental or lobar bronchus resulting in an inflation of the correspondent parenchyma. It may lead to infectious complications and in the long-term to alteration of the adjacent lung parenchyma. As it usually occurs in young and healthy patients with normal lungs, this disorder is particularly suitable for a full endoscopic pulmonary resection. We report our recent experience of two lobectomies and one segmentectomy in three patients.