AVNP2 protects against cognitive impairments induced by C6 glioma by suppressing tumour associated inflammation in rats

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).Glioblastoma is a kind of malignant tumour and originates from the central nervous system. In the last century, some researchers and clinician have noticed that the psychosocial and neurocognitive functioning of patients with malignant gliomas can be impaired. Many clinical studies have demonstrated that part of patients, adults or children, diagnosed with glioblastoma will suffer from cognitive deficiency during their clinical course, especially in long-term survivors. Many nanoparticles (NPs) can inhibit the biological functions of tumours by modulating tumour-associated inflammation, which provokes angiogenesis and tumour growth. As one of the best antiviral nanoparticles (AVNPs), AVNP2 is the 2nd generation of AVNP2 that have been conjugated to graphite-graphene for improving physiochemical performance and reducing toxicity. AVNP2 inactivates viruses, such as the H1N1 and H5N1influenza viruses and even the SARS coronavirus, while it inhibits bacteria, such as MRSA and E. coli. As antimicrobials, nanoparticles are considered to be one of the vectors for the administration of therapeutic compounds. Yet, little is known about their potential functionalities and toxicities to the neurotoxic effects of cancer. Herein, we explored the functionality of AVNP2 on inhibiting C6 in glioma-bearing rats. The novel object-recognition test and open-field test showed that AVNP2 significantly improved the neuro-behaviour affected by C6 glioma. AVNP2 also alleviated the decline of long-term potentiation (LTP) and the decreased density of dendritic spines in the CA1 region induced by C6. Western blot assay and immunofluorescence staining showed that the expressions of synaptic-related proteins (PSD-95 and SYP) were increased, and these findings were in accordance with the results mentioned above. It revealed that the sizes of tumours in C6 glioma-bearing rats were smaller after treatment with AVNP2. The decreased expression of inflammatory factors (IL-1β, IL-6 and TNF-α) by Western blotting assay and ELISA, angiogenesis protein (VEGF) by Western blotting assay and other related proteins (BDNF, NF-ĸB, iNOS and COX-2) by Western blotting assay in peri-tumour tissue indicated that AVNP2 could control tumour-associated inflammation, thus efficiently ameliorating the local inflammatory condition and, to some extent, inhibiting angiogenesis in C6-bearing rats. In conclusion, our results suggested that AVNP2 could have an effect on the peri-tumor environment, obviously restraining the growth progress of gliomas, and eventually improving cognitive levels in C6-bearing rats.Peer reviewedProo

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

NEUROPSYCHOPEDAGOGICAL PERSPECTIVE: RELATIONSHIPS BETWEEN WORKING MEMORY AND MOTOR, INHIBITORY CONTROL, AND LINGUISTIC DEVELOPMENT IN ELEMENTARY SCHOOL

Working memory plays a pivotal role in cognitive functioning, serving as a dynamic interface for processing and integrating information across various domains. It is crucial for executing complex tasks such as reading comprehension, mathematical problem-solving, and logical reasoning. This study investigates the relationship between working memory and motor skills, inhibitory control, and language abilities in elementary school students, highlighting the role of specific assessment instruments in this analysis. The research involved 1107 students, aged 7 to 10 years, from public schools in Joinville, Brazil. Working memory was evaluated using the Neuropsychopedagogical Screening Scale for Working Memory (NSSWM), which comprises 23 items that assess the temporary storage and processing of information needed for tasks such as language comprehension, arithmetic, and problem-solving. Motor skills were assessed using the Neuropsychopedagogical Screening for Children's Motor Development, a 7-item scale focusing on motor coordination, fine motor control, and organizational skills during school activities. Inhibitory control was measured with the Child Inhibitory Control Screening Scale (CICS), which includes 18 scenarios that evaluate inhibitory responses, planning, and impulsivity. Phonological skills were assessed using the Screening Scale for Phonological Skills (SSPS), which measures the ability to recognize formal language characteristics through 17 items. Lastly, reading and writing skills were evaluated using the Children's Reading and Writing Screening Scale (CRWSS), a 16-item scale designed to identify potential difficulties in acquiring these skills in a school setting. The results revealed significant correlations between working memory and other cognitive domains, with motor skills exhibiting the strongest association (r=0.916, p=0.012). Additionally, inhibitory control (r=0.732, p=0.028) and phonological awareness (r=0.815, p=0.034) showed strong correlations with working memory, indicating that students with better-developed skills in these areas tend to perform better in working memory tasks, which, in turn, positively impacts their academic performance. The study underscores the importance of early neuropsychopedagogical interventions that address both cognitive and motor development. By employing specific, targeted assessment instruments, educators and mental health professionals can better identify students at risk of academic difficulties and implement effective strategies to enhance their cognitive and behavioral development, ultimately fostering a more supportive and inclusive learning environment.  Article visualizations

Mechanosensing is critical for axon growth in the developing brain.

During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.This work was supported by the German National Academic Foundation (scholarship to D.E.K.), Wellcome Trust and Cambridge Trusts (scholarships to A.J.T.), Winston Churchill Foundation of the United States (scholarship to S.K.F.), Herchel Smith Foundation (Research Studentship to S.K.F.), CNPq 307333/2013-2 (L.d.F.C.), NAP-PRP-USP and FAPESP 11/50761-2 (L.d.F.C.), UK EPSRC BT grant (J.G.), Wellcome Trust WT085314 and the European Research Council 322817 grants (C.E.H.); an Alexander von Humboldt Foundation Feodor Lynen Fellowship (K.F.), UK BBSRC grant BB/M021394/1 (K.F.), the Human Frontier Science Program Young Investigator Grant RGY0074/2013 (K.F.), the UK Medical Research Council Career Development Award G1100312/1 (K.F.) and the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R21HD080585 (K.F.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/nn.439

Un pueblo y una clave para filosofar

Unprecedent times to reflect and ponder: Is it possible to claim an unified way of thinking? Will these circumstances help us catch a glimpse of another way to be in the world? To tear modern and post-modern parameters we need to view things from a different perspective. Dussel describes this as a new way of creating the world, transmodernity. The means to recognize and live other worlds are diverse and unknown, we will show one that existed centuries ago, when we weren't America yet and colonization, an imposition that tried to silence native peoples, didn't exist. By aiming at a decolonizing atitute, we invite ourselves to experiment an "insertion or interculturation" or an "indigenization"; they are possibilities to surpass the dominant racional paradigm and acess the ‘ayxa sk’ujol, to be between humans "with heart" and "not between cerebrals". A possible way to acess this ancestral knowledge requires a contextual key upon an unknown and disregarded language. We'll use Lenkersdorf in his book “Filosofar en clave tojolabal” as well as some papers written by mayan people on the contemporary resistance's struggle. The Mayan language has the sound "tic" as sufix and it's the key that makes we, westerns, baffled, confused or is beyond our understanding.Tiempos inéditos para reflexionar y preguntarnos ¿Será posible sospechar que hay un pensamiento único? ¿Ayudará la situación a vislumbrar una forma diferente de estar en el mundo? Para romper los parámetros de la modernidad y posmodernidad necesitamos situarnos en otro lugar, Dussel lo describe como una nueva manera de construir el mundo, la transmodernidad. Los caminos para reconocer y vivir otros mundos son desconocidos y diversos, presentaremos uno existente desde hace varios siglos, cuando no era América y no existía la colonización, imposición que intentó silenciar a pueblos originarios. Pretender una actitud descolonizadora invita a experimentar una inserción - inculturación o una indigenización; son posibilidades para superar el paradigma racional dominante y accesar el ‘ayxa sk’ujol, ser entre los humanos “con corazón” y “no entre los cerebrales”. Un posible acceso a este saber ancestral, requiere de una clave en contexto mediante una lengua desconocida y desconsiderada. Seguiremos a Lenkersdorf  en su libro Filosofar en clave tojolabal y también nos ayudaremos de algunos comunicados de pueblos mayas en lucha contemporánea de resistencia. Esta lengua maya contiene el sonido “tic”, como desinencia y es la clave que a nosotros los occidentales desconcierta, confunde o de plano no entendemos

Primary Postnatal Dorsal Root Ganglion Culture from Conventionally Slaughtered Calves

Neurological disorders in ruminants have an important impact on veterinary health, but very few host-specific in vitro models have been established to study diseases affecting the nervous system. Here we describe a primary neuronal dorsal root ganglia (DRG) culture derived from calves after being conventionally slaughtered for food consumption. The study focuses on the in vitro characterization of bovine DRG cell populations by immunofluorescence analysis. The effects of various growth factors on neuron viability, neurite outgrowth and arborisation were evaluated by morphological analysis. Bovine DRG neurons are able to survive for more than 4 weeks in culture. GF supplementation is not required for neuronal survival and neurite outgrowth. However, exogenously added growth factors promote neurite outgrowth. DRG cultures from regularly slaughtered calves represent a promising and sustainable host specific model for the investigation of pain and neurological diseases in bovines

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron-astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-a-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.This work was supported by the Marie Curie Fellowship FP7-PEOPLE-2010-IEF 273936, BIAL Foundation Grants 138/2008 and 61/2010, FEDER funds through Operational program for competitiveness factors-COMPETE -, ON2 Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN/FEDER, and by national funds through FCT-Foundation for Science and Technology-project (PTDC/SAU-NSC/118194/2010) and fellowships (SFRH/BPD/66151/2009 and SFRH/BD/89714/2012)

Disc1 variation leads to specific alterations in adult neurogenesis

Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain

RESÍDUO DA CONSTRUÇÃO E DEMOLIÇÃO - TECNOLOGIAS E PROBLEMAS: UM ESTUDO DE CASO

A destinação correta final de resíduos de qualquer tipo sempre foi uma grande problemática das cidades, a tentativa de implantação de sistemas de coleta seletiva voluntária é o início de uma reciclagem de sucesso. A falta de informação da população dificulta o processo desde seu início, o mesmo ocorre com o RCD (resíduo da construção e demolição). Apesar das leis, normas, resoluções e decretos, o processo é descontrolado já na sua origem, desencadeado em uma série de dificuldades do seu uso para reciclagem. Sem a plantas bem localizadas e sem a informação correta, o RCD  acaba sendo depositado em local impróprio causando danos ao meio ambiente. As soluções sustentáveis são as mais lógicas, gerando menos resíduos. Nosso estudo de caso é sobre a obra do Bairro Ilha Pura, construído para os Jogos Olímpicos de 2016, no Rio de Janeiro. Focando as certificações internacionais de construções verdes, buscou de muitas maneiras fazer uma obra ambientalmente sustentável

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

We would like to thank the members of the Neuroscience Research Domain at ICVS for all the helpful discussions and suggestions. We are especially thankful to the animal facility caretakers, and to Drs Sara Silva, António Melo and Ana Paula Silva and Dieter Fischer for their helpStress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.This work was supported by the Institute for the Study of Affective Neuroscience (ISAN). AJR, BC and MC were supported by Fundação para a Ciência e Tecnologia (FCT) fellowship