Genética y genómica de la longevidad y el envejecimiento / Genetics and genomics of longevity and aging

El envejecimiento y la longevidad son procesos que involucran una serie de factores genéticos, bioquímicos y ambientales. En esta revisión se tratan algunas cuestiones sobre estos dos procesos biológicos y epigenéticos. Se presentan los genes más importantes en estos procesos, así como se ejemplifican enfermedades que presentan un aceleramiento o falla en la longevidad y el envejecimiento. Se usa el análisis inteligente de datos para hallar interacciones de proteínas/genes que expliquen estos dos fenómenos biológicos.

Aging and longevity are processes that involve a series of genetic, biochemical and environmental factors. This review addresses some issues about these two biological and epigenetic processes. The most important genes in these processes are presented, as well as diseases that present an acceleration or failure in longevity and aging. Intelligent data analysis is used to find protein/gene interactions that explain these two biological phenomena.

Gestión de riesgos para cambio de Lotes de Siembra de Trabajo en el Instituto Finlay de Vacunas / Risk management for changing Working Seed Lots at Finlay Vaccine Institute

Este artículo proporciona un caso de estudio del uso del Análisis Modal de Fallos y Efectos para identificar y evaluar los riesgos de un posible cambio del lote de siembra de trabajo en el Instituto Finlay de Vacunas. Este análisis tuvo lugar en uno de los procesos críticos de las Plantas de Producción de Ingrediente Farmacéutico Activo del Instituto Finlay de Vacunas. No incluyó cambios en la tecnología de obtención del Lote de Siembra de Trabajo, ni cambios en el Lote de Siembra de Referencia. Como resultado, se identificaron ocho riesgos potenciales y de ellos se valoraron 17 causas, las cuales se asocian principalmente a la contaminación del Lote de Siembra de Trabajo o baja viabilidad del Lote de Siembra de Referencia, uso de materias primas y materiales de proveedores no calificados o posteriores al período de vigencia, errores de manipulación, parámetros de operación inadecuados, uso de medios de cultivo, soluciones y materiales contaminados, inadecuado funcionamiento del equipamiento e instalaciones y personal no capacitado. Los riesgos identificados son aceptables, con una probabilidad baja de ocurrencia y no están vinculados a la seguridad y eficacia del Ingrediente Farmacéutico Activo, ni de las vacunas. Por último, se propuso una estrategia que minimiza los posibles fallos ante un cambio de Lote de Siembra de trabajo para la fabricación de un producto biofarmacéutico(AU)

This article provides a case study of the use of Modal Failure and Effects Analysis to identify and assess the risks of a possible change in the Working Seed Lot at Finlay Vaccine Institute. This analysis took place in one of the critical processes of the Active Pharmaceutical Ingredient Production Plants of the Finlay Vaccine Institute. This analysis did not include changes in the technology for obtaining the Working Seed Lot or changes in the Reference Seed Lot. As a result, eight potential risks were identified and 17 causes were assessed, mainly associated with contamination of the Working Seed Lot or low viability of the Reference Seed Lot, use of raw materials and other materials from unqualified suppliers or after the validity period, handling errors, inadequate operating parameters, use of culture media, contaminated solutions and materials, inadequate operation of equipment and facilities, and untrained personnel. The identified risks are acceptable, with a low probability of occurrence and are not linked to the safety and efficacy of the active pharmaceutical ingredient or vaccines. Finally, a strategy was proposed that minimizes possible failures in the event of a change in Working Seed Lot for the manufacture of a biopharmaceutical product(AU)

Modern Statistical Tendencies used in Investigations in the Medical Sciences / endencias estadísticas modernas utilizadas en investigaciones en las ciencias médicas

Introduction: The name Statistics was probably used in Egypt in 1549. The term Statistics, which was connected to the development of sovereign states, was coined in Germany in 1749 and used to designate the systematic collection of demographic and economic data by states. Objective: To present the most relevant and current statistical techniques in clinical medicine and epidemiology, as well as to show examples of the use of these techniques. Material and Methods: Review of the literature on the subject; presentation of some examples developed in class by professors of the subject Research Methodology and Statistics in Medical Sciences. Development: From the very beginnig, Statistics was used to characterize data based on their properties, as well as to develop information summary measures. In the modern era, procedures and techniques were designated to facilitate valid inferences to the universe from the sampling theory, whose foundation is the probability theory. Conclusions: There is a need for the application of modern techniques and especially the multivariate ones used to explain biological phenomena, which cannot be explained by one or two variables. This makes possible that our universities, scientific research centers, and companies conduct studies using statistical techniques that involve many variables, which are supposed to be related to the variable under study(AU)

Introducción: El nombre de Estadística probablemente se usó en Egipto en 1549. El término Estadística se acuñó en Alemania en 1749, conectado con el desarrollo de estados soberanos y designando la recopilación sistemática de datos demográficos y económicos por estados. Objetivo: Presentar las técnicas estadísticas más relevantes en el campo de la clínica médica y la epidemiología actualmente y mostrar ejemplos del uso de dichas técnicas. Material y métodos: Revisión de la literatura sobre el tema, algunos ejemplos desarrollados en clases por profesores de la asignatura Metodología de la investigación y Estadística en carreras de Ciencias Médicas. Desarrollo: En sus inicios la Estadística caracterizaba los datos basados en sus propiedades, desarrollaron medidas de resumen de información. En la era moderna se diseñaron procedimientos y técnicas para realizar inferencias válidas al universo a partir de la teoría del muestreo, cuyo fundamento es la teoría de probabilidades. Conclusiones: Necesidad de la aplicación de las técnicas modernas y especialmente las multivariadas para explicar los fenómenos biológicos, que no pueden ser explicados por una o dos variables, esto hace que nuestras universidades, centros de investigaciones científicas y empresas realicen sus estudios, utilizando técnicas estadísticas que envuelvan muchas variables que se suponen se relacionen con la variable objeto de estudio(AU)

Biological Trace Information Extracted from Bioaerosols Using NGS Analysis

Bioaerosols are atmospheric particles with a biological trace, such as viruses, bacteria, fungi, and plant material such as pollen and plant debris. In this study, we analyzed the biological information in bioaerosols using next generation sequencing of the trace DNA. The samples were collected using an Andersen air sampler and separated into two groups according to particulate matter (PM) size: small (PM2.5) and large (PM10). Amplification and sequencing of the bacterial 16S rDNA gene, prokaryotic internal transcribed spacer 1 (ITS1) region and DNA sequence of a plant chloroplast gene (rbcL) were carried out using several sets of specific primers targeting animal and plant sequences. Lots of bacterial information was detected from the bioaerosols. The most abundant bacteria in several samples were of the Actinobacteria (class), Alphaproteobacteria, Bacilli, and Clostridia. For the animal detection using internal transcribed spacer 1, only uncultured fungi were detected in more than half of the hits, with a high number of Cladosporium sp. in the samples. For the plant identification, the ITS1 information only matched fungal species. However, targeting of the rbcL region revealed diverse plant information, such as Medicago papillosa. In conclusion, traces of bacteria, fungi, and plants could be detected in the bioaerosols, but not of animals using our primers.

Eucalyptus cinerea: Microscopic Profile, Chemical Composition of Essential Oil and its Antioxidant, Microbiological and Cytotoxic Activities

Abstract Eucalyptus species possess anti-inflammatory, antifungal, antibacterial, and insecticidal properties. In this study, the chemical composition and biological activities of Eucalyptus cinerea essential oil (EO) and the leaf and stem anatomy were investigated. EO was extracted by Clevenger apparatus and the compounds were identified by GC/MS. The antioxidant activity was evaluated by DPPH, ABTS, and reducing phosphomolybdenum complex. Broth microdilution was used to determine antimicrobial activity. Cytotoxicity was verified against HeLa, HRT-18, and Calu-3 cells by MTT assay. The cytotoxic mechanism was studied by cell DNA content, cell cycle, and DNA fragmentation. The microscopic analyzes of the leaves and the stems were performed by light microscopy, field emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The main constituent of the EO was 1,8-cineole (55.24%). The EO showed low antioxidant and antimicrobial activities. Calu-3 cells showed a significant reduction in viability with IC50 of 689.79 ± 29.34 μg/mL. EO at 1000 μg/mL decreased the DNA content in Jurkat cells. In general, EO increased cell percentage in sub-G0 and S phases with concomitant reduction of cell percentage in G0/G1 and G2/M phases and provided DNA fragmentation of 29.73%. Anatomical and micromorphological features of the leaves and stems can help in the species identification and its differentiation from other Eucalyptus species.

Phenology and thermal requirements of the species Cyperus difformis L. in southern Brazil

Cyperus difformis L. is a Cyperaceae, annual, of natural occurrence in marshy environments in southern Brazil, considered a weed in irrigated rice crops. Studies on its development are scarce, especially regarding its cycle and thermal requirements. Therefore, the objective of this work was to determine the base temperature, the thermal sum and the duration of the different sub-periods of the biological cycle of the species. The experiment was carried out at the Campus of the Universidade Federal de Santa Maria – UFSM, Santa Maria, Rio Grande do Sul, in four sowing seasons. In a completely delineated design and factorial scheme involving five soil water conditions (water depth and 50% soil water retention capacity [WRC]) from the sowing, water depth and 50% WRC introduced 21 days after emergence and 100% WRC during the whole cycle, with six repetitions each. Each experimental unit consisted of a cultivated in pot plant with 11 L capacity filled with soil. The cycle of the plants was subdivided into the sowing-emergence sub-periods, emergence-emission of the floral tassel and emission of the floral-maturing physiological tassel, being estimated the thermal requirements for the species. The conditions of the soil water condition the base temperature, the sum of the degree-days and the duration of the species cycle. The base temperature varies for each treatment, the sum of degrees-day decreases with the water deficit and the plants under flood accelerate the biological cycle.

Actualidad en ortodoncia: las micro-osteoperforaciones en la aceleración del tratamiento ortodóncico / An update in orthodontics: micro-osteoperforations for accelerating orthodontic treatment

La búsqueda por encontrar métodos para acortar la duración de los tratamientos de ortodoncia tiene un pasado reciente, un presente y un futuro. Las fuerzas ortodóncicas que se ejercen sobre la membrana periodontal producen movimientos dentarios por modificaciones histológicas y biomoleculares. El conocimiento de los procesos biológicos da lugar a implementar cambios para favorecer la aceleración de los procesos resortivos y neoformativos. El objetivo de esta publicación es hacer una breve síntesis de lo acontecido con este tema y exponer el procedimiento de las micro-osteoperforaciones (MOPs) como una opción complementaria al tratamiento de ortodoncia convencional. Aún no existe suficiente apoyo de ensayos clínicos en humanos para aseverar su éxito. Más aún, distintos autores publican conclusiones contradictorias. Es de esperar que, en breve, nuevas investigaciones contribuyan a respaldarlo o desestimarlo (AU)

The quest to find methods to shorten the duration of orthodontic treatments has a recent past, a present, and a future. Orthodontic forces exerted on the periodontal membrane produce tooth movements by histological and biomolecular modifications. Knowledge of biological processes results in changes to promote the acceleration of spring and neoformative processes. The objective of this publication is to make a brief synthesis of what happened with this topic and expose the micro-osteoperforations (MOPs) procedure as a complementary option to conventional orthodontic treatment. There is not yet enough support from human clinical trials to assert its success. Moreover, different authors publish conflicting conclusions. It is to be expected that, shortly, further investigations will help to support or dismiss it (AU)

Research progress on the biological regulatory function of lysophosphatidic acid in bone tissue cells / 华西口腔医学杂志

Lysophosphatidic acid (LPA) is a small phospholipid that is present in all eukaryotic tissues and blood plasma. As an extracellular signaling molecule, LPA mediates many cellular functions by binding to six known G protein-coupled receptors and activating their downstream signaling pathways. These functions indicate that LPA may play important roles in many biological processes that include organismal development, wound healing, and carcinogenesis. Recently, many studies have found that LPA has various biological effects in different kinds of bone cells. These findings suggest that LPA is a potent regulator of bone development and remodeling and holds promising application potential in bone tissue engineering. Here, we review the recent progress on the biological regulatory function of LPA in bone tissue cells.

Proteomic Signatures in Spermatozoa Reveal the Role of Paternal Factors in Recurrent Pregnancy Loss

Extracellular vesicles in infectious diseases caused by protozoan parasites in buffaloes

Extracellular vesicles (EVs) are small membrane-bound vesicles of growing interest in vetetinary parasitology. The aim of the present report was to provide the first isolation, quantification and protein characterization of EVs from buffalo (Bubalus bubalis) sera infected with Theileria spp. Methods: Infected animals were identified through optical microscopy and PCR. EVs were isolated from buffalo sera by size-exclusion chromatography and characterized using western blotting analysis, nanoparticle tracking analysis and transmission electron microscopy. Subsequently, the proteins from isolated vesicles were characterized by mass spectrometry. Results: EVs from buffalo sera have shown sizes in the 124-140 nm range and 306 proteins were characterized. The protein-protein interaction analysis has evidenced biological processes and molecular function associated with signal transduction, binding, regulation of metabolic processes, transport, catalytic activity and response to acute stress. Five proteins have been shown to be differentially expressed between the control group and that infected with Theileria spp., all acting in the oxidative stress pathway. Conclusions: EVs from buffaloes infected with Theileria spp. were successfully isolated and characterized. This is an advance in the knowledge of host-parasite relationship that contributes to the understanding of host immune response and theileriosis evasion mechanisms. These findings may pave the way for searching new EVs candidate-markers for a better production of safe biological products derived from buffaloes.(AU)

Mechanistic Target of Rapamycin Pathway in Epileptic Disorders

The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.

Human ex vivo and in vitro disease models to study food allergy

Food allergy is a growing global public health concern. As treatment strategies are currently limited to allergen avoidance and emergency interventions, there is an increasing demand for appropriate models of food allergy for the development of new therapeutics. Many models of food allergy rely heavily on the use of animals, and while useful, many are unable to accurately reflect the human system. In order to bridge the gap between in vivo animal models and clinical trials with human patients, human models of food allergy are of great importance. This review will summarize the commonly used human ex vivo and in vitro models of food allergy and highlight their advantages and limitations regarding how accurately they represent the human in vivo system. We will cover biopsy-based systems, precision cut organ slices, and coculture systems as well as organoids and organ-on-a-chip. The availability of appropriate experimental models will allow us to move forward in the field of food allergy research, to search for effective treatment options and to further explore the cause and progression of this disorder.

Prediction of itching diagnostic marker through RNA sequencing of contact hypersensitivity and skin scratching stimulation mice models

Pruritus (itching) is classically defined as an unpleasant cutaneous sensation that leads to scratching behavior. Although the scientific criteria of classification for pruritic diseases are not clear, it can be divided as acute or chronic by duration of symptoms. In this study, we investigated whether skin injury caused by chemical (contact hypersensitivity, CHS) or physical (skin-scratching stimulation, SSS) stimuli causes initial pruritus and analyzed gene expression profiles systemically to determine how changes in skin gene expression in the affected area are related to itching. In both CHS and SSS, we ranked the Gene Ontology Biological Process terms that are generally associated with changes. The factors associated with upregulation were keratinization, inflammatory response and neutrophil chemotaxis. The Kyoto Encyclopedia of Genes and Genomes pathway shows the difference of immune system, cell growth and death, signaling molecules and interactions, and signal transduction pathways. Il1a , Il1b and Il22 were upregulated in the CHS, and Tnf, Tnfrsf1b, Il1b, Il1r1 and Il6 were upregulated in the SSS. Trpc1 channel genes were observed in representative itching-related candidate genes. By comparing and analyzing RNA-sequencing data obtained from the skin tissue of each animal model in these characteristic stages, it is possible to find useful diagnostic markers for the treatment of itching, to diagnose itching causes and to apply customized treatment.

Perspective in Nuclear Theranostics Using Exosome for the Brain / 대한핵의학회잡지

Owing to its highly biocompatible property as naturally produced nanoscale particle and drug carrying ability, exosome has attracted much interest in the biomedical area. Versatile functions of exosome in biological system play an important role in elucidating mysterious and unknown biological processes and pathological disease progression. For usage of exosome as brain disease therapeutics, even though the ability of exosomes crossing blood brain barrier (BBB) is not well clearly proven, the small size and their own characteristics possessing cell-derived molecular contents may provide great and beneficial tools for brain delivery and brain-associated disease therapy. A variety of trials related to bioapplications using stem cell-derived exosome in regenerative therapy or autologous exosome shuttling inhibitor targeting brain disease-associated protein marker enhance possibility of exosome toward clinical application. The radionuclide PETor SPECT imaging of radiolabeled exosome will be clearly able to provide accurate clues for analyzing their whole body distribution, targeting efficacy, and the degree of non-specific tissue uptake. In this perspective, the practical information on thranostics of exosome for brain delivery and therapy is offered and radionuclide-based exosome applicability will be dealt with.

Regulation Mechanism of Long Noncoding RNAs in Colon Cancer Development and Progression

Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide, and its high rates of relapse and metastasis are associated with a poor prognosis. Despite extensive research, the underlying regulatory mechanisms of CRC remain unclear. Long noncoding RNAs (lncRNAs) are a major type of noncoding RNAs that have received increasing attention in the past few years, and studies have shown that they play a role in many biological processes in CRC. Here, we summarize recent studies on lncRNAs associated with CRC and the signaling pathways and mechanisms underlying this association. We show that dysregulated lncRNAs may be new prognostic and diagnostic biomarkers or therapeutic targets for clinical application. This review contributes not only to our understanding of CRC, but also suggests novel signaling pathways associated with lncRNAs that can be targeted to block or eradicate CRC.

MS-5, a Naphthalene Derivative, Induces the Apoptosis of an Ovarian Cancer Cell CAOV-3 by Interfering with the Reactive Oxygen Species Generation

Reactive oxygen species (ROS) are widely generated in biological processes such as normal metabolism and response to xenobiotic exposure. While ROS can be beneficial or harmful to cells and tissues, generation of ROS by diverse anti-cancer drugs or phytochemicals plays an important role in the induction of apoptosis. We recently identified a derivative of naphthalene, MS-5, that induces apoptosis of an ovarian cell, CAOV-3. Interestingly, MS-5 induced apoptosis by down-regulating the ROS. Cell viability was evaluated by water-soluble tetrazolium salt (WST-1) assay. Apoptosis was evaluated by flow cytometry analysis. Intracellular ROS (H₂O₂), mitochondrial superoxide, mitochondrial membrane potential (MMP) and effect on cycle were determined by flow cytometry. Protein expression was assessed by western blotting. The level of ATP was measured using ATP Colorimetric/Fluorometric Assay kit. MS-5 inhibited growth of ovarian cancer cell lines, CAOV-3, in a concentration- and time-dependent manner. MS-5 also induced G1 cell cycle arrest in CAOV-3 cells, while MS-5 decreased intracellular ROS generation. In addition, cells treated with MS-5 showed the decrease in MMP and ATP production. In this study, we found that treatment with MS-5 in CAOV-3 cells induced apoptosis but decreased ROS level. We suspect that MS-5 might interfere with the minimum requirements of ROS for survival. These perturbations appear to be concentration-dependent, suggesting that MS-5 may induce apoptosis by interfering with ROS generation. We propose that MS-5 may be a potent therapeutic agent for inducing apoptosis in ovarian cancer cell through regulation of ROS.

Association of MicroRNA Polymorphisms With Hepatocellular Carcinoma in an Iranian Population

BACKGROUND: Single nucleotide polymorphisms (SNPs) can modulate various biological processes by influencing microRNA (miRNA) biogenesis and altering target selection. Common SNPs may alter the processing of miRNA and may be associated with hepatocellular carcinoma (HCC). We investigated the relationship between miR-499A>G, miR-149C>T, miR-196a2T>C, and miR-146aG>C and HCC susceptibility, examining the interaction of the miRNAs with hepatitis B virus (HBV). METHODS: We evaluated the associations of miR-499A>G (rs3746444), miR-149C>T (rs2292832), miR-196a2T>C (rs11614913), and miR-146aG>C (rs2910164) with HCC susceptibility in 100 HCC patients (70 males and 30 females) and 120 healthy controls (70 males and 50 females), using the PCR-restriction fragment length polymorphism method. RESULTS: For miR-499A>G, the frequencies of the AG genotype and G allele were higher in female HCC patients than in female controls (P=0.02 and 0.045, respectively). The frequency of the A allele was higher in HBV-positive HCC patients than in controls (P=0.019). For miR-149C>T, the frequency of the CC genotype was higher in female HCC patients than in female controls (P=0.009). For miR-196a2T>C, the frequencies of the CT and CC genotypes and the C allele were higher in HBV-positive HCC patients than in controls (P C polymorphisms did not differ between HCC patients and controls. CONCLUSIONS: miR-499A>G, miR-149C>T, and miR-196a2T>C were associated with the development of HCC in women and/or that of HBV-related HCC. They can be considered genetic risk factors for the development of HCC among Iranians.

Anti-inflammatory Activity of Sambucus Plant Bioactive Compounds against TNF-α and TRAIL as Solution to Overcome Inflammation Associated Diseases: The Insight from Bioinformatics Study

Inflammation is the crucial biological process of immune system which acts as body's defense and protective response against the injuries or infection. However, the systemic inflammation devotes the adverse effects such as multiple inflammation associated diseases. One of the best ways to treat this entity is by blocking the tumor necrosis factor alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) to avoid the proinflammation cytokines production. Thus, this study aims to evaluate the potency of Sambucus bioactive compounds as anti-inflammation through in silico approach. In order to assess that, molecular docking was performed to evaluate the interaction properties between the TNF-α or TRAIL with the ligands. The 2D structure of ligands were retrieved online via PubChem and the 3D protein modeling was done by using SWISS Model. The prediction results of the study showed that caffeic acid (−6.4 kcal/mol) and homovanillic acid (−6.6 kcal/mol) have the greatest binding affinity against the TNF-α and TRAIL respectively. This evidence suggests that caffeic acid and homovanillic acid may potent as anti-inflammatory agent against the inflammation associated diseases. Finally, this study needs further examination and evaluation to validate the potency of Sambucus bioactive compounds.

Farnesylation-defective Rheb Increases Axonal Length Independently of mTORC1 Activity in Embryonic Primary Neurons

Rheb (Ras homolog enriched in the brain) is a small GTPase protein that plays an important role in cell signaling for development of the neocortex through modulation of mTORC1 (mammalian-target-of-rapamycin-complex-1) activity. mTORC1 is known to control various biological processes including axonal growth in forming complexes at the lysosomal membrane compartment. As such, anchoring of Rheb on the lysosomal membrane via the farnesylation of Rheb at its cysteine residue (C180) is required for its promotion of mTOR activity. To test the significance of Rheb farnesylation, we overexpressed a farnesylation mutant form of Rheb, Rheb C180S, in primary rat hippocampal neurons and also in mouse embryonic neurons using in utero electroporation. Interestingly, we found that Rheb C180S maintained promotional effect of axonal elongation similar to the wild-type Rheb in both test systems. On the other hand, Rheb C180S failed to exhibit the multiple axon-promoting effect which is found in wild-type Rheb. The levels of phospho-4EBP1, a downstream target of mTORC1, were surprisingly increased in Rheb C180S transfected neurons, despite the levels of phosphorylated mTOR being significantly decreased compared to control vector transfectants. A specific mTORC1 inhibitor, rapamycin, also could not completely abolish axon elongation characteristics of Rheb C180S in transfected cells. Our data suggests that Rheb in a non-membrane compartment can promote the axonal elongation via phosphorylation of 4EBP1 and through an mTORC1-independent pathway.