Differentiation Plasticity Research Articles

European oak chemical diversity - from ecotypes to herbivore resistance.

Climate change is increasing insect pressure and forcing plants to adapt. Although chemotypic differentiation and phenotypic plasticity in spatially separated tree populations are known for decades, understanding their importance in herbivory resistance across forests remains challenging. We studied four oak forest stands in Germany using nontarget metabolomics, elemental analysis, and chemometrics and mapped the leaf metabolome of herbivore-resistant (T-) and herbivore-susceptible (S-) European oaks (Quercus robur) to Tortrix viridana, an oak pest that causes severe forest defoliation. Among the detected metabolites, we identified reliable metabolic biomarkers to distinguish S- and T-oak trees. Chemotypic differentiation resulted in metabolic shifts of primary and secondary leaf metabolism. Across forests, T-oaks allocate resources towards constitutive chemical defense enriched of polyphenolic compounds, e.g. the flavonoids kaempferol, kaempferol and quercetin glucosides, while S-oaks towards growth-promoting substances such as carbohydrates and amino-acid derivatives. This extensive work across natural forests shows that oaks' resistance and susceptibility to herbivory are linked to growth-defense trade-offs of leaf metabolism. The discovery of biomarkers and the developed predictive model pave the way to understand Quercus robur's susceptibility to herbivore attack and to support forest management, contributing to the preservation of oak forests in Europe.

Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson's Disease.

Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson’s disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients.

Negative relationship between thermal tolerance and plasticity in tolerance emerges during experimental evolution in a widespread marine invertebrate.

Whether populations can adapt to predicted climate change conditions, and how rapidly, are critical questions for the management of natural systems. Experimental evolution has become an important tool to answer these questions. In order to provide useful, realistic insights into the adaptive response of populations to climate change, there needs to be careful consideration of how genetic differentiation and phenotypic plasticity interact to generate observed phenotypic changes. We exposed three populations of the widespread copepod Acartia tonsa (Crustacea) to chronic, sublethal temperature selection for 15 generations. We generated thermal survivorship curves at regular intervals both during and after this period of selection to track the evolution of thermal tolerance. Using reciprocal transplants between ambient and warming conditions, we also tracked changes in the strength of phenotypic plasticity in thermal tolerance. We observed significant increases in thermal tolerance in the Warming lineages, while plasticity in thermal tolerance was strongly reduced. We suggest these changes are driven by a negative relationship between thermal tolerance and plasticity in thermal tolerance. Our results indicate that adaptation to warming through an increase in thermal tolerance might not reduce vulnerability to climate change if the increase comes at the expense of tolerance plasticity. These results illustrate the importance of considering changes in both a trait of interest and the trait plasticity during experimental evolution.

Identification of Compounds Targeting HuD. Another Brick in the Wall of Neurodegenerative Disease Treatment.

ELAV-like (ELAVL) RNA-binding proteins play a pivotal role in post-transcriptional processes, and their dysregulation is involved in several pathologies. This work was focused on HuD (ELAVL4), which is specifically expressed in nervous tissues, and involved in differentiation and synaptic plasticity mechanisms. HuD represents a new, albeit unexplored, candidate target for the treatment of several relevant neurodegenerative diseases. The aim of this pioneering work was the identification of new molecules able to recognize and bind HuD, thus interfering with its activity. We combined virtual screening, molecular dynamics (MD), and STD-NMR techniques. Starting from around 51 000 compounds, four promising hits eventually provided experimental evidence of their ability to bind HuD. Among the selected best hits, folic acid was found to be the most interesting one, being able to well recognize the HuD binding site. Our results provide a basis for the identification of new HuD interfering compounds which may be useful against neurodegenerative syndromes.

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders.

In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-β stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

Striking between-population floral divergences in a habitat specialized plant.

When the habitat occupied by a specialist species is patchily distributed, limited gene flow between the fragmented populations may allow population differentiation and eventual speciation. 'Sky islands'-montane habitats that form terrestrial islands-have been shown to promote diversification in many taxa through this mechanism. We investigate floral variation in Impatiens lawii, a plant specialized on laterite rich rocky plateaus that form sky islands in the northern Western Ghats mountains of India. We focus on three plateaus separated from each other by ca. 7 to 17 km, and show that floral traits have diverged strongly between these populations. In contrast, floral traits have not diverged in the congeneric I. oppositifolia, which co-occurs with I. lawii in the plateaus, but is a habitat generalist that is also found in the intervening valleys. We conducted common garden experiments to test whether the differences in I. lawii are due to genetic differentiation or phenotypic plasticity. There were strong differences in floral morphology between experimental plants sourced from the three populations, and the relative divergences between population pairs mirrored that seen in the wild, indicating that the populations are genetically differentiated. Common garden experiments confirmed that there was no differentiation in I. oppositifolia. Field floral visitation surveys indicated that the observed differences in floral traits have consequences for I. lawii populations, by reducing the number of visitors and changing the relative abundance of different floral visitor groups. Our results highlight the role of habitat specialization in diversification, and corroborates the importance of sky islands as centres of diversification.

Effect of melanoma stem cells on melanoma metastasis.

Cancer stem cells (CSCs) are involved in the metastatic process, the resistance of many types of cancer to therapeutic treatments and consequently the onset of recurrences. The CSC concept therefore significantly extends our understanding of melanoma biology. More recently, melanoma stem cells (MSCs) have been described in melanoma as expressing specific biomarkers. These primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but may also confer virulence via immune evasion and multidrug resistance, and potentially, via vasculogenic mimicry and transition to migratory and metastasizing derivatives. This review will present the specific biomarkers of MSCs, including CD133, ATP binding cassette subfamily B member 5, CD271, CD20 and aldehyde dehydrogenase, which can regulate the transduction of tumor-related signals. These signal molecules can reversely act on tumor cells and regulate tumor angiogenesis, leading to the occurrence of melanoma metastasis. Targeting these specific biomarkers could inhibit the progression of melanoma and may help the development of novel therapeutic strategies for melanoma.

MicroRNA-26b-5p alleviates murine collagen-induced arthritis by modulating Th17 cell plasticity

Rheumatoid arthritis (RA) is a chronic autoimmune disease, and the abnormal differentiation of IL-17-producing T helper (Th17) cells is an important factor in the pathogenesis. Previous studies have shown that microRNAs (miRNAs, miR) act as key regulators of Th17 cells. However, the effects of miRNAs on Th17 cell differentiation and plasticity in RA are not clear. In this study, not only low miR-26b-5p expression and high IL-17A level were observed in the peripheral blood of RA patients, but also the negative correlation between miR-26b-5p and IL-17A was explored. The changes in collagen-induced arthritis (CIA) mice were consistent with those in RA patients. The results of in vitro experiments showed that miR-26b-5p mainly inhibited the initial differentiation of Th17 cells but did not impact the differentiation of induced-Treg into Th17-like cells. Meanwhile, miR-26b-5p mimics treatment alleviated inflammatory responses and reduced Th17 proportion in CIA mice. These results indicated that miR-26b-5p could alleviate the development of mice CIA by inhibiting the excessive Th17 cells, and that miR-26b-5p could modulate the plasticity of Th17 cell differentiation in RA, mainly block the initial differentiation. This may provide a novel strategy for the clinical treatment of RA.

The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL

AbstractB-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and sCD3 was also observed in ABT199-resistant LOUCY clones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance.

Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression

Brain-derived neurotrophic factor (BDNF) is involved in the regulation of neuronal cell growth, differentiation, neuroprotection and synaptic plasticity. Although aberrant BDNF/TrkB signaling is implicated in several neurological, neurodegenerative and psychiatric disorders, neurotrophin-based therapy is challenging and is limited by improper pharmacokinetic properties of BDNF. Dimeric dipeptide compound GSB-106 (bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide) has earlier been designed to mimic the TrkB-interaction 4 loop of BDNF. It displayed protective effect in various cell-damaging models in vitro. Animal studies uncovered antidepressive and neuroprotective properties upon GSB-106 per os administration. Current study shows that GSB-106 acts similarly to BDNF, promoting survival of serum-deprived neuronal-like SH-SY5Y cells. 100 nmol concentration of GSB-106 provided maximum neurotrophic effect, which corresponds to about 37% of the maximum effect provided by BDNF. Protective properties of GSB-106 arise from its ability to counteract cell apoptosis via activation of TrkB-dependent pro-survival mechanisms, including inactivation of pro-apoptotic BAD protein and suppression of caspases 9 and 3/7. Thus, our study has characterized neurotrophic activity of small dimeric compound GSB-106, which mimics certain biological functions of BDNF and neurotrophin-specific protective mechanisms. GSB-106 also displays similarities to some known low weight peptide and non-peptide TrkB ligands.

Evolution of Regeneration in Animals: A Tangled Story

The evolution of regenerative capacity in multicellular animals represents one of the most complex and intriguing problems in biology. How could such a seemingly advantageous trait as self-repair become consistently attenuated by the evolution? This review article examines the concept of the origin and nature of regeneration, its connection with the processes of embryonic development and asexual reproduction, as well as with the mechanisms of tissue homeostasis. The article presents a variety of classical and modern hypotheses explaining different trends in the evolution of regenerative capacity which is not always beneficial for the individual and notably for the species. Mechanistically, these trends are driven by the evolution of signaling pathways and progressive restriction of differentiation plasticity with concomitant advances in adaptive immunity. Examples of phylogenetically enhanced regenerative capacity are considered as well, with appropriate evolutionary reasoning for the enhancement and discussion of its molecular mechanisms.

Epigallocatechin Gallate Ameliorates the Effects of Prenatal Alcohol Exposure in a Fetal Alcohol Spectrum Disorder-Like Mouse Model.

Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Serotonin is a biogenic amine that acts as neurotransmitter in different brain regions and is involved in complex behaviors, such as aggression or mood regulation. Thus, this amine is found in defined circuits and activates specific receptors in different target regions. Serotonin actions depend on extracellular levels of this amine, which are regulated by its synthetic enzymes and the plasma membrane transporter, SERT. Serotonin acts also as a neurotrophic signal in ontogeny and in the mature brain, controlling cell proliferation, differentiation, neurogenesis, and neural plasticity. Interestingly, early alterations in serotonergic signaling have been linked to a diversity of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), or mental illnesses like schizophrenia or depression. It has been proposed that given the complex and numerous actions of serotonin, animal models could better serve to study the complexity of serotonin actions, while providing insights on how hindering serotonergic signaling could contribute to brain disorders. In this mini-review, it will be examined what the general properties of serotonin acting as a neurotransmitter in animals are, and furthermore, whether it is possible that Drosophila could be used to study the contribution of this amine to neurodevelopmental and mental disorders.

Satellite Glial Cells Give Rise to Nociceptive Sensory Neurons.

Dorsal root ganglia (DRG) sensory neurons can transmit information about noxious stimulus to cerebral cortex via spinal cord, and play an important role in the pain pathway. Alterations of the pain pathway lead to CIPA (congenital insensitivity to pain with anhidrosis) or chronic pain. Accumulating evidence demonstrates that nerve damage leads to the regeneration of neurons in DRG, which may contribute to pain modulation in feedback. Therefore, exploring the regeneration process of DRG neurons would provide a new understanding to the persistent pathological stimulation and contribute to reshape the somatosensory function. It has been reported that a subpopulation of satellite glial cells (SGCs) express Nestin and p75, and could differentiate into glial cells and neurons, suggesting that SGCs may have differentiation plasticity. Our results in the present study show that DRG-derived SGCs (DRG-SGCs) highly express neural crest cell markers Nestin, Sox2, Sox10, and p75, and differentiate into nociceptive sensory neurons in the presence of histone deacetylase inhibitor VPA, Wnt pathway activator CHIR99021, Notch pathway inhibitor RO4929097, and FGF pathway inhibitor SU5402. The nociceptive sensory neurons express multiple functionally-related genes (SCN9A, SCN10A, SP, Trpv1, and TrpA1) and are able to generate action potentials and voltage-gated Na+ currents. Moreover, we found that these cells exhibited rapid calcium transients in response to capsaicin through binding to the Trpv1 vanilloid receptor, confirming that the DRG-SGC-derived cells are nociceptive sensory neurons. Further, we show that Wnt signaling promotes the differentiation of DRG-SGCs into nociceptive sensory neurons by regulating the expression of specific transcription factor Runx1, while Notch and FGF signaling pathways are involved in the expression of SCN9A. These results demonstrate that DRG-SGCs have stem cell characteristics and can efficiently differentiate into functional nociceptive sensory neurons, shedding light on the clinical treatment of sensory neuron-related diseases.

Experimental Study of Population Variations on the Morphology and Reproduction of <i>Daphnia galeata</i> from Three Chinese Lakes

Environmental heterogeneity affected the genetic differentiation and phenotypic plasticity of Daphnia spp. populations in different lakes. However, the effect mechanism of lake population on the morphology and reproduction of Daphnia spp. was still unclear. This paper studied the differences of the morphology and reproduction of D. galeata populations from three Chinese lakes (CH: Lake Chaohu, NH: Lake Nanhu, EH: Lake Erhai), which the area size, nutrient levels, phytoplankton biomass and dominant fish were obviously various in the three lakes. The results showed that lake population affected significantly the morphology (helmet length and tail spine length) and reproduction (no. offspring at first reproduction per female-1) of D. galeata. Both helmet lengths and tail spine lengths of three D. galeata populations increased quickly within the first five instars, and afterwards showed various patterns. Multiple comparisons indicated that helmet lengths of NH population were significantly higher than those in EH and CH populations (P<0.001) whereas tail spine lengths of NH population were significantly smaller than those in EH (P=0.001) and CH (P=0.003) populations. The ratio of relative helmet length of CH population was significantly shorter than those of EH population (P<0.001) and NH population (P<0.001), and the ratio of relative tail spine length at first pregnancy of EH population was significantly longer than those of CH population (P<0.001) and NH population (P<0.001). Moreover, there is four juvenile instars in EH population whereas there are three juvenile instars in CH and NH populations. With the increase of adult instars, the number of offspring produced by D. galeata in all three populations displayed a similar pattern, which increased quickly at first, and then gradually decreased. Average maximum number of offspring at first reproduction (6.3±1.4 ind. per female-1) appeared in CH population, followed by EH (5.2±1.7 ind. per female-1) and NH (4.9±1.4 ind.•per female-1) populations. The innate rate of increase of CH population was relatively higher than those of EH and NH populations, but no significant differences among three populations were observed. Our results suggested that environmental heterogeneity could affect the reproduction and morphological plasticity of Daphnia spp. in different lakes.

Nerve Growth Factor: The First Molecule of the Neurotrophin Family.

Neurotrophins (NTs) are molecules regulating differentiation, maintenance, and functional plasticity of vertebrate nervous systems. Nerve growth factor (NGF) was the first to be identified in the neurotrophin family. The long scientific history of NTs provided not only advancement in the neuroscience field but opened new scenarios involving different body districts in physiological and pathological conditions, which include the immune, endocrine, and skeletal system, vascular districts, inflammation, etc. To date, many biological aspects of NTs have been clarified, but the new discoveries are still opening new insights on molecular and cellular mechanisms and systemic effects, also affecting the possible therapeutic application of NTs. This short review summarizes the main aspects of NGF biology and biochemistry, including the role of the NGF precursor molecule, high- and low-affinity receptors and related intracellular pathways, and target cells.

Functional mechanisms of MYRF DNA-binding domain mutations implicated in birth defects

Myrf is a pleiotropic membrane-bound transcription factor that plays critical roles in diverse organisms, including in oligodendrocyte differentiation, embryonic development, molting, and synaptic plasticity. Upon autolytic cleavage, the Myrf N-terminal fragment enters the nucleus as a homo-trimer and functions as a transcription factor. Homo-trimerization is essential for this function because it imparts DNA-binding specificity and affinity. Recent exome sequencing studies have implicated four de novo MYRF DNA-binding domain (DBD) mutations (F387S, Q403H, G435R, and L479V) in novel syndromic birth defects involving the diaphragm, heart, and the urogenital tract. It remains unknown whether and how these four mutations alter the transcription factor function of MYRF. Here, we studied them by introducing homologous mutations to the mouse Myrf protein. We found that the four DBD mutations abolish the transcriptional activity of the Myrf N-terminal fragment by interfering with its homo-trimerization ability by perturbing the DBD structure. Since the Myrf N-terminal fragment strictly functions as a homo-trimer, any loss-of-function mutation has the potential to act as a dominant negative. We observed that one copy of Myrf-F387S, Myrf-Q403H, or Myrf-L479V, but not Myrf-G435R, was tolerated by the Myrf N-terminal homo-trimer for structural and functional integrity. These data suggest that F387S, Q403H, and L479V cause birth defects by haploinsufficiency, while G435R does so via dominant negative functionality.

Brain-derived neurotrophic factor enhances the therapeutic effect of oleuropein in the lipopolysaccharide-induced models of depression.

Major depressive disorder (MDD) is a heterogeneous disease, involving multiple mechanisms and factors, which commonly result in injury to the psychosocial function of the central nervous system, and even suicidality of patients. However, effective treatment for MDD is still lacking. Oleuropein is a newly discovered natural compound extracted from olive leaves, which has a strong antioxidative effect by reducing the production of reactive oxygen species (ROS). Oleuropein also reduces blood pressure in humans and experimental animals, and protects blood vessels. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which supports the function of the central nervous system. BDNF plays an important role in the development of the nervous system via the regulation of cellular differentiation, survival neurogenesis and synaptic plasticity; therefore, we hypothesized that overexpression of BDNF might contribute to the therapeutic effect of oleuropein. Here, we first demonstrated that oleuropein reverses depressive-like behaviour and restores the inflammatory response in a mouse lipopolysaccharide (LPS) model of MDD. We further established a cell model of BDNF overexpression and inhibition in SH-SY5Y cells, and found that the concentration of intercellular calcium was increased after treatment with oleuropein combined with BDNF overexpression, which may be mediated by the BDNF-TrkB-CaMKII signalling pathway. In addition, we observed that the expression of neurotrophic factors, including epidermal growth factor (EGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), was increased, which may be mediated by inhibition of the RhoA-ROCK signalling pathway.

Plasticity of Epididymal Adipose Tissue in Response to Diet-Induced Obesity at Single-Nucleus Resolution

Adipose tissues display a remarkable ability to adapt to the dietary status. Here, we have applied single-nucleus RNA-seq to map the plasticity of mouse epididymal white adipose tissue at single-nucleus resolution in response to high-fat-diet-induced obesity. The single-nucleus approach allowed us to recover all major cell types and to reveal distinct transcriptional stages along the entire adipogenic trajectory from preadipocyte commitment to mature adipocytes. We demonstrate the existence of different adipocyte subpopulations and show that obesity leads to disappearance of the lipogenic subpopulation and increased abundance of the stressed lipid-scavenging subpopulation. Moreover, obesity is associated with major changes in the abundance and gene expression of other cell populations, including a dramatic increase in lipid-handling genes in macrophages at the expense of macrophage-specific genes. The data provide a powerful resource for future hypothesis-driven investigations of the mechanisms of adipocyte differentiation and adipose tissue plasticity.