Cell Signaling Mechanisms Research Articles

Phosphoproteomic Sample Preparation for Global Phosphorylation Profiling of a Fungal Pathogen.

Phosphorylation is a key post-translational modification central to the biological behavior of proteins. This reversible modification specifically regulates cell signaling mechanisms to control survival and growth. Moreover, microbial pathogens, including both fungi and bacteria, rely on this modification to coordinate protein production and functioning during infection and dissemination within a host. Understanding phosphorylation and its involvement with effector proteins and complex networks are now possible with the recent technological advancements of mass spectrometry. Herein, we describe a phosphopeptide enrichment strategy optimized for the invasive mycosis-causing fungal pathogen Cryptococcus neoformans. Our protocol details proper sample preparation for efficient lysis and protein extraction with minimal phosphorylation losses followed by outlined steps for enrichment, instrumentation handling, and data analysis to permit deep profiling of the global phosphoproteome. The high-throughput versatility of bottom-up proteomics combined with our sample preparation approach facilitates opportunities for in-depth phosphorylation mapping and novel biological discoveries.

Genome-wide identification and expression profiling of thes MAPK, MAPKK, and MAPKKK gene families in Ophiocordyceps sinensis.

Mitogen-activated protein kinase (MAPK) cascades have a universal cell signaling mechanism in eukaryotes. A typical MAPK signal transduction module comprises three kinds of sequentially phosphorylated protein kinases: MAPK, Mitogen-activated protein kinase kinase (MAPKK), and Mitogen-activated protein kinase kinase kinase (MAPKKK). However, little is known regarding the genes involved in MAPK cascades in Ophiocordyceps sinensis. Nine genes (three MAPK, three MAPKK, and three MAPKKK) were identified in this study. The MAPK, MAPKK, and MAPKKK genes were divided into three subfamilies, according to the phylogenetic analysis. TEY and TGY represented the activation domains of the MAPKs; the corresponding domains in MAPKKs were SDIWS and SDVWS, and those in the MAPKKs were GSVFYWMAPEV and GTPMYMSPEV. Transcription data analysis and quantitative real-time polymerase chain reaction showed that the MAPK cascade was related to the growth of the fruiting body. This is the first study to report a genome-wide identification of the MAPK, MAPKK, and MAPKK gene families in O. sinensis.

Effects and cell signaling mechanism of glutamine on rat cardiomyocytes intervened with serum from burned rat

Effects and cell signaling mechanism of glutamine on rat cardiomyocytes intervened with serum from burned rat

Targeted inhibition of TAK1 abrogates TGFβ1 non-canonical signaling axis, NFκB/Smad7 inhibiting human endometriotic cells proliferation and inducing cell death involving autophagy.

Transforming growth factor (TGFβ) is known to play a major role in establishment and maintenance of endometriosis as reported by our group earlier, the underlying mechanism remains to be explored. We deciphered the involvement of TAK1 in TGFβ1- induced cellular responses and delineated the signaling mechanism in human endometriotic cells. The endometriotic cells showed elevated expression of TGFβ1 signaling-effector molecules. TGFβ1 exposure to endometriotic cells induced the expression of the downstream target molecules indicating that TGFβ1 is implicated in the commencement ofTAK1/NFκB-p65/Smad7 cascade. The silencing of TAK1 in endometriotic cells attenuated the TGFβ1 -induced NFκB transcriptional activation and nuclear translocation of NFκB-p65 subunit. The pharmacological inhibition of NFκB by QNZ or knockdown of TAK1 reduced the expression of Smad7 and Cox2. The knockdown of TAK1 in endometriotic cells showed G1 phase cell-cycle arrest and showed low BrdU-incorporation in the presence of TGFβ1. The inhibition of TAK1 attenuated the TGFβ1 signaling activation indicating that TAK1 is a crucial mediator for TGFβ1 action in endometriotic cells. The exposure of endometriotic cells to TAK1 inhibitor, celastrol caused activation of caspase-3 and -9 that led to PARP cleavage and induced apoptosis. Simultaneously, autophagy occurred in celastrol-treated and TAK1-silenced cells as was evidenced by the formation of autophagosome and the increased expression of autophagic markers. Thus, TAK1 activation appears to protect the growth of endometriotic cells by suppressing the cell death process. Overall, our study provided the evidence that of TAK1 significant in the endometriotic cell regulation and mediates a functional cross-talk between TGFβ1 and NFκB-p65 that promotes the growth and inflammatory response in endometriotic cells.

Chemo-Preventive Effect of 1-Piperoyl Piperidine (Piperine) Is Mediated Through Intrinsic Signaling Mechanisms In Human Prostate Cancer Cells (Pc-3) In Vitro

Background: Prostate cancer is a heterogeneous disease and it is second deadliest malignancy in men and the most commonly diagnosed cancer among men. Current chemo-therapies are limited due to considerable side effects. Recently, many kinds of bioactive phytochemicals have contributed significantly to developing new therapies for chemo-resistant prostate cancer due to their structural diversity. Piperine, a natural alkaloid found in the fruit of black (Piper nigrum Linn) and long (Piper longum Linn), has shown antitumor activities toward various cancer cell lines. However, the antitumor effects of piperine on intrinsic and extrinsic signaling mechanisms in breast cancer has not been elucidated so far. Aim: The study aimed to assess the anticancer activity of piperine in human prostate cancer cells through intrinsic signaling pathways. Methodology: Prostate cancer (PC3) cells were treated with different concentrations of piperine (100 & 200µg/ml) to analyze Bcl-2, p53, case pase-3 and caspase-9 protein expression in PC-3 cells. Cell viability was done using MTT in order to find the optimal dose. Results: MTT assay exhibited that piperine showed cell death at the concentration of 100 and 200µg. It significantly decreased the mRNA and protein expression of anti-apoptotic proteins (Bcl-2 and p-Bcl-2) and increased the levels of p53, casepase-3 and 9 protein expression in both concentrations used. Conclusion: Our present findings show that piperine induces apoptosis in PC-3 cells by inhibition the expression of anti-apoptotic proteins with concomitant increase in the tumor suppressor proteins effectively. Hence, piperine can be considered as a potential phototherapeutic drug for the treatment of prostate cancer which may lead to clinical utility.

Dual Targeting by Inhibition of Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Attenuates the Neuroinflammatory Responses in Murine Hippocampal Cells and Seizures in C57BL/6 Mice.

Emerging evidence suggests the association of seizures and inflammation; however, underlying cell signaling mechanisms are still not fully understood. Overactivation of phosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, we speculate the PI3K/Akt/mTOR pathway as a promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in a lipopolysaccharide (LPS)-primed pilocarpine (PILO) model. We then evaluated the effects of 7-day treatment of buparlisib (PI3K inhibitor, 25 mg/kg p.o.), dactolisib (PI3K/mTOR inhibitor, 25 mg/kg p.o.), and rapamycin (mTORC1 inhibitor, 10 mg/kg p.o.) in an LPS-primed PILO model of seizures in C57BL/6 mice. LPS priming resulted in enhanced seizure severity and reduced latency. Buparlisib and dactolisib, but not rapamycin, prolonged latency to seizures and reduced neuronal loss, while all drugs attenuated seizure severity. Buparlisib and dactolisib further reduced cellular redox, mitochondrial membrane potential, cleaved caspase-3 and p53, nuclear integrity, and attenuated NF-κB, IL-1β, IL-6, TNF-α, and TGF-β1 and TGF-β2 signaling both in vitro and in vivo post-PILO and LPS+PILO inductions; however, rapamycin mitigated the same only in the PILO model. Both drugs protected against neuronal cell death demonstrating the contribution of this pathway in the seizure-induced neuronal pyknosis; however, rapamycin showed resistance in a combination model. Furthermore, LPS and PILO exposure enhanced pAkt/Akt and phospho-p70S6/total-p70S6 kinase activity, while buparlisib and dactolisib, but not rapamycin, could reduce it in a combination model. Partial rapamycin resistance was observed possibly due to the reactivation of the pathway by a functionally different complex of mTOR, i.e., mTORC2. Our study substantiated the plausible involvement of PI3K-mediated apoptotic and inflammatory pathways in LPS-primed PILO-induced seizures and provides evidence that its modulation constitutes an anti-inflammatory mechanism by which seizure inhibitory effects are observed. We showed dual inhibition by dactolisib as a promising approach. Targeting this pathway at two nodes at a time may provide new avenues for antiseizure therapies.

Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited disease has not been reported. BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert were developed and used to determine the consequences of heme demand of a semi gene copy number. Homozygous disruption of ALAS1 (−/−) was lethal for embryo development post day 6.5 but expression in heterozygotes (+/−) was sufficient for the number of offspring and survival. In both wild type (WT +/+) and +/− mice expression of ALAS1 RNA was greatest in liver and harderian gland and much lower in kidney, lung, heart, brain and spleen. The effects of one WT ALAS1 allele in +/− mice on mRNA levels in liver and harderian gland were less marked compared to brain and other organs that were examined. Many other genes were up-regulated by heterozygosity in liver and brain but to a minimal extent. Hepatic heme oxygenase 1 (HMOX1) mRNA expression was significantly lower in +/− mice but not in brain. No elevated translation of WT allele ALAS1 mRNA was detected in +/− liver as a compensatory mechanism for the disabled allele. Fasting induced ALAS1 mRNA in both WT and +/− mice but only in +/− was this manifest as increased ALAS1 protein. The hepatic protoporphyria-inducing drug 4-ethyl-DDC caused induction of hepatic ALAS1 mRNA and protein levels in both WT and +/− mice but markedly less in the mice with only one intact allele. The findings illustrate the complex response of ALAS1 expression for heme demand but limited evidence that upregulation of a wild type allele can compensate for a null allele.

Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.

Anti-Hepatocellular Carcinoma Biomolecules: Molecular Targets Insights

This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure–activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.

Circulating exosomes induced by respiratory viral infections in lung transplant recipients activate cellular stress, innate immune pathways and epithelial to mesenchymal transition

BackgroundChronic lung transplant rejection occurs in over 50% of lung transplant recipients and mechanism of chronic rejection is unknown. Evaluation of potential mechanism of exosomes from lung transplant recipients diagnosed with respiratory viral infection (RVI) in inducing chronic lung allograft dysfunction (CLAD). MethodExosomes were isolated from lung transplant recipients followed by DNA and RNA isolation from exosomes. Cell signaling mechanisms were studied by co-culturing exosomes with human epithelial cells. Mice were immunized with exosomes and lung homogenates were studied for immune signaling proteins. ResultsExosomes from lung transplant recipients with RVI carry nucleic acids which are capable of inducing innate immune signaling, endoplasmic reticulum stress, and epithelial mesenchymal transition. ConclusionTherefore, we propose that RVI can lead to induction of exosomes that initiate the process leading to CLAD in mice models. These novel findings identified the molecular mechanisms by which RVI increases the risk of CLAD.

Biofilm mediated strategies to mitigate heavy metal pollution: A critical review in metal bioremediation

Mining and various industrial activities, along with generation and accumulation of heavy metals due to agricultural and domestic activities are languishing human health and the environment as a whole. Employment of conventional strategies in eradicating these toxic loads, are way expensive and concerned with the production of secondary wastes. Biofilm being a syntropic microbial consortium, through the mechanism of cell communication and signaling, quorum sensing and modulating strategies accomplish the removal of contaminant metals from environment. Such biofilm mediated bioremediation may be explicitly explained by implementing synthetic biology models and through unique mathematical modelling of mechanisms of multi species biofilm formation and survival strategies in toxic environments. Microbial metabolism for extracellular electron transfer (EET) and development of niche-specific microbial electrochemistry-driven biotechnologies, exploit the bio electrochemical system of electroactive biofilms (EABs) for removal of metal ions from environment. The multi omics platform predicts the pathways of modified metal-biofilm interaction and sequestration strategies as crucial mechanism to accelerate biofilm mediated bioremediation processes.

Monitoring the Activation of Caspases-1/3/4 for Describing the Pyroptosis Pathways of Cancer Cells.

Pyroptosis is closely related to inhibiting the occurrence and development of tumors. However, the pyroptosis pathways (PPs) impacted by different stimulants are still unknown. To accurately understand the PP in cancer cells, we designed a multicolor fluorescent nanoprobe (Cas-NP) to monitor the activation of caspases-1/3/4 during pyroptosis. The Cas-NP was prepared by the assembly of three different fluorophores-labeled peptides, specific response to caspases-1/3/4 on Au nanoparticles via the Au-Se bond to in situ monitor caspase-1/3/4 with high selectivity and sensitivity. Moreover, the selenopeptide specific to caspase-4 (Cyanine-5-LEVD-SeH) was synthesized for the first time to overcome the difficulty in commercial synthesis. During the pyroptosis of cancer cells induced by adenosine triphosphate (ATP), only the fluorescence of caspase-1 significantly increases. When the cells are stimulated with lipopolysaccharide (LPS), the fluorescence signals corresponding to caspases-3 and 4 first appear and then the fluorescence of caspase-1 is observed. Furthermore, the inhibitor study indicates that the activated caspase-4 can lead to the activation of caspase-1 after the LPS treatment. We first discovered that caspase-3 is activated during the pyroptosis process stimulated by LPS and further verified the activation sequence of caspases-1/3/4 via visualized fluorescence detection. The study provides an effective tool for understanding complex signaling mechanisms in pyroptosis cells and new ideas to explore useful therapeutic inhibitors based on pyroptosis.

KRAS Inhibitor Resistance in MET-Amplified KRAS G12C Non-Small Cell Lung Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms.

Treatment with KRAS G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS G12C NSCLC cells. Clones of sotorasib-sensitive KRAS G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo. Unbiased screening detected subclonal evolution of MET amplification in KRAS G12C NSCLC cells that had developed resistance to sotorasib in vitro. MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/KRAS G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. MET amplification leads to the development of resistance to KRAS G12C inhibitors in NSCLC. Dual blockade of MET and KRAS G12C could be a treatment option for MET-amplified, KRAS G12C-mutated NSCLC.

P–149 Calcium ionophores as an aid to surgically retrieved sperms in male factor infertility for increasing cumulative live birth rate

Abstract Study question Does the addition of calcium ionophores for artificial oocyte activation(AOA) help in improving Cumulative Live Birth Rate in surgically retrieved sperms for male factor infertility? Summary answer AOA significantly improved cumulative live birth rate in Micro-TESE (M-TESE), TESA for non- azoospermia (TESTICULAR) and Non-Obstructive Azoospermia(NOA)-TESA but not in Obstructive Azoospermia (OA)-TESA. What is known already The main cause of Total Fertilization Failure after ICSI is thought to be due to oocyte activation deficiency (OAD) because of oocyte-related or sperm-related factors. Studies have shown that artificial oocyte activation (AOA) is helpful in these situations, but is most effective in couples who have clear sperm-related OAD. Oocyte activation, by Phospholipase- C- Zeta (PLCζ) present in the sperm, leads to series of events resulting in calcium oscillation, oocyte activation and fertilization. AOA increases the free intracellular calcium thereby mimicking physiologic cell signaling mechanisms that result in oocyte activation and fertilization. Study design, size, duration This is a retrospective cohort study done in an academic private ART center, in which patient’s records were analyzed, from January 2016 to December 2019 (total 4 years’ duration) and all ICSI cycles with surgically retrieved sperms were included (n = 365). Study subjects were divided into 4 groups- M-TESE (n = 143), NOA-TESA (n = 38), OA-TESA (n = 62) and TESTICULAR (n = 92). Subdivision was done into cases if AOA was done and control were with conventional ICSI without AOA. Participants/materials, setting, methods Method- Immediately after ICSI, in case group (AOA), all metaphase II oocytes were treated with calcium ionophore (GM508- CultActive) for 15 minutes, then thoroughly washed and incubated under standard conditions. Primary outcome measured was cumulative live birth rate(CLBR) and Secondary outcomes were fertilization rate (Fert. rate), Cleavage rate, clinical pregnancy rate (CPR) and miscarriage rate (MA). Statistical analysis was performed with Chi-square and Mann-Whitney- U test, with significance at P < 0.05. Institutional committee clearance was obtained. Main results and the role of chance The CLBR was significantly higher with AOA- M-TESE (55.8% vs 33.3%, p- 0.008), AOA-NOA-TESA (55.55% vs 15%, p- 0.027) and AOA-TESTICULAR (62.9% vs 32.3%, p- 0.006) group. Fert. rate was significantly higher with AOA-M-TESE (81 ± 0.84 vs 64 ± 0.97, p- 0.001), AOA-NOA-TESA (86 ± 0.76 vs 64 ± 0.13, p- 0.001) and AOA-TESTICULAR (72 ± 0.12 vs 57 ± 0.11, p- 0.001). Cleavage rate, CPR also showed similar significant differences while MA was comparable. However, significant differences were not observed in any of the outcome measured in OA-TESA group between cases and controls - CBLR (51.6% vs 41.9%, p- 0.611), Fert.rate (0.77±0.14 vs 0.75±0.11, p- 0.539), CPR and MA, p- value > 0.05. It may be hypothesized that surgically retrieved sperms in cases of NOA or non- azoospermia where TESTICULAR sperms are taken have reduced or absent capacity to cause Calcium oscillations due to deficient or inadequate PLCζ or there may be some chromatin level abnormalities in these sperms, leading to lesser fertilization and lesser good quality embryos in control group in which AOA was not done. Limitations, reasons for caution This study is retrospective in nature. Sibling oocytes were not compared. The study neither looked at obstetrics complication nor the neonatal outcomes. Further studies are required for long term impact on children born from AOA cycles. Wider implications of the findings: To our knowledge, this is the first study in the literature evaluating the efficacy of calcium ionophores for NOA (M-TESE, TESA), OA (TESA) and TESTICULAR sperms. Further research is needed for use of calcium ionophores in cases of unexplained infertility and recurrent implantation failure. Trial registration number Not applicable

Molecular mechanisms of stomatal closure in response to rising vapour pressure deficit.

Vapour pressure deficit (VPD), the difference between the saturation and actual air vapour pressures, indicates the level of atmospheric drought and evaporative pressure on plants. VPD increases during climate change due to changes in air temperature and relative humidity. Rising VPD induces stomatal closure to counteract the VPD-mediated evaporative water loss from plants. There are important gaps in our understanding of the molecular VPD-sensing and signalling mechanisms in stomatal guard cells. Here, we discuss recent advances, research directions and open questions with respect to the three components that participate in VPD-induced stomatal closure in Arabidopsis, including: (1) abscisic acid (ABA)-dependent and (2) ABA-independent regulation of the protein kinase OPEN STOMATA 1 (OST1), and (3) the passive hydraulic stomatal response. In the ABA-dependent component, two models are proposed: ABA may be rapidly synthesised or its basal levels may be involved in the stomatal VPD response. Further studies on stomatal VPD signalling should clarify: (1) whether OST1 activation above basal activity is needed for VPD responses, (2) which components are involved in ABA-independent regulation of OST1, (3) the role of other potential OST1 targets in VPD signalling, and (4) to which extent OST1 contributes to stomatal VPD sensitivity in other plant species.

Crk adaptor proteins are necessary for the development of the zebrafish retina.

The development of the central nervous system (CNS) requires critical cell signaling molecules to coordinate cell proliferation and migration in order to structure the adult tissue. Chicken tumor virus #10 Regulator of Kinase (CRK) and CRK-like (CRKL) are adaptor proteins with pre-metazoan ancestry and are known to be required for patterning laminated structures downstream of Reelin (RELN), such as the cerebral cortex, cerebellum, and hippocampus. CRK and CRKL also play crucial roles in a variety of other growth factor and extracellular matrix signaling cascades. The neuronal retina is another highly laminated structure within the CNS that is dependent on migration for proper development, but the cell signaling mechanisms behind neuronal positioning in the retina are only partly understood. We find that crk and crkl have largely overlapping expression within the developing zebrafish nervous system. We find that their disruption results in smaller eye size and loss of retinal lamination. Our data indicate that Crk adaptors are critical for proper development of the zebrafish neural retina in a crk/crkl dose-dependent manner.

Mental Health in Childhood and Adolescence: The Role of Polyunsaturated Fatty Acids.

There is increasing awareness of the importance of polyunsaturated fatty acids (PUFAs) for optimal brain development and function. In recent decades, researchers have confirmed the central role of PUFAs in a variety of patho-physiological processes. These agents modulate the mechanisms of brain cell signalling including the dopaminergic and serotonergic pathways. Therefore, nutritional insufficiencies of PUFAs may have adverse effects on brain development and developmental outcomes. The role of n-3 PUFAs has been studied in several psychiatric disorders in adulthood: schizophrenia, major depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, eating disorders, substance use disorder, and borderline personality disorder. In contrast to the great number of studies conducted in adults, there are only limited data on the effects of n-3 PUFA supplementation in children and adolescents who suffer from mental disorders or show a high risk of developing psychiatric disorders. The aim of this review is to provide a complete and updated account of the available evidence of the impact of polyunsaturated fatty acids on developmental psychopathology in children and adolescents and the effect of fatty acid supplementation during developmental milestones, particularly in high-risk populations of children with minimal but detectable signs or symptoms of mental disorders.

Plants have neither synapses nor a nervous system

The alleged existence of so-called synapses or equivalent structures in plants provided the basis for the concept of Plant Neurobiology (Baluska et al., 2005; Brenner et al., 2006). More recently, supporters of this controversial theory have even speculated that the phloem acts as a kind of nerve system serving long distance electrical signaling (Mediano et al., 2021; Baluska and Mancuso, 2021). In this review we have critically examined the literature cited by these authors and arrive at a completely different conclusion. Plants do not have any structures resembling animal synapses (neither chemical nor electrical). While they certainly do have complex cell contacts and signaling mechanisms, none of these structures provides a basis for neuronal-like synaptic transmission. Likewise, the phloem is undoubtedly a conduit for the propagation of electrical signaling, but the characteristics of this process are in no way comparable to the events underlying information processing in neuronal networks. This has obvious implications in regard to far-going speculations into the realms of cognition, sentience and consciousness.

Integrated Multi-Class Classification and Prediction of GPCR Allosteric Modulators by Machine Learning Intelligence.

G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell surface receptors that respond to various extracellular signals. The allosteric modulation of GPCRs has emerged in recent years as a promising approach for developing target-selective therapies. Moreover, the discovery of new GPCR allosteric modulators can greatly benefit the further understanding of GPCR cell signaling mechanisms. It is critical but also challenging to make an accurate distinction of modulators for different GPCR groups in an efficient and effective manner. In this study, we focus on an 11-class classification task with 10 GPCR subtype classes and a random compounds class. We used a dataset containing 34,434 compounds with allosteric modulators collected from classical GPCR families A, B, and C, as well as random drug-like compounds. Six types of machine learning models, including support vector machine, naïve Bayes, decision tree, random forest, logistic regression, and multilayer perceptron, were trained using different combinations of features including molecular descriptors, Atom-pair fingerprints, MACCS fingerprints, and ECFP6 fingerprints. The performances of trained machine learning models with different feature combinations were closely investigated and discussed. To the best of our knowledge, this is the first work on the multi-class classification of GPCR allosteric modulators. We believe that the classification models developed in this study can be used as simple and accurate tools for the discovery and development of GPCR allosteric modulators.

Turmeric and its bioactive constituents trigger cell signaling mechanisms that protect against diabetes and cardiovascular diseases.

Turmeric, the rhizome of Curcuma longa plant belonging to the ginger family Zingiberaceae, has a history in Ayurvedic and traditional Chinese medicine for treatment of chronic diseases, including metabolic and cardiovascular diseases (CVD). This parallels a prevalence of age- and lifestyle-related diseases, especially CVD and type 2 diabetes (T2D), and associated mortality which has occurred in recent decades. While the chemical composition of turmeric is complex, curcuminoids and essential oils are known as two major groups that display bioactive properties. Curcumin, the most predominant curcuminoid, can modulate several cell signaling pathways involved in the etiology and pathogenesis of CVD, T2D, and related morbidities. Lesser bioactivities have been reported from other curcuminoids and essential oils. This review examines the chemical compositions of turmeric, and related bioactive constituents. A focus was placed on the cellular and molecular mechanisms that underlie the protective effects of turmeric and turmeric-derived compounds against diabetes and CVD, compiled from the findings obtained with cell-based and animal models. Evidence from clinical trials is also presented to identify potential preventative and therapeutic efficacies. Clinical studies with longer intervention durations and specific endpoints for assessing health outcomes are warranted in order to fully evaluate the long-term protective efficacy of turmeric.