Gene Activation Research Articles

LbSakA-mediated phosphorylation of the scaffolding protein LbNoxR in the ectomycorrhizal basidiomycete Laccaria bicolor regulates NADPH oxidase activity, ROS accumulation and symbiosis development.

Ectomycorrhizal symbiosis, which involves mutually beneficial interactions between soil fungi and tree roots, is essential for promoting tree growth. To establish this symbiotic relationship, fungal symbionts must initiate and sustain mutualistic interactions with host plants while avoiding host defense responses. This study investigated the role of reactive oxygen species (ROS) generated by fungal NADPH oxidase (Nox) in the development of Laccaria bicolor/Populus tremula × alba symbiosis. Our findings revealed that L. bicolor LbNox expression was significantly higher in ectomycorrhizal roots than in free-living mycelia. RNAi was used to silence LbNox, which resulted in decreased ROS signaling, limited formation of the Hartig net, and a lower mycorrhizal formation rate. Using Y2H library screening, BiFC and Co-IP, we demonstrated an interaction between the mitogen-activated protein kinase LbSakA and LbNoxR. LbSakA-mediated phosphorylation of LbNoxR at T409, T477 and T480 positively modulates LbNox activity, ROS accumulation and upregulation of symbiosis-related genes involved in dampening host defense reactions. These results demonstrate that regulation of fungal ROS metabolism is critical for maintaining the mutualistic interaction between L. bicolor and P. tremula × alba. Our findings also highlight a novel and complex regulatory mechanism governing the development of symbiosis, involving both transcriptional and posttranslational regulation of gene networks.

Maternal High Fat Diet and its expressions in the Heart and Liver in the Mice Embryogenesis.

The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear. The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, and SREBP-1C expression in the high fat-fed mice with the normal-fed diet mice in the process of developmen-tal and embryo-genesis biology. Tissue preparation was done by RIPA lysis. Different protein content was obtained via western blot for the 6 samples namely A.3 months embryo B.4 months embryo C.Birth day embryo D.3 days infant E. 2 weeks infant F. 4 weeks infant. Protein lysates from the heart tissues of the mice were obtained via ho-mogenization and centrifugation. Hematoxylin and Eosin staining (H and E) were done to see the fat droplets in the liver tissues at the different developmental stages. LXRα,SREBP-1C expression in 3 months embryo and 4 months embryo is highly expressed in the high-fat diet. LDL-R in the high-fat diet mice is increased in 3 days infant heart but in 3 months and 4 months embryo it has low expression but from the 0th day to the 4 weeks the expression is in a decreasing trend. Similarly, LPL is highly expressed in 3 months embryo and 0th day(Birthday) and thus low expression indecreasing order until 4 weeks infant. Thus, these results collectively show that a maternal HF diet in-creases the expression of proteins such as LPL, and LDLr in the embryo phase and thus getting normal ex-pressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also, maternal high-fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression. In summary, using a pregnant mice model, we found that a maternal high-fat diet increases fe-tal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesi-ty-induced fetal fat accumulation.

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize. However, insights into the molecular features enabling its metastatic potential are limited. We mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin state (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to those without metastasis (localized). This difference shapes the transcriptional profile of OS. We identified novel candidate genes, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met. Loss of PREX1 in primary met OS cells significantly diminishes OS proliferation, invasion, migration, and colony formation capacity. Differential chromatin activity in primary met is associated with genes regulating cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Chromatin profiling of tumors from metastatic lung lesions shows increased chromatin activity in genes involved in cell migration and Wnt pathway. This data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors, with cellular chromatin profiles further adapting for successful dissemination, migration, and colonization at the distal site. Implications: Our study demonstrates that metastatic potential is intrinsic to primary metastatic osteosarcoma tumors, with chromatin profiles further adapting for successful dissemination, migration and colonization at distal metastatic site.

Increased transcriptional elongation andRNA stability of GPCR ligand binding genes unveiled via RNA polymerase II degradation.

RNA polymerase II drives mRNA gene expression, yet our understanding of Pol II degradation is limited. Using auxin-inducible degron, we degraded Pol II's RPB1 subunit, resulting in global repression. Surprisingly, certain genes exhibited increased RNA levels post-degradation. These genes are associated with GPCR ligand binding and are characterized by being less paused and comprising polycomb-bound short genes. RPB1 degradation globally increased KDM6B binding, which was insufficient to explain specific gene activation. In contrast, RPB2 degradation repressed nearly all genes, accompanied by decreased H3K9me3 and SUV39H1 occupancy. We observed a specific increase in serine 2 phosphorylated Pol II and RNA stability for RPB1 degradation-upregulated genes. Additionally, α-amanitin or UV treatment resulted in RPB1 degradation and global gene repression, unveiling subsets of upregulated genes. Our findings highlight the activated transcription elongation and increasedRNA stability of signaling genes as potential mechanisms for mammalian cells to counter RPB1 degradation during stress.

Mapping putative enhancers in mouse oocytes and early embryos reveals TCF3/12 as key folliculogenesis regulators.

Dynamic epigenomic reprogramming occurs during mammalian oocyte maturation and early development. However, the underlying transcription circuitry remains poorly characterized. By mapping cis-regulatory elements using H3K27ac, we identified putative enhancers in mouse oocytes and early embryos distinct from those in adult tissues, enabling global transitions of regulatory landscapes around fertilization and implantation. Gene deserts harbour prevalent putative enhancers in fully grown oocytes linked to oocyte-specific genes and repeat activation. Embryo-specific enhancers are primed before zygotic genome activation and are restricted by oocyte-inherited H3K27me3. Putative enhancers in oocytes often manifest H3K4me3, bidirectional transcription, Pol II binding and can drive transcription in STARR-seq and a reporter assay. Finally, motif analysis of these elements identified crucial regulators of oogenesis, TCF3 and TCF12, the deficiency of which impairs activation of key oocyte genes and folliculogenesis. These data reveal distinctive regulatory landscapes and their interacting transcription factors that underpin the development of mammalian oocytes and early embryos.

Single-cell nascent RNA sequencing unveils coordinated global transcription.

Transcription is the primary regulatory step in gene expression. Divergent transcription initiation from promoters and enhancers produces stable RNAs from genes and unstable RNAs from enhancers1,2. Nascent RNA capture and sequencing assays simultaneously measure gene and enhancer activity in cell populations3. However, fundamental questions about the temporal regulation of transcription and enhancer-gene coordination remain unanswered, primarily because of the absence of a single-cell perspective on active transcription. In this study, we present scGRO-seq-a new single-cell nascent RNA sequencing assay that uses click chemistry-and unveil coordinated transcription throughout the genome. We demonstrate the episodic nature of transcription and the co-transcription of functionally related genes. scGRO-seq can estimate burst size and frequency by directly quantifying transcribing RNA polymerases in individual cells and can leverage replication-dependent non-polyadenylated histone gene transcription to elucidate cell cycle dynamics. The single-nucleotide spatial and temporal resolution of scGRO-seq enables the identification of networks of enhancers and genes. Our results suggest that the bursting of transcription at super-enhancers precedes bursting from associated genes. By imparting insights into the dynamic nature of global transcription and the origin and propagation of transcription signals, we demonstrate the ability of scGRO-seq to investigate the mechanisms of transcription regulation and the role of enhancers in gene expression.

Regulatory roles of N6-methyladenosine (m6A) methylation in RNA processing and non-communicable diseases.

Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A's diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.

Teleocidin B-4, a PKC Activator, Upregulates Hypoxia-Inducible Factor 1 (HIF-1) Activity by Promoting the Accumulation of HIF-1α Protein via the PKCα/mTORC Signaling Pathway.

Hypoxia-inducible factor 1 (HIF-1) signaling is upregulated in an oxygen-dependent manner under hypoxic conditions. Activation of HIF-1 signaling increases the expression of HIF-1 target genes involved in cell survival, proliferation, and angiogenesis. Therefore, compounds that activate HIF-1 signaling have therapeutic potential in ischemic diseases. Screening for compounds that activate HIF-1 activity identified a microbial metabolite, teleocidin B-4, a PKC activator. Other PKC activators, such as TPA and 10-Me-Aplog-1, also activated HIF-1 activity. PKC activators induced HIF-1α protein accumulation through PKCα/mTORC activation. These results suggest that PKC activators without tumor-promoting activity have potential as therapeutic agents via HIF-1 target gene activation.

Focused cancer pathway analysis revealed unique therapeutic targets in retinoblastoma.

Retinoblastoma (RB) is a pediatric cancer of the eye that occurs in 1/15000 live births worldwide. Albeit RB is initiated by the inactivation of RB1 gene, the disease progression relies largely on transcriptional alterations. Therefore, evaluating gene expression is vital to unveil the therapeutic targets in RB management. In this study, we employed an RT2 Profiler™ PCR array for a focused analysis of 84 cancer-specific genes in RB. An interaction network was built with gene expression data to identify the dysregulated pathways in RB. The key transcript alterations identified in 13 tumors by RT2 Profiler™ PCR array was further validated in 15 tumors by independent RT-qPCR. Out of 84 cancer-specific genes, 68 were dysregulated in RB tumors. Among the 68 genes, 23 were chosen for further analysis based on statistical significance and abundance across multiple tumors. Pathway analysis of altered genes showed the frequent perturbations of cell cycle, angiogenesis and apoptotic pathways in RB. Notably, upregulation of MCM2, MKI67, PGF, WEE1, CDC20 and downregulation of COX5A were found in all the tumors. Western blot confirmed the dysregulation of identified targets at protein levels as well. These alterations were more prominent in invasive RB, correlating with the disease pathogenesis. Our molecular analysis thus identified the potential therapeutic targets for improving retinoblastoma treatment. We also suggest that PCR array can be used as a tool for rapid and cost-effective gene expression analysis.

Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

Differential involvement of cAMP/PKA-, PLC/PKC- and Ca2+/calmodulin-dependent pathways in GnRH-induced prolactin secretion and gene expression in grass carp pituitary cells.

Gonadotropin-releasing hormone (GnRH) is a key stimulator for gonadotropin secretion in the pituitary and its pivotal role in reproduction is well conserved in vertebrates. In fish models, GnRH can also induce prolactin (PRL) release, but little is known for the corresponding effect on PRL gene expression as well as the post-receptor signalling involved. Using grass carp as a model, the functional role of GnRH and its underlying signal transduction for PRL regulation were examined at the pituitary level. Using laser capture microdissection coupled with RT-PCR, GnRH receptor expression could be located in carp lactotrophs. In primary cell culture prepared from grass carp pituitaries, the native forms of GnRH, GnRH2 and GnRH3, as well as the GnRH agonist [D-Arg6, Pro9, NEt]-sGnRH were all effective in elevating PRL secretion, PRL mRNA level, PRL cell content and total production. In pituitary cells prepared from the rostral pars distalis, the region in the carp pituitary enriched with lactotrophs, GnRH not only increased cAMP synthesis with parallel CREB phosphorylation and nuclear translocation but also induced a rapid rise in cytosolic Ca2+ by Ca2+ influx via L-type voltage-sensitive Ca2+ channel (VSCC) with subsequent CaM expression and NFAT2 dephosphorylation. In carp pituitary cells prepared from whole pituitaries, GnRH-induced PRL secretion was reduced/negated by inhibiting cAMP/PKA, PLC/PKC and Ca2+/CaM/CaMK-II pathways but not the signalling events via IP3 and CaN/NFAT. The corresponding effect on PRL mRNA expression, however, was blocked by inhibiting cAMP/PKA/CREB/CBP and Ca2+/CaM/CaN/NFAT2 signalling but not PLC/IP3/PKC pathway. At the pituitary cell level, activation of cAMP/PKA pathway could also induce CaM expression and Ca2+ influx via VSCC with parallel rises in PRL release and gene expression in a Ca2+/CaM-dependent manner. These findings, as a whole, suggest that the cAMP/PKA-, PLC/PKC- and Ca2+/CaM-dependent cascades are differentially involved in GnRH-induced PRL secretion and PRL transcript expression in carp lactotrophs. During the process, a functional crosstalk between the cAMP/PKA- and Ca2+/CaM-dependent pathways may occur with PRL release linked with CaMK-II and PKC activation and PRL gene transcription caused by nuclear action of CREB/CBP and CaN/NFAT2 signalling.

XIST dampens X chromosome activity in a SPEN-dependent manner during early human development.

XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) is responsible for X chromosome inactivation (XCI) in placental mammals, yet it accumulates on both X chromosomes in human female preimplantation embryos without triggering X chromosome silencing. The XACT (X-active coating transcript) lncRNA coaccumulates with XIST on active X chromosomes and may antagonize XIST function. Here, we used human embryonic stem cells in a naive state of pluripotency to assess the function of XIST and XACT in shaping the X chromosome chromatin and transcriptional landscapes during preimplantation development. We show that XIST triggers the deposition of polycomb-mediated repressive histone modifications and dampens the transcription of most X-linked genes in a SPEN-dependent manner, while XACT deficiency does not significantly affect XIST activity or X-linked gene expression. Our study demonstrates that XIST is functional before XCI, confirms the existence of a transient process of X chromosome dosage compensation and reveals that XCI and dampening rely on the same set of factors.

UPBEAT1-ROS-POD-PAL System under Different Xylogenesis Scenarios in Karelian Birch [Betula pendula Roth var. carelica (Mercl.) Hämet-Ahti

In this study, UPBEAT1 (UPB1), which regulates superoxide radical hydrogen peroxide ratio together with Peroxidase (POD) activity and PAL gene expression, has been studied under apical meristem development during the xylem structural elements' formation in unique woody plants B. pendula var. pendula with straight-grained wood and B. pendula var. carelica with figured wood. The differentiation process has been found to predominate in straight-- grained wood (B. pendula var. pendula) or proliferate in the figured wood. The investigation has been conducted on the radial row (cambial zone-differentiating xylem-mature xylem) during the active cambial growth period. The study aimed to study the xylogenesis processes occurring in the 16-year-old straight-grained silver birch (Betula pendula Roth) and Karelian birch (Betula pendula Roth var. carelica (Mercl.) Hämet-Ahti)with figured wood. Hydrogen peroxide and superoxide radical contents and peroxidase activity were determined spectrophotometrically. Gene expression for PAL family genes and the UPBEAT1 gene was assessed using qRT-PCR. Principal component analysis has confirmed trees with straight-grained and figured wood to be different according to UPBEAT1-ROS-POD-PAL system functioning. The higher superoxide radical/hydrogen peroxide ratio in figured Karelian birch, along with UPBEAT1 transcription factor and PAL genes upregulation, distinguished it from straight-grained silver birch. This metabolic picture confirmed the shift of Karelian birch xylogenesis towards proliferation processes, accompanied by ROS and phenolic compounds' flow and POD activity.

CaMKIV-Mediated Phosphorylation Inactivates Freud-1/CC2D1A Repression for Calcium-Dependent 5-HT1A Receptor Gene Induction.

Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.

Y Chromosome Loss and Implications for Oncology.

The Y chromosome has recognized functions in promoting male sex determination and regulating aspects of fertility. However, recent work has demonstrated important roles for the Y chromosome and Y-encoded genes in multiple domains of male health, including cancer. It is well-established that males experience shorter life spans than females, and this sex bias on overall mortality is ac-centuated in populations with longer life expectancy, in part related to elevated rates of cancer. The majority of human malignancies exhibit a sex bias with elevated frequencies in males. For many of these cancer types, the disparity has not been explained by environmental risk factors such as tobacco use. Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY (mLOY) is a common event that is related to advancing age and is associated with a shortened lifespan. mLOY is linked to increased incidence and mortality across a range of malignancies. Further, tumors arising in different anatomic sites exhibit different frequencies of partial or complete Y chromosome loss. Causal oncogenic or tumor suppressive roles have been documented for several Y-encoded genes, such as KDM5D, that exert pleiotropic effects on cellular functions by virtue of genome-wide regulation of gene activity. In this review, we discuss aspects of the Y chromosome relevant to oncology. The recent completion of the entire human Y-chromosome sequence provides a reference map of Y-encoded genes and regulatory elements to enable causal molecular studies that may explain and exploit the marked disparity in male cancer risk and mortality.

Identification of a longevity gene through evolutionary rate covariation of insect mito-nuclear genomes.

Oxidative phosphorylation, essential for energy metabolism and linked to the regulation of longevity, involves mitochondrial and nuclear genes. The functions of these genes and their evolutionary rate covariation (ERC) have been extensively studied, but little is known about whether other nuclear genes not targeted to mitochondria evolutionarily and functionally interact with mitochondrial genes. Here we systematically examined the ERC of mitochondrial and nuclear benchmarking universal single-copy ortholog (BUSCO) genes from 472 insects, identifying 75 non-mitochondria-targeted nuclear genes. We found that the uncharacterized gene CG11837-a putative ortholog of human DIMT1-regulates insect lifespan, as its knockdown reduces median lifespan in five diverse insect species and Caenorhabditis elegans, whereas its overexpression extends median lifespans in fruit flies and C. elegans and enhances oxidative phosphorylation gene activity. Additionally, DIMT1 overexpression protects human cells from cellular senescence. Together, these data provide insights into the ERC of mito-nuclear genes and suggest that CG11837 may regulate longevity across animals.

Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT

Radiotherapy (RT), including external beam radiation therapy (EBRT) and radionuclide therapy (RNT), realizes physical killing of local tumors and activates systemic anti-tumor immunity. However, these effects need to be further strengthened and the difference between EBRT and RNT should be discovered. Herein, bacterial outer membrane (OM) was biomineralized with manganese oxide (MnO2) to obtain OM@MnO2-PEG nanoparticles for enhanced radio-immunotherapy via amplifying EBRT/RNT-induced immunogenic cell death (ICD) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. OM@MnO2-PEG can react with H2O2 and then gradually produce O2, Mn2+ and OM fragments in the tumor microenvironment. The relieved tumor hypoxia improves the radio-sensitivity of tumor cells, resulting in enhanced ICD and DNA damage. Mn2+ together with the DNA fragments in the cytoplasm activate the cGAS-STING pathway, further exhibiting a positive role in various aspects of innate immunity and adaptive immunity. Besides, OM fragments promote tumor antigen presentation and anti-tumor macrophages polarization. More importantly, our study reveals that OM@MnO2-PEG-mediated RNT triggers much stronger cGAS-STING pathway-involved immunotherapy than that of EBRT, owing to the duration difference of RT. Therefore, this study develops a powerful sensitizer of radio-immunotherapy and uncovers some differences between EBRT and RNT in the activation of cGAS-STING pathway-related anti-tumor immunity.Graphical

Circadian and ultradian rhythms: Clinical implications.

The hypothalamic-pituitary-adrenal axis is an extremely dynamic system with a combination of both circadian and ultradian oscillations. This state of 'continuous dynamic equilibration' provides a platform that is able to anticipate events, is sensitive in its response to stressors, remains robust during perturbations of both the internal and external environments and shows plasticity to adapt to a changed environment. In this review, we describe these oscillations of glucocorticoid (GC) hormones and why they are so important for GC-dependent gene activation in the brain and liver, and their consequent effects on the regulation of synaptic and memory function as well as appetite control and metabolic regulation. Abnormalities of mood, appetite and metabolic regulation are well-known consequences of GC therapy, and we suggest that the pattern of GC treatment and hormone replacement should be a much higher priority for endocrinologists and the pharmaceutical industry. One of the major impediments to our research on the importance of these cortisol rhythms in our patients has been our inability to measure repeated levels of hormones across the day in patients in their home or work surroundings. We describe how new wearable methodologies now allow the measurement of 24-h cortisol profiles - including during sleep - and will enable us to define physiological normality and allow us both to develop better diagnostic tests and inform, at an individual patient level, how to improve replacement therapy.

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing-which produces various mature mRNAs and, eventually, protein variants from a single gene-may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.

Evaluating the Potential of Green Light Exposure on Nociception-A Mini Review.

The capacity of animals to react to unpleasant stimuli that might endanger their integrity is known as nociception. Pharmacological treatments do not show satisfactory results in response to nociception. In the recent era, light therapy emerged as a potential non-pharmacological approach for treating various diseases, including seasonal affective disorders, migraine, pain, and others. Evaluating the potential of green light exposure on nociception involves studying its effects on different types of pain and pain-related conditions and determining the optimal exposure methods. This review provides the beneficial effects of green light on the reduction in the frequency of pain. The green light exposure on nociception changes the activity of pain-related genes and proteins in cells. This review could provide insights into the underlying mechanisms by which green light modulates pain. Overall, evaluating the potential of green light exposure on nociception requires a multidisciplinary approach and should consider the safety, efficacy, optimal dose, and duration of green light exposure and the type of pain. However, few studies have been reported so far; therefore, light therapy for treating migraines require more studies on animal models to provide precise results of light effects on nociception.