Dissecting early life stress-induced adolescent depression through epigenomic approach.

Early life stress (ELS), such as abuse and neglect during childhood, can lead to psychiatric disorders in later life. Previous studies have suggested that ELS can cause profound changes in gene expression through epigenetic mechanisms, which can lead to psychiatric disorders in adulthood; however, studies on epigenetic modifications associated with ELS and psychiatric disorders in adolescents are limited. Moreover, how these epigenetic modifications can lead to psychiatric disorders in adolescents is not fully understood. Commonly, DNA methylation, histone modification, and the regulation of noncoding RNAs have been attributed to the reprogramming of epigenetic profiling associated with ELS. Although only a few studies have attempted to examine epigenetic modifications in adolescents with ELS, existing evidence suggests that there are commonalities and differences in epigenetic profiling between adolescents and adults. In addition, epigenetic modifications are sex-dependent and are influenced by the type of ELS. In this review, we have critically evaluated the current evidence on epigenetic modifications in adolescents with ELS, particularly DNA methylation and the expression of microRNAs in both preclinical models and humans. We have also clarified the impact of ELS on psychiatric disorders in adolescents to predict the development of neuropsychiatric disorders and to prevent and recover these disorders through personalized medicine.

Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals.

Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.

Potential of Circulating miRNAs as Molecular Markers in Mood Disorders and Associated Suicidal Behavior.

Mood disorders are the most prevalent psychiatric disorders associated with significant disability, morbidity, and mortality. The risk of suicide is associated with severe or mixed depressive episodes in patients with mood disorders. However, the risk of suicide increases with the severity of depressive episodes and is often presented with higher incidences in bipolar disorder (BD) patients than in patients with major depression (MDD). Biomarker study in neuropsychiatric disorders is critical for developing better treatment plans by facilitating more accurate diagnosis. At the same time, biomarker discovery also provides more objectivity to develop state-of-the-art personalized medicine with increased accuracy through clinical interventions. Recently, colinear changes in miRNA expression between brain and systemic circulation have added great interest in examining their potential as molecular markers in mental disorders, including MDD, BD, and suicidality. A present understanding of circulating miRNAs in body fluids implicates their role in managing neuropsychiatric conditions. Most notably, their use as prognostic and diagnostic markers and their potential role in treatment response have significantly advanced our knowledge base. The present review discusses circulatory miRNAs and their underlying possibilities to be used as a screening tool for assessing major psychiatric conditions, including MDD, BD, and suicidal behavior.

An attitude-behavioral model to understand people's behavior towards tourism during COVID-19 pandemic.

The impact of pandemics on the tourism industry should be explored from the perspective of those who will travel, go to the tourist places on vacation, and avail services from tourism and hospitality-related organizations. This study has aimed to identify the reasons for the changed human psychology towards tourism during the COVID-19 Pandemic to develop an attitude-behavioral model. This investigation thus conducted an extensive empirical study among tourists to capture their social, emotional, and financial beliefs. The research then examined the measurement model through confirmatory factor analysis (CFA) before investigating the cause-effect relationship through the structural model. Analysis revealed that the negative effect of attitude on behavioral intention toward this new equilibrium is controlled by the emotional aspect of attitude. Furthermore this paper made several contributions to the literature on human psychology, crisis management, human behavior, marketing, and tourism.

M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats.

BACKGROUND: Impaired synaptic plasticity has been linked to dynamic gene regulatory network changes. Recently, gene regulation has been introduced with the emerging concept of unique N6-methyladenosine (m6A)-based reversible transcript methylation. In this study, we tested whether m6A RNA methylation may potentially serve as a link between the stressful insults and altered expression of plasticity-related genes. METHODS: Expression of plasticity genes Nr3c1, Creb1, Ntrk2; m6A-modifying enzymes Fto, methyltransferase like (Mettl)-3 and 14; DNA methylation enzymes Dnmt1, Dnmt3a; transcription factor C/ebp-α; and miRNA-124-3p were determined by quantitative polymerase chain reaction (qPCR) in the hippocampus of rats that showed susceptibility to develop stress-induced depression (learned helplessness). M6A methylation of plasticity-related genes was determined following m6A mRNA immunoprecipitation. Chromatin immunoprecipitation was used to examine the endogenous binding of C/EBP-α to the Fto promoter. MiR-124-mediated post-transcriptional inhibition of Fto via C/EBPα was determined using an in vitro model. RESULTS: Hippocampus of learned helplessness rats showed downregulation of Nr3c1, Creb1, and Ntrk2 along with enrichment in their m6A methylation. A downregulation in demethylating enzyme Fto and upregulation in methylating enzyme Mettl3 were also noted. The Fto promoter was hypomethylated due to the lower expression of Dnmt1 and Dnmt3a. At the same time, there was a lower occupancy of transcription factor C/EBPα on the Fto promoter. Conversely, C/ebp-α transcript was downregulated via induced miR-124-3p expression. CONCLUSIONS: Our study mechanistically linked defective C/EBP-α-FTO-axis, epigenetically influenced by induced expression of miR-124-3p, in modifying m6A enrichment in plasticity-related genes. This could potentially be linked with abnormal neuronal plasticity in depression.

Has Covid-19 accelerated opportunities for digital entrepreneurship? An Indian perspective.

Covid-19 has challenged many businesses to orient themselves towards digital solutions for their survival. Due to the rising digital wave during Covid-19, there has been a plethora of opportunities for aspiring entrepreneurs to enter the market. Hence, this study focuses on understanding emerging areas and technologies for digital entrepreneurship. This study adopted a qualitative approach with semi-structured interviews through the lens of the diffusion of innovations theory. A total of 23 entrepreneurs responded and presented their views on Covid-19-induced opportunities for digital entrepreneurship. A structured process of open, axial, and selective coding was adopted for the thematic analysis. The study presents a framework based on four promising propositions. Results of the thematic analysis indicate the emergence of digital entrepreneurship opportunities in technology (EdTech, FinTech, cybersecurity), healthcare (diagnostics, virtual care, fitness), entertainment (over the top, gaming, social media), and e-commerce (contactless delivery, payment methods, augmented reality). In this study, entrepreneurs presented their views based on their experience with the platform or technology they operated. To this end, the present study offers implications both for scholars and entrepreneurs working in and aspiring to digital entrepreneurship along with future scope of research.

Early life and adult stress promote sex dependent changes in hypothalamic miRNAs and environmental enrichment prevents stress-induced miRNA and gene expression changes in rats.

BACKGROUND: The hypothalamus plays a key role in the stress response. While early life stress (ELS) increases susceptibility to psychiatric disorders including major depressive disorder (MDD), acute stress during adulthood can also precipitate MDD after ELS. AIM: Here, we tested the expression of miRNAs following ELS and susceptibility to depression-like behavior and whether sex or acute stress exacerbates this response. We also tested whether environmental enrichment (Enr) promotes early life and adult behavioral stress resilience and its effect on hypothalamic miRNA and gene expression. Following rat maternal separation (MS) as an ELS model, Enr from weaning through adulthood, and restraint (RS) as acute adult stress, we tested both animal behavior and miRNA expression in the hypothalamus. Target genes and their enrichment and ontology were analyzed using bioinformatic tools. Target gene expression changes were tested using qPCR, and miRNA promoter methylation was studied using methylated-DNA immunoprecipitation qPCR. RESULTS: MS, Enr, RS, and sex altered hypothalamic miRNAs, including several previously reported in MS literature: miRs-29, - 124, - 132, - 144, - 504. Sex had a significant effect on the greatest number of miRNAs. Also, Enr reversed downregulation of miR-29b-1-5p and -301b-3p in MS. qPCR showed that MAPK6 and MMP19, targets of miR-301b-3p, were upregulated in MS and reversed by Enr. Additionally, miR-219a was hypermethylated in MS coinciding with decreased miR-219a expression. CONCLUSIONS: This study found that sex plays a critical role in the hypothalamic miRNA response to both ELS and acute stress, with males expressing greater changes following postnatal stress. Moreover, enrichment significantly altered behavior as well as hypothalamic miRNA expression and their gene targets. Because of its role as the initiator of the autonomic stress response and connection to hedonic and motivational behavior, the hypothalamic miRNA landscape may significantly alter both the short and long-term behavioral response to stress.

MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior.

Childhood environment can have a profound impact on brain structure and function. Epigenetic mechanisms have been shown to play a critical role in adaptive and maladaptive processes by regulating gene expression without changing the genome. Over the past few years, early life stress (ELS) has been established as a major risk factor for major depression and suicidal behavior along with other psychiatric illnesses in adulthood. In recent years, the emergence of small noncoding RNAs as a mega controller of gene expression has gained attention for their role in various disease processes. Among various noncoding RNAs, microRNAs (miRNAs) are the most studied and well characterized and have emerged as a major regulator of neural plasticity and higher brain functioning. More recently, although limited in number, studies are focusing on how miRNAs can play a role in the maladaptive processes associated with ELS both at adolescent and adult age and whether these processes are critical in developing depression and suicidal behavior. In this review, we critically evaluate how postnatal ELS relates to abnormalities in miRNA expression and functions from both animal and human literature and draw connections from these findings to depression and suicidal behavior later in life.

Prevalence and predictors of left atrial appendage inactivity in patients of rheumatic mitral stenosis in sinus rhythm: An observational study.

BACKGROUND: Systemic thromboembolism is a known complication of rheumatic mitral stenosis (RMS) in sinus rhythm (SR). Left atrial appendage (LAA), the commonest site of thrombus formation is usually hypocontractile (inactive) in such patients. We aimed to study the prevalence of LAA inactivity (LAAI) in severe RMS and assess its independent predictors. METHODS: The study population consisted of 100 patients of severe RMS in SR. Transthoracic and transesophageal echocardiography were done to assess LAA contractile function. Patients with LAA-peak emptying velocity < 25 cm/seconds were defined as having LAAI. RESULTS: The mean age of study subjects was 31.66±8.69 years and 56% were females. 73% patients had LAAI (Group A), while remaining 27% had normal LAA function (Group B). Mitral-valve area (MVA) and lateral annulus systolic velocity (Sa-wave) were significantly lower while mitral valve mean gradient (MVMG) and serum fibrinogen were significantly higher (all p-values < 0.001) in group A patients. On multivariate binary logistic regression analysis, MVMG (p < 0.001), Sa-wave (p = 0.02), and serum fibrinogen (p = 0.005) were independent predictors of LAAI. Optimal cut-off values of MVMG, Sa-wave and serum fibrinogen for predicting LAAI were 11.5 mm Hg, 6.8 cm/seconds and 300 mg/dl, respectively. Sixty-Seven (90.55%) patients in group A compared to 13(48.1%) in group B had LA/LAA smoke. LAAI was the only independent predictor of left atrium (LA)/LAA smoke with or without associated thrombus. CONCLUSION: There is high prevalence of LAAI in patients of severe MS in SR. MVMG, Sa-wave, and serum fibrinogen levels are independent predictors of LAAI. LAAI is an independent predictor of LA/LAA smoke with or without associated thrombus.

Lockdown and sustainability: An effective model of information and communication technology.

Covid-19, a corona virus, has maintained its momentum in spreading among communities. In this context of social crisis, this study seeks to identify the reasons for the partial failure to fulfill the intended goal of lockdown, and to formulate an inclusive behavioral model reflecting comprehensive human behavior and social psychology. In order to answer the research questions, this study has conducted extensive interviews among individuals who were targets of the lockdown system. From this exploratory and qualitative investigation, researchers have recognized four paradigms as the key to understanding human behavior and social psychology in violating lockdown as a social isolation system during this period of crisis. The identified parameters depicting social behavior are: Derogation and Argument (SDA), Tangible Need and Deficiency (TND), Intangible Desire and Expectancy (IDE), and Evaluation of Benefit and Loss (UBL). Finally, as a comprehensive guideline, a grounded theory of the social behavior 'paradigm for lockdown violation (PLV)' is explored as the reason for the violation of the social system.

Amygdala-Based Altered miRNome and Epigenetic Contribution of miR-128-3p in Conferring Susceptibility to Depression-Like Behavior via Wnt Signaling.

BACKGROUND: Recent studies suggest that microRNAs (miRNAs) can participate in depression pathogenesis by altering a host of genes that are critical in corticolimbic functioning. The present study focuses on examining whether alterations in the miRNA network in the amygdala are associated with susceptibility or resiliency to develop depression-like behavior in rats. METHODS: Amygdala-specific altered miRNA transcriptomics were determined in a rat depression model following next-generation sequencing method. Target prediction analyses (cis- and trans) and qPCR-based assays were performed to decipher the functional role of altered miRNAs. miRNA-specific target interaction was determined using in vitro transfection assay in neuroblastoma cell line. miRNA-specific findings from the rat in vivo model were further replicated in postmortem amygdala of major depressive disorder (MDD) subjects. RESULTS: Changes in miRNome identified 17 significantly upregulated and 8 significantly downregulated miRNAs in amygdala of learned helpless (LH) compared with nonlearned helpless rats. Prediction analysis showed that the majority of the upregulated miRNAs had target genes enriched for the Wnt signaling pathway. Among altered miRNAs, upregulated miR-128-3p was identified as a top hit based on statistical significance and magnitude of change in LH rats. Target validation showed significant downregulation of Wnt signaling genes in amygdala of LH rats. A discernable increase in expression of amygdalar miR-128-3p along with significant downregulation of key target genes from Wnt signaling (WNT5B, DVL, and LEF1) was noted in MDD subjects. Overexpression of miR-128-3p in a cellular model lead to a marked decrease in the expression of Dvl1 and Lef1 genes, confirming them as validated targets of miR-128-3p. Additional evidence suggested that the amygdala-specific diminished expression of transcriptional repressor Snai1 could be potentially linked to induced miR-128-2 expression in LH rats. Furthermore, an amygdala-specific posttranscriptional switching mechanism could be active between miR-128-3p and RNA binding protein Arpp21 to gain control over their target genes such as Lef1. CONCLUSION: Our study suggests that in amygdala a specific set of miRNAs may play an important role in depression susceptibility, which could potentially be mediated through Wnt signaling.

Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications.

Depression is a devastating mental disorder that affects millions of people worldwide. Inflammation has been shown to be a key factor involved in the underlying pathophysiology of depression and has been shown in a substantial proportion of cases of depression. Changes attributed with morphological deformities and immunomodulation in susceptible regions of the depressed brain raised the possibility of altered cellular homeostasis transduced by the intracellular stress response. How emotional stressors can lead to an inflamed brain that directly affects physiology and activity is yet to be fully understood. The unfolded protein response (UPR) has been shown to be active in both models of depression as well as in postmortem brain of depressed individuals. The UPR is the cellular response to stress which results in misfolded proteins. Interestingly, UPR activation is directly linked to both inflammatory cytokine production and Toll-like receptor (TLR) expression. The TLRs are part of the innate immune response which typically reacts to "classic invasions" such as bacteria or viruses as well as trauma. TLRs have also been shown to be upregulated in depression, thus solidifying the connection between inflammation and depression. In this review, we aim to tie the UPR-TLR response and depression, and describe the implications of such an association. We also propose future directions for their role in treatment for depression.

Application of industry 4.0 technologies in SMEs for ethical and sustainable operations: Analysis of challenges.

In the era of Industry 4.0 and circular economy, small and medium enterprises (SMEs) are under huge pressure to make their manufacturing operations ethical and sustainable. Business with ethical and sustainable operations has become the need of the day in the present environment of Industry 4.0 and circular economy. It has been observed that the application of Industry 4.0 technologies may help in achieving the goal of ethical and sustainable operations. Although a lot of research has been done in context to larger enterprises, limited research is available on the application of Industry 4.0 technologies in SMEs for ethical and sustainable operations. The espousal of Industry 4.0 technologies is a challenging task for SMEs due to various operational and financial constraints. The problem is more acute, specifically in context to developing countries like India. Keeping in mind the role of technologies in ethical business and circular economy, we have identified fifteen challenges, impacting the application of Industry 4.0 technologies in SMEs. A questionnaire was designed for collecting the response from industry and academic experts. On the collected data, the DEMATEL approach has been applied to check the degree of influence and interrelationship among challenges. It has also helped in the categorization of factors as cause and effect. Sensitivity analysis is also performed to validate the results obtained from the DEMATEL approach. Authors have observed that lack of motivation from partners and customers on the application of I4.0 technologies is the leading challenge. Fear of failure of I4.0 technologies is the main effect group challenge. The findings of the study will help SMEs in formulating strategies for implementing Industry 4.0 technologies for ethical and sustainable business processes.

Long Noncoding RNA-Associated Transcriptomic Changes in Resiliency or Susceptibility to Depression and Response to Antidepressant Treatment.

Background: Recent emergence of long noncoding RNAs in regulating gene expression and thereby modulating physiological functions in brain has manifested their possible role in psychiatric disorders. In this study, the roles of long noncoding RNAs in susceptibility and resiliency to develop stress-induced depression and their response to antidepressant treatment were examined. Methods: Microarray-based transcriptome-wide changes in long noncoding RNAs were determined in hippocampus of male Holtzman rats who showed susceptibility (learned helplessness) or resiliency (nonlearned helplessness) to develop depression. Changes in long noncoding RNA expression were also ascertained after subchronic administration of fluoxetine to learned helplessness rats. Bioinformatic and target prediction analyses (cis- and trans-acting) and qPCR-based assays were performed to decipher the functional role of altered long noncoding RNAs. Results: Group-wise comparison showed an overrepresented class of long noncoding RNAs that were uniquely associated with nonlearned helplessness or learned helplessness behavior. Chromosomal mapping within the 5-kbp flank region of the top 20 dysregulated long noncoding RNAs in the learned helplessness group showed several target genes that were regulated through cis- or trans-actions, including Zbtb20 and Zfp385b from zinc finger binding protein family. Genomic context of differentially expressed long noncoding RNAs showed an overall blunted response in the learned helplessness group regardless of the long noncoding RNA classes analyzed. Gene ontology exhibited the functional clustering for anatomical structure development, cellular architecture modulation, protein metabolism, and cellular communications. Fluoxetine treatment reversed learned helplessness-induced changes in many long noncoding RNAs and target genes. Conclusions: The involvement of specific classes of long noncoding RNAs with distinctive roles in modulating target gene expression could confer the role of long noncoding RNAs in resiliency or susceptibility to develop depression with a reciprocal response to antidepressant treatment.

Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease.

The human genome project has revolutionized our understanding of the underlying mechanisms in psychiatric disease. It is now abundantly clear that neurobehavioral phenotypes are epigenetically controlled by noncoding RNAs (ncRNAs). The microRNA (miRNA) class of ncRNAs are ubiquitously expressed throughout the brain and govern all major neuronal pathways. The attractive therapeutic potential of miRNAs is underscored by their pleiotropic capacities, putatively targeting multiple pathways within a single neuron. Many psychiatric diseases stem from a multifactorial origin, thus conventional drug targeting of single proteins may not prove most effective. In this exciting post-genome sequencing era, many new epigenetic targets are emerging for therapeutic investigation. Here we review the reported roles of miRNAs, as well as other ncRNA classes, in the pathology of psychiatric disorders; there are both common and unique ncRNA mechanisms that influence the various diagnoses. Collectively, these potent epigenetic regulators may clarify the disrupted signaling networks in psychiatric phenotypes.

Altered ERK1/2 Signaling in the Brain of Learned Helpless Rats: Relevance in Vulnerability to Developing Stress-Induced Depression.

Extracellular signal-regulated kinase 1/2- (ERK1/2-) mediated cellular signaling plays a major role in synaptic and structural plasticity. Although ERK1/2 signaling has been shown to be involved in stress and depression, whether vulnerability to develop depression is associated with abnormalities in ERK1/2 signaling is not clearly known. The present study examined ERK1/2 signaling in frontal cortex and hippocampus of rats that showed vulnerability (learned helplessness, (LH)) or resiliency (non-learned helplessness, (non-LH)) to developing stress-induced depression. In frontal cortex and hippocampus of LH rats, we found that mRNA and protein expressions of ERK1 and ERK2 were significantly reduced, which was associated with their reduced activation and phosphorylation in cytosolic and nuclear fractions, where ERK1 and ERK2 target their substrates. In addition, ERK1/2-mediated catalytic activities and phosphorylation of downstream substrates RSK1 (cytosolic and nuclear) and MSK1 (nuclear) were also lower in the frontal cortex and hippocampus of LH rats without any change in their mRNA or protein expression. None of these changes were evident in non-LH rats. Our study indicates that ERK1/2 signaling is differentially regulated in LH and non-LH rats and suggests that abnormalities in ERK1/2 signaling may be crucial in the vulnerability to developing depression.

The involvement of microRNAs in major depression, suicidal behavior, and related disorders: a focus on miR-185 and miR-491-3p.

Major depressive disorders are common and disabling conditions associated with significant psychosocial impairment and suicide risk. At least 3-4 % of all depressive individuals die by suicide. Evidence suggests that small non-coding RNAs, in particular microRNAs (miRNAs), play a critical role in major affective disorders as well as suicide. We performed a detailed review of the current literature on miRNAs and their targets in major depression and related disorders as well as suicidal behavior, with a specific focus on miR-185 and miR-491-3p, which have been suggested to participate in the pathogenesis of major depression and/or suicide. miRNAs play a fundamental role in the development of the brain. Several miRNAs are reported to influence neuronal and circuit formation by negatively regulating gene expression. Global miRNA reduced expression was found in the prefrontal cortex of depressed suicide completers when compared to that of nonpsychiatric controls who died of other causes. One particular miRNA, miR-185, was reported to regulate TrkB-T1, which has been associated with suicidal behavior upon truncation. Furthermore, cAMP response element-binding protein-brain-derived neurotrophic factor pathways may regulate, through miRNAs, the homeostasis of neural and synaptic pathways playing a crucial role in major depression. miRNAs have gained attention as key players involved in nervous system development, physiology, and disease. Further evidence is needed to clarify the exact role that miRNAs play in major depression and related disorders and suicidal behavior.

Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3ß and ß-catenin.

Glycogen synthase kinase (GSK)-3ß and ß-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3ß and ß-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3ß and ß-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3ß protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3ß-ser(9) were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3ß mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of ß-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in ß-catenin and pGSK-3ß-ser(9) in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide.

Involvement of brain-derived neurotrophic factor in late-life depression.

Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons, synaptic integrity, and synaptic plasticity. Evidence suggests that BDNF is involved in major depression, such that the level of BDNF is decreased in depressed patients and that antidepressants reverse this decrease. Stress, a major factor in depression, also modulates BDNF expression. These studies have led to the proposal of the neurotrophin hypothesis of depression. Late-life depression is associated with disturbances in structural and neural plasticity as well as impairments in cognitive behavior. Stress and aging also play a crucial role in late-life depression. Many recent studies have suggested that not only expression of BDNF is decreased in the serum/plasma of patients with late-life depression, but structural abnormalities in the brain of these patients may be associated with a polymorphism in the BDNF gene, and that there is a relationship between a BDNF polymorphism and antidepressant remission rates. This review provides a critical review of the involvement of BDNF in major depression, in general, and in late-life depression, in particular.

An insight into the sprawling microverse of microRNAs in depression pathophysiology and treatment response.

Stress-related neuropathologies are pivotal in developing major depressive disorder (MDD) and are often governed by gene-regulatory changes. Being a stress-responsive gene-regulatory factor, microRNAs (miRNAs) have tremendous biomolecular potential to define an altered gene-regulatory landscape in the MDD brain. MiRNAs' regulatory roles in the MDD brain are closely aligned with changes in plasticity, neurogenesis, and stress-axis functions. MiRNAs act at the epigenetic interface between stress-induced environmental stimuli and cellular pathologies by triggering large-scale gene expression changes in a highly coordinated fashion. The parallel changes in peripheral circulation may provide an excellent opportunity for miRNA to devise more effective treatment strategies and help explore their potential as biomarkers in treatment response. This review discusses the role of miRNAs as epigenetic modifiers in the etiopathogenesis of MDD. Concurrently, key research is highlighted to show the progress in using miRNAs as predictive biomarkers for treatment response.