Patient-derived induced pluripotent stem cells: Tools to advance the understanding and drug discovery in Major Depressive Disorder.

Major Depressive Disorder (MDD) is a pleomorphic disease with substantial patterns of symptoms and severity with mensurable deficits in several associated domains. The broad spectrum of phenotypes observed in patients diagnosed with depressive disorders is the reflection of a very complex disease where clusters of biological and external factors (e.g., response/processing of life events, intrapsychic factors) converge and mediate pathogenesis, clinical presentation/phenotypes and trajectory. Patient-derived induced pluripotent stem cells (iPSCs) enable their differentiation into specialised cell types in the central nervous system to explore the pathophysiological substrates of MDD. These models may complement animal models to advance drug discovery and identify therapeutic approaches, such as cell therapy, drug repurposing, and elucidation of drug metabolism, toxicity, and mechanisms of action at the molecular/cellular level, to pave the way for precision psychiatry. Despite the remarkable scientific and clinical progress made over the last few decades, the disease is still poorly understood, the incidence and prevalence continue to increase, and more research is needed to meet clinical demands. This review aims to summarise and provide a critical overview of the research conducted thus far using patient-derived iPSCs for the modelling of psychiatric disorders, with a particular emphasis on MDD.

Insights into Candida Colonization in Intensive Care Unit Patients: A Prospective Multicenter Study.

The skin mycobiota plays a significant role in infection risk, pathogen transmission, and personalized medicine approaches in intensive care settings. This prospective multicenter study aimed to enhance our understanding of intensive care units' (ICUs') Candida colonization dynamics, identify modifiable risk factors, and assess their impact on survival risk. Specimens were taken from 675, 203, and 110 patients at the admission (D1), 5th (D5), and 8th (D8) days of ICU stay, respectively. The patient's demographic and clinical data were collected. Candida isolates were identified by conventional culture-based microbiology combined with molecular approaches. Overall, colonization was 184/675 (27.3%), 87/203 (42.8%), and 58/110 (52.7%) on D1, D5, and D8, respectively. Candida colonization dynamics were significantly associated with ICU type (odds ratio (OR) = 2.03, 95% CI 1.22-3.39, p = 0.007), respiratory infection (OR = 1.74, 95% CI 1.17-2.58, p = 0.006), hemodialysis (OR = 2.19, 95% CI 1.17-4.10, p = 0.014), COVID-19 (OR = 0.37, 95% CI 0.14-0.99, p = 0.048), and with a poor 3-month outcome (p = 0.008). Skin Candida spp. colonization can be an early warning tool to generate valuable insights into the epidemiology, risk factors, and survival rates of critically ill patients, and should be considered for epidemiological surveillance.

Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.

Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.

Evaluation of properties of concrete coating composites based on polyurethane and reinforcing fibers.

The objective of this study is to evaluate the effect of Fiber-Reinforced Polymer (FRP) coatings on the mechanical properties of concrete structures, especially those used in the production of power distribution poles. These coatings consist of carbon, glass, hybrid, and aramid fibers embedded within a polyurethane matrix. Aramid fabrics from discarded ballistic garments were used to produce FRP. To achieve this, flexural, Charpy impact, and adhesion tests were conducted on the FRP-reinforced concrete. Additionally, Scanning Electron Microscopy (SEM) analyses were performed on the fracture regions of materials tested for impact resistance. The results indicated that all fabrics utilized in the study enhanced the mechanical properties of the concrete specimens in terms of flexural strength and toughness. The observed differences between the fiber types can be attributed to the unique chemical structures of each fiber and their respective interactions with the PU matrix at the interface. These findings suggest that such coatings can significantly improve the mechanical performance of concrete structures.

Glial-Restricted Precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.

Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like and depressive-like deficits, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescueing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.

Validation of the Acute Physiology and Chronic Health Evaluation (APACHE) II Score in COVID-19 Patients Admitted to the Intensive Care Unit in Times of Resource Scarcity.

Introduction During the coronavirus disease 2019 (COVID-19) pandemic, a high number of patients needed to be admitted to the intensive care units (ICUs). Such a high demand led to periods where resources were insufficient and the triage of patients was needed. This study aims to evaluate the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II as a predictor of mortality in periods where triage protocols were implemented. Methods A single-center, longitudinal, retrospective cohort study was performed on patients admitted to the ICU between January 2020 and December 2021. Patients were divided into two periods: Period 1 (where patients needing ICU admission outnumbered the available resources) and Period 2 (where resources were adequate). The discriminative power of the APACHE II was checked using the receiver operating characteristic (ROC) curves. Calibration was accessed, and survival analysis was performed. Results Data from 428 patients were analyzed (229 in Period 1 and 199 in Period 2). The area under the ROC curve (AUROC) was 0.763 for Period 1 and 0.761 for Period 2, reflecting a good discriminative power. Logistic regression showed the APACHE II to be a significant predictor of mortality. The Hosmer-Lemeshow test demonstrated good calibration. The Youden index was determined, and a log-rank test showed a significantly lower survival for patients with higher APACHE II scores in both periods. Conclusions The APACHE II score is an effective tool in predicting mortality in patients with COVID-19 admitted to the ICU in a period where resource allocation and triage of patients are needed, paving a way for the future development of better and improved triage systems.

StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats.

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.

Beyond New Neurons in the Adult Hippocampus: Imipramine Acts as a Pro-Astrogliogenic Factor and Rescues Cognitive Impairments Induced by Stress Exposure.

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants-fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.

Suppression of adult cytogenesis in the rat brain leads to sex-differentiated disruption of the HPA axis activity.

OBJECTIVES: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences. MATERIALS AND METHODS: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG). RESULTS: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG. CONCLUSIONS: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated.

The underestimated sex: A review on female animal models of depression.

Major depression (MD) is the most common psychiatric disorder, predicted to affect around 264 million people worldwide. Although the etiology of depression remains elusive, the interplay between genetics and environmental factors, such as early life events, stress, exposure to drugs and health problems appears to underlie its development. Whereas depression is twice more prevalent in women than in men, most preclinical studies are performed in male rodents. In fact, females' physiology and reproductive experience are associated with changes to brain, behavior and endocrine profiles that may influence both stress, an important precipitating factor for depression, and response to treatment. These specificities emphasize the need to choose the most suitable models and readouts in order to better understand the pathophysiological mechanisms of depression in females. With this review, we aim to provide an overview of female animal models of depression highlighting the major differences between models, regarding behavioral, physiological, and molecular readouts, but also the major gaps in research, attending to the role of etiological factors, protocol variability and sex.

Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods.

The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.

Cell Cycle Regulation of Hippocampal Progenitor Cells in Experimental Models of Depression and after Treatment with Fluoxetine.

Changes in adult hippocampal cell proliferation and genesis have been largely implicated in depression and antidepressant action, though surprisingly, the underlying cell cycle mechanisms are largely undisclosed. Using both an in vivo unpredictable chronic mild stress (uCMS) rat model of depression and in vitro rat hippocampal-derived neurosphere culture approaches, we aimed to unravel the cell cycle mechanisms regulating hippocampal cell proliferation and genesis in depression and after antidepressant treatment. We show that the hippocampal dentate gyrus (hDG) of uCMS animals have less proliferating cells and a decreased proportion of cells in the G2/M phase, suggesting a G1 phase arrest; this is accompanied by decreased levels of cyclin D1, E, and A expression. Chronic fluoxetine treatment reversed the G1 phase arrest and promoted an up-regulation of cyclin E. In vitro, dexamethasone (DEX) decreased cell proliferation, whereas the administration of serotonin (5-HT) reversed it. DEX also induced a G1-phase arrest and decreased cyclin D1 and D2 expression levels while increasing p27. Additionally, 5-HT treatment could partly reverse the G1-phase arrest and restored cyclin D1 expression. We suggest that the anti-proliferative actions of chronic stress in the hDG result from a glucocorticoid-mediated G1-phase arrest in the progenitor cells that is partly mediated by decreased cyclin D1 expression which may be overcome by antidepressant treatment.

Hippocampal cytogenesis abrogation impairs inter-regional communication between the hippocampus and prefrontal cortex and promotes the time-dependent manifestation of emotional and cognitive deficits.

Impaired ability to generate new cells in the adult brain has been linked to deficits in multiple emotional and cognitive behavioral domains. However, the mechanisms by which abrogation of adult neural stem cells (NSCs) impacts on brain function remains controversial. We used a transgenic rat line, the GFAP-Tk, to selectively eliminate NSCs and assess repercussions on different behavioral domains. To assess the functional importance of newborn cells in specific developmental stages, two parallel experimental timeframes were adopted: a short- and a long-term timeline, 1 and 4 weeks after the abrogation protocol, respectively. We conducted in vivo electrophysiology to assess the effects of cytogenesis abrogation on the functional properties of the hippocampus and prefrontal cortex, and on their intercommunication. Adult brain cytogenesis abrogation promoted a time-specific installation of behavioral deficits. While the lack of newborn immature hippocampal neuronal and glial cells elicited a behavioral phenotype restricted to hyperanxiety and cognitive rigidity, specific abrogation of mature new neuronal and glial cells promoted the long-term manifestation of a more complex behavioral profile encompassing alterations in anxiety and hedonic behaviors, along with deficits in multiple cognitive modalities. More so, abrogation of 4 to 7-week-old cells resulted in impaired electrophysiological synchrony of neural theta oscillations between the dorsal hippocampus and the medial prefrontal cortex, which are likely to contribute to the described long-term cognitive alterations. Hence, this work provides insight on how newborn neurons and astrocytes display different functional roles throughout different maturation stages, and establishes common ground to reconcile contrasting results that have marked this field.

Adult neurogenic process in the subventricular zone-olfactory bulb system is regulated by Tau protein under prolonged stress.

OBJECTIVES: The area of the subventricular zone (SVZ) in the adult brain exhibits the highest number of proliferative cells, which, together with the olfactory bulb (OB), maintains constant brain plasticity through the generation, migration and integration of newly born neurons. Despite Tau and its malfunction is increasingly related to deficits of adult hippocampal neurogenesis and brain plasticity under pathological conditions [e.g. in Alzheimer's disease (AD)], it remains unknown whether Tau plays a role in the neurogenic process of the SVZ and OB system under conditions of chronic stress, a well-known sculptor of brain and risk factor for AD. MATERIALS AND METHODS: Different types of newly born cells in SVZ and OB were analysed in animals that lack Tau gene (Tau-KO) and their wild-type littermates (WT) under control or chronic stress conditions. RESULTS: We demonstrate that chronic stress reduced the number of proliferating cells and neuroblasts in the SVZ leading to decreased number of newborn neurons in the OB of adult WT, but not Tau-KO, mice. Interestingly, while stress-evoked changes were not detected in OB granular cell layer, Tau-KO exhibited increased number of mature neurons in this layer indicating altered neuronal migration due to Tau loss. CONCLUSIONS: Our findings suggest the critical involvement of Tau in the neurogenesis suppression of SVZ and OB neurogenic niche under stressful conditions highlighting the role of Tau protein as an essential regulator of stress-driven plasticity deficits.

Use of iron mine tailing as fillers to polyethylene.

The iron mine tailings accumulation in dams is an environmental and economic problem. The composite based on high-density polyethylene/iron mine tailing production for the application of wood plastic and some items of domestic plastic industry can be a good alternative to reduce the rejects in the environment. This work presents the influence of the processing methodology in the mechanical, thermal and morphological properties of composites based on the high-density polyethylene/iron mine tailing. Four methodology processing by continuous and/or batch mixing were available. The iron mine tailing particles in the polymer matrix promoted an increase in mechanical strength and thermal stability. Besides, the particles acted as flame retardant. The iron mine tailing materials produced using batch mixing showed more significant modifications in the properties due to the better dispersion of the filler as shown by scanning electron microscopy.

Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression.

Astrocytes are now known to play crucial roles in the central nervous system, supporting and closely interacting with neurons and therefore able to modulate brain function. Both human postmortem studies in brain samples from patients diagnosed with Major Depressive Disorder and from animal models of depression reported numerical and morphological astrocytic changes specifically in the hippocampus. In particular, these studies revealed significant reductions in glial cell density denoted by a decreased number of S100B-positive cells and a decrease in GFAP expression in several brain regions including the hippocampus. To reveal plastic astrocytic changes in the context of recurrent depression, we longitudinally assessed dynamic astrocytic alterations (gene expression, cell densities and morphologic variations) in the hippocampal dentate gyrus under repeated exposure to unpredictable chronic mild stress (uCMS) and upon treatment with two antidepressants, fluoxetine and imipramine. Both antidepressants decreased astrocytic complexity immediately after stress exposure. Moreover, we show that astrocytic alterations, particularly an increased number of S100B-positive cells, are observed after recurrent stress exposure. Interestingly, these alterations were prevented at the long-term by either fluoxetine or imipramine treatment.

Procoagulant microparticles are associated with arterial disease in patients with systemic lupus erythematosus.

Microparticles (MPs) have been associated with inflammatory and thrombotic disease. High levels of MPs have been identified in patients with systemic lupus erythematosus (SLE) and associated with cardiovascular disease. We analyzed the procoagulant activity of MPs and its correlation with arteriosclerosis and arterial thrombosis in SLE patients. Eighty-seven patients with SLE were included: 22 (25.3%) with associated antiphospholipid syndrome (APS), 32 (36.8%) without antiphospholipid antibodies (aPL) and 33 (37.9%) with aPL but without APS. Subclinical arteriosclerosis, defined as the presence and number of plaques, was evaluated by ultrasonography of carotid arteries. Thrombotic events were confirmed by objective methods. The procoagulant activity of MPs was determined by a functional assay with annexin V. Subclinical arteriosclerosis was found in 19 (21.8%) patients. Thirteen episodes of arterial thrombosis and eight of venous thrombosis were recorded. The procoagulant activity of MPs was greater in patients with arterial thrombosis (17.28 ± 8.29 nM vs 12.96 ± 7.90 nM, p < 0.05). In patients without arterial thrombosis, greater procoagulant activity of MPs was identified in patients with multiple (≥ 2) carotid plaques (17.26 ± 10.63 nM vs 12.78 ± 7.15 nM, p = 0.04). In the multivariate analysis, the procoagulant activity of MPs was independently associated with multiple (≥ 2) carotid plaques and arterial thrombosis [OR = 1.094 (95%CI 1.010-1.185), p = 0.027 and OR = 1.101 (95%CI 1.025-1.182), p = 0.008; respectively]. In conclusion, the procoagulant activity of MPs is associated with arteriosclerosis burden and arterial thrombosis in patients with SLE.

Recent Advances in the Synthesis of the Antidepressant Paroxetine.

Paroxetine is a potent inhibitor of serotonin reuptake and is widely prescribed for the treatment of depression and other neurological disorders. The synthesis of paroxetine and the possibility to prepare derivatives with a specific substitution pattern that may allow their use as biological probes is an attractive topic especially for medicinal chemists engaged in neurosciences research. Considering the extensive work that was developed in the last decade on the total synthesis of paroxetine, this review summarizes the most important contributions in this field, organized according to the reagent that was used as a starting material. Most of the methods allowed to prepare paroxetine in 4-9 steps with an overall yield of 9-66%. Despite the progress made in this area, there is still room for improvement, searching for new eco-friendly and sustainable synthetic alternatives.