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Psychedelics, recognized for their impact on perception, are resurging as promising treatments with rapid onset for mood and substance use disorders. Despite increasing evidence from clinical trials, questions persist about the cellular and molecular mechanisms and their precise correlation with treatment outcomes. Murine neurons and immortalized non-neural cell lines harboring overexpressed constructs have shed light on neuroplastic changes mediated by the serotonin 2A receptor (5-HT2AR) as the primary mechanism. However, limitations exist in capturing human- and disease-specific traits. Here, we discuss current accomplishments and prospects for incorporating human pluripotent stem cells (PSCs) to complement these models. PSCs can differentiate into various brain cell types, mirroring endogenous expression patterns and cell identities to recreate disease phenotypes. Brain organoids derived from PSCs resemble cell diversity and patterning, while region-specific organoids simulate circuit-level phenotypes. PSC-based models hold significant promise to illuminate the cellular and molecular substrates of psychedelic-induced phenotypic recovery in neuropsychiatric disorders., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential viral molecular targets have not been fully elucidated. Here we explore the proteomic alterations induced by ZIKV by comparing the Brazilian (Br ZIKV) and the African (MR766) viral strains, in addition to comparing them to the molecular responses to the Dengue virus type 2 (DENV). Neural stem cells (NSCs) derived from induced pluripotent stem (iPSCs) were cultured both as monolayers and in suspension (resulting in neurospheres), which were then infected with ZIKV (Br ZIKV or ZIKV MR766) or DENV to assess alterations within neural cells. Large-scale proteomic analyses allowed the comparison not only between viral strains but also regarding the two- and three-dimensional cellular models of neural cells derived from iPSCs, and the effects on their interaction. Altered pathways and biological processes were observed related to cell death, cell cycle dysregulation, and neurogenesis. These results reinforce already published data and provide further information regarding the biological alterations induced by ZIKV and DENV in neural cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

SARS-CoV-2 infects cardiac cells and causes heart dysfunction. Conditions such as myocarditis and arrhythmia have been reported in COVID-19 patients. The Sigma-1 receptor (S1R) is a ubiquitously expressed chaperone that plays a central role in cardiomyocyte function. S1R has been proposed as a therapeutic target because it may affect SARS-CoV-2 replication; however, the impact of the inhibition of S1R in human cardiomyocytes remains to be described. In this study, we investigated the consequences of S1R inhibition in iPSC-derived human cardiomyocytes (hiPSC-CM). SARS-CoV-2 infection in hiPSC-CM was productive and reduced cell survival. S1R inhibition decreased both the number of infected cells and viral particles after 48 hours. S1R inhibition also prevented the release of pro-inflammatory cytokines and cell death. Although the S1R antagonist NE-100 triggered those protective effects, it compromised cytoskeleton integrity by downregulating the expression of structural-related genes and reducing beating frequency. Our findings suggest that the detrimental effects of S1R inhibition in human cardiomyocytes' integrity may abrogate its therapeutic potential against COVID and should be carefully considered., Competing Interests: Rafael Dariolli and Diogo Biagi were employed by PluriCell Biotech. The remaining authors declare that they have no competing interests., (©2021 Salerno et al.)

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect several organs, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 is myocardial injury, which is associated with a high risk of mortality. Myocardial injury, caused directly or indirectly by SARS-CoV-2 infection, can be triggered by inflammatory processes that lead to damage to the heart tissue. Since one of the hallmarks of severe COVID-19 is the "cytokine storm", strategies to control inflammation caused by SARS-CoV-2 infection have been considered. Cannabinoids are known to have anti-inflammatory properties by negatively modulating the release of pro-inflammatory cytokines. Herein, we investigated the effects of the cannabinoid agonist WIN 55,212-2 (WIN) in human iPSC-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. WIN did not modify angiotensin-converting enzyme II protein levels, nor reduced viral infection and replication in hiPSC-CMs. On the other hand, WIN reduced the levels of interleukins six, eight, 18 and tumor necrosis factor-alpha (TNF-α) released by infected cells, and attenuated cytotoxic damage measured by the release of lactate dehydrogenase (LDH). Our findings suggest that cannabinoids should be further explored as a complementary therapeutic tool for reducing inflammation in COVID-19 patients., Competing Interests: Diogo Biagi, Estela M. Cruvinel and Rafael Dariolli are employed by Pluricell Biotech., (© 2021 Aragão et al.)

Coronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that several other organs are affected, including the brain. Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but the neurotropic potential of the virus is still debated. Herein, we sought to investigate SARS-CoV-2 infection in human neural cells. We demonstrated that SARS-CoV-2 infection of neural tissue is non-permissive, however, it can elicit inflammatory response and cell damage. These findings add to the hypothesis that most of the neural damage caused by SARS-CoV-2 infection is due to a systemic inflammation leading to indirect harmful effects on the central nervous system despite the absence of local viral replication., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

"Stem cell tourism," the practice of offering unproven cellular preparations to patients as approved therapy, is rising in neurology. Currently, the experiences of patients and reported complications from these procedures are unknown in the United States. We evaluate academic neurologists' experiences with stem cell tourism and assess perceived competency on discussing this topic with patients. We found a lack of neurologist preparedness to discuss stem cell therapies with patients and an alarming list of unreported complications from these unregulated procedures. We also identified an urgent need for neurologist education and the creation of a national registry for reporting patient complications resulting from experimental stem cell interventions. ANN NEUROL 2020;88:661-668., (© 2020 American Neurological Association.)

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animals, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human-induced pluripotent stem cells (iPSC)-derived astrocytes which replicate temporally intertwined aspects of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, production of cytokines, changes in morphology and function of iPSC-derived astrocytes exposed to TNF-α. We observed NF-kB p65 subunit nuclear translocation and increased gene expression of IL-1β, IL-6, and TNF-α in the first hours following TNF-α stimulation. After 24 hr, conditioned media from iPSC-derived astrocytes exposed to TNF-α exhibited increased secretion of inflammation-related cytokines. After 5 days, TNF-α-stimulated cells presented a typical phenotype of astrogliosis such as increased immunolabeling of Vimentin and GFAP and nuclei with elongated shape and shrinkage. Moreover, ~50% decrease in aspartate uptake was observed during the time course of astrogliosis with no evident cell damage, suggesting astroglial dysfunction. Together, our results indicate that human iPSC-derived astrocytes reproduce canonical events associated with astrogliosis in a time dependent fashion. The approach described here may contribute to a better understanding of mechanisms governing human astrogliosis with potential applicability as a platform to uncover novel biomarkers and drug targets to prevent or mitigate astrogliosis associated with human brain disorders., (© 2020 Wiley Periodicals, Inc.)

Zika virus (ZIKV) has been extensively studied since it was linked to congenital malformations, and recent research has revealed that astrocytes are targets of ZIKV. However, the consequences of ZIKV infection, especially to this cell type, remain largely unknown, particularly considering integrative studies aiming to understand the crosstalk among key cellular mechanisms and fates involved in the neurotoxicity of the virus. Here, the consequences of ZIKV infection in iPSC-derived astrocytes are presented. Our results show ROS imbalance, mitochondrial defects and DNA breakage, which have been previously linked to neurological disorders. We have also detected glial reactivity, also present in mice and in post-mortem brains from infected neonates from the Northeast of Brazil. Given the role of glia in the developing brain, these findings may help to explain the observed effects in congenital Zika syndrome related to neuronal loss and motor deficit.

Functioning as key players in cellular regulation of membrane curvature, BAR domain proteins bend bilayers and recruit interaction partners through poorly understood mechanisms. Using electron cryomicroscopy, we present reconstructions of full-length endophilin and its N-terminal N-BAR domain in their membrane-bound state. Endophilin lattices expose large areas of membrane surface and are held together by promiscuous interactions between endophilin's amphipathic N-terminal helices. Coarse-grained molecular dynamics simulations reveal that endophilin lattices are highly dynamic and that the N-terminal helices are required for formation of a stable and regular scaffold. Furthermore, endophilin accommodates different curvatures through a quantized addition or removal of endophilin dimers, which in some cases causes dimerization of endophilin's SH3 domains, suggesting that the spatial presentation of SH3 domains, rather than affinity, governs the recruitment of downstream interaction partners., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ethically conducted research involving human participants is a cornerstone of the academic medical research establishment. However, there is public mistrust of clinical research and, as a result, low participation rates in research studies among minorities and in communities where health disparities are glaring. Specific initiatives have been undertaken by the National Institutes of Health (NIH) to restore public confidence in biomedical research and to ensure that research is conducted ethically and responsibly. The T15 program, instituted in 1997, made awards beginning in 1998 to institutions for up to three years to develop, conduct, and evaluate short-term courses on ethical issues in research. A companion solicitation (K01 program) targeted the career development of independent investigators in applied research ethics through mentored scientist development awards in research ethics. Both programs emphasized ethical research involving human participants and outreach to minority scientists. The author asks how the success of these programs should be gauged, especially in light of new--and often unforeseen--ethical challenges that are likely to confront the research community. Participation in some T15 programs indicates that few researchers and practitioners perceived the need to increase their proficiency in analyzing the ethical dimensions of their work. To improve participation and, ultimately, ethical approaches to human participants research, the NIH should foster appreciation for the centrality of bioethics in the biomedical research enterprise. The author calls on the NIH to provide leadership for bioethics by further developing a national agenda for bioethics training and research.

Introduction: Phrenic nerve injury (PNI) is a complication that can occur with catheter ablation., Methods: Data from 17 patients with PNI following different catheter ablation techniques were reviewed. PNI was defined as decreased motility (transient) or paralysis (persistent) of the hemi-diaphragm on fluoroscopy or chest X-ray. Patient's recovery was monitored. Normalization of chest images and sniff test would be considered as complete clinical recovery., Results: Out of the 17 PNI patients (16 right, 1 left), 13 (11 persistent, 2 transient) occurred after pulmonary veins isolation with or without superior vena cava ablation. Three patients had persistent PNI after sinus node modification and one other patient experienced PNI after epicardial ventricular tachycardia ablation. Ablation was performed with different energy source including radiofrequency (n = 13), cryothermal (n = 1), ultrasound (n = 2) and laser (n = 1). Patient's symptoms varied broadly from asymptomatic to dyspnea, and even to respiratory insufficiency that required temporary mechanical ventilation support. Two patients with transient PNI resolved immediately after the procedure and the other 15 persistent PNI patients resolved within a mean time of 8.3 +/- 6.6 months., Conclusions: PNI caused by catheter ablation appears to functionally recover over time regardless of the energy sources used for the procedure.

Aims: This multicentre prospective randomised trial was undertaken to evaluate the usefulness of an electrophysiological study (EPS)-guided/implantable cardioverter defibrillator (ICD) strategy in patients at high risk of sudden death (SD) early after myocardial infarction (MI). Previous studies have shown the benefits of such a strategy only in high-risk patients late after MI., Methods and Results: We enrolled 143 survivors of acute MI (<1 month) with left ventricular ejection fraction < or = 35% and either frequent (> or =10/h) premature ventricular complexes (PVCs), or depressed heart rate variability (SDNN < 70 ms) or abnormal signal-averaged ECG, who were able to tolerate optimised beta-blocker therapy (68 +/- 40 mg/day of metoprolol). Of these, 138 were randomised, in a 2:3 ratio, to two therapeutic strategies: conventional (CONV) strategy (n = 59) or EPS-guided/ICD strategy (n = 79). The latter resulted in ICD implantation in 24 inducible patients and in CONV therapy in the remaining 55. During a mean follow-up of 540 +/- 378 days, 26 patients (19%) died: nine (6.5%) SD, nine (6.5%) non-SD, and four (3%) non-cardiac death; in four patients (3%) the cause of death was unknown. The actuarial overall mortality for the CONV and EPS-guided/ICD arms was 18% vs 14% after 1 year and 29.5% vs 20% after 2 years, respectively (P = 0.3 and 0.2)., Conclusions: Despite optimal therapy, mortality remains significant in high-risk patients following MI. Although there is a trend in favour of EPS-guided/ICD, our data are insufficient to demonstrate a survival benefit of this strategy early after MI.

Introduction: The incidence and characteristics of dissociated arrhythmia confined to the pulmonary vein (PV) following disconnection have not been described in a large number of patients with paroxysmal atrial fibrillation., Methods and Results: This was a prospective study of 152 patients (29 female, mean age 51 +/- 11 years) referred for catheter ablation of drug-refractory paroxysmal atrial fibrillation. Following ostial ablation, the rate and regularity of any dissociated venous activity was analyzed with and without isoproterenol infusion (to achieve a heart rate of 120-140 beats/min). Patients then were classified according to their venous dissociated activity. Group 1 consisted of patients in whom the dissociated PV spike had a slow rhythm >1,200 ms. Group 2 consisted of patients with spontaneous repetitive dissociated discharges confined in the vein with a cycle length <400 ms. A total of 384 PVs were ablated in 152 patients. Disappearance of all venous potentials was observed in 88% of the treated veins; at least one dissociated venous potential was observed in the remaining 12%. Group 1 activity was seen more often than group 2 (23 patients, mean cycle length 2,300 +/- 1,100 ms vs 13 patients, mean cycle length 179 +/- 77 ms). Dissociated PV arrhythmia was seen most often in the right superior PV (19%)., Conclusion: Dissociation as the endpoint of PV disconnection was observed in 12% of PVs. Due to the capricious nature of this activity, the actual incidence is almost certainly higher. The dissociated venous rhythm usually is slow and, less commonly, is rapid and repetitive.

With the increasing numbers of the population aging, we are paying close attention to the opportunities and to the challenges of growing older. The needs of an aging populace are being met with a dramatic increase in research into the biology of aging, reducing disease and disability, and behavioral and cognitive aspects of aging.

Dual chamber ICDs are increasingly implanted nowadays, mainly to improve discrimination between supraventricular and ventricular arrhythmias but also to maintain AV synchrony in patients with bradycardia. The aim of this study was to investigate a new single pass right ventricular defibrillation lead capable of true bipolar sensing and pacing in the right atrium and integrated bipolar sensing and pacing in the right ventricle. The performance of the lead was evaluated in 57 patients (age 61 +/- 12 years; New York Heart Association 1.9 +/- 0.6, left ventricular ejection fraction 0.38 +/- 0.15) at implant, at prehospital discharge, and during a 1-year follow-up. Sensing and pacing behavior of the lead was evaluated in six different body positions. In four patients, no stable position of the atrial electrode could intraoperatively be found. The intraoperative atrial sensing was 2.3 +/- 1.6 mV and the atrial pacing threshold 0.8 +/- 0.5 V at 0.5 ms. At follow-up, the atrial sensing ranged from 1.5 mV to 2.2 mV and the atrial pacing threshold product from 0.8 to 1.7 V/ms. In 11 patients, an intermittent atrial sensing problem and in 24 patients an atrial pacing dysfunction were observed in at least one body position. In 565 episodes, a sensitivity of 100% and a specificity of 96.5% were found for ventricular arrhythmias. In conclusion, this single pass defibrillation lead performed well as a VDD lead and for dual chamber arrhythmia discrimination. However, loss of atrial capture in 45% of patients preclude its use in patients depending on atrial pacing.