Post-translational modifications of vertebrate striated muscle myosin heavy chains.

Post-translational modifications (PTMs) play a crucial role in regulating the function of many sarcomeric proteins, including myosin. Myosins comprise a family of motor proteins that play fundamental roles in cell motility in general and muscle contraction in particular. A myosin molecule consists of two myosin heavy chains (MyHCs) and two pairs of myosin light chains (MLCs); two MLCs are associated with the neck region of each MyHC's N-terminal head domain, while the two MyHC C-terminal tails form a coiled-coil that polymerizes with other MyHCs to form the thick filament backbone. Myosin undergoes extensive PTMs, and dysregulation of these PTMs may lead to abnormal muscle function and contribute to the development of myopathies and cardiovascular disorders. Recent studies have uncovered the significance of PTMs in regulating MyHC function and showed how these PTMs may provide additional modulation of contractile processes. Here, we discuss MyHC PTMs that have been biochemically and/or functionally studied in mammals' and rodents' striated muscle. We have identified hotspots or specific regions in three isoforms of myosin (MYH2, MYH6, and MYH7) where the prevalence of PTMs is more frequent and could potentially play a significant role in fine-tuning the activity of these proteins.

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Medición de la fuerza muscular en adultos como predictor de extubación en Unidades de Cuidados Intensivos. Revisión narrativa / Measurement of muscular strength in adults as a predicator of extubation in intensive care units. Narrative review

Resumen: Introducción: uno de los principales efectos de la ventilación mecánica invasiva es la lesión de los músculos respiratorios, específicamente, sobre el diafragma en el que pueden ocurrir alteraciones estructurales y funcionales que modifican parcial o totalmente su función. Durante la ventilación mecánica se produce un proceso de atrofia por desuso de dicho músculo. Por ello la utilidad clínica de la medición de la fuerza muscular diafragmática es importante para conocer si el paciente tiene la capacidad de activar los mecanismos protectores de la vía aérea para lograr la extubación exitosa y el retiro del ventilador mecánico en el menor tiempo posible. Objetivos: describir la medición de la fuerza muscular como predictor de la extubación en las unidades de cuidados intensivos. Material y métodos: se realizó una revisión de la literatura, entre 2011 y 2022. Resultados: los pacientes que son sometidos a ventilación mecánica invasiva prolongada generalmente desarrollan una afección muscular diafragmática, lo que se convierte en una problemática para el proceso de extubación temprana, por lo cual es vital conocer los métodos de medición de fuerza muscular como predictor de extubación.

Abstract: Introduction: one of the main effects of invasive mechanical ventilation is injury to the respiratory muscles, specifically the diaphragm. In which structural and functional alterations can occur that partially or totally modify its function. During mechanical ventilation, a process of disuse atrophy of said muscle occurs. Therefore, the clinical utility of measuring diaphragmatic muscle strength is important to know if the patient has the ability to activate the protective mechanisms of the airway to achieve successful extubation and removal of the mechanical ventilator in the shortest time possible. Objective: describe the measurement of muscle strength as a predictor of extubation in intensive care units. Material and methods: a literature review was carried out, carried out between 2011 and 2022. Results: patients who are subjected to prolonged mechanical ventilation generally develop a diaphragmatic muscle disorder, becoming a problem for the weaning, for it is important know the methods of measuring muscle strength.

Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair.

The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood-brain-barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated. Targeting and activation of CB2R was accomplished by a novel and highly specific chromenopyrazole based CB2R agonist, PM289. This study demonstrates that CB2R upregulation is induced as early as 8 h in the cortical vasculature in an experimental mouse model of TBI. Unlike CB2R, CB1R was marginally detected and not significantly induced. In the human brain endothelial cell line, hCMEC/D3 cells, similar induction of CB2R was observed upon stimulation with TNFα. Analysis of transendothelial electrical resistance shows that PM289 markedly prevented the barrier-leakiness induced by TNFα. The BBB is also responsible for maintaining an immunological barrier. The five-fold increase in ICAM1 expression in stimulated endothelial cells was significantly diminished due to CB2R activation. Utilizing wounding assays, results showed that wound repair could be accomplished in nearly half the time when the novel CB2R agonist is present compared to the untreated control. Lastly, mechanistically, the effects of CB2R may be explained by the observed inhibition of the p65 NFκB subunit. Overall, these studies support the notion that targeting and activating CB2R in the brain vasculature could aid in BBB and vascular protection in the context of neuroinflammation.

Drug-Induced Kounis Syndrome: Latest Novelties.

Kounis syndrome (KS) is defined by an acute coronary syndrome associated with hypersensitivity reactions, an under-diagnosed life-threatening medical emergency. Although multiple causes have been described, drugs constitute the most frequent cause. The purpose of this review is to update knowledge about drug-induced KS, to give guidelines on the correct diagnosis and treatment. This article reviews the literature on drug-induced KS from the last 5 years. Antibiotics and NSAIDs are the most frequently implicated drugs. In addition, data on pathophysiology, clinical presentation, diagnosis, and management are reviewed in detail. Highlight that there is a great deal of variability in the diagnosis and especially in the treatment of KS. This review provides a valuable selection of practical resources for all stakeholders to support effective care for KS, from a cardiologic and allergologic point of view. Future research should focus on developing validated, evidence-based, and patient-centered tools to improve the management of KS.

Viewpoint on the Second Transatlantic GPCR Symposium for Early Career Investigators.

The second Transatlantic Early Career Investigator (ECI) G Protein-Coupled Receptor (GPCR) Symposium was an online scientific meeting geared at young GPCR investigators, with the primary goal of expanding opportunities for sharing research and networking among trainees in North America and Europe. Here, we discuss the format of our meeting, its impact, and the challenges and opportunities facing meetings like it in the future.

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship.

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using ß-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

Use of Telehealth Among Cancer Survivors: A Scoping Review.

Background: Long-term cancer survivors have specific needs that are frequently neglected. Telehealth, as a new form of health care, can benefit this growing population. Objective: To identify, analyze, and synthesize the existing evidence on the use of telehealth in the care of cancer survivors after the end of treatment. Methods: A scoping review was conducted in the databases PubMed, CINAHL, COCHRANE, SCIELO, DIALNET, and LILACS and reference institutions in cancer. Results: The initial search yielded 406 publications with 59 articles meeting the eligibility criteria. There are different types of telehealth (video calls, phone calls, websites, mobile applications, and short message services) used for the care of cancer survivors. Most telehealth interventions focus on improving the physical and mental spheres of quality of life in the extended survival phase (from 1 to 3 years postdiagnosis), with only two articles (3%) on long-term cancer survivors (>5 years postdiagnosis). Survivors are satisfied with telehealth interventions, noting the importance of improving comprehensibility, personalization of the platforms, and the lack of excessive information included. Conclusions: Telehealth is a feasible modality for cancer survival care. The scarcity of interventions aimed at long-term survivors stands out, as does the general neglect of the social and spiritual spheres of quality of life. Implications for Practice: Telehealth platforms must adapt their content, format, and items to the preferences reported by the survivors.

Eficacia y tolerabilidad de Nitazoxanida para parasitismo intestinal en escolares atendidos en el Centro de Salud de la Universidad del Quindío / Efficacy and tolerability of Nitazoxanide for intestinal parasitism in schoolchildren treated at the Health Center of the University of Quindío

Resumen Objetivo: Describir la efectividad del tratamiento antiparasitario intestinal brindado a niños de cuatro a nueve años atendidos en el centro de Salud de la Universidad del Quindío entre Julio de 2017 a marzo de 2018. Materiales y métodos: Estudio observacional prospectivo. Se extrajeron datos de historias clínicas de pacientes con rango de edad de 4 a 9 años, quienes consultaron en el Centro de Salud de la Universidad del Quindío y se diagnosticaron mediante coprológico con blastocistosis o giardiasis. Se seleccionaron las historias cuyo tratamiento fuese Nitazoxanida y tuviesen un coprológico control postratamiento. Se presentan estadísticas descriptivas; porcentaje de eficacia y tolerabilidad. Resultados: De 15 niños tratados con Nitazoxanida, respondieron al tratamiento 10, en quienes no se hallaron parásitos en el coprológico control. Con una eficacia del 83,3% (IC95% 60 - 100) en blastocistosis, 57,1% (IC95% 32 - 82%) en giardiasis. Conclusión: Se evidenciaron resultados porcentuales similares a los reportados en la literatura, siendo más eficaz en blastocisotisis que en giardiasis.

Abstract Objective: To describe the effectiveness of the intestinal antiparasitic treatment given to children ranging between 4 and 9 years old that were attended in the Health Center of the University of Quindío in the period of July 2017 and March 2018. Materials and methods: Prospective observational study. Data were extracted from medical records of patients with an age range of 4 to 9 years, who consulted at the Health Center of the University of Quindío and were diagnosed through coprological tests with Blastocystis and Giardiasis. The clinical records were selected by whose treatment was done with Nitazoxanide or Albendazole with coprological results of post-treatment check-up. Descriptive statistics are presented along with percentage of efficacy and tolerability. Results: From 15 children treated with Nitazoxanide, 10 responded to the treatment, who presented no parasites in the coprological check-up. The remaining population presented some type of parasitic infection (n = 5). With an efficiency of 83,3% (IC95% 32 - 82%) in blastocystis, and 57,1% (IC95% 32 - 82%) in giardiasis. Conclusion: Percentage results similar to those reported in the literature were evidenced, being more effective in blastocystis than in giardiasis.

The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling.

GPR55 is a class A orphan G protein-coupled receptor that has drawn important therapeutic attention in the last decade because of its role in pathophysiological processes including vascular functions, metabolic dysfunction, neurodegenerative disorders, or bone turnover among others. Several cannabinoids of phytogenic, endogenous, and synthetic nature have shown to modulate this receptor leading to propose it as a member of the endocannabinoid system. The putative endogenous GPR55 ligand is L-α-lysophosphatidylinositol (LPI) and it has been associated with several processes that control cell survival and tumor progression. The relevance of GPR55 in cancer is currently being extensively studied in vitro and in vivo using diverse cancer models. The LPI/GPR55 axis has been reported to participate in pro-oncogenic processes including cellular proliferation, differentiation, migration, invasion, and metastasis being altered in several cancer cells via G12/13 and Gq signaling. Moreover, GRP55 and its bioactive lipid have been proposed as potential biomarkers for cancer diagnosis. Indeed, GPR55 overexpression or high expression has been shown to correlate with cancer aggressiveness in specific tumors including acute myeloid leukemia, uveal melanoma, low grade glioma and renal cancer. This review aims to analyze and summarize current evidence on the cancerogenic role of the LPI/GPR55 axis providing a critical view of the therapeutic prospects of this promising target.

The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors.

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CB2R conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CB2R ligands in order to fine-tune signaling effects and therapeutic propositions.

Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators.

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis.

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson's disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.

Impact of COVID-19 on the Mental Health and Well-Being of Latinx Caregivers of Children with Intellectual and Developmental Disabilities.

The COVID-19 pandemic has impacted the entire world in unprecedented ways. However, populations that have had a history of marginalization have experienced a more profound impact. One such group is Latinx families of children with intellectual and developmental disabilities (IDD) in the Unites States. In this study, we used a mixed methods approach to explore the impact of the pandemic on the mental health and well-being of Latinx caregivers of children with IDD. Specifically, we (1) identified which social determinants of health are correlated with maternal caregivers perceived general health, mental health, and well-being; (2) explored the impact of the pandemic on families' overall eating and physical activity routines; and (3) identified emergent themes from caregivers' experiences during the pandemic. Thirty-seven Latinx caregivers participated in three interviews in which several validated instruments were administered. The results indicated that perceived social support, annual family income, food security, and receipt of financial benefits were correlated with fewer depressive symptoms. Annual family income was also significantly correlated with perceived general health. Most caregivers reported that the pandemic had placed a strain on their economic situation; increased their isolation; and disrupted their child's therapeutic supports, online education, eating routines, and engagement in physical activity. Meanwhile, some caregivers reported positive changes as a result of the pandemic. Implications for future research and practice are discussed.

Synthetic and Natural Derivatives of Cannabidiol.

The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.

Chronic Pain and Psychological Distress Among Undocumented Latinx Immigrants in the USA.

BACKGROUND: Undocumented immigration is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain. OBJECTIVE: This study aimed to identify the prevalence of chronic pain and its association with psychological distress among undocumented Latinx immigrants in the USA. DESIGN/PARTICIPANTS: We used respondent-driven sampling to collect and analyze data from clinical interviews with 254 undocumented Latinx immigrants, enabling inference to a population of 22,000. MAIN MEASURES: Chronic pain was assessed using the World Health Organization Composite International Diagnostic Interview (CIDI) Chronic Conditions Module. For all analyses, inferential statistics accounted for design effects and sample weights to produce weighted estimates. We conducted logistic regression analyses to assess the association between chronic pain and psychological distress after controlling for age, years in the USA, and history of trauma. RESULTS: A total of 28% of undocumented Latinx immigrants reported having chronic pain, and 20% of those had clinically significant psychological distress. Significant differences in the prevalence of chronic pain were reported across age groups, years in the USA, and trauma history. After controlling for relevant covariates, chronic pain was significantly associated with psychological distress (OR = 1.06, 95% CI [1.02, 1.09]), age (OR = 1.05, 95% CI [1.02; 1.09]), and history of trauma (OR = 1.10 per additional traumatic event, 95% CI [1.02; 1.19]; C-statistic = 0.79). CONCLUSION: Among undocumented Latinx immigrants, chronic pain is significantly associated with psychological distress, older age, and trauma history. Given that undocumented immigrants have restricted access to healthcare and are at high risk for chronic pain, developing alternatives to facilitate access to chronic pain interventions and risk-reduction prevention are needed.