Molecular basis for pericyte-induced capillary tube network assembly and maturation.

Here we address the functional importance and role of pericytes in capillary tube network assembly, an essential process that is required for vascularized tissue development, maintenance, and health. Healthy capillaries may be directly capable of suppressing human disease. Considerable advances have occurred in our understanding of the molecular and signaling requirements controlling EC lumen and tube formation in 3D extracellular matrices. A combination of SCF, IL-3, SDF-1α, FGF-2 and insulin ("Factors") in conjunction with integrin- and MT1-MMP-induced signaling are required for EC sprouting behavior and tube formation under serum-free defined conditions. Pericyte recruitment to the abluminal EC tube surface results in elongated and narrow tube diameters and deposition of the vascular basement membrane. In contrast, EC tubes in the absence of pericytes continue to widen and shorten over time and fail to deposit basement membranes. Pericyte invasion, recruitment and proliferation in 3D matrices requires the presence of ECs. A detailed analysis identified that EC-derived PDGF-BB, PDGF-DD, ET-1, HB-EGF, and TGFß1 are necessary for pericyte recruitment, proliferation, and basement membrane deposition. Blockade of these individual factors causes significant pericyte inhibition, but combined blockade profoundly interferes with these events, resulting in markedly widened EC tubes without basement membranes, like when pericytes are absent.

Experiencia de grupo terapéutico durante el confinamiento por COVID-19 en una unidad de agudos de psiquiatría / Therapeutic group experience during confinement by COVID-19 in an acute psychiatry unit

El presente trabajo consiste en la descripciónde las sesiones grupales que se efectuarondurante el confinamiento por COVID-19en la Unidad de Agudos 1 de Psiquiatría generaldel Hospital Sagrat Cor de Martorell,en Barcelona.Se planteó un grupo abierto con aquellospacientes ingresados que voluntariamenteaccedieran a participar, como una propuestaa la alta respuesta emocional del momento.Se efectuó una sesión grupal semanal de unahora de duración a lo largo de seis semanas.El equipo terapéutico quedó constituidotanto por profesionales de la unidad comode los provenientes de recursos ambulatoriostomando un carácter interdisciplinar. Participaronun total de 41 pacientes con unaheterogeneidad diagnóstica; trastornos dela personalidad (26,83%), trastorno bipolar(19.51%), esquizofrenia y otros trastornospsicóticos (19,51%) y trastornos depresivos(14,61%). El porcentaje restante (19,54%)corresponde a otros diagnósticos. El 46,34%del total de los pacientes ha presentadoconsumo de sustancias en comorbilidad. Seaprecian como temas principales: La aceptacióndel ingreso, la compresión de lasnormativas por COVID-19, el manejo de laangustia por el ingreso bajo las condicionesde confinamiento y el desarrollo de capacidadesde diálogo, responsabilidad y cuidadode los participantes. Se describieron en las terapeutas intervenciones más directivas alinicio de las sesiones a intervenciones deacompañamiento y facilitación a medida quese desarrollaba el grupo.ConclusionesLa actividad grupal permitió un espacio decontención emocional, seguridad, información,reflexión, educación e integración paralos participantes. (AU)

The present work consists of the descriptionof the group sessions that were carriedout during the confinement becauseof COVID-19 in the Acute Unit 1 of GeneralPsychiatry of the Hospital Sagrat Cor de Martorell,in Barcelona.An open group was proposed with thoseadmitted patients who voluntarily agreed toparticipate, as a proposal to the high emotionalresponse of the moment. A weeklyone-hour group session was held over sixweeks. The therapeutic team was constitutedby both professionals from the unit andthose from outpatient resources, adoptingan interdisciplinary character. The outstandingthemes extracted from the summariesof each session were described. A total of 41patients with diagnostic heterogeneity participated;personality disorders (26.83%), bipolar disorder (19.51%), schizophreniaand other psychotic disorders (19.51%) anddepressive disorders (14.61%). The remainingpercentage (19.54%) corresponds toother diagnoses. 46.34% of the total of patientshave presented substance use in comorbidity.The main themes are the management ofanxiety due to admission under confinementconditions; compression of regulations becauseof COVID-19; and the development ofa dialogue capacity, responsibility and careof the participants. More directive interventionswere described in the therapists at thebeginning of the sessions towards accompanimentinterventions as the group develops.ConclusionsThe group activity allowed a space foremotional containment, security, information,reflection, education and integrationfor the participants. (AU)

ß-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.

Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. ß-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with ß-arrestin2-/- mice, show that ß-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms. Genetic ablation of ß-arrestin2 markedly ablates tau pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, ß-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized ß-arrestin2 with virus encoding ß-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing ß-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.

Biased TAS2R Bronchodilators Inhibit Airway Smooth Muscle Growth by Downregulating Phosphorylated Extracellular Signal-regulated Kinase 1/2.

Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides their coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) extracellular signal-related kinase 1/2 (ERK1/2), but the cellular effects are not known. In the present study, we show in HASM cells that TAS2R agonists initially stimulate phosphorylated ERK1/2 (pERK1/2) but by 24 hours cause a marked (50-70%) downregulation of pERK1/2 without a change in total ERK1/2. It was hypothesized that TAS2R agonists suppress cell growth through this pERK1/2 downregulation. Agonist-dependent inhibition of cell proliferation was indeed found in HASM cells derived from normal and asthmatic human lungs, as well as in an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase). Various structurally diverse TAS2R agonists evoked a range of inhibition of HASM proliferation, the magnitude of which directly correlated with the downregulation of pERK1/2 (R2 = 0.86). Some TAS2R agonists were as effective as pharmacological inhibitors of Raf1 and MEK1/2 in suppressing growth. siRNA silencing of TAS2Rs (subtypes 10, 14, and 31) ablated the pERK1/2 and growth-inhibitory effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G protein Gαi and by knocking down ß-arrestin 1/2, indicating a dual pathway, although there may be additional mechanisms involved in this HASM TAS2R multidimensional signaling. Thus, TAS2R agonist structure can be manipulated to maintain the relaxation response and can be biased toward suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, in which an increase in smooth muscle mass contributes to airway obstruction.