Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment

Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.     

Upregulation of Dopamine D2 Receptors in the Nucleus Accumbens Indirect Pathway Increases Locomotion but Does Not Reduce Alcohol Consumption

Brain imaging studies performed in humans have associated low striatal dopamine release and D2R binding with alcohol dependence. Conversely, high striatal D2R binding has been observed in unaffected members of alcoholic families suggesting that high D2R function may protect against alcohol dependence. A possible protective role of increased D2R levels in the striatum is further supported by preclinical studies in non-human primates and rodents. Here, we determined whether there is a causal relationship between D2R levels and alcohol intake. To this end, we upregulated D2R expression levels in the nucleus accumbens of the adult mouse, but selectively restricted the upregulation to the indirect striatal output pathway, which endogenously expresses D2Rs. After overexpression was established, mice were tested in two models of free-choice alcohol drinking: the continuous and intermittent access two-bottle choice models. As anticipated, we found that D2R upregulation leads to hyperactivity in the open field. Contrary to our expectation, D2R upregulation did not reduce alcohol intake during continuous or intermittent access or when alcohol drinking was tested in the context of aversive outcomes. These data argue against a protective role of accumbal indirect pathway D2Rs in alcohol consumption but emphasize their importance in promoting locomotor activity.     

Food Insecurity Among Hispanic/Latino Youth: Who Is at Risk and What Are the Health Correlates?

Purpose

We examined the correlates and health implications of household food insecurity among Hispanic/Latino youth (aged 8–16 years), a high food insecurity–risk population.

Disruption of neonatal Purkinje cell function underlies injury-related learning deficits

It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury. Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex.

Perinatal complications of preterm or term neonates often result in adaptive behavioral deficits. While injury to the developing cerebellum has been correlated to long-term behavioral abnormalities, especially in locomotor function, the specific neural circuits and physiological mechanisms that are disrupted are unknown. Recent work characterized the spatial and temporal components of interlimb coordination in cerebellum-dependent locomotor learning (1). However, the sparsity of techniques available to directly measure neuronal activity during adaptive cerebellar behavior hampers efforts to identify the functional and mechanistic basis of behavioral pathology.We designed a unique method to measure Purkinje cell (PC) activity during an adaptive cerebellum-dependent locomotor learning task. We utilized the ErasmusLadder––an automated behavioral system that can accurately quantify cerebellum-dependent locomotor learning and adaptive behavior. The ErasmusLadder enables the use of an associative conditioned-learning paradigm that is temporally tuned to define cerebellum-specific aspects of motor learning over multiple trials (2, 3). By directly integrating fiber photometry of the genetically encoded Ca²⁺ indicator—GCaMP6f—with the ErasmusLadder, we successfully and simultaneously recorded population responses of PCs in mice in real time during unrestrained behavior on the ErasmusLadder. We used our method to integrate PC activity measurement with adaptive behavioral quantification to identify a mechanistic basis for locomotor learning dysfunction in a clinically relevant mouse model of neonatal brain injury (4).     

The Cascading Effects of Multiple Dimensions of Implementation on Program Outcomes: a Test of a Theoretical Model

This study tests a theoretical cascade model in which multiple dimensions of facilitator delivery predict indicators of participant responsiveness, which in turn lead to improvements in targeted program outcomes. An effectiveness trial of the 10-session New Beginnings Program for divorcing families was implemented in partnership with four county-level family courts. This study included 366 families assigned to the intervention condition who attended at least one session. Independent observers provided ratings of program delivery (i.e., fidelity to the curriculum and process quality). Facilitators reported on parent attendance and parents’ competence in home practice of program skills. At pretest and posttest, children reported on parenting and parents reported child mental health. We hypothesized effects of quality on attendance, fidelity and attendance on home practice, and home practice on improvements in parenting and child mental health. Structural Equation Modeling with mediation and moderation analyses were used to test these associations. Results indicated quality was significantly associated with attendance, and attendance moderated the effect of fidelity on home practice. Home practice was a significant mediator of the links between fidelity and improvements in parent-child relationship quality and child externalizing and internalizing problems. Findings provide support for fidelity to the curriculum, process quality, attendance, and home practice as valid predictors of program outcomes for mothers and fathers. Future directions for assessing implementation in community settings are discussed.     

Relationship between kinematic center and TMJ anatomy and function

The kinematic center (KC)-defined by coinciding jaw-opening/-closing and protrusion-retrusion trajectories-has been proposed in the literature as a reference point to represent TMJ movements. In this study, we tested whether the KC lies in a peculiar anatomical point and whether its trajectory reflects intra-articular distance. In 11 asymptomatic individuals (seven females, four males, aged 24-37 yrs), 4 openings/closings and 4 protrusions/retrusions were tracked with dynamic stereometry. In a 3D lattice (0.5 mm grid) constructed solidly around each condyle, the KC was the point with maximal cross-correlation between opening-closing and protrusion-retrusion paths. KC trajectories were more cranial on closing than on opening, consistent with intra-articular distances being smaller on closing than on opening. However, KCs were never located on condylar main axes (distance, 4.5 +/- 2.9 mm), nor did they coincide with points best approximating fossa shapes (distance, 12.5 +/- 6.4 mm). The kinematic center's anatomical and functional significance therefore appears to be questionable.