Activation of Alveolar Epithelial ER Stress by ß-Coronavirus Infection Disrupt Surfactant Homeostasis in Mice: Implications for Covid-19 Respiratory Failure.

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar Type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, SARS-CoV-2 and other ß-coronavirus genus members induce an ER stress response in vitro, however the consequences for host AT2 function in vivo are less understood. To study this, two murine models of coronavirus infection were employed- mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse adapted SARS-CoV-2 strain. MHV-1 infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased IRE1α signaling and a biphasic response in PERK signaling accompanied marked reductions in AT2 and BALF surfactant protein (SP-B, SP-C) content, increases in surfactant surface tension, and emergence of a re-programmed epithelial cell population (Krt8+, Cldn4+). The loss of a homeostatic AT2 endophenotype was attenuated by treatment with the IRE1α inhibitor OPK711. As proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from ß-coronavirus infection results from an aberrant host response activating multiple AT2 UPR pathways, altering surfactant metabolism/function, and changing AT2 endophenotypes offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure.

Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-ß1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFß1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER - SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α/FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

Development of a probability discounting task of communication for adults who stutter.

Previous research indicates speaking may be emotionally and socially risky for adults who stutter (AWS) due to psychological distress induced by others following a dysfluency. This may impact communication-related decision-making; however, no measure had been developed to objectively quantify this variable. The present study aimed to develop and validate the Probability Discounting for Communication (PDC) task, a behavioral measure of risk taking that characterizes decreasing subjective value of hypothetical communication engagement as the probability of stuttering and listener reaction change. AWS (n = 67) and adults who do not stutter (AWNS; n = 93) were recruited from an online listserv and MTurk. Across a series of trials, participants completed the PDC by using a visual analog scale to indicate their subjective value of communication as probabilities of stuttering (1%-99%) and magnitudes of negative listener reaction risk (10%, 50%, 90%) were manipulated. They also completed measures of stuttering, communication, and demographics. Results revealed communication was discounted hyperbolically across increasing dysfluency odds. AWS showed more systematic discounting patterns compared to AWNS suggesting AWS may be more sensitive to communication due to experiences with stuttering. A magnitude effect was found with both AWS and AWNS discounting communication more steeply with increasing negative listener reaction risk. Significant associations were observed between discounting, stuttering, and communication measures among AWS, which indicates that sensitivity to risk in the context of stuttering and social reaction may influence communication engagement. Overall, the PDC functions as a measure to assess underlying decision-making patterns related to communication among AWS, which may inform treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.

Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.

The common ABCA3E292V variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.

ATP-binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing enhanced green fluorescent protein (EGFP)-tagged ABCA3 isoforms show a functional deficiency of the ABCA3E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3E292V demonstrate the presence of small electron-dense lamellar bodies, time-dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age-dependent inflammation and fibrillary collagen deposition in alveolar septa. Older ABCA3E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 cell autophagy.

Delay discounting and obesity in food insecure and food secure women.

OBJECTIVES: The relation between food insecurity (FI) and delay discounting (DD) and probability discounting (PD) for food and money was tested in women. In addition, discounting was tested as a variable that mediates the relation between obesity and FI. METHOD: Women recruited from a community sample (N = 92) completed questionnaires. They completed the food choice questionnaire, the monetary choice questionnaire, measures for food and money probability discounting (which quantify sensitivity to risk aversion), and demographic measures. RESULTS: Women with FI had higher rates of obesity and higher food DD compared to food-secure women. However, DD for money or probability discounting for food or money did not significantly differ between FI and food secure groups when controlling for significant covariates. Neither DD or PD significantly mediated the relation between FI and obesity. CONCLUSIONS: These results suggest that FI is associated with greater impulsive food choice, but its association with other monetary discounting and probability discounting for food and money appears contingent upon other demographic factors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Middle fossa meningiomas.

The middle cranial fossa is bounded anteriorly by the sphenoid ridge, medially by the lateral wall of the cavernous sinus and Meckel's cave, posteriorly by the sphenoid wing and petrous bone, and laterally by the greater wing of sphenoid and squamous temporal bone. In normal individuals, unnamed venous channels within the dura and arachnoid granulations can be seen on the floor of this fossa by the operating surgeon. Meningiomas arising mainly from the dura of the floor are uncommon, and middle fossa meningiomas have been arbitrarily named so based on an attachment of more than 75% to this location. They tend to present clinically at a large size and require special considerations for surgical treatment.

Global Gene Expression Analysis in an in vitro Fibroblast Model of Idiopathic Pulmonary Fibrosis Reveals Potential Role for CXCL14/CXCR4.

Idiopathic Pulmonary Fibrosis (IPF) is a progressive disorder that is marked by an over accumulation of activated fibroblast populations. Despite the improved understanding of many mechanisms within this disease, global gene expression analysis has few focused studies on the fibroblast, the central effector cell of progressive fibrosis. We present a unique analysis of IPF pulmonary fibroblasts as they transition through cell culture and identify in vitro altered cellular processes. Fibroblasts were isolated from diseased (n = 8) and non-diseased (n = 4) lungs. Global gene expression analysis was carried out at the initial point of isolation and after 3 weeks of culture. We identify several genes that are altered by removal of the fibroblast from the IPF environment. Comparison of this subset of genes to four previously published whole lung analyses refined our list to a small subset of key fibroblast specific genes important in IPF. Application of STRING database analysis and confirmation via in-vitro and histological assay highlights the CXCL14/CXCR4 chemokine axis with a possible role in the progression and/or activation of fibroblasts within the IPF lung. Our findings, present a possible therapeutic target for IPF and a model for the study and discovery of novel protein and processes in this terrible disease.

Factores asociados al síndrome de boca ardiente / Burning mouth syndrome and associated factors

Introducción: el síndrome de boca ardiente se caracteriza por la presencia de síntomas crónicos de ardor o dolor en la mucosa bucal clínicamente normal. Objetivo: identificar la presencia de factores asociados al síndrome de boca ardiente. Métodos: se realizó un estudio analítico de casos y controles entre mayo del 2010 y abril del 2014 en la Clínica Docente Victoria de Santa Clara. Se integraron dos grupos: el de estudio formado por 23pacientes que padecían esta afección, y uno de control formado por 46 que no presentaban el síndrome. Se estudiaron diversas variables, como edad, sexo, xerostomía subjetiva, presencia o no de síntomas ardientes, la intensidad de los síntomas, su localización, momento y forma de aparición, presencia de disgeusia, cancerofobia, ingestión nocturna de agua, sensación de cuerpo extraño, tasade flujo salival en reposo y estimulado, el consumo de medicamentos xerostomizantes así como la ansiedad y la depresión. El tratamiento de los datos se realizó mediante el empleo de un software de procesamiento estadístico, versión 15.5 para Windows.Resultados: predominó el sexo femenino, la sensación de ardor continuo e insoportable en la lenguay durante el día. La xerostomía subjetiva, disgeusia, cancerofobia, sensación de cuerpo extraño,ingestión nocturna de agua y la nicturia caracterizaron los síntomas del grupo de estudio. Conclusiones: la ansiedad y la depresión fueron los factores que más se asociaron al síndrome. No ocurrió así con el flujo salival y los medicamentos xerostomizantes(AU)

The utility of behavioral economics in expanding the free-feed model of obesity.

Animal models of obesity are numerous and diverse in terms of identifying specific neural and peripheral mechanisms related to obesity; however, they are limited when it comes to behavior. The standard behavioral measure of food intake in most animal models occurs in a free-feeding environment. While easy and cost-effective for the researcher, the free-feeding environment omits some of the most important features of obesity-related food consumption-namely, properties of food availability, such as effort and delay to obtaining food. Behavior economics expands behavioral measures of obesity animal models by identifying such behavioral mechanisms. First, economic demand analysis allows researchers to understand the role of effort in food procurement, and how physiological and neural mechanisms are related. Second, studies on delay discounting contribute to a growing literature that shows that sensitivity to delayed food- and food-related outcomes is likely a fundamental process of obesity. Together, these data expand the animal model in a manner that better characterizes how environmental factors influence food consumption.

Natural Prey Preferences and Spatial Variability of Predation Pressure by Cyphoma gibbosum (Mollusca: Gastropoda) on Octocoral Communities off La Parguera, Puerto Rico.

This study evaluated the natural prey preferences and spatial variability of predation pressure (PP = proportion of colonies with snails and/or clear predation signs) by the gastropod Cyphoma gibbosum on octocoral communities off the La Parguera Natural Reserve, Puerto Rico. All octocoral colonies were checked for presence of C. gibbosum and/or clear predation signs in four permanent band-transects (2 × 10 m), along three depth intervals (0-5, 7-12, >15 m deep) in each of six reefs along an inshore offshore gradient. Results indicate that C. gibbosum preys on at least 16 species, six of which (Briareum asbestinum, Gorgonia ventalina, Pseudoterogorgia americana, P. acerosa, Plexaura flexuosa, and Pseudoplexaura porosa) consistently showed significantly higher (K-W, P < 0.05) (17-37%) PP compared to all other species. Plexaura flexuosa, P. americana, and P. porosa had significantly higher PP (11-38%) among inner and mid-shelf reefs, and G. ventalina had higher PP in shelf-edge reefs (16-20%). A combination of differential spatial distributions and octocoral species abundances seems to explain the observed patterns of predation by C. gibbosum. Prey preference and higher abundances of 3-dimensional octocorals providing increased refuge or microhabitats utilized for mating or egg-deposition could be driving the spatial distribution of C. gibbosum and the observed differential predation pressure.

Tumor de células gigantes de hueso: Aspectos generales de 11 casos / Giant cells bone tumor: General aspects in 11 cases

El tumor de células gigantes de hueso es uno de los tumores menos frecuentes, más controversial y menos predecible en su comportamiento. Los casos de esta serie tuvieron un franco predominio en el sexo femenino (75 por ciento). Con excepción de un caso que afectó a los huesos cortos del pie, el resto se localizó en los extremos dístales de los huesos largos de extremidades superiores e inferiores a partes iguales. Todas fueron lesiones grandes y sintomáticas, con pérdida parcial o total de la función. En ocho pacientes se realizó resección en bloque, uno con amputación y en dos con legrado óseo, más crioterapia en uno de ellos. Tres pacientes recibieron radioterapia adyuvante y uno quimioterapia. Dos lesiones recurrieron siete y nueve meses después de la cirugía; uno de éstos tratado con legrado y crioterapia. Ninguno desarrolló metástasis