FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration.

FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here, we identify that FOXK2 undergoes degradation in lung epithelia in the presence of the virulent pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae through ubiquitin-proteasomal processing. FOXK2 through its carboxyl terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within the mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxy terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to WT littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.

Single Cell MALDI-MS Imaging of Lipids and Proteins in Senescent Fibroblasts.

In this study, we evaluate the lipidomic and proteomic profiles of human lung fibroblasts (hLFs) to interrogate changes occurring due to senescence. To study single cell populations, a comparison of cell adhered onto slides utilizing poly-D-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-D-lysine approach was than utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-IHC platform for single-cell level analyses. Altogether, our results show the ability to detect lipids implicated in senescence and alterations to protein expression between normal and senescent fibroblast populations. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level for analyzing the expression of proteins.

Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

scResolve: Recovering single cell expression profiles from multi-cellular spatial transcriptomics.

Many popular spatial transcriptomics techniques lack single-cell resolution. Instead, these methods measure the collective gene expression for each location from a mixture of cells, potentially containing multiple cell types. Here, we developed scResolve, a method for recovering single-cell expression profiles from spatial transcriptomics measurements at multi-cellular resolution. scResolve accurately restores expression profiles of individual cells at their locations, which is unattainable from cell type deconvolution. Applications of scResolve on human breast cancer data and human lung disease data demonstrate that scResolve enables cell type-specific differential gene expression analysis between different tissue contexts and accurate identification of rare cell populations. The spatially resolved cellular-level expression profiles obtained through scResolve facilitate more flexible and precise spatial analysis that complements raw multi-cellular level analysis.

Calidad de vida y balance sagital en la evolución de los pacientes con mieloma múltiple tratados con vertebroplastia percutánea / Quality of Life and Sagittal Balance in the Evolution of Patients with Multiple Myeloma Who Received Treatment

RESUMEN Introducción: El mieloma múltiple representa el 1 por ciento de las neoplasias y el 10 por ciento de las hemopatías malignas. La edad media de presentación es 65 años. El dolor óseo en columna vertebral y costillas constituye su manifestación inicial. El tratamiento quirúrgico del mieloma múltiple en la columna consiste en descompresión amplia y artrodesis. La vertebroplastia se considera técnica de elección porque restablece el balance sagital y coronal, contribuye al fortalecimiento del cuerpo vertebral, y disminuye el dolor asociado a fracturas. Objetivo: Evaluar el efecto de la vertebroplastia sobre la calidad de vida y el balance sagital, en la disminución del dolor. Métodos: Se estudiaron 192 pacientes con mieloma múltiple con fractura en la columna, 80 tratados con vertebroplastia y 112 en forma conservadora. Se utilizó el cuestionario de Oswestry y la escala de Karnosfky. Resultados: La vertebroplastia disminuyó 0,52 veces el uso de analgésicos opioides. Conclusiones: La vertebroplastia representa un mayor beneficio de la calidad de vida de los pacientes aquejados de mieloma múltiple con fractura vertebral; repercute en el mejoramiento del balance sagital, el nivel de discapacidad y la capacidad para realizar tareas cotidianas(AU)

ABSTRACT Introduction: Multiple myeloma accounts for 1 percent of neoplasms and for 10 percent of malignant hematomas. The mean onset age is 65 years. Bone pain in the spine and ribs is its initial manifestation. Surgical treatment for multiple myeloma in the spine consists in wide decompression and arthrodesis. Vertebroplasty is considered the choice technique because it restores sagittal and coronal balance, contributes to the strengthening of the vertebral body, and reduces pain associated with fractures. Objective: To assess the effect of vertebroplasty on quality of life and the effect of sagittal balance in reducing pain. Methods: 192 patients with multiple myeloma and spinal fracture were studied, 80 treated with vertebroplasty and 112 treated conservatively. The Oswestry questionnaire and the Karnofsky scale were used. Results: Vertebroplasty decreased the use of opioid analgesics by 0.52 times. Conclusions: Vertebroplasty represents a greater benefit for the quality of life of patients suffering from multiple myeloma with vertebral fracture. It affects the improvement of sagittal balance, the level of disability, and the ability to perform daily tasks(AU)

Evaluación de la efectividad de un método de medición directa sobre modelos para arco maxilar en pacientes sanos y pacientes con labio y paladar fisurado unilateral izquierdo completo de los 4 a 7 meses de edad / Maxillar arches in healthy patients

En este estudio se buscó establecer la confiabilidad de 33 modelos de arcos maxilares de pacientes sanos y 18 en pacientes con labio y paladar fisurado unilateralmente completo izquierdo en edades de 4 a 7 meses de edad, pertenecientes a la clínica odontológica de la Escuela Colombiana de Medicina en el Hospital Infantil Lorencita de Villegas de Santos. Se usó un método de Medición estandarizado llevado a cabo por 5 examinadores, y comparando así el promedio de cada medida se observó que es un método confiable en las medidas donde el valor P de A, C, D, E,=>0.05; y no fué confiable en puntos de referencia de difícil localización como es el largo y el ancho de la fisura en pacientes con labio y paladar fisurado unilateral completo izquierdo