The Brink of the Abyss: From Transcatheter Aortic Valve Implantation, to Impella, to Left Ventricular Assist Device Destination Therapy

Acute valvular emergencies are common causes of cardiogenic shock. Patients with critical aortic pathologies causing shock frequently undergo percutaneous interventions for valve replacement. However, in cases of persistent cardiogenic shock after valve replacement, there are limited options for further mechanical support. In this case study, we report a patient with a prior history of aortic valve replacement who presented in cardiogenic shock. After a transcatheter aortic valve-in-valve replacement, he remained in persistent shock with worsening clinical parameters requiring escalating inotropic and vasopressor support. With input from a multidisciplinary care team, an Impella 5.5 (Abiomed, Inc.) was placed through the valve for mechanical circulatory support, ultimately serving as a bridge to a durable left ventricular assist device as destination therapy. This technically challenging approach was successful, and the patient was discharged to acute rehabilitation with improved symptoms

CENP-A and topoisomerase-II antagonistically affect chromosome length

The size of mitotic chromosomes is coordinated with cell size in a manner dependent on nuclear trafficking. In this study, we conducted an RNA interference screen of the Caenorhabditis elegans nucleome in a strain carrying an exceptionally long chromosome and identified the centromere-specific histone H3 variant CENP-A and the DNA decatenizing enzyme topoisomerase-II (topo-II) as candidate modulators of chromosome size. In the holocentric organism C. elegans , CENP-A is positioned periodically along the entire length of chromosomes, and in mitosis, these genomic regions come together linearly to form the base of kinetochores. We show that CENP-A protein levels decreased through development coinciding with chromosome-size scaling. Partial loss of CENP-A protein resulted in shorter mitotic chromosomes, consistent with a role in setting chromosome length. Conversely, topo-II levels were unchanged through early development, and partial topo-II depletion led to longer chromosomes. Topo-II localized to the perimeter of mitotic chromosomes, excluded from the centromere regions, and depletion of topo-II did not change CENP-A levels. We propose that self-assembly of centromeric chromatin into an extended linear array promotes elongation of the chromosome, whereas topo-II promotes chromosome-length shortening

Proliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviour

The central portion of the midbody, a cytoplasmic bridge between nascent daughter cells at the end of cell division, has generally been thought to be retained by one of the daughter cells, but has, recently, also been shown to be released into the extracellular space. The significance of midbody-retention versus -release is unknown. Here we show, by quantitatively analysing midbody-fate in various cell lines under different growth conditions, that the extent of midbody-release is significantly greater in stem cells than cancer-derived cells. Induction of cell differentiation is accompanied by an increase in midbody-release. Knockdown of the endosomal sorting complex required for transport family members, Alix and tumour-suppressor gene 101, or of their interaction partner, centrosomal protein 55, impairs midbody-release, suggesting mechanistic similarities to abscission. Cells with such impaired midbody-release exhibit enhanced responsiveness to a differentiation stimulus. Taken together, midbody-release emerges as a characteristic feature of cells capable of differentiation

Coordinated genomic control of ciliogenesis and cell movement by RFX2

The mechanisms linking systems-level programs of gene expression to discrete cell biological processes in vivo remain poorly understood. In this study, we have defined such a program for multi-ciliated epithelial cells (MCCs), a cell type critical for proper development and homeostasis of the airway, brain and reproductive tracts. Starting from genomic analysis of the cilia-associated transcription factor Rfx2, we used bioinformatics and in vivo cell biological approaches to gain insights into the molecular basis of cilia assembly and function. Moreover, we discovered a previously unrecognized role for an Rfx factor in cell movement, finding that Rfx2 cell-autonomously controls apical surface expansion in nascent MCCs. Thus, Rfx2 coordinates multiple, distinct gene expression programs in MCCs, regulating genes that control cell movement, ciliogenesis, and cilia function. As such, the work serves as a paradigm for understanding genomic control of cell biological processes that span from early cell morphogenetic events to terminally differentiated cellular functionsclose171

In vivo analysis of cell division during vertebrate development

textIn this work, we identified and characterized developmentally regulated aspects to cell division in the Xenopus laevis. We found that cells in the early neural plate divide in an oriented manner. This orientation is established by Cdc42 controlled maintenance of stable interactions between the spindle and the cell cortex. This role of Cdc42 is developmentally regulated and cells dividing later in a related tissue, the tail epidermis, are not under this control. Moreover, we find that the cell divisions in the early neural plate are further specialized in their mechanisms of cell division. Cells in the early neural plate exhibit exaggerated anaphase-B movements, a delayed onset of cytokinesis, low density of midzone microtubules and a rapid cytokinetic furrow ingression as compared to the late tail epidermis, another ectodermally derived tissue. These modifications to the mechanism of cell division appear to be because of a reduced level of PRC1, a microtubule bundling protein, and thus modifications to the central spindle structure. Finally, we find that cytokinetic mechanisms may be functionally related to the process of ciliogenesis. We find proteins known to localize to the central spindle localized to the rootlet of the basal body of cilia in multiciliated cells of the mucociliary epidermis. This localization may be related to vesicle transport during both these processes. This work reveals unexpected plasticity to fundamental mechanisms of cell division.Institute for Cellular and Molecular Biolog