Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress.

Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo

Paediatric tonsillectomy in england a cohort study of clinical practice and outcomes using Hospital Episode Statistics data (2008‐2019)

Objectives: To assess the safety of paediatric tonsillectomy procedures conducted in NHS hospitals in England between 2008 and 2019. Design: Retrospective observational cohort study using Hospital Episode Statistics (HES) data. Setting: Acute NHS trusts in England conducting paediatric tonsillectomy procedures Participants: Children (≤16 years old) undergoing bilateral tonsillectomy Main outcome measures: Number of tonsillectomies performed per year by procedural method. In‐hospital complications including return to theatre for arrest of haemorrhage. Readmission within 28 days, including those for pain, haemorrhage and surgical arrest of haemorrhage. Long‐term outcomes: all‐cause mortality, revision tonsillectomy. Results: A total of 318,453 paediatric tonsillectomies were performed from 2008 to 2019: 278,772 dissection (87.5%), 39,681 coblation (12.5%). The proportion of tonsillectomy performed using coblation increased from 7% in 2008/9 to 27% in 2018/9. Five patients died in hospital (including 4 due to respiratory complications). In‐hospital complications occurred in 4,202 children (1.3%), with the most frequent being haemorrhage. Within 28 days of tonsillectomy, 28,170 patients (8.8%) were readmitted and 7 deaths occurred. Readmission rates for haemorrhage and pain have increased since 2008. The proportion of children undergoing revision tonsillectomy procedures within 5 years following coblation tonsillectomy (1.4%) was approximately double that of dissection (0.6%). Conclusions: Clinical practice of paediatric tonsillectomy has changed in England over the past 11 years. The overall mortality rate associated with the procedure is 0.0037%. Differences in outcomes have been identified for different procedural methods. However, routine administrative data is limited in differentiating procedural detail (e.g. we are unable to differentiate intra or extra‐capsular techniques from current clinical coding of tonsillectomy procedures). Therefore prospective national data collection or more granular clinical coding is essential to capture relative outcomes of the different tonsillectomy methods and techniques being used in the NHS

Models and Mechanisms of Adult Lung Repair and Regeneration

Until recently, adult lung regeneration has been a poorly defined phenomena in mammals. Publications from the 1970s demonstrated in small mammals the ability for tissue to expand, through a process called alveologenesis, post-pneumonectomy. Only recently have the molecular processes involved in adult alveologenesis begun to be defined. Using methods of non-pathologic lung injury and lineage tracing analysis, we demonstrate that the alveolar epithelial type II cells (AECII) are the predominant, proliferative epithelial cell population that contribute to formation of new alveolar epithelium. We also show that pneumonectomy induces proliferation in AECIIs in-vitro and in-vivo, and that two separate molecular pathways, Notch and Wnt, are seemingly necessary for both the proliferation and differentiation phase of AECIIs into AECIs during adult alveologenesis. For the first time, we have strongly suggestive evidence that non-human primate lungs are capable of adult alveologenesis, and that the AECII cell is the predominant proliferative cell type as well. These findings further support the potential for adult alveologenesis in humans and define a cell type of interest to pursue. In a separate study, we looked to better define heterogeneity within an adult lipofibroblast progenitor cell population. Initially, we used a cell transplantation technique after bleomycin injury to show that the PDGFR-A+ lipofibroblast cell can integrate themselves into areas of fibrosis in the lung. We then performed single-cell sequencing to demonstrate cell heterogeneity within this lipofibroblast population. This analysis led us to the TCF21 gene, a gene which has been associated with lung branching morphogenesis and also the cell of origin for cardiac myofibroblasts. Again, using lineage tracing techniques, we demonstrated that TCF21 cells are capable of differentiating in to pulmonary myofibroblasts in the context of bleomycin injury

An Edition of the Rutgers Manuscript of Donne's Elegy, "Love's Progress," and Matthew Mainwaring's "Sonnet"

This article consists of a complete transcription of the two poems and an illustration of the manuscript

Induced pluripotent stem cell line from an atopic dermatitis patient heterozygous for c.2282del4 mutation in filaggrin: KCLi001-A

We have generated an induced pluripotent stem cell (iPSC) line KCLi001-A (iOP118) from a female atopic dermatitis (AD) patient, heterozygous for the loss-of-function mutation c.2282del4 in the filaggrin gene (FLG). Epidermal keratinocytes were reprogrammed using non-integrating Sendai virus vectors. The entire process of derivation and expansion of AD-iPSCs were performed under xeno-free culture conditions. Characterization of KCLi001-A line included molecular karyotyping, mutation screening using restriction enzyme digestion and Sanger sequencing, while pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and by in vivo teratoma assay

Prospects for the Use of Induced Pluripotent Stem Cells (iPSC) in Animal Conservation and Environmental Protection

Summary Stem cells are unique cell populations able to copy themselves exactly as well as specialize into new cell types. Stem cells isolated from early stages of embryo development are pluripotent, i.e., can be differentiated into multiple different cell types. In addition, scientists have found a way of reverting specialized cells from an adult into an embryonic‐like state. These cells, that are as effective as cells isolated from early embryos, are termed induced pluripotent stem cells (iPSCs). The potency of iPSC technology is recently being employed by researchers aimed at helping wildlife and environmental conservation efforts. Ambitious attempts using iPSCs are being made to preserve endangered animals as well as reanimate extinct species, merging science fiction with reality. Other research to sustain natural resources and promote animal welfare are exploring iPSCs for laboratory grown animal products without harm to animals offering unorthodox options for creating meat, leather, and fur. There is great potential in iPSC technology and what can be achieved in consumerism, animal welfare, and environmental protection and conservation. Here, we discuss current research in the field of iPSCs and how these research groups are attempting to achieve their goals. Stem Cells Translational Medicine 2019;8:7–1

Induced pluripotent stem cell line from an atopic dermatitis patient heterozygous for c.2282del4 mutation in filaggrin: KCLi001-A.

We have generated an induced pluripotent stem cell (iPSC) line KCLi001-A (iOP118) from a female atopic dermatitis (AD) patient, heterozygous for the loss-of-function mutation c.2282del4 in the filaggrin gene (FLG). Epidermal keratinocytes were reprogrammed using non-integrating Sendai virus vectors. The entire process of derivation and expansion of AD-iPSCs were performed under xeno-free culture conditions. Characterization of KCLi001-A line included molecular karyotyping, mutation screening using restriction enzyme digestion and Sanger sequencing, while pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and by in vivo teratoma assay

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1fl/fl mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction