Zim17/Tim15 links mitochondrial iron–sulfur cluster biosynthesis to nuclear genome stability

Genomic instability is related to a wide-range of human diseases. Here, we show that mitochondrial iron–sulfur cluster biosynthesis is important for the maintenance of nuclear genome stability in Saccharomyces cerevisiae. Cells lacking the mitochondrial chaperone Zim17 (Tim15/Hep1), a component of the iron–sulfur biosynthesis machinery, have limited respiration activity, mimic the metabolic response to iron starvation and suffer a dramatic increase in nuclear genome recombination. Increased oxidative damage or deficient DNA repair do not account for the observed genomic hyperrecombination. Impaired cell-cycle progression and genetic interactions of ZIM17 with components of the RFC-like complex involved in mitotic checkpoints indicate that replicative stress causes hyperrecombination in zim17Δ mutants. Furthermore, nuclear accumulation of pre-ribosomal particles in zim17Δ mutants reinforces the importance of iron–sulfur clusters in normal ribosome biosynthesis. We propose that compromised ribosome biosynthesis and cell-cycle progression are interconnected, together contributing to replicative stress and nuclear genome instability in zim17Δ mutants

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Ligands involved in Pb immobilization and transport in lettuce, radish, tomato and Italian ryegrass

Lead (Pb) and other heavy metals represent a great source of concern in agriculture because they may disperse from polluted sources and accumulate in crop organs. This research study was performed with three edible crops and one pasture species (lettuce: Lactuca sativa L. cv. Romana; radish: Raphanus sativus L. var. radicicola; tomato: Lycopersicon lycopersicum L. Karst.; Italian ryegrass: Lolium multiflorum Lam). It was aimed at (1) assessing how species affect Pb distribution among plant organs, (2) determining the extent to which Pb is localized in edible organs, and (3) ascertaining whether it could be possible to distinguish which compounds are responsible for the transport of Pb from one plant organ to another and which compounds are responsible for the accumulation of this metal inside each plant organ. The experiment was conducted in the greenhouse. Plants were grown in plastic pots using a Pb-spiked sandy soil as substrate. Total Pb concentrations in different plant organs and in soil were determined. Within plants, the maximum accumulation of Pb was found in roots while the remaining part of Pb was mainly located in leaves. Pb L-III edge XANES (X-ray Absorption Near Edge Spectroscopy) was applied to identify the principal Pb carrier molecules in the different plant organs. The data suggest that in roots Pb immobilization is mainly due to the complexing ability of histidine, which binds the metal and, to a lesser extent, to precipitation of Pb as carbonate. The transport to the upper plant organs is mainly attributed to Pb complexes with organic acids. In stems and leaves, Pb bonding is mainly carboxylic and amino acid-like, thus confirming the role of these substances in promoting Pb mobility. Thio amino acidic (glutathione and cysteine-like) Pb complexes, which in this study were only found in stems, can also be held responsible for Pb long-distance transport from roots to shoots

Congenital diaphragmatic hernia: intensive care unit or operating room?

I.F. 0.829 Abstract Despite improvements in prenatal diagnosis and neonatal intensive care, the Congenital Diaphragmatic Hernia (CDH) Registry still records a 64% survival rate. Many reports demonstrate, however, that approximately 80% of CDH patients with no other malformations may survive if managed with permissive hypercapnia, gentle ventilation, high-frequency oscillatory ventilation (HFOV), surfactant, inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO), and delayed surgical repair. We wished to define the evolving outcome of CDH newborns using a protocol approach to management, which includes surgery in the neonatal intensive care unit (NICU) or operating room (OR). From January 1996, data were collected prospectively on 42 consecutive live-born infants with CDH. Newborns symptomatic at birth were sedated and paralyzed in the delivery room, and treated with elective HFOV, iNO, surfactant, and ECMO as necessary, delaying surgical repair until their clinical conditions were stable. Once the CDH newborn was stabilized, a trial on conventional ventilation was started at least 24 hours before surgery; however, if the patient was unstable, therapy was switched back to HFOV and surgery was performed in the NICU. Demographic and clinical parameters were compared between CDH newborns who underwent surgery in the NICU and in the OR. The two groups were comparable in terms of clinical characteristics and baseline ventilatory and blood gas values. Mean age at surgery was 3 +/- 2 days. After surgery, the NICU group had more infectious complications. However, the survival rate of uncomplicated CDH was 78% and a low rate of chronic lung disease was reported. A prolonged phase of presurgery stabilization is proposed and strict control of infection is recommended for the CDH newborns who might benefit from an exclusive HFOV and NICU surgery

Pulmonary Surfactant Disaturated-Phosphatidylcholine (DSPC) Turnover and Pool Size in Newborn Infants with Congenital Diaphragmatic Hernia (CDH)

In animal CDH models, surfactant deficiency contributes to the pathophysiology of the condition but information on human disease is very limited. The aim of our study was to investigate surfactant kinetics in CDH newborns. We studied surfactant disaturated-phosphatidylcholine (DSPC) half-life, turnover and apparent pool size by stable isotope methodology in CDH new-borns with no ExtraCorporeal Membrane Oxygenation (ECMO) support (n = 13, birth weight (BW) 3.2 \ub1 2.2 kg, gestational age (GA) 39 \ub1 0.4 wks, postnatal age 43 \ub1 11 h) and in 8 term infants with no lung disease (CONTROLS, BW 2.7 \ub1 0 kg, GA 38 \ub1 0.8 wks, postnatal age 96 +\ub1 26 h). We administered a trace dose of 13C-palmitic acid dipalmitoyl-phosphatidylcholine (DPPC) through the endotracheal (ET) tube and we measured DSPC kinetics by gas chromatography-mass spectrometry from DSPC 13C-enrichment decay curves obtained from sequential tracheal aspirates. DSPC amount from tracheal aspirates (TA-DSPC) was measured by gas chromatography. In CDH infants DSPC half-life was shorter (24 \ub1 4 and 53 \ub1 11 h, p = 0.01), turnover faster (0.6 \ub1 0.1 and 1.5 \ub1 0. 3 d-1 p = 0.01), apparent pool size smaller (34 \ub1 6 and 57 \ub1 7 mg/kg body weight, p = 0.02) and tracheal aspirates DSPC amount lower (2.4 \ub1 0.4 and 4.6 \ub1 0.5 mg/mL Epithehal Lining Fluid (ELF), p = 0.007) than in CONTROLS. In conclusion surfactant kinetics is grossly abnormal in mechanically ventilated CDH. Whether alterations of DSPC kinetics in CDH infants are caused by a primary surfactant deficiency or are secondary to oxygen therapy and ventilator support has still to be determined