The Non-Ohmic Proton Leak—25 Years On

The proton conductance of the mitochondrial inner membrane can be quantified by applying Ohm's law to the experimentally determined protonmotive force and the proton current flowing around the proton circuit in the absence of ATP synthesis or ion transport. This last parameter is derived from the rate of State 4 respiration multiplied by the H⁺/O stoichiometry for the substrate. When the activity of the dehydrogenase supplying electrons to the respiratory chain is progressively increased the proton conductance increases rapidly when the protonmotive force is greater than 220 mV. The consequences of this non-ohmic relationship are discussed.     

Liver Transplantation in Man—IV,Haemorrhage and Thrombosis

Blood coagulation and fibrinolytic factors have been measured in 13 patients treated by liver transplantation. During operation intravascular coagulation and fibrinolysis were increased, but seldom to a degree which would cause abnormal bleeding. Measurement of the catabolism of radioactive fibrinogen showed that increased intravascular coagulation continued for long periods after the operation. Despite secondarily increased fibrinolysis, there was a high incidence of thrombosis. Treatment with anticoagulants or with fibrinolysis inhibitors may be valuable in these patients.     

New Diagnosis and Therapy Model for Ischemic-Type Biliary Lesions following Liver Transplantation—A Retrospective Cohort Study

Ischemic-type biliary lesions (ITBLs) are a major cause of graft loss and mortality after orthotopic liver transplantation (OLT). Impaired blood supply to the bile ducts may cause focal or extensive damage, resulting in intra- or extrahepatic bile duct strictures or dilatations that can be detected by ultrasonography, computed tomography, magnetic resonance cholangiopancreatography, and cholangiography. However, the radiographic changes occur at an advanced stage, after the optimal period for therapeutic intervention. Endoscopic retrograde cholangio-pancreatography (ERCP) and percutaneous transhepatic cholangiodrainage (PTCD) are the gold standard methods of detecting ITBLs, but these procedures cannot be used for continuous monitoring. Traditional methods of follow-up and diagnosis result in delayed diagnosis and treatment of ITBLs. Our center has used the early diagnosis and intervention model (EDIM) for the diagnosis and treatment of ITBLs since February 2008. This model mainly involves preventive medication to protect the epithelial cellular membrane of the bile ducts, regular testing of liver function, and weekly monitor of contrast-enhanced ultrasonography (CEUS) to detect ischemic changes to the bile ducts. If the liver enzyme levels become abnormal or CEUS shows low or no enhancement of the wall of the hilar bile duct during the arterial phase, early ERCP and PTCD are performed to confirm the diagnosis and to maintain biliary drainage. Compared with patients treated by the traditional model used prior to February 2008, patients in the EDIM group had a lower incidence of biliary tract infection (28.6% vs. 48.6%, P = 0.04), longer survival time of liver grafts (24±9.6 months vs. 17±12.3 months, P = 0.02), and better outcomes after treatment of ITBLs.     

The Legacy of Fred Sanger—100 Years on from 1918

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Paraquat Poisoning—Lung Transplantation

A 15-year-old boy ingested a mouthful of paraquat and developed severe respiratory distress. Treatment included the transplantation of one lung, but subsequently changes developed in the graft which are thought to have been due to paraquat, and the patient died two weeks after the operationThe dangers of keeping poisonous substances in incorrectly labelled bottles has once again been demonstrated, while the pattern of paraquat poisoning, especially the development of proliferative alveolitis and terminal bronchiolitis, is confirmed.Immediate forced diuresis followed by haemodialysis is necessary to remove paraquat, thereby perhaps avoiding initiation of the changes in the lungs. The technical feasibility of human lung transplantation has again been demonstrated. It has also been shown that infection does not necessarily pose an insuperable problem, at any rate if, as in the case described, there was no preoperative pulmonary infection in either recipient or donor.     

Anillin: The First Proofreading-like Scaffold?

Scaffolds are fundamental to many cellular signaling pathways. In this essay, a novel class of scaffolds are proposed, whose action bears striking resemblance to kinetic proofreading. Commonly, scaffold proteins are thought to work as tethers, bringing different components of a pathway together to improve the likelihood of their interaction. However, recent studies show that the cytoskeletal scaffold, anillin, supports contractile signaling by a novel, non-tethering mechanism that controls the membrane dissociation kinetics of RhoA. More generally, such proof-reading-like scaffolds are distinguished from tethers by a rare type of cooperativity, manifest as a super-linear relationship between scaffold concentration and signaling efficiency. The evidence for this hypothesis is reviewed, its conceptual ramifications are considered, and research questions for the future are discussed.     

The Role of Interferon-γ Inducible Protein-10 in a Mouse Model of Acute Liver Injury Post Induced Pluripotent Stem Cells Transplantation

Background

Liver injuries are important medical problems that require effective therapy. Stem cell or hepatocyte transplantation has the potential to restore function of the damaged liver and ameliorate injury. However, the regulatory factors crucial for the repair and regeneration after cell transplantation have not been fully characterized. Our study investigated the effects and the expression of the regulatory factors in mouse models of acute liver injury either transplanted with the induced pluripotent stem cells (iPS) or the hepatocytes that differentiated from iPS cells (iHL).

Methods/Principal Findings

Mice received CCl₄ injection and were randomized to receive vehicle, iPS, or iHL transfusions vial tail veins and were observed for 24, 48 or 72 hours. The group of mice with iPS transplantation performed better than the group of mice receiving iHL in reducing the serum alanine aminotransferase, aspartate aminotransferase, and liver necrosis areas at 24 hours after CCl₄ injury. Moreover, iPS significantly increased the numbers of proliferating hepatocytes at 48 hours. Cytokine array identified that chemokine IP-10 could be the potential regulatory factor that ameliorates liver injury. Further studies revealed that iPS secreted IP-10 in vitro and transfusion of iPS increased IP-10 protein and mRNA expressions in the injured livers in vivo. The primary hepatocytes and non-parenchyma cells were isolated from normal and injured livers. Hepatocytes from injured livers that received iPS treatment expressed more IP-10 mRNA than their non-hepatocyte counter-parts. In addition, animal studies revealed that administration of recombinant IP-10 (rIP-10) effectively reduced liver injuries while IP-10-neutralizing antibody attenuated the protective effects of iPS and decreased hepatocyte proliferation. Both iPS and rIP-10 significantly reduced the 72-hour mortality rate in mice that received multiple CCl₄-injuries.

Conclusions/Significance

These findings suggested that IP-10 may have an important regulatory role in facilitating the repair and regeneration of injured liver after iPS transplantation.     

The First Bite— Profiling the Predatosome in the Bacterial Pathogen Bdellovibrio

Bdellovibrio bacteriovorus is a Gram-negative bacterium that is a pathogen of other Gram-negative bacteria, including many bacteria which are pathogens of humans, animals and plants. As such Bdellovibrio has potential as a biocontrol agent, or living antibiotic. B. bacteriovorus HD100 has a large genome and it is not yet known which of it encodes the molecular machinery and genetic control of predatory processes. We have tried to fill this knowledge-gap using mixtures of predator and prey mRNAs to monitor changes in Bdellovibrio gene expression at a timepoint of early-stage prey infection and prey killing in comparison to control cultures of predator and prey alone and also in comparison to Bdellovibrio growing axenically (in a prey-or host independent “HI” manner) on artificial media containing peptone and tryptone. From this we have highlighted genes of the early predatosome with predicted roles in prey killing and digestion and have gained insights into possible regulatory mechanisms as Bdellovibrio enter and establish within the prey bdelloplast. Approximately seven percent of all Bdellovibrio genes were significantly up-regulated at 30 minutes of infection- but not in HI growth- implicating the role of these genes in prey digestion. Five percent were down-regulated significantly, implicating their role in free-swimming, attack-phase physiology. This study gives the first post- genomic insight into the predatory process and reveals some of the important genes that Bdellovibrio expresses inside the prey bacterium during the initial attack.