Supramolecular structure of the OXPHOS system in highly thermogenic tissue of Arum maculatum

The protein complexes of the mitochondrial respiratory chain associate in defined ways forming supramolecular structures called respiratory supercomplexes or respirasomes. In plants, additional oxidoreductases participate in respiratory electron transport, e.g. the so-called "alternative NAD(P)H dehydrogenases" or an extra terminal oxidase called "alternative oxidase" (AOX). These additional enzymes were previously reported not to form part of respiratory supercomplexes. However, formation of respiratory supercomplexes might indirectly affect "alternative respiration" because electrons can be channeled within the supercomplexes which reduces access of the alternative enzymes towards their electron donating substrates. Here we report an investigation on the supramolecular organization of the respiratory chain in thermogenic Arum maculatum appendix mitochondria, which are known to have a highly active AOX for heat production. Investigations based on mild membrane solubilization by digitonin and protein separation by blue native PAGE revealed a very special organization of the respiratory chain in A. maculatum, which strikingly differs to the one described for the model plant Arabidopsis thaliana: (i) complex I is not present in monomeric form but exclusively forms part of a I + III2 supercomplex, (ii) the III2 + IV and I + III2 + IV supercomplexes are detectable but of low abundance, (iii) complex II has fewer subunits than in A. thaliana, and (iv) complex IV is mainly present as a monomer in a larger form termed "complex IVa". Since thermogenic tissue of A. maculatum at the same time has high AOX and I + III2 supercomplex abundance and activity, negative regulation of the alternative oxidase by supercomplex formation seems not to occur. Functional implications are discussed. © 2010 Elsevier Masson SAS. All rights reserved

Multiple prebiotic metals mediate translation.

Today, Mg2+ is an essential cofactor with diverse structural and functional roles in life's oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O2, high Fe2+, and high Mn2+) can revert the ribosome to a functional ancestral state. First, SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) was used to compare the effect of Mg2+, Fe2+, and Mn2+ on the tertiary structure of rRNA. Then, we used in vitro translation reactions to test whether Fe2+ or Mn2+ could mediate protein production, and quantified ribosomal metal content. We found that (i) Mg2+, Fe2+, and Mn2+ had strikingly similar effects on rRNA folding; (ii) Fe2+ and Mn2+ can replace Mg2+ as the dominant divalent cation during translation of mRNA to functional protein; and (iii) Fe and Mn associate extensively with the ribosome. Given that the translation system originated and matured when Fe2+ and Mn2+ were abundant, these findings suggest that Fe2+ and Mn2+ played a role in early ribosomal evolution

Resolution of paraneoplastic hypoglycemia following nephroureterectomy for treatment of canine renal cell carcinoma: Case report

ObjectivesTo describe the clinicopathologic findings, imaging results, surgical treatment, and outcome of a dog with renal cell carcinoma (RCC) and paraneoplastic hypoglycemia.AnimalsA 13-year-old female spayed mixed breed dog that was presented for facial twitching and neurologic decline and diagnosed with a renal mass and paraneoplastic hypoglycemia.Study designCase report.MethodsSerum chemistry revealed severe hypoglycemia and normal renal values. Abdominal ultrasonography showed a large, heterogeneous, cavitated mass associated with the left kidney and no evidence of abdominal metastatic disease. Thoracic radiographs revealed no evidence of pulmonary metastatic disease. Fasted serum insulin was low concurrently with severe hypoglycemia. No other causes of hypoglycemia were detected, and paraneoplastic hypoglycemia was suspected.ResultsAfter initial medical management of the dog's hypoglycemia, left nephroureterectomy was performed. Histopathology was consistent with RCC. Postoperatively, the dog's hypoglycemia resolved, and supplementation was discontinued. The dog remained stable and was discharged from the hospital 3 days after surgery. At 2-week, 3-month, and 5-month follow up evaluations, the dog remained euglycemic, and no definitive evidence of disease progression was detected. Eight months postoperatively, the dog was euthanized due to decline in mobility. Necropsy and histopathology revealed cerebral and spinal cord multifocal myelin sheath dilation and two primary pulmonary carcinomas with no evidence of recurrence or metastasis of the RCC.ConclusionSurgical treatment of RCC with subsequent resolution of paraneoplastic hypoglycemia has not previously been reported in veterinary medicine. In this dog, nephroureterectomy for RCC resulted in immediate and sustained resolution of paraneoplastic hypoglycemia

Virtually Hosting a National Medical Society Conference. Lessons Learned from the 2020 Association of Pulmonary and Critical Care Medicine Program Directors Conference

The coronavirus pandemic forced the Association of Pulmonary and Critical Care Medicine Program Directors to change the 2020 annual conference to a virtual format with relatively short notice. Using the experience of the planning committee and survey feedback from attendees, we describe the steps taken to implement a virtual conference and lessons learned in the process. The lessons described include frequent and concise communication, establishment of roles within a discrete production team, preparing speakers with a protocolized training session, active moderation of the chat box, using interactive polling and online documents to improve interactivity, a shorter agenda with more frequent breaks, encouraging “virtual happy hours” to connect with colleagues, and establishing facilitators for breakout rooms

Flavor Physics in an SO(10) Grand Unified Model

In supersymmetric grand-unified models, the lepton mixing matrix can possibly affect flavor-changing transitions in the quark sector. We present a detailed analysis of a model proposed by Chang, Masiero and Murayama, in which the near-maximal atmospheric neutrino mixing angle governs large new b -> s transitions. Relating the supersymmetric low-energy parameters to seven new parameters of this SO(10) GUT model, we perform a correlated study of several flavor-changing neutral current (FCNC) processes. We find the current bound on B(tau -> mu gamma) more constraining than B(B -> X_s gamma). The LEP limit on the lightest Higgs boson mass implies an important lower bound on tan beta, which in turn limits the size of the new FCNC transitions. Remarkably, the combined analysis does not rule out large effects in B_s-B_s-bar mixing and we can easily accomodate the large CP phase in the B_s-B_s-bar system which has recently been inferred from a global analysis of CDF and DO data. The model predicts a particle spectrum which is different from the popular Constrained Minimal Supersymmetric Standard Model (CMSSM). B(tau -> mu gamma) enforces heavy masses, typically above 1 TeV, for the sfermions of the degenerate first two generations. However, the ratio of the third-generation and first-generation sfermion masses is smaller than in the CMSSM and a (dominantly right-handed) stop with mass below 500 GeV is possible.Comment: 44 pages, 5 figures. Footnote and references added, minor changes, Fig. 2 corrected; journal versio

On the Correlations between Flavour Observables in Minimal U(2)^3 Models

The stringent correlations between flavour observables in models with CMFV are consistent with the present data except for the correlation Delta M_{s,d}-epsilon_K. Motivated by the recent work of Barbieri et al, we compare the CMFV correlations with the ones present in a special class of models with an approximate global U(2)^3 flavour symmetry, constrained by a minimal set of spurions governing the breakdown of this symmetry and the assumption that only SM operators are relevant in flavour physics. This analog of CMFV to be called MU(2)^3 allows to avoid the Delta M_{s,d}-epsilon_K tension in question because of reduced flavour symmetry and implied non-MFV contributions to Delta M_{s,d}. While the patterns of flavour violation in K meson system is the same as in CMFV models, the CP-violation in B_{s,d} meson systems can deviate from the one in the SM and CMFV models. We point out a stringent triple S_{psi K_S}-S_{psi phi}-|V_ub| correlation in this class of models that could in the future provide a transparent distinction between different MU(2)^3 models and in the context of these models determine |V_ub| by means of precise measurements of S_{psi K_S} and S_{psi phi} with only small hadronic uncertainties. For fixed S_{psi K_S} the correlation between B(B^+ -> tau^+nu_tau) and S_{psi phi} follows. We also find that MU(2)^3 models could in principle accommodate a negative value of S_{psi phi}, provided |V_ub| is found to be in the ballpark of exclusive determinations and the particular MU(2)^3 model provides a 25% enhancement of epsilon_K. A supersymmetric U(2)^3 model worked out in the Barbieri-School appears to satisfy these requirements. However if B(B^+ -> tau^+nu_tau)>1.0 10^{-4} will be confirmed by future experiments only positive S_{psi phi} is allowed in this framework. We summarize briefly the pattern of flavour violation in rare K and B_{s,d} decays in MU(2)^3 models.Comment: 28 pages, 6 figures; v2: Few references and discussion on CP violation in B_s-> mu^+ mu^- added; v3: Several clarifying comments added, conclusions unchanged, version accepted for publication in JHE

PRO B: evaluating the effect of an alarm-based patient-reported outcome monitoring compared with usual care in metastatic breast cancer patients—study protocol for a randomised controlled trial

Background: Despite the progress of research and treatment for breast cancer, still up to 30% of the patients afflicted will develop distant disease. Elongation of survival and maintaining the quality of life (QoL) become pivotal issues guiding the treatment decisions. One possible approach to optimise survival and QoL is the use of patient-reported outcomes (PROs) to timely identify acute disease-related burden. We present the protocol of a trial that investigates the effect of real-time PRO data captured with electronic mobile devices on QoL in female breast cancer patients with metastatic disease. Methods: This study is a randomised, controlled trial with 1:1 randomisation between two arms. A total of 1000 patients will be recruited in 40 selected breast cancer centres. Patients in the intervention arm receive a weekly request via an app to complete the PRO survey. Symptoms will be assessed by study-specific optimised short forms based on the EORTC QLQ-C30 domains using items from the EORTC CAT item banks. In case of deteriorating PRO scores, an alarm is sent to the treating study centre as well as to the PRO B study office. Following the alarm, the treating breast cancer centre is required to contact the patient to inquire about the reported symptoms and to intervene, if necessary. The intervention is not specified and depends on the clinical need determined by the treating physician. Patients in the control arm are prompted by the app every 3 months to participate in the PRO survey, but their response will not trigger an alarm. The primary outcome is the fatigue level 6 months after enrolment. Secondary endpoints include among others hospitalisations, use of rescue services and overall QoL. Discussion: Within the PRO B intervention group, we expect lower fatigue levels 6 months after intervention start, higher levels of QoL, less unplanned hospitalisations and less emergency room visits compared to controls. In case of positive results, our approach would allow a fast and easy transfer into clinical practice due to the use of the already nationwide existing IT infrastructure of the German Cancer Society and the independent certification institute OnkoZert

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis

Association between microvessel density (MVD) and tumor characteristics among breast cancer cases (n = 44). (DOC 54 kb