Mihai Gheorghiade, MD-Life and Concepts

How do you capture an idea, shape it, and then bring it into the world? Of his many talents, this ability was a fundamental characteristic of Mihai Gheorghiade. A quick glance through PubMed confirms his prodigious output, likely to overwhelm any novice or even expert scholar. His contribution to heart failure, especially acute heart failure (AHF), is profound, He authored several major concepts in acute heart failure, disseminated further by his students. Most concepts remained indelibly linked to his name: Digoxin trials research(1–3), AHFS (acute heart failure syndromes) definition(4), hemodynamic congestion(5), hospitalized heart failure (HHF) (6), the vulnerable phase(7,8), neutral hemodynamic agents(9), registries(10–12) and pre-trial registries(13), the “6-axis model”(14) and then the “8-axis model”(15). His work shaped the field of AHF

Backup without redundancy: genetic interactions reveal the cost of duplicate gene loss.

Many genes can be deleted with little phenotypic consequences. By what mechanism and to what extent the presence of duplicate genes in the genome contributes to this robustness against deletions has been the subject of considerable interest. Here, we exploit the availability of high-density genetic interaction maps to provide direct support for the role of backup compensation, where functionally overlapping duplicates cover for the loss of their paralog. However, we find that the overall contribution of duplicates to robustness against null mutations is low ( approximately 25%). The ability to directly identify buffering paralogs allowed us to further study their properties, and how they differ from non-buffering duplicates. Using environmental sensitivity profiles as well as quantitative genetic interaction spectra as high-resolution phenotypes, we establish that even duplicate pairs with compensation capacity exhibit rich and typically non-overlapping deletion phenotypes, and are thus unable to comprehensively cover against loss of their paralog. Our findings reconcile the fact that duplicates can compensate for each other's loss under a limited number of conditions with the evolutionary instability of genes whose loss is not associated with a phenotypic penalty

Acute Dyspnea and Decompensated Heart Failure

The majority of patients hospitalized with acute heart failure (AHF) initially present to the emergency department (ED). Correct diagnosis followed by prompt treatment ensures optimal outcomes. Paradoxically, identification of high risk is not the unmet need, given nearly all ED AHF patients are hospitalized; rather, it is identification of low-risk. Currently, no risk-stratification instrument can be universally recommended to safely discharge ED patients. With the exception of diagnosis, management recommendations are largely expert opinion, informed by existing evidence and tradition. In the absence of robust evidence, we propose a framework for management to guide the busy clinician

A strategy for extracting and analyzing large-scale quantitative epistatic interaction data

Recently, approaches have been developed for high-throughput identification of synthetic sick/lethal gene pairs. However, these are only a specific example of the broader phenomenon of epistasis, wherein the presence of one mutation modulates the phenotype of another. We present analysis techniques for generating high-confidence quantitative epistasis scores from measurements made using synthetic genetic array and epistatic miniarray profile (E-MAP) technology, as well as several tools for higher-level analysis of the resulting data that are greatly enhanced by the quantitative score and detection of alleviating interactions

J/Psi Production from Electromagnetic Fragmentation in Z decay

The rate for $Z^{0}\to J/ \psi + \ell^{+}\ell^{-}$ is suprisingly large with about one event for every million $Z^{0}$ decays. The reason for this is that there is a fragmentation contribution that is not suppressed by a factor of $M^{2}_{\psi}/M^{2}_{Z}$. In the fragmentation limit $M_{Z}\to\infty$ with $E_{\psi}/M_{Z}$ fixed, the differential decay rate for $Z^{0}\to J/ \psi + \ell^{+}\ell^{-}$ factors into electromagnetic decay rates and universal fragmentation functions. The fragmentation functions for lepton fragmentation and photon fragmentation into $J/\psi$ are calculated to lowest order in $\alpha$. The fragmentation approximation to the rate is shown to match the full calculation for $E_{\psi}$ greater than about $3 M_{\psi}$.Comment: 16 pages and 8 figure

Defining the current distribution of the imperiled Black-spotted Newt across south Texas, USA

The Black-spotted Newt (Notophthalmus meridionalis) is a chronically understudied salamander species, with many aspects of its natural history, ecology, and distribution poorly known. Previous studies using traditional methodologies have had limited success documenting N. meridionalis on the landscape, detecting individuals at 6% (7 of 114) and 1% (2 of 221) of sites surveyed. A novel environmental DNA (eDNA) assay was designed and implemented with the goals of assessing the current distribution of N. meridionalis across south Texas, USA, and better understanding the conditions for positive eDNA detections. We conducted eDNA sampling and traditional surveys at 80 sites throughout south Texas. Notophthalmus meridionalis was detected at 12 localities in total: four localities using eDNA surveys, four localities using traditional methods, and four localities with both methodologies. eDNA detections were obtained from five counties, including one where N. meridionalis has never been reported and another where N. meridionalis has not been observed since the 1930s. eDNA detections were obtained in all four seasons, generally following moderate to heavy rainfall events. Our results support the increased use of eDNA surveys to detect rare and cryptic amphibians and to better understand the current distribution of this imperiled species

Improving Postdischarge Outcomes in Acute Heart Failure

The global burden that acute heart failure (AHF) carries has remained unchanged over the past several decades (1). European registries (2–5) showed that 1-year outcome rates remain unacceptably high (Table 1) and confirm that hospitalization for AHF represents a change in the natural history of the disease process(6). As patients hospitalized for HF have a bad prognosis, it is crucial to utilize hospitalization as an opportunity to: 1) assess the individual components of the cardiac substrate; 2) identify and treat comorbidities; 3) identify early, safe endpoints of therapy to facilitate timely hospital discharge and outpatient follow-up; and 4) implement and begin optimization guideline-directed medical therapies (GDMTs). As outcomes are influenced by many factors, many of which are incompletely understood, a systematic approach is proposed that should start with admission and continues through post-discharge (7)

Mechanism of Prion Propagation: Amyloid Growth Occurs by Monomer Addition

Abundant nonfibrillar oligomeric intermediates are a common feature of amyloid formation, and these oligomers, rather than the final fibers, have been suggested to be the toxic species in some amyloid diseases. Whether such oligomers are critical intermediates for fiber assembly or form in an alternate, potentially separable pathway, however, remains unclear. Here we study the polymerization of the amyloidogenic yeast prion protein Sup35. Rapid polymerization occurs in the absence of observable intermediates, and both targeted kinetic and direct single-molecule fluorescence measurements indicate that fibers grow by monomer addition. A three-step model (nucleation, monomer addition, and fiber fragmentation) accurately accounts for the distinctive kinetic features of amyloid formation, including weak concentration dependence, acceleration by agitation, and sigmoidal shape of the polymerization time course. Thus, amyloid growth can occur by monomer addition in a reaction distinct from and competitive with formation of potentially toxic oligomeric intermediates

A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria.

To broadly explore mitochondrial structure and function as well as the communication of mitochondria with other cellular pathways, we constructed a quantitative, high-density genetic interaction map (the MITO-MAP) in Saccharomyces cerevisiae. The MITO-MAP provides a comprehensive view of mitochondrial function including insights into the activity of uncharacterized mitochondrial proteins and the functional connection between mitochondria and the ER. The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components. MitOS physically and functionally interacts with both outer and inner membrane components and localizes to extended structures that wrap around the inner membrane. We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology. We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria