Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature.

Fluorometric Methods to Measure Bioavailable and Total Heme.

Heme b (iron protoporphyrin IX) is an essential but potentially cytotoxic cofactor, signaling molecule, and nutritional source of iron. Its importance in cell biology and metabolism is underscored by the fact that numerous diseases, including various cancers, neurodegenerative disorders, infectious diseases, anemias, and porphyrias, are associated with the dysregulation of heme synthesis, degradation, trafficking, and/or transport. Consequently, methods to measure, image, and quantify heme in cells are required to better understand the physiology and pathophysiology of heme.

The molecular mechanism of on-demand sterol biosynthesis at organelle contact sites.

Contact-sites are specialized zones of proximity between two organelles, essential for organelle communication and coordination. The formation of contacts between the Endoplasmic Reticulum (ER), and other organelles, relies on a unique membrane environment enriched in sterols. However, how these sterol-rich domains are formed and maintained had not been understood.

Neurotropin ameliorates chronic pain associated with scar formation in a mouse model: A gene expression analysis of the inflammatory response.

: Scar formation after trauma and surgery involves an inflammatory response and can lead to the development of chronic pain. Neurotropin (NTP) is a nonprotein extract of inflamed skin of rabbits inoculated with vaccinia virus. It has been widely used for the treatment of chronic pain.

Generation of LexA enhancer-trap lines in Drosophila by an international scholastic network.

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons.

Measuring the Oxidation State and Enzymatic Activity of Glyceraldehyde Phosphate Dehydrogenase (GAPDH).

Glyceraldehyde phosphate dehydrogenase (GAPDH) is a highly conserved, essential, and abundant enzyme that catalyzes a rate-determining step of glycolysis. GAPDH catalyzes the nicotinamide adenine dinucleotide (NAD)- and inorganic phosphate-dependent oxidation and phosphorylation of glyceraldehyde phosphate (GAP) to form 1,3-bisphosphoglycerate (BPG). As part of its mechanism of action, GAPDH employs a redox-sensitive cysteine that serves as a nucleophile to form a covalent adduct with GAP in order to set-up subsequent oxidation and phosphorylation steps.

Role of the Mycobacterium tuberculosis ESX-4 Secretion System in Heme Iron Utilization and Pore Formation by PPE Proteins.

Mycobacterium tuberculosis () is transmitted through aerosols and primarily colonizes within the lung. The World Health Organization estimates that kills ~1.4 million people every year.

Depletion assisted hemin affinity (DAsHA) proteomics reveals an expanded landscape of heme-binding proteins in the human proteome.

Heme b (iron protoporphyrin IX) plays important roles in biology as a metallocofactor and signaling molecule. However, the targets of heme signaling and the network of proteins that mediate the exchange of heme from sites of synthesis or uptake to heme dependent or regulated proteins are poorly understood. Herein, we describe a quantitative mass spectrometry (MS)-based chemoproteomics strategy to identify exchange labile hemoproteins in human embryonic kidney HEK293 cells that may be relevant to heme signaling and trafficking.

Contrast-Induced Acute Kidney Injury: Evidence in Support of Its Existence and a Review of Its Pathogenesis and Management.

The role of contrast-induced nephropathy (CIN) remains controversial. Many experts contend that CIN does not exist or is extremely rare. The diagnosis was previously made too frequently and inappropriately in the presence of coexisting and confounding comorbidities and risk factors making it difficult to singularly isolate the etiologic role of intravenous contrast media in acute kidney injury (AKI).

HRG-9 homologues regulate haem trafficking from haem-enriched compartments.

Haem is an iron-containing tetrapyrrole that is critical for a variety of cellular and physiological processes. Haem binding proteins are present in almost all cellular compartments, but the molecular mechanisms that regulate the transport and use of haem within the cell remain poorly understood. Here we show that haem-responsive gene 9 (HRG-9) (also known as transport and Golgi organization 2 (TANGO2)) is an evolutionarily conserved haem chaperone with a crucial role in trafficking haem out of haem storage or synthesis sites in eukaryotic cells.

Osteogenic Competence and Potency of the Bone Induction Principle: Inductive Substrates That Initiate "Bone: Formation by Autoinduction".

The de novo induction of bone has always been a fascinating phenomenon, keeping skeletal reconstructionists and cellular developmental biologists continuously engaged to finally provide a molecular and cellular approach to the induction of bone formation. A significant advancement was made by the purification and cloning of the human recombinant bone morphogenetic proteins, members of the transforming growth factor-β supergene family. Human bone morphogenetic proteins are powerful inducers of bone in animal models including nonhuman primates.

Providing access to high-quality, low-cost medicines across low and middle-income countries (LMICs), working with governments and generic manufacturers around the globe - A business case.

Background: Gilead Sciences, under Dr. John Martin's leadership, created its Global Access Program to deliver high-quality, affordable medicines to treat and ultimately eliminate some of the world's most challenging-to-treat, pervasive, life-limiting diseases not as philanthropy but based on a self-sustaining business model-a highly novel concept in the pharmaceutical realm. John was determined to bring together all key stakeholders from public health officials to doctors and patients around the globe to understand barriers and opportunities in HIV, viral hepatitis, and visceral leishmaniasis (VL) and in so doing, pushed the Gilead team to devise novel strategies to address healthcare disparities in resource-challenged geographies.

Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells.

Heme oxygenases (HOs) detoxify heme by oxidatively degrading it into carbon monoxide, iron, and biliverdin, which is reduced to bilirubin and excreted. Humans express two isoforms of HO: the inducible HO-1, which is upregulated in response to excess heme and other stressors, and the constitutive HO-2. Much is known about the regulation and physiological function of HO-1, whereas comparatively little is known about the role of HO-2 in regulating heme homeostasis.

Sod1 integrates oxygen availability to redox regulate NADPH production and the thiol redoxome.

Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O) by catalyzing its conversion to dioxygen (O) and hydrogen peroxide (HO). Using and mammalian cells, we discovered that a major aspect of the antioxidant function of Sod1 is to integrate O availability to promote NADPH production. The mechanism involves Sod1-derived HO oxidatively inactivating the glycolytic enzyme, GAPDH, which in turn reroutes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH.

Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase.

Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied and its biosynthetic enzymes structurally characterized to varying extents.

Neurologic Outcomes After Extracorporeal Cardiopulmonary Resuscitation: Recent Experience at a Single High-Volume Center.

Extracorporeal cardiopulmonary resuscitation (ECPR)-veno-arterial extracorporeal membrane oxygenation (ECMO) for refractory cardiac arrest-has grown rapidly, but its widespread adoption has been limited by frequent neurologic complications. With individual centers developing best practices, utilization may be increasing with an uncertain effect on outcomes. This study describes the recent ECPR experience at the University of Maryland Medical Center from 2016 through 2018, with attention to neurologic outcomes and predictors thereof.

Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation.

Objective: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions.

Methods: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes.

Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway.

Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O) into oxygen (O) and hydrogen peroxide (HO), a key signaling molecule. In Saccharomyces cerevisiae, we previously discovered that Sod1 participates in an HO-mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O, Sod1-derived HO stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration.

Using genetically encoded heme sensors to probe the mechanisms of heme uptake and homeostasis in Candida albicans.

Candida albicans is a major fungal pathogen that can utilise hemin and haemoglobin as iron sources in the iron-scarce host environment. While C. albicans is a heme prototroph, we show here that it can also efficiently utilise external heme as a cellular heme source.

One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers.

Heme, as a hydrophobic iron-containing organic ring, is lipid soluble and can interact with biological membranes. The very same properties of heme that nature exploits to support life also renders heme potentially cytotoxic. In order to utilize heme, while also mitigating its toxicity, cells are challenged to tightly control the concentration and bioavailability of heme.

Human ribosomal G-quadruplexes regulate heme bioavailability.

The formation of stable G-quadruplexes (G4s) in human rRNA was recently reported. However, their formation in cells and their cellular roles were not resolved. Here, by taking a chemical biology approach that integrates results from immunofluorescence, G4 ligands, heme-affinity reagents, and a genetically encoded fluorescent heme sensor, we report that human ribosomes can form G4s that regulate heme bioavailability.

Discovery of bone morphogenetic proteins - A historical perspective.

Bone morphogenetic proteins (BMPs) were purified from demineralized bone matrix by their ability to induce new bone formation in vivo. BMPs represent a large sub-family of proteins structurally related to TGF-beta and activins. Two BMP bone graft substitutes, BMP2 (InFuse®) and BMP7 (OP1®) have been developed as products for the repair of long bone non-union fractures and lumbar spinal fusion in humans.

Cutting in-line with iron: ribosomal function and non-oxidative RNA cleavage.

Divalent metal cations are essential to the structure and function of the ribosome. Previous characterizations of the ribosome performed under standard laboratory conditions have implicated Mg2+ as a primary mediator of ribosomal structure and function. Possible contributions of Fe2+ as a ribosomal cofactor have been largely overlooked, despite the ribosome's early evolution in a high Fe2+ environment, and the continued use of Fe2+ by obligate anaerobes inhabiting high Fe2+ niches.