Bryan J. Mathis

Electricity generation by thermophilic microorganisms from marine sediment

The search for microorganisms that are capable of catalyzing the reduction of an electrode within a fuel cell has primarily been focused on bacteria that operate mesobiotically. Bacteria that function optimally under extreme conditions are beginning to be examined because they may serve as more effective catalysts (higher activity, greater stability, longer life, capable of utilizing a broader range of fuels) in microbial fuel cells. An examination of marine sediment from temperate waters (Charleston, SC) proved to be a good source of thermophilic electrode-reducing bacteria. Electric current normalized to the surface area of graphite electrodes was approximately ten times greater when sediment fuel cells were incubated at 60°C (209 to 254xa0mA/m2) vs 22°C (10 to 22xa0mA/m2). Electricity-generating communities were selected in sediment fuel cells and then maintained without sediment or synthetic electron-carrying mediators in single-chambered fuel cells. Current was generated when cellulose or acetate was added as a substrate to the cells. The 16S ribosomal ribonucleic acid genes from the heavy biofilms that formed on the graphite anodes of acetate-fed fuel cells were cloned and sequenced. The preponderance of the clones (54 of 80) was most related to a Gram-positive thermophile, Thermincola carboxydophila (99% similarity). The remainder of clones from the community was most related to T. carboxydophila, or uncultured Firmicutes and Deferribacteres. Overall, the data indicate that temperate aquatic sediments are a good source of thermophilic electrode-reducing bacteria.

CYLD-Mediated Signaling and Diseases

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NFkB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLDs expression, function and regulation with emerging reports on its role in cardiovascular disease.

Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2

Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.

Inhibitory role of reactive oxygen species in the differentiation of multipotent vascular stem cells into vascular smooth muscle cells in rats: a novel aspect of traditional culture of rat aortic smooth muscle cells.

Proliferative or synthetic vascular smooth muscle cells (VSMCs) are widely accepted to be mainly derived from the dedifferentiation or phenotypic modulation of mature contractile VSMCs, i.e., a phenotype switch from a normally quiescent and contractile type into a proliferative or synthetic form. However, this theory has been challenged by recent evidence that synthetic VSMCs predominantly originate instead from media-derived multipotent vascular stem cells (MVSCs). To test these hypotheses further, we re-examine whether the conventional rat aortic SMC (RASMC) culture involves the VSMC differentiation of MVSCs or the dedifferentiation of mature VSMCs and the potential mechanism for controlling the synthetic phenotype of RASMCs. We enzymatically isolated RASMCs and cultured the cells in both a regular growth medium (RGM) and a stem cell growth medium (SCGM). Regardless of culture conditions, only a small portion of freshly isolated RASMCs attaches, survives and grows slowly during the first 7xa0days of primary culture, while expressing both SMC- and MVSC-specific markers. RGM-cultured cells undergo a process of synthetic SMC differentiation, whereas SCGM-cultured cells can be differentiated into not only synthetic SMCs but also other somatic cells. Notably, compared with the RGM-cultured differentiated RASMCs, the SCGM-cultured undifferentiated cells exhibit the phenotype of MVSCs and generate greater amounts of reactive oxygen species (ROS) that act as a negative regulator of differentiation into synthetic VSMCs. Knockdown of phospholipase A2, group 7 (Pla2g7) suppresses ROS formation in the MVSCs while enhancing SMC differentiation of MVSCs. These results suggest that cultured synthetic VSMCs can be derived from the SMC differentiation of MVSCs with ROS as a negative regulator.

CDDO and Its Role in Chronic Diseases

There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes. CDDOs therapeutic effect is due to its upregulation of the master antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) through conformational change of Nrf2-repressing, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and multiple animal and human studies have verified subsequent activation of Nrf2-controlled antioxidant genes via upstream Antioxidant Response Element (ARE) regions. At the present time, positive results have been obtained in the laboratory and clinical trials with CDDO derivatives treating conditions such as lung injury, inflammation and chronic kidney disease. However, clinical trials for cancer and cardiovascular disease have not shown equally positive results and further exploration of CDDO and its derivatives is needed to put these shortcomings into context for the purpose of future therapeutic modalities.

Predictors of Pericardial Effusion in Patients Undergoing Pulmonary Artery Banding

Background: Although pulmonary artery banding (PAB) is a common palliative procedure for pediatric heart malformation, there are concerns of pressure overload and concomitant immune reactions in the right ventricle causing postsurgical complications such as pericardial effusion. At this time, no clear guidelines as to potential risk factors or procedural contraindications have been widely disseminated. Therefore, a study was undertaken to examine wide-ranging factors to find potential biomarkers for postsurgical pericardial effusion formation risk. Methods: A retrospective study was conducted on all cardiac surgeries performed over an eight-year period, and the main inclusion criterion was pericardial effusion development after PAB that required surgical drainage. Nine cases were then analyzed against a control group of 45 cases with respect to body measurements, concomitant surgeries, genetic screens, laboratory tests results, and cardiac function parameters. Results: Trisomy 21 was strongly associated with the development of severe pericardial effusion after PAB, and postoperative serum albumin levels in patients with trisomy 21 were associated with pericardial effusion development. Other parameters showed no significant correlation with pericardial effusion development. Conclusions: Our data indicate a strong association between trisomy 21 and pericardial effusion requiring drainage after PAB, which is in line with translational research findings. Pressure overload from PAB may play a role in the formation of severe pericardial effusion that is exacerbated by cardiac structural defects commonly associated with trisomy 21. Surgical teams should therefore use caution and plan to implement drainage in PAB cases, and postoperative serum albumin may serve as a useful biomarker for pericardial effusion formation.

Polycomplexes of Hyaluronic Acid and Borates in a Solid State and Solution: Synthesis, Characterization and Perspectives of Application in Boron Neutron Capture Therapy

In this report, we propose a new polyborate fragment synthesis strategy along the whole chain of the polysaccharide hyaluronic acid (HA) to produce boron neutron capture therapy (BNCT) compounds. Under high pressure and deformatory solid-state conditions, polymolecular system formation takes place due to association of phase-specific transition components into a more or less distinct microscopic organization. Fourier transform infrared (FTIR) spectroscopy shows that HA and polyborates form a network of cyclic polychelate complexes. HA acts as a multidentate ligand using carboxylic and hydroxyl proton donor groups to link oxygen atoms in B–O–B bonds and borate-anions B–O(−): O–H···O, O–H···(−)O. With free electron pairs in heteroatoms –O(:)···B, –N(:)···B, HA can act simultaneously as an electron donor. Nuclear magnetic resonance (NMR) with 13C and 1H reveals a preserved complex interaction after both solubilizing and attenuating the HA-polyborate system. Stability of the product in water, low cost, ease of synthesis and scalability of manufacturing indicate that HA-polyborate complexes might have advantages over current chemotherapeutic approaches in creating therapeutic agents for BNCT.

MRI reveals menstrually-related muscle edema that negatively affects athletic agility in young women

Context About 10% of Japanese female athletes are afflicted by menstrually-related edema, mainly in the lower limbs, and, with few studies on this problem, the effect on performance remains unclear. Objective To quantitatively evaluate fluid retention in the calf in female students over their menstrual cycle using magnetic resonance imaging (MRI) and to determine the relationship of MRI changes and athletic performance. Design The menstrual cycle was divided into 5 phases: menstrual, follicular, ovulatory, early luteal, and late luteal with sampling done in either morning (AM) or afternoon (PM) sessions. At each phase, MRI of the calf (7:00–8:00, 14:00–16:00), body composition and hormones (7:00–8:00), and athletic performance (14:00–16:00) were evaluated. Participants 13 adult healthy Japanese female students with eumenorrhea. Results Estradiol levels decreased significantly in the menstrual phase and the follicular phase compared to the early luteal phase (P = 0.001, P = 0.024 respectively). Menstrual phase estradiol levels were significantly lower compared to the ovulatory phase (P = 0.015), and the late luteal phase (P = 0.003). Progesterone levels decreased significantly in the menstrual phase and the follicular phase compared to the ovulatory phase (P = 0.012, P = 0.009 respectively), the early luteal phase (both P = 0.007), and the late luteal phase (P = 0.028, P = 0.029 respectively), and it along with a significant decrease in the ovulatory phase compared to the early luteal phase (P = 0.010). AM T2 signals were significantly lower in the menstrual phase compared to the ovulatory phase (P = 0.043) but not other phases. PM T2 signals increased significantly in the menstrual phase compared to the follicular phase (P = 0.003), ovulatory phase (P = 0.009), and the late luteal phase (P = 0.032), and the difference between the AM and PM values increased significantly in the menstrual phase compared to the other 4 phases (P<0.01). A negative correlation between fluid retention and agility was observed. Conclusion In female students fluid retention during the menstrual phase could be a factor that influences athletic agility.

Radiobiological response of U251MG, CHO-K1 and V79 cell lines to accelerator-based boron neutron capture therapy

Abstract In the current article, we provide in vitro efficacy evaluation of a unique accelerator-based neutron source, constructed at the Budker Institute of Nuclear Physics (Novosibirsk, Russian Federation), for boron neutron capture therapy (BNCT), which is particularly effective in the case of invasive cancers. U251MG, CHO-K1 and V79 cells were incubated and irradiated in various concentrations of boric acid with epithermal neutrons for 2–3 h in a plexiglass phantom, using 2.0 MeV proton energy and 1.5–3.0 mA proton current, resulting in a neutron fluence of 2.16 × 1012 cm−2. The survival curves of cells loaded with boron were normalized to those irradiated without boron (to exclude the influence of the fast neutron and gamma dose components) and fit to the linear–quadratic (LQ) model. Colony formation assays showed the following cell survival rates (means ± SDs): CHO-K1: 0.348 ± 0.069 (10 ppm), 0.058 ± 0.017 (20 ppm), 0.018 ± 0.005 (40 ppm); V79: 0.476 ± 0.160 (10 ppm), 0.346 ± 0.053 (20 ppm), 0.078 ± 0.015 (40 ppm); and U251MG: 0.311 ± 0.061 (10 ppm), 0.131 ± 0.022 (20 ppm), 0.020 ± 0.010 (40 ppm). The difference between treated cells and controls was significant in all cases (P < 0.01) and confirmed that the neutron source and irradiation regimen were sufficient for control over cell colony formation. We believe our study will serve as a model for ongoing in vitro experiments on neutron capture therapy to advance in this area for further development of accelerator-based BNCT into the clinical phase.

Rolipram plus Sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model

Cardiopulmonary bypass (CPB) recovery is complicated by lung inflammation from bone marrow (BM)-derived polymorphonuclear leukocytes (PMNs) and monocytes (MO). Although Sivelestat reduces inflammatory mediators and Rolipram inhibits PMN and MO activation, any kinetic effects to improve CPB recovery in vivo are unknown. We hypothesized that intraoperative co-administration of these compounds would reduce CPB-induced lung inflammation through downregulation of PMN and MO recruitment. A 2-h CPB was surgically established in cynomolgus monkeys (nu2009=u200913), and BM leukocyte release and lung recruitment were monitored postoperatively by flow cytometry with 5′-bromo-2′-deoxyuridine (BrdU) and cytokine ELISA. Either Sivelestat, Sivelestat plus Rolipram, or saline (control) was administered intraoperatively and both peripheral and perfusion sampling courses revealed BrdU-labeled cells representative of activated leukocyte infiltration. Levels of cytokines CD11b and CD18 were leukocytic activation markers. Sivelestat plus Rolipram attenuated increases in CPB-associated circulating band cells, prolonged BM-transit time (PMN: 121.0u2009±u20093.7 to 96.2u2009±u20094.3xa0h [control], pu2009=u20090.012; MO: 84.4u2009±u20094.1 to 61.4u2009±u20093.0xa0h [control], pu2009=u20090.003), and reduced their alveolar appearance. CD11b-mediated PMN and MO changes during CPB and the post-surgical increases of Interleukin (IL)-6 and IL-8 in the bronchoalveolar lavage fluid were suppressed. Sivelestat alone increased PMN transit time to 115.8u2009±u20096.6xa0h, but monocytes were unaffected. Therefore, Rolipram has additive inhibitory effects with Sivelestat on the CPB-induced activation and release of BM-derived PMNs and MO and their recruitment to the lungs. Co-administration of these compounds could, therefore, hold value for preventing CPB-induced lung injury.