Ichthyological Bulletin of the J.L.B. Smith Institute of Ichthyology; No. 52

Thirteen species of Mullidae (goatfishes or red mullets) occur in the Red Sea: Mulloides flavolineatus, M. vanicolensis, Parupeneus cyclostomus, P. forsskali, P. heptacanthus, P. macronemus, P. rubescens, Upeneus asymmetricus, U. moluccensis, U. subvittatus (previously known only from the western Pacific), 0. sulphureus, U. tragula and U. vittatus. Descriptions, biological observations and black and white photographs are given for each of these 13 species. Keys are provided to the genera of Mullidae, to the species occurring in the Red Sea, and to the two Mediterranean species of Mullus that have been reported from the Suez Canal. The distinction between the genera Pseudupeneus and Parupeneus is discussed.Rhodes University Libraries (Digitisation

Diplodus levantinus (Teleostei: Sparidae), una nueva especie de sargo del Mediterráneo sudeste frente a Israel, con una lista de especies y una clave de clasificación de las especies del grupo Diplodus sargus

The sea bream Diplodus levantinus n. sp. is described from off the coasts of Israel in the eastern Mediterranean Sea, where it replaces Diplodus sargus (Linnaeus, 1758). The new species is characterized by 11-12 spines and 10-16 soft rays in the dorsal fin, 3 spines and 11-13 soft rays in the anal fin, 15-17 pectoral fin rays, 6-9 + 8-12 gill rakers on the first gill arch, upper and lower jaws with a single row of 4 incisors on each side, followed by a total of 16-19 molariform teeth in the upper jaw and 12-14 molariform teeth in the lower jaw, with the molariforms of the upper jaw separated from the incisors by a wide, toothless gap, and the sides of the body in adults with 8 vertical bars of equal width which are present even in large adults, followed by a broad bar on the caudal peduncle which usually nearly reaches the ventral margin of the caudal peduncle. An updated checklist of the species of the genus Diplodus, and a key to species of the Diplodus sargus species group from the eastern Atlantic and Mediterranean Sea, are presented.El sargo levantino Diplodus levantinus n. sp. se describe a partir de ejemplares de las costas de Israel, en el Mediterráneo oriental, donde reemplaza a Diplodus sargus (Linnaeus, 1758). La nueva especie se caracteriza por: 11-12 espinas y 10-16 radios blandos en la aleta dorsal, 3 espinas y 11-13 radios blandos en la aleta anal, 15-17 radios en las pectorales, 6-9 + 8-12 branquispinas en el primer arco branquial; las mandíbulas superior e inferior con una sola fila de 4 incisivos en cada lado, seguidos por un total de 16-19 molares en la mandíbula superior y 12-14 molares en la mandíbula inferior, con los molares de la mandíbula superior separados de los incisivos por una gran distancia sin dientes; los lados del cuerpo, en los adultos, con 8 bandas verticales de igual anchura, presentes incluso en adultos de gran tamaño, seguidas de una amplia banda en el pedúnculo caudal que, por lo general, casi alcanza el margen ventral del pedúnculo caudal. Se diferencia principalmente de D. sargus por el menor número de dientes molares en las mandíbulas superior e inferior, y por la amplia separación, sin dientes, entre molares e incisivos de la mandíbula superior. Se presenta una lista actualizada de las especies del género Diplodus y una clave para las especies del grupo de especies Diplodus sargus del Atlántico este y el Mediterráneo

The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp

The ubiquitin (Ub) domain protein Herp plays a crucial role in the maintenance of calcium homeostasis during endoplasmic reticulum (ER) stress. We now show that Herp is a substrate as well as an activator of the E3 Ub ligase POSH. Herp-mediated POSH activation requires the Ubl domain and exclusively promotes lysine-63–linked polyubiquitination. Confocal microscopy demonstrates that Herp resides mostly in the trans-Golgi network, but, shortly after calcium perturbation by thapsigargin (Tpg), it appears mainly in the ER. Substitution of all lysine residues within the Ubl domain abolishes lysine-63–linked polyubiquitination of Herp in vitro and calcium-induced Herp relocalization that is also abrogated by the overexpression of a dominant-negative POSHV14A. A correlation exists between the kinetics of Tpg-induced Herp relocalization and POSH-dependent polyubiquitination. Finally, the overexpression of POSH attenuates, whereas the inhibition of POSH by the expression of POSHV14A or by RNA interference enhances Tpg-induced calcium burst. Altogether, these results establish a critical role for POSH-mediated ubiquitination in the maintenance of calcium homeostasis through the spatial control of Herp

Identifying patients at risk: multi-centre comparison of HeartMate 3 and HeartWare left ventricular assist devices

Aims: Since the withdrawal of HeartWare (HVAD) from the global market, there is an ongoing discussion if and which patients require prophylactically exchange for a HeartMate 3 (HM3). Therefore, it is important to study outcome differences between HVAD and HM3 patients. Because centres differ in patient selection and standard of care, we performed a propensity score (PS)-based study including centres that implanted both devices and aimed to identify which HVAD patients are at highest risk. Methods and results: We performed an international multi-centre study (n = 1021) including centres that implanted HVAD and HM3. PS-matching was performed using clinical variables and the implanting centre. Survival and complications were compared. As a sensitivity analysis, PS-adjusted Cox regression was performed. Landmark analysis with conditional survival >2 years was conducted to evaluate long-term survival differences. To identify which HVAD patients may benefit from a HM3 upgrade, Cox regression using pre-operative variables and their interaction with device type was performed. Survival was significantly better for HM3 patients (P 2 years after implantation (P = 0.03). None of the pre-operative variable interactions in the Cox regression were significant. Conclusions: HM3 patients have a significantly better survival and a lower incidence of ischaemic strokes and pump thrombosis than HVAD patients. This survival difference persisted after 2 years of implantation. Additional research using post-operative variables is warranted to identify which HVAD patients need an upgrade to HM3 or expedited transplantation

Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): a randomized placebo-controlled multicentre trial

Aims: Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT. The aim of this study was to determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT. Methods and results: The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomized, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-min walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (interquartile range [IQR] 62–74) years, median left ventricular ejection fraction 29% (IQR 24–35), median PASP 45 (IQR 42–55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%). Conclusion: Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.publishedVersio

Effects of exergaming on exercise capacity in patients with heart failure: results of an international multicentre randomized controlled trial

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The E3 Ubiquitin-Ligase Bmi1/Ring1A Controls the Proteasomal Degradation of Top2α Cleavage Complex – A Potentially New Drug Target

The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha.We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2alpha degradation, increases the persistence of Top2alpha-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2alpha in-vitro and cellular overexpression of Bmi1 increases drug induced Top2alpha ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2alpha ubiquitination and drug-induced Top2alpha degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.The discovery that poisoned Top2alpha is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure—Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but—per definition—causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient’s hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g., catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents