Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

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Further studies on the inhibition of chemical carcinogenesis by Corynebacterium parvum

Summary The conditions under which administration of Corynebacterium parvum (CP) inhibits the development of tumours in response to methylcholanthrene (MC) have been further delineated. After subcutaneous (SC) injection of a single large dose of MC in solution (0.5 mg to CBA mice, 0.25 mg to BALB/c), repeated intravenous (IV) injection of CP starting 4 days before injection of the carcinogen delays or prevents the development of fibrosarcomas, whereas a similar course of injections starting 4 weeks later, and single injections of CP at various times, have little or no inhibitory effect. After injection of only 0.1 mg MC repeated injection of CP, even when started before injection of carcinogen, is ineffective. Carcinogenesis may also be inhibited by repeated IV injection of CP starting 4 days before implantation of Millipore discs impregnated either with MC alone or with a mixture of MC and paraffin wax. In untreated mice SC implantation of a disc impregnated with 0.1 mg MC was more strongly carcinogenic than SC injection of the same quantity of MC in solution. The effect of CP depended on the site of implantation, the type of disc and the regimen of CP administration. With MC wax discs implanted in the peritoneal cavity the development of tumours was completely prevented by repeated administration of CP starting before insertion of the disc. Similar treatment resulted in more modest inhibition of carcinogenesis after SC implantation of MC wax discs and MC discs of small pore size. In previous papers three possible mechanisms have been suggested to account for the inhibitory effect of CP on chemical carcinogenesis by MC: (1) destruction of transformed cells by CP-activated macrophages; (2) accelerated conversion of the MC to completely non-carcinogenic substances; and (3) inhibition of the conversion of MC to a highly carcinogenic epoxide. The present results do not exclude any of these possibilities but the observation that single injections of CP have little effect suggests that modification of the metabolism of MC is not the whole explanation. The different results obtained with carcinogenic discs implanted in different sites, and with different types of disc, are attributed to differences in the degree of macrophage activation and in the extent to which activated macrophages made effective contact with the carcinogen and with developing tumour cells. Two possible explanations of the failure of repeated injection of CP to reduce the incidence or rate of development of tumours in response to injection of only 0.1 mg MC are suggested.     

Exercise endurance and fuel utilization: a reevaluation of the effects of fasting

The effect of fasting on energy utilization during running or swimming was studied in adult male Wistar rats. Compared with fed rats, fasted animals displayed a decreased contribution of carbohydrates in energy supply, with decreased liver and muscle glycogen contents and decreased rate of glycogen breakdown. This was compensated by an enhanced rate of beta-oxidation. In addition, fasting induced an exaggerated sympathoadrenal response during exercise, reflected by a greater epinephrine plasma level and a higher norepinephrine turnover rate in both liver and soleus. Nevertheless, endurance capacity was similar in fasted and fed animals. These results contrast with the impairment of endurance observed in fasting humans but also with the improvement of endurance in rats previously reported by Dohm et al. (J. Appl. Physiol. 55: 830-833, 1983). These data suggest that the metabolic responses to exercise subsequent to food deprivation depend not only on the considered species but also, in the same species (rat), on the age of the animals and the duration of the fast. These factors probably determine the hormonal secretion and substrate utilization during prolonged exercise in fasting conditions.     

Lethal Sectoring and the Delayed Induction of Aneuploidy in Yeast

Persistent lethal sectoring in a homothallic strain of yeast has been ascribed to tetrasomy for chromosome I. Such aneuploids can appear many generations after irradiation. The data thus indicate that an induced predisposition towards aneuploidy can be prolonged through successive post-irradiation cell divisions. Sporadic cell death in tetrasomics for chromosome I was found to result from a metabolic imbalance and not from a genetic instability conseqent to aneuploidy. This imbalance may be due to a dosage effect involving cistrons for ribosomal RNA since many of these are known to be located on chromosome I. Tetrasomy is not the only cause of persistent lethal sectoring; the phenomenon has been initiated through genetic recombination involving normal diploids. It has also been concluded that, in trisomics, equational division of the supernumerary chromosome sometimes occurs at the first meiotic division.     

Caudal vertebral body articular surface morphology correlates with functional tail use in anthropoid primates

Prehensile tails, capable of suspending the entire body weight of an animal, have evolved in parallel in New World monkeys (Platyrrhini): once in the Atelinae (Alouatta, Ateles, Brachyteles, Lagothrix), and once in the Cebinae (Cebus, Sapajus). Structurally, the prehensile tails of atelines and cebines share morphological features that distinguish them from nonprehensile tails, including longer proximal tail regions, well‐developed hemal processes, robust caudal vertebrae resistant to higher torsional and bending stresses, and caudal musculature capable of producing higher contractile forces. The functional significance of shape variation in the articular surfaces of caudal vertebral bodies, however, is relatively less well understood. Given that tail use differs considerably among prehensile and nonprehensile anthropoids, it is reasonable to predict that caudal vertebral body articular surface area and shape will respond to use‐specific patterns of mechanical loading. We examine the potential for intervertebral articular surface contour curvature and relative surface area to discriminate between prehensile‐tailed and nonprehensile‐tailed platyrrhines and cercopithecoids. The proximal and distal intervertebral articular surfaces of the first (Ca1), transitional and longest caudal vertebrae were examined for individuals representing 10 anthropoid taxa with differential patterns of tail‐use. Study results reveal significant morphological differences consistent with the functional demands of unique patterns of tail use for all vertebral elements sampled. Prehensile‐tailed platyrrhines that more frequently use their tails in suspension (atelines) had significantly larger and more convex intervertebral articular surfaces than all nonprehensile‐tailed anthropoids examined here, although the intervertebral articular surface contour curvatures of large, terrestrial cercopithecoids (i.e., Papio sp.) converge on the ateline condition. Prehensile‐tailed platyrrhines that more often use their tails in tripodal bracing postures (cebines) are morphologically intermediate between atelines and nonprehensile tailed anthropoids. J. Morphol. 275:1300–1311, 2014. © 2014 Wiley Periodicals, Inc.     

Phagocytosis in the spleen of the sunfish Lepomis spp.

A histological investigation of the filtering function of the spleen of the sunfish Lepomis spp. was conducted by light, scanning, and transmission electron microscopy. The parenchyma of the organ is predominantly red pulp, a system of splenic cords and sinuses. The white pulp consists of loose lymphoid tissue which forms a cuff around the pulp arteries. Filtering of particulate matter from the blood occurs in the red pulp by phagocytes of the pulp cords and ellipsoids (periarterial macrophage sheaths). The ellipsoids are pale-staining cuffs of macrophages and reticular cells in a framework of reticular fibres surrounding the arterial capillaries. Destruction of effete blood cells (especially erythrocytes) is confined to the pigment nodules; particulate matter is not taken up by the nodules. These yellow-brown bodies are dispersed throughout the red pulp and are bounded by a reticular capsule. They contain masses of phagocytes and have the appearance of a morula. They are associated with blood vessels and are surrounded by sinusoids. Prussian Blue stain shows the presence of haemosiderin within their phagocytes. The phagocytes of the pigment nodules are filled with inclusions such as residual bodies, siderosomes, and fragments of erythrocytes. The early filtering of particulate matter by the phagocytes of the pulp cords and ellipsoids may allow for a more efficient phagocytosis of erythrocytes by the pigment nodules, followed by storage and reutilization of iron-containing compounds uncontaminated by other phagocytosed material.     

High-throughput strategies for the discovery and engineering of enzymes for biocatalysis

Bioprocess and Biosystems Engineering - Innovations in novel enzyme discoveries impact upon a wide range of industries for which biocatalysis and biotransformations represent a great challenge,...     

Solar activity cycle and the incidence of foetal chromosome abnormalities detected at prenatal diagnosis

We studied 2001 foetuses during the period of minimal solar activity of solar cycle 21 and 2265 foetuses during the period of maximal solar activity of solar cycle 22, in all women aged 37 years and over who underwent free prenatal diagnosis in four hospitals in the greater Tel Aviv area. There were no significant differences in the total incidence of chromosomal abnormalities or of trisomy between the two periods (2.15% and 1.8% versus 2.34% and 2.12%, respectively). However, the trend of excessive incidence of chromosomal abnormalities in the period of maximal solar activity suggests that a prospective study in a large population would be required to rule out any possible effect of extreme solar activity.     

Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing’s syndrome

Rare diseases are often not fully understood and efforts put in investigating it from patient perspective are usually met with challenges. We performed a systematic literature review (SLR) for the last 20?years in Cushing’s Syndrome (CS) to illustrate Patient-Reported Outcome (PRO) challenges, and show what solutions were found.PROs and other Clinical Outcome Assessment (COA) used with CS patients were reviewed in 36 studies. Two CS-specific Health Related Quality of Life (HRQL) measures were identified (i.e., CushingQoL, Tuebingen CD-25), as well as depression and neurocognitive measures. For CS-specific HRQL measures, the CushingQoL was the most widely used measure due in part to being the first CS-specific HRQL measure developed. With algorithms mapping the CushingQoL to both the SF-6D and EQ-5D, the CushingQoL could be used to facilitate economic modelling studies in the absence of a generic HRQL measure. While the CushingQoL offers only the global scale and two subscales compared to the six subscales of the Tuebingen CD-25, there is not yet adequate statistical validation data available for the Tuebingen CD-25 to suggest it can withstand the scrutiny of review by multiple stakeholders. Results of this review indicate that the inclusion of a measure of depressive symptoms, such as the BDI-II or similar measure, would be reasonable to include given the high level of comorbidity of depression among CS patients. A brief neurocognitive performance outcome, such as Trail Making tasks A and D or Digit Symbol, could help inform the interpretation of HRQL results. Neurocognitive differences may be an unassessed mediator of HRQL outcomes, partly accounting for the persistence of depressive symptoms and HRQL deficits despite treatment. Results suggest that HRQL improvements are possible within this population. These results are limited by small sample sizes and pre/post study design.CS showcases the difficulties encountered in measuring PROs in rare diseases. A solution for this specific case was developed in the form of dedicated PRO instruments, the CushingQOL and the Tuebingen-25. However, some aspects of CS may not be fully answered or not yet validated (e.g., depressive and cognitive symptoms). Further research needs to be done to address them.