Capillary blood flow in the testes and testosterone secretion in the starved rat

Summary The average capillary blood flow in the testes was found to be 181 l/min/g testis tissue (n=19) in rats starved for 5 days and 273 l/min/g (n=18, p<0.01) in the control group. Plasma testosterone was significantly decreased in the starved animals (1.00±0.06 ng/ml vs 5.43±0.63 ng/ml). When starved and control rats were stimulated with human chorion gonadotropin, testosterone values in plasma were greatly increased in both groups. The capillary blood flow was not altered. The data indicate that human chorion gonadotropin can stimulate testosterone production in the starved rat without influencing the reduced capillary blood flow.     

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.     

Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis

Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.     

Robust forecast aggregation: Fourier L2E regression

The Good Judgment Team led by psychologists P. Tetlock and B. Mellers of the University of Pennsylvania was the most successful of five research projects sponsored through 2015 by the Intelligence Advanced Research Projects Activity to develop improved group forecast aggregation algorithms. Each team had at least 10 algorithms under continuous development and evaluation over the 4‐year project. The mean Brier score was used to rank the algorithms on approximately 130 questions concerning categorical geopolitical events each year. An algorithm would return aggregate probabilities for each question based on the probabilities provided per question by thousands of individuals, who had been recruited by the Good Judgment Team. This paper summarizes the theorized basis and implementation of one of the two most accurate algorithms at the conclusion of the Good Judgment Project. The algorithm incorporated a number of pre‐ and postprocessing steps, and relied upon a minimum distance robust regression method called L₂E. The algorithm was just edged out by a variation of logistic regression, which has been described elsewhere. Work since the official conclusion of the project has led to an even smaller gap.     

Governing a Collective Bad: Social Learning in the Management of Crop Diseases

Systemic Practice and Action Research - There has been strong research interest in designing and testing learning approaches for enhancing and sustaining the capacity of communities to manage...     

Treatment of zinc deficiency without zinc fortification

Zinc （Zn） deficiency in animals became of interest until the 1950s. In this paper, progresses in researches on physiology of Zn deficiency in animals, phytate effect on bioavailability of Zn, and role of phytase in healing Zn deficiency of animals were reviewed. Several studies demonstrated that Zn is recycled via the pancreas; the problem of Zn deficiency was controlled by Zn homeostasis. The endogenous secretion of Zn is considered as an important factor influencing Zn deficiency, and the critical molar ratio is 10. Phytate （inositol hexaphosphate） constituted up to 90% of the organically bound phosphorus in seeds. Great improvement has been made in recent years on isolating and measuring phytate, and its structure is clear. Phytate is considered to reduce Zn bioavailability in animal. Phytase is the enzyme that hydrolyzes phytate and is present in yeast, rye bran, wheat bran, barley, triticale, and many bacteria and fungi. Zinc nutrition and bioavailability can be enhanced by addition of phytase to animal feeds. Therefore, using phytase as supplements, the most prevalent Zn deficiency in animals may be effectively corrected without the mining and smelting of several tons of zinc daily needed to correct this deficiency by fortification worldwide.     

Bimodal expression of Sprouty2 during the cell cycle is mediated by phase-specific Ras/MAPK and c-Cbl activities

Sprouty2 is an important inhibitor of cell proliferation and signal transduction. In this study, we found a bimodal expression of Sprouty2 protein during cell cycle progression after exit from quiescence, whereas elevated Sprouty4 expression in the G1 phase stayed high throughout the rest of the cell cycle. Induction of the mitogen-activated protein kinase via activated Ras was crucial for increased Sprouty2 expression at the G0/G1 transition. Following the first peak, accelerated proteasomal protein degradation caused a transient attenuation of Sprouty2 abundance during late G1. Since the decline in its expression was abolished by dominant negative c-Cbl and the timely restricted interaction between Sprouty2 and c-Cbl disappeared at the second peak of Sprouty2 expression, we conclude that the second phase in the cell cycle-specific expression profile of Sprouty2 is solely dependent on ubiquitination by c-Cbl. Our results suggest that Sprouty2 abundance is the result of strictly coordinated activities of Ras and c-Cbl.