In this paper, the behavior of a Jarratt family of iterative methods applied to quadratic polynomials is studied. Some anomalies are found in this family be means of studying the dynamical behavior ...of this fourth-order family of methods. Parameter spaces are shown and the study of the stability of all the fixed points is presented. Dynamical planes for members with good and bad dynamical behavior are also provided.
Was Darwin really inspired by Galápagos finches? Did Einstein's wife secretly contribute to his theories? Did Franklin fly a kite in a thunderstorm? Did a falling apple lead Newton to universal ...gravity? Did Galileo drop objects from the Leaning Tower of Pisa? Did Einstein really believe in God?Science Secretsanswers these questions and many others. It is a unique study of how myths evolve in the history of science. Some tales are partly true, others are mostly false, yet all illuminate the tension between the need to fairly describe the past and the natural desire to fill in the blanks.Energetically narrated, Science Secrets pits famous myths against extensive research from primary sources in order to accurately portray important episodes in the sciences. Alberto A. Martínez analyzes how such myths grow and rescues neglected facts that are more captivating than famous fictions. Moreover, he shows why opinions that were once secret and seemingly impossible are now scientifically compelling. The book includes new findings related to the Copernican revolution, alchemy, Pythagoras, young Einstein, and other events and figures in the history of science.
This paper proposes energy-efficient approximate multipliers based on the Mitchell’s log multiplication, optimized for performing inferences on convolutional neural networks (CNN). Various design ...techniques are applied to the log multiplier, including a fully-parallel LOD, efficient shift amount calculation, and exact zero computation. Additionally, the truncation of the operands is studied to create the customizable log multiplier that further reduces energy consumption. The paper also proposes using the one’s complements to handle negative numbers, as an approximation of the two’s complements that had been used in the prior works. The viability of the proposed designs is supported by the detailed formal analysis as well as the experimental results on CNNs. The experiments also provide insights into the effect of approximate multiplication in CNNs, identifying the importance of minimizing the range of error.The proposed customizable design at ww = 8 saves up to 88 percent energy compared to the exact fixed-point multiplier at 32 bits with just a performance degradation of 0.2 percent for the ImageNet ILSVRC2012 dataset.
Mosquito-borne diseases are responsible for several million human deaths annually around the world. One approach to controlling mosquito populations is to disrupt molecular processes or antagonize ...novel metabolic targets required for the production of viable eggs. To this end, we focused our efforts on identifying proteins required for completion of embryonic development that are mosquito selective and represent potential targets for vector control. We performed bioinformatic analyses to identify putative protein-coding sequences that are specific to mosquito genomes. Systematic RNA interference (RNAi) screening of 40 mosquito-specific genes was performed by injecting double-stranded RNA (dsRNA) into female Aedes aegypti mosquitoes. This experimental approach led to the identification of eggshell organizing factor 1 (EOF1, AAEL012336), which plays an essential role in the formation and melanization of the eggshell. Eggs deposited by EOF1-deficient mosquitoes have nonmelanized fragile eggshells, and all embryos are nonviable. Scanning electron microscopy (SEM) analysis identified that exochorionic eggshell structures are strongly affected in EOF1-deficient mosquitoes. EOF1 is a potential novel target, to our knowledge, for exploring the identification and development of mosquito-selective and biosafe small-molecule inhibitors.
Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine ...(DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.
Abstract We herein review various pharmacological and clinical aspects of pegylated liposomal doxorubicin (PLD), the first nanomedicine to be approved for cancer therapy, and discuss the gap between ...its potent antitumor activity in preclinical studies and its comparatively modest achievements in clinical studies and limited use in clinical practice. PLD is a complex formulation of doxorubicin based on pharmaceutical nanotechnology with unique pharmacokinetic and pharmacodynamic properties. Its long circulation time with stable retention of the payload and its accumulation in tumors with high vascular permeability both result in important advantages over conventional chemotherapy. The ability of PLD to buffer a number of undesirable side effects of doxorubicin, including a major risk reduction in cardiac toxicity, is now well-established and confers a major added value in a number of disease conditions. PLD is approved for the treatment of ovarian cancer, breast cancer, multiple myeloma, and Kaposi sarcoma. In addition, clinically significant antitumor activity of PLD has been reported in a number of other cancer types, including lymphomas and soft tissue sarcomas. In spite of this, PLD has not replaced conventional doxorubicin in common applications such as the adjuvant and neoadjuvant treatment of breast cancer, and its use in the clinic has not become as widespread as one may have predicted. Exploiting the unique pharmacology of PLD, analyzing its selective biodistribution and homing to tumors in cancer patients with proper theranostic tools, and harnessing its complex interaction with the immune system, will lead to a more selective and rational use of PLD that may have great impact on future clinical results and may help realize its largely untapped potential.
References to the descriptions and redescriptions of the 742 species of Ixodidae published from 1758 to December 31, 2019 are compiled, with the goal of enabling tick taxonomists to readily access ...this diffuse and often confusing literature. Additionally, data resulting from this effort are critically analyzed to demonstrate the problems attending correct identification of several tick species that are of medical, veterinary and/or evolutionary importance, and to highlight the need for new or enhanced diagnostic techniques. Recent morphological and molecular studies indicate that some ixodid species names represent more than one taxon; therefore, it is expected that new species will be described in the near future, based partly on material already deposited in museums around the world.
Reliance on just one drug to treat the prevalent tropical disease, schistosomiasis, spurs the search for new drugs and drug targets. Inhibitors of human cyclic nucleotide phosphodiesterases (huPDEs), ...including PDE4, are under development as novel drugs to treat a range of chronic indications including asthma, chronic obstructive pulmonary disease and Alzheimer's disease. One class of huPDE4 inhibitors that has yielded marketed drugs is the benzoxaboroles (Anacor Pharmaceuticals).
A phenotypic screen involving Schistosoma mansoni and 1,085 benzoxaboroles identified a subset of huPDE4 inhibitors that induced parasite hypermotility and degeneration. To uncover the putative schistosome PDE4 target, we characterized four PDE4 sequences (SmPDE4A-D) in the parasite's genome and transcriptome, and cloned and recombinantly expressed the catalytic domain of SmPDE4A. Among a set of benzoxaboroles and catechol inhibitors that differentially inhibit huPDE4, a relationship between the inhibition of SmPDE4A, and parasite hypermotility and degeneration, was measured. To validate SmPDE4A as the benzoxaborole molecular target, we first generated Caenorhabditis elegans lines that express a cDNA for smpde4a on a pde4(ce268) mutant (hypermotile) background: the smpde4a transgene restored mutant worm motility to that of the wild type. We then showed that benzoxaborole inhibitors of SmPDE4A that induce hypermotility in the schistosome also elicit a hypermotile response in the C. elegans lines that express the smpde4a transgene, thereby confirming SmPDE4A as the relevant target.
The orthogonal chemical, biological and genetic strategies employed identify SmPDE4A's contribution to parasite motility and degeneration, and its potential as a drug target. Transgenic C. elegans is highlighted as a potential screening tool to optimize small molecule chemistries to flatworm molecular drug targets.
Congenital muscular dystrophies: What is new? Zambon, Alberto A.; Muntoni, Francesco
Neuromuscular disorders : NMD,
October 2021, 2021-10-00, 20211001, Letnik:
31, Številka:
10
Journal Article
Recenzirano
Odprti dostop
•We outline recent natural history studies that provide additional information on disease progression.•We discuss recently discovered genes and highlight newly discovered pathophysiological ...mechanisms.•We present the current status of the most promising therapeutic options for CMDs.
Congenital muscular dystrophies (CMDs) are a group of inherited conditions defined by muscle weakness occurring before the acquisition of ambulation, delayed motor milestones, and characterised by muscle dystrophic pathology. A large number of genes - at least 35- are responsible for CMD phenotypes, and it is therefore not surprising that CMDs comprise a wide spectrum of phenotypes, with variable involvement of cardiac/respiratory muscles, central nervous system, and ocular structures. The identification of several new genes over the past few years has further expanded both the clinical and the molecular spectrum underlying CMDs. Comprehensive gene panels allow to arrive at a final diagnosis in around 60% of cases, suggesting that both new genes, and unusual mutations of the currently known genes are likely to account for the remaining cases. The aim of this review is to present the most recent advances in this field. We will outline recent natural history studies that provide additional information on disease progression, discuss recently discovered genes and the current status of the most promising therapeutic options.
Pharmaceuticals and their metabolites are released into the environment by domestic, hospital, and pharmaceutical industry wastewaters. Conventional wastewater treatment technology does not guarantee ...effluents of high quality, and apparently clean water may be loaded with pollutants. In this study, we assess the performance and efficiency of free and immobilised cells of microalgae
sp. in removing four pharmaceuticals, chosen for their occurrence or persistence in the environment. These are paracetamol, ibuprofen, olanzapine and simvastatin. The results showed that free microalgae cells remain alive for a longer time than the immobilised ones, suggesting the inhibition of cell proliferation by the polymeric matrix polyvinyl alcohol. Both cells, free and immobilised, respond differently to each pharmaceutical. The removal of paracetamol and ibuprofen by
sp., after 24 h of culture, was significantly higher in immobilised cells. Free cells removed a significantly higher concentration of olanzapine than immobilised ones, suggesting a higher affinity to this molecule than to paracetamol and ibuprofen. The results demonstrate the effectiveness of
sp. free cells for removing olanzapine and
sp. immobilised cells for removing paracetamol and ibuprofen.
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