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The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs ...frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets.
The purpose of this study was to examine whether improvement in motor function could be demonstrated in old rats, and to see if GDNF affected post-synaptic DA function. Aged (20 month old) versus ...young rats were tested following GDNF treatment for postural control by using an inclined balance beam and a wire grip strength test. Rats were also examined electrophysiologically for spontaneous striatal cell firing rate alone and in the presence of DA receptor agonists, and histologically for the intensity of striatal TH staining, and number of DA containing nigral cells. Behavior was significantly improved in the aged animals who received central GDNF infusions, although the extent of improvement was less than what has been observed in 16-month-old rats. There was no effect of GDNF treatment in the aged animals on spontaneous firing rate in the striatum, or on the post synaptic response to locally applied D
1 and D
2 receptor family agonists. However, there was an effect of age alone on firing rate, and on the response to locally applied SKF 38393 and quinpirole. By using unbiased cell counting we observed no age-related decline in the number of TH positive cells in the substantia nigra. There was no effect of GDNF on the number of TH positive cells in the substantia nigra in either young or aged rats, although there were morphological improvements in DA neurons of the GDNF treated aged rats. These results replicate earlier studies showing an effect of age on striatal firing rate and dopamine receptor function, and suggest that the GDNF mediated improvement in behavior may be located other than post synaptically within the striatum.
* Healthcare organizations spend millions of dollars annually on both charity care and bad debt, some of which is caused by needless hospitalizations and medical treatments due to a lack of ...preventive, proactive care. * These expenditures continue the trend of rising healthcare costs, which threaten to break the back of American economics. * Moving uninsured patients who access the emergency department after an exacerbation of a chronic illness to a more proactive, interprofessional medical home clinic model may assist that population to achieve a healthier, happier lifestyle, with an overall reduction in healthcare cost.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Previous studies have shown deficits in DA neuronal systems in senescence. Other studies indicate that prolonged dietary restriction can attenuate many of the detrimental effects of age. We have ...shown previously using in vivo electrochemistry that K+-evoked striatal DA overflow decreases as a function of age. This was a regional effect that appeared to be due to functional changes in DA neurons, rather than a decrease in the storage and synthesis of DA. In the present studies, we used in vivo electrochemistry to investigate the effects of caloric restriction on age related decreases in K+-evoked DA overflow along a dorsal to ventral axis in the striatum of aged female Fischer 344 rats. Aged (26–28-month-old) diet restricted animals (DRF) showed evoked DA overflow that was significantly greater in amplitude and duration compared to aged (26–28-month-old) ad lib fed animals (ALF). These results provide additional evidence that decreased DA neuronal function resulting from age is improved by caloric restriction.
Trypanosoma cruzi is an obligate intracellular parasite that is the causative agent for Chagas Disease, a chronic bloodborne infection endemic to the Americas. Inositol-tetrakisphosphate 1-kinase ...(ITPK1) has been described as an enzyme that may mediate an alternative lipid-independent inositol polyphosphate synthesis pathway through phosphorylation of inositol monophosphate and other intermediates. Bioinformatics research has identified hypothetical protein TcCLB.503885.50 as a potential T. cruzi ITPK1 (TcITPK1) homolog and is orthologous to other higher-order eukaryotic ITPK1. The ability of TcITPK1 to act as the mediator for this alternative pathway has been established through yeast complementation assays and SAX-HPLC analysis of radioactively-labeled inositol phosphate species in complemented yeast. Immunofluorescence assays of T. cruzi epimastigotes with endogenously tagged TcITPK1 localizes to the cytosol. Additionally, preliminary data demonstrates TcITPK1 may be essential to T. cruzi survival as multiple CRISPR/Cas9 knockout experiments have resulted in no viable in vitro parasites in the epimastigote stage.
Rapid chronoamperometric recordings coupled with local application of drugs by pressure ejection were used to investigate the effects of nomifensine and ethanol (EtOH) on exogenous norepinephrine ...(NE) clearance in the cerebellum of young (5-month-old) and aged (24–26-month-old) male Fischer 344 rats. In the young rats, local nomifensine application prolonged exogenous NE clearance, indicating transporter mediated uptake inhibition. NE clearance was modestly but significantly prolonged in the aged rats as compared to the young rats, suggesting less efficient uptake. Consistent with this, there was little effect of nomifensine on NE clearance in the aged rats. In contrast to the effect of nomifensine, EtOH inhibited NE clearance in both young and aged rats. These data further support the hypothesis that one effect of EtOH in cerebellar NE systems is inhibition of NE uptake into NE-containing nerve terminals, and they also demonstrate that the effect of nomifensine on exogenous NE clearance in vivo in the cerebellum is altered by the aging process, while the effect of EtOH is not.
This dissertation discusses two different projects. The first project involves the development of cyclic-peptide acridine conjugates in the effort to identify molecules that can selectively bind to ...and stabilize G-quadruplex DNA. The second project seeks to probe the role of the cation-pi interaction in the binding of the HP1 chromodomain to trimethylated lysine 9 of histone 3 (H3). In recent years, interest in the G-quadruplex DNA structure has increased enormously due to the unique physical properties of this secondary DNA structure as well as the presence of guanine-rich sequences in biologically functional regions of many genomes. Given the propensity of G-quadruplex structures to control many biological functions, it has become desirable to identify small molecules that can bind to and stabilize G-quadruplexes. This work aims to develop quadruplex ligands that exhibit selectively over not only duplex DNA but also over various quadruplex sequences. It was believed that cyclic peptides could deliver selectivity for the quadruplex structure over duplex DNA while also providing the added advantages of mimicking native protein structure, displaying enhanced metabolic stability and possessing structural preorganization. Using a strategy that has been developed in our lab, we propose screening libraries of cyclic peptides generated in situ using thiol-thioester exchange for dynamic combinatorial chemistry (DCC). These libraries can efficiently be screen against different quadruplex sequences as well as duplex DNA in order to determine the selectivity of each species. In the second project, we sought to characterize the noncovalent interactions responsible for the recognition of trimethylated lysine 9 of histone 3 by the aromatic pocket of the HP1 chromodomain. Lysine can exist in three distinct methylation states under the control of highly specific methyl transferases or demethylases. These methylation states serve to turn on specific protein-protein interactions with partners that specifically recognize the methylated side chain. Recognition and affinity is mainly derived from cation-pi interactions between the positively charged cationic side chain and the electron rich pi surfaces of nearby aromatic rings. This interaction can be quantified by incorporation of fluorinated derivatives of the aromatic amino acids responsible for the binding of H3K9Me3 to the HP1 chromodomain. The cation-π interaction between the aromatic pocket of the HP1 chromodomain and H3K9Me3 can be revealed by incorporation of a series of fluorinated amino acid analogues. A linear correlation between binding affinity and the calculated magnitude of the cation-pi interaction of those groups indicates a cation-pi interaction. Because many reader proteins for methylated lysine have an aromatic cage in their binding pockets, findings from the investigation of the HP1 chromodomain will provide broad insight into this class of proteins.
Huajian has plans to build a Chinese-style “shoe city” in the coming years, a 341-acre industrial zone that will employee as many as 50,000 workers (more than the current total of the entire ...Ethiopian garment industry) and host some 45 different manufacturers, from textiles, garments and leather makers to chemicals and metal factories—it is also projected to suck up 53 megawatts of power and 15,555 metric cubes of water per day, according to one source, which equals more than four million gallons. The leather and leather footwear industries, known for being notorious polluters, stand to be two of the fastest-growing subsectors in Ethiopia as the country has the world’s fifth-largest cattle stock, and skins go for as low as $2 a piece. Though the partnership is in the very early stages, Swedfund’s rep says they plan to set standards for and monitor the factories’ water usage, wastewater treatment, environmental impact and working conditions based on International Labour Organization (ILO) standards. Huajian’s vice president told BBC that the company feels justified paying lower wages as it is offering workers shoe-making training instead, as well as tennis courts, uniforms, food, and, in the future, free accommodation.
THE CLOTHES MAKE THE MOVEMENT Cline, Elizabeth
The Nation (New York, N.Y.),
08/2013, Letnik:
297, Številka:
5/6
Magazine Article
Nearly three months after a factory collapse stole the lives of 1,129 garment workers in Bangladesh--and, along with them, people's peace of mind about what they wear--progress for Bangladesh's ...factory workers has been slow at best. The New York Times has described just how "disorganized and haphazard," and in some cases entirely ineffective, the process of inspecting the country's factories has been thus far. Indeed, reading some of the reports, it's easy to despair about what an ordinary shopper can do. And yet, despite all of the daunting challenges laid bare by Rana Plaza, there are ways consumers can have an impact, ranging from being conscious about which companies are making efforts to be more responsible, to adjusting their buying habits and patterns, to thinking about what it means to support domestically made clothes. Here, Cline discusses how Rana Plaza changed the fashion industry.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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