Targets Of Particular Interest Research Articles

The Serotonin 4 Receptor Subtype: A Target of Particular Interest, Especially for Brain Disorders.

In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT4 receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT4 receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT4 receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT4 receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT4 receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT4 receptor is also altered in various eating disorders, and its activation by the 5-HT4 agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT4 receptor agonists in the pharmacological management of gastrointestinal disorders.

Analysis of trends in productivity metrics in assessing land degradation: A case study in the Campania region of southern Italy

Land degradation is a critical issue at a global level and its progressive increasing greatly reduces soil ecosystem services. In this context, the 2030 Agenda for Sustainable Development, adopted by all United Nations Member States in 2015, defined the Sustainable Development Goals (SDGs) and indicated some targets of particular interest for a territory to be integrated into short- and medium-term national programs. Target 15.3, which aims to end desertification and restore degraded lands, is currently monitored by indicator 15.3.1, measured as the combination of three sub-indicators (trends in land cover change, land productivity and carbon stocks) as suggested by the United Nations Convention to Combat Desertification (UNCCD), the custodian agency for the SDG indicator. In our opinion, this assessment shows some weakness that are generally caused by a lack of information from direct field observations. The greatest limitation regards land productivity dynamics linked to the NDVI trajectory adopted by the UNCCD methodological approach. For this reason, the paper proposes an alternative approach that consists of using annual maximum NDVI value assessments instead of annual mean values for trajectory calculation. To come to these conclusions, the study addresses a reliability assessment by using remote sensing techniques via the Google Earth Engine (GEE) and analysing the NDVI evolution over time at 450 locations spread around the Campania region (southern Italy). To this end, a customised Graphical User Interface (GUI) was built on the GEE platform and a Google Earth time slider tool was applied to visualize land cover changes which occurred at each location over a period of 18 years (2001–2018). The survey was carried out on MODIS and Landsat 7 collections and showed that the new approach had a better performance than the UNCCD approach (90 % vs 62 % of successful reliability tests, up to 96 % considering results from Landsat images). The application of maximum NDVI values to assess productivity dynamics spatially shows, with regard to UNCCD data, more than double the percentages of degraded and stable lands and a drastic reduction in improved areas within the Campania region. Overall, this innovative approach appears to agree more closely with ground truth and the use of finer resolution data is more suitable for investigating land degradation processes within a regional context.

Electromagnetic tomographic cerebral angiography

World Health Organization stated that “Cardiovascular diseases (CVDs) are the leading cause of death globally. Angiography is an important method in diagnostic of CVD. Standard-of-Care methods of angiography, such as X-Ray or CT- or MRI- angiography methods, being accurate and widely adopted in clinical practice, are bulky, expensive and energy in-efficient. X-ray and CT- angiography methods are also potentially hazardous as techniques require the use of ionizing contrast agents. Electromagnetic tomography (EMT) is an emerging medical imaging modality. EMT is applicable for safe functional imaging but suffers from a limited spatial resolution because of relatively large wavelength of electromagnetic radiation as compared to sizes of biological targets of particular interest, such as, for example blood vessels. Novel approach and method, presented in the study is capable to overcome such limitations and provide a mean for a dynamic, on-line EMT angiography. New method of EMT angiography was presented in application to cerebral angiography. Achieved imaging results clearly demonstrate applicability of the method for detecting small cerebral vessels of the diameter as small as 1.3 mm and to distinguish vessels with different dimensions. The technical challenges in the development of angiography capable EMT systems are assessed and discussed.

Prevalence and Risk Factors for Angiotensin Converting Enzyme Inhibitor Induced Cough among Diabetic Patients in a Tertiary Institution in Southeast Nigeria

Introduction: The prevalence of diabetes mellitus (DM) is increasing worldwide, with the attendant cardiovascular morbidity and mortality especially heightened by co-existing hypertension and proteinuria. The renin–angiotensin system (RAS) has been a drug target of particular interest because of its involvement in the cardiovascular and renal disease progression. The ACE inhibitors (ACEI) have been proven effective for reducing cardiovascular events and mortality in patients with cardiovascular disease. However, these medications are associated with cough in certain subjects which could lead to poor drug adherence and increased cardiovascular morbidity and mortality. This study sought to determine the prevalence of ACEI-induced subjects in DM patients. Methodology: A total of 100 patients who fit eligibility criteria were included in the study. A questionnaire was administered on subjects who were on ACEI while data was abstracted from the medical records of subjects who had been on the medication in the preceding two years. Results: The prevalence of ACEI-induced cough was 20%. Female gender (p=0.022) and prolonged use of the medication (p=0.017) positively correlated with cough among DM subjects who had received ACEI in the preceding 2 years, or were on the medication at the time of this study. There was no correlation between the type of ACEI, anthropometry, and glycaemic control and the prevalence of cough among the subjects. Conclusion: Our study suggests that the prevalence of cough among patients with diabetes mellitus who have been exposed to ACEI is substantial. Keywords: ACE inhibitors; cough; diabetes mellitus.

FRI290 Proteomic Identification Of Secretoneurin-Stimulated Proteins In Purified Mouse Gonadotropes

Abstract Disclosure: A. Herdman: None. A. Lagasse: None. A. Haney: None. S. Byrum: None. U. Boehm: None. M.C. MacNicol: None. A.M. MacNicol: None. G.V. Childs: None. A.K. Odle: None. Secretoneurin (SN) is a proteolytic product of secretogranin II (SCG2), a member of the granin family of proteins. Both SCG2 and SN have been localized in the anterior pituitary (AP), and SCG2 co-localizes to gonadotrope granules containing luteinizing hormone (LH). Preliminary studies from others have shown that exogenous SN is capable of stimulating LH secretion from the mouse LßT2 cell line and goldfish pituitaries, and SN may provide a paracrine signal from other AP cells to support LH production/secretion. Despite the implications for regulatory reproductive signaling, a comprehensive study of the effect of SN on female mammalian gonadotropes has not been conducted. To define the pathways and processes affected by exogenous secretoneurin (SN) on murine gonadotrope protein expression, pituitaries from 18 proestrous female mice expressing Gnrhr-driven Cre and a floxed fluorescent Cre reporter were collected and dispersed. Half of the dispersed pituitaries were stimulated with 1 μM SN, and all cells were incubated for 3 hours. Gonadotropes were purified via fluorescence-activated cell sorting. After pooling to optimize cell counts, control and SN-stimulated gonadotropes were submitted for mass-spectrometry proteomics. A differential expression analysis was performed to determine fold-change (FC) in proteins from SN-stimulated samples over control (unstimulated), and false discovery rate (FDR)-controlled adjusted p values were used to assign significance (Adj p≤0.05). A total of 948 proteins were identified in the purified gonadotrope pools. Of these, 136 proteins were significantly differentially expressed between control and SN-stimulated gonadotrope pools; 53 proteins were upregulated and 83 were downregulated in SN-stimulated gonadotropes. Upregulated targets of particular interest include the SN precursor SCG2 (FC = 12, p<0.05), as well as prohormone convertase 2 (PC2: FC = 8, p<0.05) which can cleave SCG2 to produce SN. Also upregulated is ELAV-like protein 1 (ELAVL1: FC=5, p<0.05), an RNA-binding protein known to regulate gonadotropin-releasing hormone receptor (GnRHR) expression and bind other gonadotrope-critical mRNAs. Although LHß was unchanged, the glycoprotein alpha subunit (CGA) was decreased 4-fold following SN stimulation (p = 0.05). This is consistent with previous reports showing decreased Cga mRNA following SN stimulation. In addition to the expected “cell signaling” and “response to stimulation”, gene ontology analysis showed that the major biological processes altered by SN stimulation include processing of RNA (including RNA binding, translation regulation, etc.) and regulation of cell structure. Indeed, several RNA-binding proteins and actin-related proteins were significantly changed. Our data confirm previous results from LßT2 cells and define new SN targets and pathways that may play a broader role in gonadotrope physiology. Presentation: Friday, June 16, 2023

CRISPRi-mediated characterization of novel anti-tuberculosis targets: Mycobacterial peptidoglycan modifications promote beta-lactam resistance and intracellular survival.

The lack of effective therapeutics against emerging multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) prompts the identification of novel anti-tuberculosis targets. The essential nature of the peptidoglycan (PG) layer of the mycobacterial cell wall, which features several distinctive modifications, such as the N-glycolylation of muramic acid and the amidation of D-iso-glutamate, makes it a target of particular interest. To understand their role in susceptibility to beta-lactams and in the modulation of host-pathogen interactions, the genes encoding the enzymes responsible for these PG modifications (namH and murT/gatD, respectively) were silenced in the model organism Mycobacterium smegmatis using CRISPR interference (CRISPRi). Although beta-lactams are not included in TB-therapy, their combination with beta-lactamase inhibitors is a prospective strategy to treat MDR-TB. To uncover synergistic effects between the action of beta-lactams and the depletion of these PG modifications, knockdown mutants were also constructed in strains lacking the major beta-lactamase of M. smegmatis BlaS, PM965 (M. smegmatis ΔblaS1) and PM979 (M. smegmatis ΔblaS1 ΔnamH). The phenotyping assays affirmed the essentiality of the amidation of D-iso-glutamate to the survival of mycobacteria, as opposed to the N-glycolylation of muramic acid. The qRT-PCR assays confirmed the successful repression of the target genes, along with few polar effects and differential knockdown level depending on PAM strength and target site. Both PG modifications were found to contribute to beta-lactam resistance. While the amidation of D-iso-glutamate impacted cefotaxime and isoniazid resistance, the N-glycolylation of muramic acid substantially promoted resistance to the tested beta-lactams. Their simultaneous depletion provoked synergistic reductions in beta-lactam MICs. Moreover, the depletion of these PG modifications promoted a significantly faster bacilli killing by J774 macrophages. Whole-genome sequencing revealed that these PG modifications are highly conserved in a set of 172 clinical strains of Mtb, demonstrating their potential as therapeutic targets against TB. Our results support the development of new therapeutic agents targeting these distinctive mycobacterial PG modifications.

Preferential destruction of NH2-bearing complex interstellar molecules via gas-phase proton-transfer reactions.

Complex, nitrogen-bearing interstellar molecules, especially amines, are targets of particular interest for detection in star- and planet-forming regions, due to their possible relevance to prebiotic chemistry. However, these NH2-bearing molecules are not universally detected in sources where other, oxygen-bearing complex organic molecules (COMs) are often plentiful. Nevertheless, recent astrochemical models have often predicted large abundances for NH2-bearing complex organics, based on their putative production on dust grains. Here we investigate a range of new gas-phase proton-transfer reactions and their influence on the destruction of COMs. As in past studies, reactions between protonated COMs and ammonia (NH3) are found to be important in prolonging gas-phase COM lifetimes. However, for molecules with proton affinities (PA) greater than that of ammonia, proton-transfer reactions result in drastic reductions in abundances and lifetimes. Ammonia acts as a sink for proton transfer from low-PA COMs, while passing on protons to high-PA species; dissociative recombination with electrons then destroys the resulting ions. Species strongly affected include methylamine (CH3NH2), urea (NH2C(O)NH2) and others bearing the NH2 group. The abundances of these species show a sharp time dependence, indicating that their detectability may rest on the precise chemical age of the source. Rapid gas-phase destruction of glycine (NH2CH2COOH) in the models suggests that its future detection may be yet more challenging than previously hoped.

The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target?

Calcitonin gene-related peptide (CGRP)-antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-targeting antibodies and chemical inhibitors in wild-type mice (ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-antagonizing drugs.

Targeting the stress response in pediatric pain: current evidence for psychosocial intervention and avenues for future investigation.

Nonpharmacological treatments for chronic pain in youth have been identified as first-line treatments over and above medication. Therapies such as cognitive-behavioral therapy and mindfulness-based stress reduction have shown good efficacy in reducing the psychological correlates (eg, anxiety, depression, and stress) and social or behavioral sequelae (eg, limited physical activity and lack of school engagement) associated with pediatric chronic pain. However, minimal research has examined the physiological mechanism(s) of action for these interventions. A recent review (Cunningham, et al., 2019) emphasized the need for objective (ie, physiological) assessment of treatment response in pediatric pain populations. The current review adds to this literature by identifying the physiological stress response as a particular target of interest in interventions for pediatric pain. Research indicates that youth with chronic pain report high rates of psychological stress, posttraumatic stress symptoms, and exposure to adverse childhood experiences (abuse/neglect, etc). In addition, a host of research has shown strong parallels between the neurobiology of pain processing and the neurobiology of stress exposure in both youth and adults. Interventions such as narrative or exposure therapy (eg, trauma-focused cognitive-behavioral therapy) and mindfulness-based or meditation-based therapies have shown particular promise in alleviating the neurobiological impact that stress and pain can have on the body, including reduction in allostatic load and altered connectivity in multiple brain regions. However, no study to date has specifically looked at these factors in the context of pediatric pain treatment. Future research should further explore these constructs to optimize prevention in and treatment of these vulnerable populations.

Target-Constrained Interference-Minimized Band Selection for Hyperspectral Target Detection

Wealthy spectral information provided by hyperspectral image (HSI) offers great benefits for many applications in hyperspectral data exploitation. However, processing such high-dimensional data volumes that may result in redundant bands due to its high interband correlation will be a challenge. For target detection and classification, this is particularly true since there may only need a relatively small number of bands that respond one particular target of interest well, while most of other bands do not. Band selection (BS) is a major dimensionality reduction technique to remove the redundant bands and selects a few bands to represent the entire image. However, how to eliminate the effect of uninteresting targets with similar spectra on detection of interesting targets is a severe issue arising in target detection for BS. This article develops a new approach called target-constrained interference-minimized BS (TCIMBS) which can be used to select band subset for specific target detection, while annihilating targets of no interest and suppressing interferers and background. Its idea is derived from target-constrained interference-minimized filter (TCIMF). By taking advantage of TCIMF, two band prioritization (BP) criteria called forward minimum variance BP (FMinV-BP) and backward maximum variance BP (BMaxV-BP) along with their three band search-based BS counterparts called sequential forward TCIMBS (SF-TCIMBS), sequential backward TCIMBS (SB-TCIMBS), and improved SB-TCIMBS (SB-TCIMBS*) are derived. The experimental results suggest that TCIMBS can improve the detection accuracy and also achieve better performance in comparison with several state-of-the-art methods.

Escape from model-land

Abstract Both mathematical modelling and simulation methods in general have contributed greatly to understanding, insight and forecasting in many fields including macroeconomics. Nevertheless, we must remain careful to distinguish model-land and model-land quantities from the real world. Decisions taken in the real world are more robust when informed by estimation of real-world quantities with transparent uncertainty quantification, than when based on “optimal” model-land quantities obtained from simulations of imperfect models optimized, perhaps optimal, in model-land. The authors present a short guide to some of the temptations and pitfalls of model-land, some directions towards the exit, and two ways to escape. Their aim is to improve decision support by providing relevant, adequate information regarding the real-world target of interest, or making it clear why today’s model models are not up to that task for the particular target of interest.

Recurrent Laryngeal Nerve Reinnervation in Rats Posttransection: Neurotrophic Factor Expression over Time.

Recurrent laryngeal nerve (RLN) injury causes vocal fold paralysis from which functional recovery is typically absent due to nonselective reinnervation. This study investigates expression of axon guidance cues and their modulators relative to the chronology of reinnervation by examining the expression of glial-derived neurotrophic factor (GDNF), netrin 1, and laminin 111 (LAMA1) in nonpooled laryngeal muscles. This study is the first to describe the post-RLN injury expression pattern of LAMA1, a target of particular interest as it has been shown to switch netrin 1-mediated growth cone attraction to repulsion. Animal experiment (rat model). Basic science laboratory. The right RLNs of 64 female Sprague-Dawley rats were transected, with sacrifice at 1, 3, 7, 21, 28, and 56 days postinjury (DPI). Single-animal messenger RNA was isolated from the ipsilateral posterior cricoarytenoid (PCA), lateral thyroarytenoid (LTA), and medial thyroarytenoid (MTA) for quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Immunostaining for LAMA1 expression was performed in the same muscles. LAMA1 was elevated in the PCA at 3 to 56 DPI, LTA at 7 DPI, and MTA at 14 and 28 DPI. This correlates with the chronology of laryngeal reinnervation. Using a new protocol, single-animal muscle qRT-PCR possible and expression results for GDNF and netrin 1 were similar to previous pooled investigations. Reliable qRT-PCR is possible with single rat laryngeal muscles. The expression of netrin 1 and LAMA1 is chronologically coordinated with muscle innervation in the LTA and MTA. This suggests that LAMA1 may influence netrin 1 to repel axons and delay LTA and MTA reinnervation.

Thin Layer Activation analysis in 16O + 169Tm system at low energies

Abstract In this paper authors have explored the use of Thin Layer Activation in a material formed by the irradiation of heavy ion beams on the particular target of interest and its further applications from industrial point of view. Activity depth distributions resulting from the irradiation of Thulium-169 by heavy ion Oxygen-16 beams have been calculated. A pre-calibrated high purity germanium detector was used for radioactive counting of samples. The measured cross-sections for different radio-isotopes have been used to deduce the practical yields for several reaction products; 182, 181Ir, 182, 181Os, 181, 178Re, 175Hf, 172Lu from the intensity of characteristic γ-lines at different energies of 16O beam in the energy range≈ 70-100 MeV employing stacked foil activation technique. Calibration curves obtained from various reaction products have been determined with the help of yield curves. The main purpose of this work is to study the surface wear with increased sensitivity by applying heavy ion in thin layer activation technique.

Integrated geological-geophysical characterizations of deeply buried fractured-vuggy carbonate reservoirs in Ordovician strata, Tarim Basin

Abstract The Central Uplift region of the Tarim Basin contains a series of thick Ordovician carbonates that form fractured-vuggy hydrocarbon-rich reservoirs along an unconformity. These fractured-vuggy reservoirs are difficult to characterize using traditional well logging and seismic interpretation methods because these carbonates feature complex and heterogeneous lithologies and variations in scale, geometry and spatial distribution. In this paper, a series of deeply buried fractured-vuggy carbonate reservoirs are characterized on micro-, macro- and mega-scales. These characterizations are based on previous studies detailing the carbonate sedimentation, diagenesis, and tectonic processes in the study area and abundant geological and geophysical data, including core samples, thin sections, and well logging and seismic datasets, which have been obtained and upscaled using the “choosing-classification-evaluation- generalizing-upscaling” (CCEGU) method. In this area, different facies can be identified at different scales: (1) Detailed core and thin section observations performed based on the Dunham classification demonstrate that 7 lithofacies and 19 rock types are present at the micro-scale (0.01 m); (2) logging data and assorted reservoir characteristics indicate that these 19 different rock types consist of 9 different electro facies at the macro-scale (0.1 m–1 m), and the presence of electro facies in individual wells can be recognized; and (3) these 9 different electro facies comprise 6 distinct seismic facies at the mega-scale (10 m), and can be used to delineate the spatial outlines of potential reservoirs and evaluate their properties. The targets of particular interest in the study area are a series of partially dissolved dolomites located near large faults and a series of vuggy soluble limestones located near NE-trending strike-slip faults. This study combines geological and geophysical response data from fractured-vuggy carbonate reservoirs to achieve seamless connections among micro-scale, macro-scale and mega-scale observations to effectively characterize a series of strongly heterogeneous fractured-vuggy reservoirs. This method can also be applied to characterize other deeply buried paleokarst reservoirs in the Tarim Basin, as well as other strongly heterogeneous reservoirs.

Twilight on Ligeia: Implications of communications geometry and seasonal winds for exploring Titan’s seas 2020–2040

Titan’s lakes and seas are targets of particular interest for future exploration. We review candidate splashdown areas in Ligeia and Kraken Mare, and Ontario Lacus. Titan’s thick and dense atmosphere means that landing dispersions of spacecraft are dominated by uncertainties in wind drift, and thus the feasibility of landing safely in the sea with a simple Huygens-like descent system (i.e. without guidance or propulsion) is dependent upon these uncertainties being small enough that the landing point dispersion lies within the sea. Because Titan’s winds vary with season, notably through the formation of a high-speed stratospheric jet in the winter hemisphere, landing point dispersions are seasonally-dependent as well as latitude-dependent. Ligeia Mare, at 78oN, sees relatively small dispersions but offers viable Direct-to-Earth (DTE) communication only until 2024. A wide part of Kraken Mare (450×90km) at 70oN can be comfortably reached at all times, and is viable for assured Direct-to-Earth communication until 2026, or with a relay spacecraft thereafter. The seasonal geometry permits DTE from the northern seas again after 2040. Wind dispersions are always too large for Ontario, unless a steerable parachute or similar system is used to tighten the landing ellipse.

Identification of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin (Part I): Virtual Screening and Activity Assays

BackgroundThere has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.Methodology/Principal FindingsWe predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.Conclusions/SignificanceWe have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.

Aedes aegypti: An Emerging Model for Vector Mosquito Development: Figure 1.

Blood-feeding mosquitoes, including the dengue and yellow fever vector Aedes aegypti, transmit many of the world's deadliest diseases. Such diseases have resurged in developing countries and pose clear threats for epidemic outbreaks in developed countries. Recent mosquito genome projects have stimulated interest in the potential for arthropod-borne disease control by genetic manipulation of vector insects. Targets of particular interest include genes that regulate development. However, although the Ae. aegypti genome project uncovered homologs of many known developmental regulatory genes, little is known of the genetic regulation of development in Ae. aegypti or other vector mosquitoes. This article provides an overview of the background, husbandry, and potential uses of Ae. aegypti as a model species. Methods for culturing, collecting and fixing developing tissues, analyzing gene and protein expression, and knocking down genes are permitting detailed analyses of the functions of developmental regulatory genes and the selective inhibition of such genes during Ae. aegypti development. This methodology, much of which is applicable to other mosquito species, is useful to both the comparative development and vector research communities.

Proteomic analyses identify a diverse array of nuclear processes affected by small ubiquitin-like modifier conjugation in Arabidopsis

The covalent attachment of SUMO (small ubiquitin-like modifier) to other intracellular proteins affects a broad range of nuclear processes in yeast and animals, including chromatin maintenance, transcription, and transport across the nuclear envelope, as well as protects proteins from ubiquitin addition. Substantial increases in SUMOylated proteins upon various stresses have also implicated this modification in the general stress response. To help understand the role(s) of SUMOylation in plants, we developed a stringent method to isolate SUMO-protein conjugates from Arabidopsis thaliana that exploits a tagged SUMO1 variant that faithfully replaces the wild-type protein. Following purification under denaturing conditions, SUMOylated proteins were identified by tandem mass spectrometry from both nonstressed plants and those exposed to heat and oxidative stress. The list of targets is enriched for factors that direct SUMOylation and for nuclear proteins involved in chromatin remodeling/repair, transcription, RNA metabolism, and protein trafficking. Targets of particular interest include histone H2B, components in the LEUNIG/TOPLESS corepressor complexes, and proteins that control histone acetylation and DNA methylation, which affect genome-wide transcription. SUMO attachment site(s) were identified in a subset of targets, including SUMO1 itself to confirm the assembly of poly-SUMO chains. SUMO1 also becomes conjugated with ubiquitin during heat stress, thus connecting these two posttranslational modifications in plants. Taken together, we propose that SUMOylation represents a rapid and global mechanism for reversibly manipulating plant chromosomal functions, especially during environmental stress.

The rationale for choosing telmisartan and ramipril in the ONTARGET programme

The renin–angiotensin system (RAS) has been a drug target of particular interest because of its involvement in the cardiovascular and renal disease progression. The angiotensin-converting enzyme (ACE) inhibitors and the selective angiotensin II receptor blockers (ARBs) inhibit the RAS by different mechanisms of action that may have therapeutic implications. The ACE inhibitors have been proven effective for reducing cardiovascular events and mortality in patients with cardiovascular disease. Evidence from clinical trials has shown that ARBs and ACE inhibitors can reduce the risk of cardiovascular and renal events in specific patient populations. Ramipril is an ACE inhibitor proven, in the HOPE trial, to reduce cardiovascular risk. Telmisartan is an ARB with a high degree of lipophilicity, tissue penetration, and high affinity for the angiotensin II type 1 receptor. The ONTARGET study demonstrated that telmisartan provided equivalent efficacy to ramipril in preventing morbidity and mortality from cardiovascular causes in a broad cross section of high-risk patients, but with better tolerability and fewer discontinuations. The combination of telmisartan and ramipril was no more effective but was associated with worse tolerability.

Book Review - Innovative Leukemia and Lymphoma Therapy

Medical oncology has undergone profound changes in the past decade, driven in part by the explosive growth in the field of molecular biology. In turn, drug development has progressed from empirical screening to rationally identified targets. New drugs that have been developed differ markedly from traditional cytotoxic drugs in that they target specific proteins or processes that alter malignant cells. Standard chemotherapy for malignant hematological diseases is presently far from ideal but is a disappointing reality because the same treatment strategies are still used after several decades. Disappointment regarding results of current chemotherapy programs is particularly evident in patients older than 60 years of age, who represent the majority of patients with hematological malignancies. Although intensified cytotoxic therapy has improved the prognosis in children, young and middle-aged adults, this approach provides only little benefit to older adults, with few long-term survivors. New strategies may focus on exploiting untargeted pathways governing stem cell renewal and differentiation. A myriad of new agents are recently available that have the potential to change the standard of care for patients with hematological malignancy. Targets of particular interest for therapeutics development are those involved in signaling pathways controlling cell-cycle progression, gene transcription, motility, apoptosis and cell metabolism. Many agents were designed to target selected components of key signal-transduction pathways, or critical components of pathways aimed at repairing DNA damage. Epigenetic modulatory approaches might promote apoptosis or silenced genes involved in the differentiation. Immunomodulatory approaches may find their greatest efficacy in the minimal residual disease state. These new drugs, used alone or in combination with approved chemotherapy, are currently under investigation. Combination of several agents targeting more than one gene mutation, signal transduction pathway or antigenic determinant may be the most effective.