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- Fomesafen impacts bacterial communities and enzyme activities in the rhizosphere. [Journal Article]
- EPEnviron Pollut 2019 Jul 09; 253:302-311
- Fomesafen, a long-lived protoporphyrinogen-oxidase inhibitor, specially developed for post-emergence control of broad-leaf weeds, is used widely in soybean fields in northern China (Dayan and Duke, 2…
Fomesafen, a long-lived protoporphyrinogen-oxidase inhibitor, specially developed for post-emergence control of broad-leaf weeds, is used widely in soybean fields in northern China (Dayan and Duke, 2010). The impact of fomesafen on microbial communities in rhizosphere soils, however, is unknown. In this study we examined fomesafen degradation as well as its effects in the rhizosphere of soybean plants grown in a greenhouse. Fomesafen had shorter half-life in rhizosphere soil than previously reported for bulk soil from the same location (87 vs 120 days). The enzyme activity of soil extracts and the microbial community composition of 16S rRNA genes (16S) amplified from soil DNA were also investigated. Although not immediately apparent, both the high (37.5 mg kg-1) and low (18.75 mg kg-1) doses of fomesafen significantly decreased urease and invertase activities in the rhizosphere soil from days 30 and 45 respectively until the end of the experiment (90 days). Analysis of 16S amplicons demonstrated that fomesafen had a dose dependent effect, decreasing alpha diversity and altering beta diversity. Significant phylum level decreases were observed in five of the ten phyla that were most abundant in the control. Proteobacteria was the only phylum whose relative abundance increased in the presence of fomesafen, driven by increases in the genera Methylophilacaea, Dyella, and Sphingomonas. The functional implications of changes in 16S abundance as predicted using PICRUSt suggested that fomesafen enriched for enzymes involved in xenobiotic metabolism and detoxification (cytochrome P450s and glutathione metabolism). Our data suggest that, despite being degraded more rapidly in the rhizosphere than in bulk soil, fomesafen had long-lasting functional impacts on the soil microbial community.
- Characterizing fucoxanthin as a selective dopamine D3/D4 receptor agonist: Relevance to Parkinson's disease. [Journal Article]
- CBChem Biol Interact 2019 Jul 16; :108757
- Fucoxanthin and fucosterol are archetypal lipid components of edible brown algae that provide several health benefits. Lately, their protective role in Aβ1-42-induced cognitive dysfunction in animal …
Fucoxanthin and fucosterol are archetypal lipid components of edible brown algae that provide several health benefits. Lately, their protective role in Aβ1-42-induced cognitive dysfunction in animal models has been reported (Alghazwi et al., 2019; Oh et al., 2018). However, their role in the aminergic system and as a prime treatment approach for multifactorial neurodegenerative diseases still requires exploration. The main aims of the present study are to characterize the role of fucoxanthin and fucosterol in the aminergic pathway via in vitro human monoamine oxidase (hMAO) inhibition and cell-based functional G-protein coupled receptor (GPCR) assays and to underline their possible mechanisms of action via in silico molecular docking studies. Fucoxanthin displayed weak inhibition with IC50 values of 197.41 ± 2.20 and 211.12 ± 1.17 μM over two isoenzymes hMAO-A and hMAO-B, respectively. Fucosterol remained inactive up to 500 μM. In functional assay results, fucoxanthin showed a concentration-dependent agonist effect on dopamine D3 and D4 receptors. The half maximal effective concentration (EC50) of fucoxanthin for dopamine D3 and D4 receptors was 16.87 ± 3.41 and 81.87 ± 6.11 μM, respectively. For dopamine as a reference agonist, the EC50 values for these two receptors were 3.7 and 24 nM, respectively. Fucosterol showed no agonist activity on any of the tested receptors. Similarly, fucoxanthin showed a mild antagonist effect on dopamine D1 and tachykinin (NK1) receptor with inhibition of control agonist response by approximately 40% at 100 μM. Fucosterol displayed mild antagonist effects only on dopamine D1 and D4 receptors. In silico studies revealed potential mechanisms by which fucoxanthin binds to dopamine receptors to exert its agonist effects, including low binding energy and H-bond interactions with Ser196 and Thr115 at the D3 receptor and with Ser196 and Asp115 at the D4 receptor. Our results collectively suggest that fucoxanthin is a potential D3/D4 agonist for the management of neurodegenerative diseases, such as Parkinson's disease.
- Quality of Life During Chemotherapy for Breast Cancer in a West African Population in Dakar, Senegal: A Prospective Study. [Journal Article]
- JGJ Glob Oncol 2019; (5):1-9
- CONCLUSIONS: Our study confirmed the feasibility of standardized QoL assessment in Senegalese patients with breast cancer. Our results indicated a potential improvement of QoL over the course of chemotherapy. Optimizing nausea and vomiting prevention may improve QoL.
- Strategies to Counteract Botulinum Neurotoxin A: Nature's Deadliest Biomolecule. [Journal Article]
- ACAcc Chem Res 2019 Jul 19
- Botulinum neurotoxin serotype A (BoNT/A), marketed commercially as Botox, is the most toxic substance known to man with an estimated intravenous lethal dose (LD50) of 1-2 ng/kg in humans. Despite its…
Botulinum neurotoxin serotype A (BoNT/A), marketed commercially as Botox, is the most toxic substance known to man with an estimated intravenous lethal dose (LD50) of 1-2 ng/kg in humans. Despite its widespread use in cosmetic and medicinal applications, no postexposure therapeutics are available for the reversal of intoxication in the event of medical malpractice or bioterrorism. Accordingly, the Centers for Disease Control and Prevention categorizes BoNT/A as a Category A pathogen, posing the highest risk to national security and public health as a result of the ease with which BoNT/A can be weaponized and disseminated. BoNT/A-mediated lethality results from neurons impeded from releasing acetylcholine, which ultimately causes muscle paralysis and possible death by asphyxiation with the loss of diaphragm function. Currently, the only available respite for BoNT/A poisoning is antibody-based therapy; however, this intervention is only effective within 12-24 h postexposure. Small molecule therapeutics remain the only opportunity to reverse BoNT/A intoxication after neuronal poisoning and are urgently needed. Nevertheless, no small molecule BoNT/A inhibitors have reached the clinic or even advanced to clinical trials. This Account highlights the accomplishments and existing challenges facing BoNT/A drug discovery today. Using the comprehensive body of work from our laboratory, we illustrate our nearly two-decade endeavor to discover a clinically relevant BoNT/A inhibitor. Specifically, a discussion on the identification and characterization of new chemical leads, the development of in vitro and in vivo assays, and pertinent discoveries in BoNT/A structural biology related to small molecule inhibition is presented. Lead discovery efforts in our laboratory have leveraged both in vitro high-throughput screening and rational design, and an array of mechanistic strategies for inhibiting BoNT/A has been discovered, including noncovalent inhibition, metal-binding active site inhibition, covalent inhibition, and α- and β-exosite inhibition. We contrast the strengths and weaknesses of each of these mechanistic strategies and propose the most favorable approach for success. Finally, we discuss multiple serendipitous discoveries of antibotulism small molecules with alternative mechanisms of action. Remaining challenges facing clinically relevant BoNT/A inhibition are presented and analyzed, including the current inability to reconcile toxin half-life (months to greater than one year) in neurons with in vivo pharmaceutical lifetimes and reoccurring inconsistencies between in vitro, cellular, and in vivo translation. Our Account of BoNT/A chemical research emphasizes the present accomplishments and critically analyzes the remaining obstacles for drug discovery. Importantly, we call for an increased focus on the discovery of safe and effective covalent inhibitors of BoNT/A that compete with the inherent half-life of the toxin.
- Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT. [Clinical Trial]
- HTHealth Technol Assess 2019; 23(35):1-48
- CONCLUSIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.
- Glycemic Control in Patients with Diabetic Kidney Disease; Time to Recognize Perils of Iatrogenic Hypoglycemia?Moving away from Intensive Glycemic Control. [Journal Article]
- JAJ Assoc Physicians India 2018; 66(9):70-75
- The chronic complications of Diabetes Mellitus (DM), which may be present in as many as 50% of the patients at the time of diagnosis, are a major burden for both individuals with the disease and heal…
The chronic complications of Diabetes Mellitus (DM), which may be present in as many as 50% of the patients at the time of diagnosis, are a major burden for both individuals with the disease and health systems and it has been estimated that as much as 60-70% of healthcare expenditure related to diabetes (about 670 billion dollars a year) is currently attributable to chronic complications of the disease. These high prevalence rates are widely acknowledged to further rise as poor lifestyle choices and their consequences continue to rise. Adding to that is an aging population and urbanization that together will make situation even more challenging. Type 2 diabetes affects about 90-95% of newly diagnosed patients of diabetes and accounts for majority of cases of Chronic Kidney Disease (CKD). In other words, CKD affects about 20-40% of individuals with diabetes making it one of the most common complication related to the disease. The risk of renal failure is 25 times higher in diabetic patients than in the non-diabetic population. Thus patients with diabetes and renal failure represent a special risk group as they have higher morbidity and mortality and are at a higher risk of hypoglycaemia than diabetic individuals with normal renal function. In addition, for all the physicians who are taking care of patients of diabetes and kidney disease, formulation of comprehensive plan of management directed at modification of risk factors of cardiovascular disease (CVD) is of utmost importance as majority of patients with CKD die as a result of cardiovascular complications rather than progression to ESRD, (accounting for about 70% of deaths over the age of 65). The contrasting results available from clinical trials in recent years have generated perplexity amid concerns that glucose-lowering therapies, under certain circumstances, might even be detrimental; in light of the fact that intensive glycemic control increased the risk for death by 22% in the ACCORD trial. Moreover it should be pooled data of some extensive reviews which has been carried in last one and half year have demonstrated that intensive glycemic control significantly increases the risk of cardiovascular and all-cause mortality in patients of CKD. So it is increasingly problematic for clinicians to continue aggressive glycemic control for the treatment of renal outcome in patients of advanced renal insufficiency with multiple co-morbidities. Thus, a lower survival benefit due to multiple comorbidities combined with general lower life expectancy necessitates a balanced approach. Suggesting the need for revised and extended target of HBA1C in this patient population.
- Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft. [Journal Article]
- CCCancer Chemother Pharmacol 2019 Jul 18
- CONCLUSIONS: The efficacy of a macromolecular prodrug can be optimized for a given species by balancing the rate of drug release from the carrier with the rate of prodrug elimination.
- Does Kidney Transplantation Affect Sleep and Fatigue in Patients With Kidney Disease? [Journal Article]
- TDTransplant Direct 2019; 5(6):e461
- CONCLUSIONS: More than half of the KTx recipients had SA. There was no significant change in SA severity with KTx. Clinically meaningful moderate size improvements in patient-reported fatigue and health-related quality of life may be seen with KTx.
- Paired-end mappability of transposable elements in the human genome. [Journal Article]
- MDMob DNA 2019; 10:29
- Though transposable elements make up around half of the human genome, the repetitive nature of their sequences makes it difficult to accurately align conventional sequencing reads. However, in light …
Though transposable elements make up around half of the human genome, the repetitive nature of their sequences makes it difficult to accurately align conventional sequencing reads. However, in light of new advances in sequencing technology, such as increased read length and paired-end libraries, these repetitive regions are now becoming easier to align to. This study investigates the mappability of transposable elements with 50 bp, 76 bp and 100 bp paired-end read libraries. With respect to those read lengths and allowing for 3 mismatches during alignment, over 68, 85, and 88% of all transposable elements in the RepeatMasker database are uniquely mappable, suggesting that accurate locus-specific mapping of older transposable elements is well within reach.
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- Mutagenesis of odorant coreceptor Orco fully disrupts foraging but not oviposition behaviors in the hawkmoth Manduca sexta. [Journal Article]
- PNProc Natl Acad Sci U S A 2019 Jul 18
- The hawkmoth Manduca sexta and one of its preferred hosts in the North American Southwest, Datura wrightii, share a model insect-plant relationship based on mutualistic and antagonistic life-history …
The hawkmoth Manduca sexta and one of its preferred hosts in the North American Southwest, Datura wrightii, share a model insect-plant relationship based on mutualistic and antagonistic life-history traits. D. wrightii is the innately preferred nectar source and oviposition host for M. sexta Hence, the hawkmoth is an important pollinator while the M. sexta larvae are specialized herbivores of the plant. Olfactory detection of plant volatiles plays a crucial role in the behavior of the hawkmoth. In vivo, the odorant receptor coreceptor (Orco) is an obligatory component for the function of odorant receptors (ORs), a major receptor family involved in insect olfaction. We used CRISPR-Cas9 targeted mutagenesis to knock out (KO) the MsexOrco gene to test the consequences of a loss of OR-mediated olfaction in an insect-plant relationship. Neurophysiological characterization revealed severely reduced antennal and antennal lobe responses to representative odorants emitted by D. wrightii In a wind-tunnel setting with a flowering plant, Orco KO hawkmoths showed disrupted flight orientation and an ablated proboscis extension response to the natural stimulus. The Orco KO gravid female displayed reduced attraction toward a nonflowering plant. However, more than half of hawkmoths were able to use characteristic odor-directed flight orientation and oviposit on the host plant. Overall, OR-mediated olfaction is essential for foraging and pollination behaviors, but plant-seeking and oviposition behaviors are sustained through additional OR-independent sensory cues.