Small-Molecule Allosteric Activators of Sirtuins

The mammalian sirtuins (SIRT1–7) are NAD[superscript +]-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.Glenn Foundation for Medical ResearchNational Institute on Agin

Springs geomorphology influences on physical and vegetation ecosystem characteristics, Grand Canyon Ecoregion, USA

The Grand Canyon Ecoregion (GCE) represents the entire landscape that drains into Grand Canyon. This region encompasses a wide array of environments and corresponding plant communities of biological interest. Springs are numerous in the GCE and play a multitude of roles in this generally arid land. Springs serve as critical sources of water and support many endangered and endemic species, many of which are springs-dependent species including Flaveria mcdougalii, Epipactis gigantea, and Eleocharis palustris. I conducted a statistical community analysis of 352 springs in the Grand Canyon Ecoregion across four spring types – helocrene wet meadows; hanging gardens; rheocrene flowing springs; and hillslope springs – and examined their physical traits and floral assemblages. Mann-Whitney tests were used to detect differences between spheres of discharge and correlation and multiple regression were used to determine relations of physical and geomorphic traits with plant species diversity. An astounding species packing was demonstrated with nearly 1000 species recorded across all springs, representing over 45% of the region’s entire flora in less than one square kilometer of springs habitat area. Geomorphic microhabitat diversity was positively related to springs diversity (p<0.00001; multiple linear regression). All springs types were distinguished by differences in physical site characters which in turn were associated with plant community structure and specific species. Geomorphic features including microhabitat features and substrate composition were important in distinguishing springs types. There were also different physical characteristics distinguishing springs types including elevation and water chemistry. These features were correlated strongly with plant assemblages at springs and sets of indicator species were associated with each spring type. Multivariate regression analysis identified suites of variables related to springs biodiversity metrics explaining nearly half of the variation in species richness between springs. Microhabitat richness, area, and elevation were most important in explaining species richness. Grazing intensity did not have any discernable impact on species richness but did have a negative relation to the percentage of native species found at springs. In this study, I identified key differences between spring types; however, springs are highly individualistic and each spring needs to be understood in an individual context. Stewardship efforts should aim to protect geomorphic microhabitats and restore them to natural conditions. Their concentrations of biodiversity warrant further conservation and additional inventory and study will prove useful in furthering understanding of springs of the GCE

Protective effects of sirtuins in cardiovascular diseases: from bench to bedside

Sirtuins (Sirt1-Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation—all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD+, we anticipate that this field will move quickly from bench to bedsid

A checklist of the land Mollusca (Gastropoda) of the islands of São Tomé and Príncipe, with new records and description of new taxa

The first comprehensive checklists since the works of Germain in 1916 are presented for the terrestrial mollusca of São Tomé and Príncipe. The fauna currently known comprises 59 species for São Tomé, 45 for Príncipe, and a total of 86 species in the country as a whole. Seven species of terrestrial Gastropoda are newly described from the island of São Tomé and six more from the island of Príncipe. The genera involved are Cyathopoma (Cyclophoridae), Maizania and Thomeomaizania (Maizaniidae), Pseudoveronicella (Veronicellidae), Nothapalus (Achatinidae), Gulella and Streptostele (Streptaxidae), Truncatellina (Truncatellinidae), Afroconulus (Euconulidae), Principicochlea n. gen., Principotrochoidea n. gen., Thomithapsia n. gen. and Thomitrochoidea n. gen. (Urocyclidae). Most of these are from natural forest habitats and are likely to be singleisland endemics. Aporachis n. gen. (Achatinidae s.l.) and Apothapsia n. gen. (Helicarionidae) are also described to accommodate previously known species. Rachis burnayi (Dohrn) and R. eminula (Morelet) are placed in the genus Gittenedouardia. Additional new island records are of ten species on São Tomé, one on Príncipe and two more on both islands. These include six species of “microgastropods” with wider ranges in tropical Africa that are likely to be hitherto overlooked parts of the indigenous fauna and six anthropogenic introductions. Pseudopeas crossei previously known only from Príncipe and Bioko is newly recorded on São Tomé. More detailed taxonomic notes are provided on identification and delimitation of species and genera in Cyclophoridae/ Maizaniidae, Veronicellidae, Achatinidae, Cerastidae, Helicarionidae, and on the forgotten but apparently valid Pseudoveronicella thomensis (Veronicellidae).info:eu-repo/semantics/publishedVersio

Lazarus Effect of High Dose Corticosteroids in a Patient With West Nile Virus Encephalitis: A Coincidence or a Clue?

West Nile virus (WNV) causes severe neuroinvasive disease in humans characterized by meningitis, encephalitis, and acute flaccid paralysis (poliomyelitis variant). In neuroinvasive disease, WNV infection of neurons resulting in neuronal loss is generally presumed to be the anatomical substrate for the high morbidity and mortality. However, on a molecular level, WNV infection also results in a significant upregulation of important proinflammatory molecules that have been reported to promote neuroinflammation and cytotoxicity. Currently, there is no specific treatment for the neurological complications of WNV infection. We present a 71-year-old woman who developed WNV infection that rapidly progressed to severe generalized weakness and encephalitis manifesting with bulbar signs (dysphagia, dysarthria) and persistent delirium and stupor. Consciousness remained impaired for 9 days and then she received a 5-day course of high-dose intravenous methylprednisolone (1,000 mg daily). After the first day, voluntary movement and spontaneous eye-opening increased and by the end of the second day, she was awake and responding to commands. Thereafter, she remained awake and responsive. Although the rapid improvement from stupor to wakefulness following treatment with an anti-inflammatory immunosuppressant could merely be coincidence, since these observations are of one patient, it may also provide a clue that in some cases of WNV neuroinvasive disease a post-infectious pro-inflammatory state, rather than neuronal loss, may also contribute to morbidity. Further clinical trials are warranted to determine if high dose corticosteroids and other drugs that can alter this neuro-inflammatory cascade may be potentially beneficial in the treatment of WNV neuroinvasive disease

Random polynomials, random matrices, and LL-functions

We show that the Circular Orthogonal Ensemble of random matrices arises naturally from a family of random polynomials. This sheds light on the appearance of random matrix statistics in the zeros of the Riemann zeta-function.Comment: Added background material. Final version. To appear in Nonlinearit

Exploring Research Priorities of Parents Who Have Children With Down Syndrome, Cleft Lip With or Without Cleft Palate, Congenital Heart Defects, and Spina Bifida Using ConnectEpeople:A Social Media Coproduction Research Study

Background: Using social media for research purposes is novel and challenging in terms of recruitment, participant knowledge about the research process, and ethical issues. This paper provides insight into the recruitment of European parents of children with specific congenital anomalies to engage in coproduction research by using social media. Secret Facebook groups, providing optimal security, were set up for newly recruited research-aware parents (RAPs) to communicate privately and confidentially with each other and for the research team to generate questions and to interpret findings. Objective: This study aimed to use social media for the recruitment and engagement of parents in research and to determine the research priorities of parents who have children with Down syndrome, cleft lip with or without cleft palate, congenital heart defects, and spina bifida. Methods: The design was exploratory and descriptive with 3 phases. Phase 1 included the recruitment of RAPs and generation of research questions important to them; phase 2 was a Web-based survey, designed using Qualtrics software, and phase 3 included analysis and ranking of the top 10 research questions using an adapted James Lind Alliance approach. Simple descriptive statistics were used for analysis, and ethical approval was obtained from the Ethics Filter Committee of the Institute of Nursing and Health Research, Ulster University. Results: The recruitment of 32 RAPs was a sensitive process, varying in the time taken to consent (mean 51 days). However, parents valued the screening approach using the State-Trait Anxiety Inventory as a measure to ensure their well-being (mean 32.5). In phase 1, RAPs generated 98 research questions. In phase 2, 251 respondents accessed the Web-based survey, 248 consented, and 80 completed the survey, giving a completeness rate of 32.3% (80/248). Most parents used social media (74/80, 92%). Social media, online forums, and meeting in person were ranked the most preferable methods for communication with support groups networks and charities. Most respondents stated that they had a good understanding of research reports (71/80, 89%) and statistics (68/80, 85%) and could differentiate among the different types of research methodologies (62/80, 78%). Phase 3 demonstrated consensus among RAPs and survey respondents, with a need to know the facts about their child's condition, future health, and psychosocial and educational outcomes for children with similar issues. Conclusions: Social media is a valuable facilitator in the coproduction of research between parents and researchers. From a theoretical perspective, ocularcentrism can be an applicable frame of reference for understanding how people favor visual contact.This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 733001.info:eu-repo/semantics/publishedVersio