Potent and selective inhibitors of histone deacetylase-3 containing chiral oxazoline capping groups and a N-(2-Aminophenyl)-benzamide binding unit

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines

Zooplankton Gut Passage Mobilizes Lithogenic Iron for Ocean Productivity

Iron is an essential nutrient for phytoplankton, but low concentrations limit primary production and associated atmospheric carbon drawdown in large parts of the world’s oceans [1 and 2]. Lithogenic particles deriving from aeolian dust deposition, glacial runoff, or river discharges can form an important source if the attached iron becomes dissolved and therefore bioavailable [3, 4 and 5]. Acidic digestion by zooplankton is a potential mechanism for iron mobilization [6], but evidence is lacking. Here we show that Antarctic krill sampled near glacial outlets at the island of South Georgia (Southern Ocean) ingest large amounts of lithogenic particles and contain 3-fold higher iron concentrations in their muscle than specimens from offshore, which confirms mineral dissolution in their guts. About 90% of the lithogenic and biogenic iron ingested by krill is passed into their fecal pellets, which contain ∼5-fold higher proportions of labile (reactive) iron than intact diatoms. The mobilized iron can be released in dissolved form directly from krill or via multiple pathways involving microbes, other zooplankton, and krill predators. This can deliver substantial amounts of bioavailable iron and contribute to the fertilization of coastal waters and the ocean beyond. In line with our findings, phytoplankton blooms downstream of South Georgia are more intensive and longer lasting during years with high krill abundance on-shelf. Thus, krill crop phytoplankton but boost new production via their nutrient supply. Understanding and quantifying iron mobilization by zooplankton is essential to predict ocean productivity in a warming climate where lithogenic iron inputs from deserts, glaciers, and rivers are increasing [7, 8, 9 and 10]

A Therapeutic Landscape for Some but Not for All: An Ethnographic Exploration of the Bethlem Royal Hospital Parkrun

This study sought to explore the experiences of those involved in the Bethlem parkrun. A mobile ethnography employing participant observation and informal discussion was conducted on the grounds of the hospital in London, United Kingdom. The findings focused on “what it is like” to participate in this parkrun and were organized into two themes: (a) Bethlem as a Shared Leisure Space and (b) Shared Leisure Space, But for Whom? Findings illustrated the emplaced and relational experiences of some participants in this “therapeutic landscape,” while highlighting that the events were exclusionary for others, namely service-users. These findings contrast the therapeutic landscapes literature, which largely assumes their benefits are experienced equally. This work may provide further understanding of the individual and collective experiences of parkrun

Regulators of complement activity mediate inhibitory mechanisms through a common C3b‐binding mode

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Association between air pollution and asthma admission among children in Hong Kong

OBJECTIVE: To examine the association of air pollutants with hospital admission for childhood asthma in Hong Kong. METHODS: Data on hospital admissions for asthma, influenza and total hospital admissions in children aged ≤18 years at all Hospital Authority hospitals during 1997–2002 were obtained. Data on daily mean concentrations of particles with aerodynamic diameter <10 μm (i. e. PM(10)) and <2.5 μm (i. e. PM(2.5)), nitrogen dioxide (NO(2)), sulphur dioxide (SO(2)), and ozone (O(3)) and data on meteorological variables were associated with asthma hospital admissions using Poisson's regression with generalized additive models for correction of yearly trend, temperature, humidity, day-of-week effect, holiday, influenza admissions and total hospital admission. The possibility of a lag effect of each pollutant and the interaction of different pollutants were also examined. RESULTS: The association between asthma admission with change of NO(2), PM(10), PM(2.5) and O(3) levels remained significant after adjustment for multi-pollutants effect and confounding variables, with increase in asthma admission rate of 5.64% (3.21–8.14) at lag 3 for NO(2), 3.67% (1.52–5.86) at lag 4 for PM(10), 3.24% (0.93–5.60) at lag 4 for PM(2.5) and 2.63% (0.64–4.67) at lag 2 for O(3). Effect of SO(2) was lost after adjustment. CONCLUSION: Ambient levels of PM(10), PM(2.5), NO(2) and O(3) are associated with childhood asthma hospital admission in Hong Kong

Defining the key wintering habitats in the Sahel for declining African-Eurasian migrants using expert assessment

SummaryThe Sahel in West Africa is a major wintering area for many western Palearctic migrants. The breeding populations of many of these have declined over the past 50 years. However, there have been few intensive field studies on migrant ecology in the Sahel and these were generally within a very restricted area. Consequently our knowledge of the distribution of species within this extensive area and the habitat associations of these species is limited. Understanding these habitat associations is essential for the effective conservation management of populations. We brought together a group of experts and consulted a wider group by email to assess the main Sahelian habitat types used by 68 African-Eurasian migrant bird species. Those species that showed strongest declines during 1970–1990 were associated with more open habitats than those newly declining during 1990–2000, when declining species were associated with habitats with more shrubs and trees. Populations of species that winter in the Sahel are generally stable or increasing now as rainfall has increased and is now near the long-term average for the Sahel. Those which use the Sahel only as a staging area are, in many cases, in rapid decline at present.We would like to thank Andy Clements, Paul Donald, Lincoln Fishpool and Mike Mortimore for contributing to the workshop and Peter Jones, Ian Newton, Volker Salewski, Tim Wacher, Eddy Wymenga and Leo Zwarts for useful comments by email on draft habitat importance scores. This study was funded by the Newton Trust and the Cambridge Conservation Initiative Collaborative Fund, supported by Arcadia. WJS is funded by Arcadia.This is the accepted manuscript of a paper published in Bird Conservation International, Volume 24, Issue 04, December 2014, pp 477-491, DOI: http://dx.doi.org/10.1017/S0959270913000531, Published online: 24 February 201

Statistical modeling of ground motion relations for seismic hazard analysis

We introduce a new approach for ground motion relations (GMR) in the probabilistic seismic hazard analysis (PSHA), being influenced by the extreme value theory of mathematical statistics. Therein, we understand a GMR as a random function. We derive mathematically the principle of area-equivalence; wherein two alternative GMRs have an equivalent influence on the hazard if these GMRs have equivalent area functions. This includes local biases. An interpretation of the difference between these GMRs (an actual and a modeled one) as a random component leads to a general overestimation of residual variance and hazard. Beside this, we discuss important aspects of classical approaches and discover discrepancies with the state of the art of stochastics and statistics (model selection and significance, test of distribution assumptions, extreme value statistics). We criticize especially the assumption of logarithmic normally distributed residuals of maxima like the peak ground acceleration (PGA). The natural distribution of its individual random component (equivalent to exp(epsilon_0) of Joyner and Boore 1993) is the generalized extreme value. We show by numerical researches that the actual distribution can be hidden and a wrong distribution assumption can influence the PSHA negatively as the negligence of area equivalence does. Finally, we suggest an estimation concept for GMRs of PSHA with a regression-free variance estimation of the individual random component. We demonstrate the advantages of event-specific GMRs by analyzing data sets from the PEER strong motion database and estimate event-specific GMRs. Therein, the majority of the best models base on an anisotropic point source approach. The residual variance of logarithmized PGA is significantly smaller than in previous models. We validate the estimations for the event with the largest sample by empirical area functions. etc

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

parkrun participation, impact and perceived social inclusion among runners/walkers and volunteers with mental health conditions

Supplemental material is available online at: https://www.tandfonline.com/doi/full/10.1080/13548506.2023.2185643#supplemental-material-section .Engagement in recreation can positively impact the physical and mental health of those experiencing mental health challenges; however, the impact of engaging in other aspects of such recreation, such as volunteering, remain largely unexplored in this population. Volunteering is known to have a wealth of health and wellbeing benefits among the general population; therefore, the impact of recreational-based volunteering for those with mental health conditions deserves to be explored. The current study sought to examine the health, social and wellbeing impacts of parkrun engagement among runners and volunteers living with a mental health condition. Participants with a mental health condition (N = 1661, M(SD)age = 43.4 (12.8) years, 66% female) completed self-reported questionnaires. A MANOVA was conducted to examine the differences in health and wellbeing impacts between those who run/walk vs. those who run/walk and volunteer, while chi-square analyses examined variables of perceived social inclusion. Findings suggest that there was a statistically significant multivariate effect of participation type on perceived parkrun impact (F (10, 1470) = 7.13; p < 0.001; Wilk’s Λ = 0.954, partial η2 = 0.046). It was also found that for those who run/walk and volunteer, compared to those who only run/walk, parkrun made them more feel part of a community (56% v 29% respectively, X2(1) = 116.70, p < 0.001) and facilitated them meeting new people (60% v 24% respectively, X2 (1) = 206.67, p < 0.001). These results suggest that the health, wellbeing, and social inclusion benefits of parkrun participation are different for those who run and volunteer, compared to those who only run. These findings may have public health implications and clinical implications for mental health treatment, as they convey that it is not simply the physical engagement in recreation that may play a role in one’s recovery, but also the volunteer aspect.GAF was funded by a Canadian Institutes of Health Research (CIHR) Doctoral Fellowship throughout this research